Antiparasitic drugs for paediatrics: systematic review ... · Antiparasitic drugs for paediatrics: systematic review, formulations, pharmacokinetics, safety, eﬃcacy and implications

Antiparasitic drugs for paediatrics systematic reviewformulations pharmacokinetics safety efficacy andimplications for control

JENNIFER KEISER12 KATRIN INGRAM12 and JUumlRG UTZINGER23

1Department of Medical Parasitology and Infection Biology Swiss Tropical and Public Health Institute PO BoxCHndash4002 Basel Switzerland2University of Basel PO Box CHndash4003 Basel Switzerland3Department of Epidemiology and Public Health Swiss Tropical and Public Health Institute PO Box CHndash4002 BaselSwitzerland

(Received 14 November 2010 revised 21 December 2010 accepted 22 December 2010 first published online 24 February 2011)

SUMMARY

Drug development for paediatric applications entails a number of challenges such as the wide age spectrum covered ndash frombirth to adolescence ndash and developmental changes in physiology during biological maturation that influence the efficacy andtoxicity of drugs Safe and efficacious antiparasitic drugs for children are of pivotal importance given the large proportion ofburden attributable to parasitic diseases in this age group and growing efforts to administer as widely as possibleantiparasitic drugs to at-risk populations such as infants and school-aged children often without prior diagnosis Thepurpose of this review is to investigate whether antiparasitic drugs have been adequately studied for use in paediatrics Weapproached this issue through a systematic review using PubMed and the Cochrane Central Register of Trials covering aperiod of 10 years and 8 months until the end of August 2010 to identify trials that investigated efficacy safety andpharmacokinetic (PK) parameters of antiparasitic drugs for paediatrics Overall 269 clinical drug trials and 17 PK studiesmet our inclusion criteria Antimalarial drugs were the most commonly studied medicines (82middot6) Most trials were carriedout in Africa and children aged 2ndash11 years were the age group most often investigated Additionally we critically examinedavailable drug formulations for anthelminthics and identified a number of shortcomings that are discussed Finally we shednew light on current proposals to expand lsquopreventive chemotherapyrsquo to preschool-aged children and emphasise that newresearch including risk-benefit analyses are needed before such a strategy can be adopted more widely

Key words Antiparasitic drugs antimalarials anthelminthics preventive chemotherapy paediatrics infants childrenadolescence systematic review drug formulation

INTRODUCTION

Drug development for the paediatric population isa challenging endeavour since a wide age spectrumfrom birth to adolescence is covered A usefulstratification of the paediatric population is the oneproposed by the World Health Organization (WHO)using the following five classes (1) preterm newborninfants (2) term newborn infants (0 to 28 days)(3) infants and toddlers (gt28 days to 23 months)(4) children (2 to 11 years) and (5) adolescents(12 to 16ndash18 years) (WHO 2007a) Importantly thedevelopmental changes in physiology during bio-logical maturation from newborns to adolescenceinfluence the efficacy and toxicity of drugs Indeedabsorption distribution metabolism excretion andtoxicity (ADMET see Glossary) are all age depen-dent Textbooks and detailed reviews are available

that summarise key factors responsible for differencesin drug disposition between paediatric and adultpopulation such as proportions of body fat pro-tein extracellular water organ size membranepermeability plasma proteins enzymes glomerularfiltration or tubular secretion (Strolin Benedetti et al2005 Rakhmanina and van den Anker 2009) Forexample body water is decreased from 80 innewborns to 60 in 5-month-old infants (WHO2007a) Moreover absorption stability and ionis-ation of drugs depend on gastric pH which is age-dependent In the neonatal period an elevated pH isobserved (ie the pH is neutral rather than acidic as inadults) which explains that in younger age groupsa greater bioavailability of acid-labile compoundsoccurs (eg penicillin) (Kearns et al 2003)

In view of the aforementioned issues it is notsurprising that the need for age-appropriate pharma-cotherapy was already recognised more than 100years ago (Kearns et al 2003) The InternationalConference on Harmonisation of Technical Require-ments for the Registration of Pharmaceuticals forHuman Use (ICH-E-11) states that ldquoPaediatric

Corresponding author Jennifer Keiser Department ofMedical Parasitology and Infection Biology SwissTropical and Public Health Institute PO Box CHndash4002 Basel Switzerland Tel +4161 284-8218 Fax+41 61 284-8105 E-mail jenniferkeiserunibasch

1620

Parasitology (2011) 138 1620ndash1632 copy Cambridge University Press 2011doi101017S0031182011000023

httpswwwcambridgeorgcoreterms httpsdoiorg101017S0031182011000023Downloaded from httpswwwcambridgeorgcore University of Basel Library on 30 May 2017 at 195048 subject to the Cambridge Core terms of use available at

patients should be given medicines that have beenappropriately evaluated for their userdquo (httpwwwfdagov) We pose the question whether antiparasiticdrugs have been adequately evaluated prior to widerapplication in paediatric populations Indeed ad-dressing this question served as the main motivationfor the current paper which forms part of a specialissue of Parasitology pertaining to ldquoProgress in Pae-diatric Parasitologyrdquo (see Stothard and Booth edi-torial in this special issue)We first provide a short historical background on

paediatric drug development and highlight practicalethical and economic issues We then juxtapose thelatest United Nations (UN) population figuresand disease burden estimates in the lowest incomecountries To strengthen the current evidence-base ofantiparasitic drugs in the paediatric population weperformed a systematic review using two readilyavailable electronic databases We examined the typeof drugs investigated the age of the study partici-pants and performed a temporal and geographicalanalysis of studies meeting our inclusion criteriaPaediatric pharmacokinetic (PK) studies were alsoexaminedWith an emphasis on anthelminthic drugswe critically reviewed available drug formulationsFinally in the current era of lsquopreventive (anthel-minthic) chemotherapyrsquo (see Glossary) that is theregular administration of antiparasitic drugs to entireat-risk populations (WHO 2006 2010a) we discussimplications for control programmes that aim atincluding also preschool-aged children

PAEDIATRIC DRUG DEVELOPMENT

Regulatory ethical commercial and economic issues

Regulatory efforts to protect children from harm-ful medications began in the mid-20th century inresponse to serious adverse events such as limbmalformations caused by thalidomide (Barsch andOtte 2010) Indeed thalidomide (Conterganreg)which had been used as a treatment for recurringmorning sickness in pregnant women during the1950s and the early 1960s caused peripheral neuritisand malformations eg phocomelia in babies ofmothers who had taken thalidomide over the courseof their pregnancies (Stoumltter 2007 Barsch and Otte2010) Once the evidence of these serious adverseevents of thalidomide had been established throughcase-control studies the medication was withdrawnfrom the market (Mellin and Katzenstein 1962)As a consequence many drugs received marketingauthorisation for use in adults only However anincrease in off-label use (see Glossary) was sub-sequently observed amounting to 80 in paediatricpatients (Pandolfini and Bonati 2005 Stoumltter 2007)Bearing the aforementioned dilemmas in mind

over the past two decades regulations have beenenacted upon and incentives created first in the US

(eg Food and Drug Administration ModernizationAct (FDAMA) instigated in 1998 and Best Pharma-ceuticals for Children Act (BPCA) put forth in 2002see Glossary) and second by a number of EU pae-diatric guidelines (Rose 2009) The purpose of theseregulations was to improve paediatric drug develop-ment particularly in terms of safety (Schachter andRamoni 2007 Macleod 2010) It is clear that theseinitiatives and regulations have changed the land-scape for paediatric drug development For examplethere are recent signs of enhanced research activitiesgoing hand-in-hand with clinical trials on the efficacyand safety of drugs in children including PK studiesand the development of drug formulations that aresuitable for the paediatric population (Macleod2010)Nonetheless there are a number of challenges

regarding clinical trials in children Ethical issuesinclude the complexity to obtain written informedconsent from parents and legal guardians as well asassents from participating children (Kuepfer andBurri 2009) Furthermore the level of invasivenessshould be kept as little as possible and hence thenumber of blood samples and the amount of bloodtaken in PK studies should be minimised (Howie2011) Scientific issues comprise for example thenecessity to stratify the patient population into dif-ferent age groups or the need to develop microassaysto analyse small amounts of biological samples thatare typically obtained from paediatric populations(Conroy et al 2000 WHO 2007a Choonara 2009)Finally there are commercial and economic issues

as the market for paediatric medicines is small com-pared to the adult population (estimated to be lessthan 10 of the total prescription drug market(Milne 2009)) and hence lacks attractiveness forthe international pharmaceutical industry Whileblockbusters mainly address highly prevalent chronicdiseases children often experience acute illnessesand the chronic conditions that do exist in the pae-diatric population are mostly rare disorders (WHO2007b Milne and Bruss 2008)


DEMOGRAPHY AND DISEASE BURDEN

In the US since the FDAMA institutionalised anincentive of a 6-monthpatent extension for previouslyapproved drugs in July 1998 a total of 173 drugs weregranted paediatric exclusivity (httpwwwfdagovdownloadsDrugsDevelopmentApprovalProcessDevelopmentResourcesUCM223058pdf) Thesedevelopments it was claimed showed the achieve-ments made by FDAMA for the paediatric popu-lation However it should be noted that most of thesepatent extensions were for drugs targeting the centralnervous system (CNS) (eg anti-depressants) cardi-ovascular system (eg ACE inhibitors) alimentarytract and metabolism (eg anti-diabetic drugs) and

1621Antiparasitic drugs for paediatrics


anti-infectives (eg antibiotics) Indeed a deeperanalysis revealed a major discrepancy between drugsgranted exclusivity and those frequently used bychildren (eg respiratory drugs dermatologicals andanti-infectives) (Boots et al 2007) Hence the realneeds in paediatric drug development and use havenot been addressed by exclusivity rights granted byFDAMA In contrast they were primarily driven bythe adult drug market (Boots et al 2007)

Those drugs that are currently available and areessential for children must be prioritised for paedia-tric development Indeed there is growing recog-nition that among essential medicines issues ofsafety access and formulations for the paediatricpopulation are of pressing global public healthrelevance This can be further underscored byjuxtaposing population figures put forth by the UN(United Nations 2009) In 2010 an estimated 2middot47billion were newborns infants children and ado-lescents below the age of 19 years The paediatricpopulation therefore currently accounts for morethan a third (35middot7) of the worldrsquos populationMeanwhile it has been estimated that 432middot5 millionchildren and adolescents currently live in the leastdeveloped countries which comprise 49 countries ofwhich 33 are in Africa 10 in Asia five in Oceania andone in Latin America and the Caribbean Comparedto the total population in these 49 countries (ie 854million) the paediatric population therefore accountsfor more than 50 (United Nations 2009)

It is encouraging to note that new campaigns havebeen launched with the goal to expedite paediatricdrug development For example ldquoMake medicineschild sizerdquo is a global initiative launched inDecember2007 under the leadership of WHO in order ldquoto raiseawareness and accelerate action to address the needfor improved availability and access to safe child-specific medicines for all children under 12rdquo (httpwwwwhointchildmedicinesen)Highprioritythe-rapeutic areas include respiratory diseases as well asparasitic and infectious diseases The importance ofthe latter group of diseases must be emphasisedwhich is clear when one examines global burden ofdisease estimates In 2004 for example children agedbelow 14 years experienced the loss of 548middot3 milliondisability-adjusted life years (DALYs see Glossary)Three-quarter of this burden (409middot8 million DALYs)occurred among children from low-income countriesInfectious and parasitic diseases were responsiblefor more than 300 million DALYs with 79 ofthis burden concentrated in low-income countriesdisproportionally shared by children younger than14 years (58) (WHO 2008a) The proportion ofdisease burden attributable to infectious and parasiticdiseases in children in low-income countries was 38(154middot3 million DALYs) (WHO 2008a) Moreoverinfectious diseases are a leading cause of death inchildren younger than 5 years particularly in low-income countries The latest estimates for the year

2008 suggest that among the 8middot80 million deaths inchildren under the age of 5 years two-third (68 or5middot97 million deaths) were due to infectious diseasesthe three most important of which were pneumonia(1middot56 million deaths) diarrhoea (1middot34 million deaths)and malaria (732000 deaths) (Black et al 2010)Of note intestinal parasites are responsible forreductions in appetite absorption digestion andincreasing intestinal nutrient losses (Lunn andNorthrop-Clewes 1993) and hence might contrib-ute to undernutrition which is the underlying causeof a third of deaths in children younger than 5 years(Black et al 2010)

CLINICAL TRIALS WITH ANTIPARASITIC

DRUGS FOR PAEDIATRICS

Search strategy and selection criteria of asystematic review

We were interested in clinical trials involving anti-parasitic drugs in the paediatric population as wellas PK studies covering a period of 10 years and8 months until the end of August 2010 Previousarticles highlighted the paucity of paediatric clinicaltrials involving children in the developing world(Sammons and Choonara 2005 Nor Aripin et al2010ab) For example in 2007 only one out of fourtrials were carried out in developing countries (NorAripin et al 2010b) Between 1996 and 2002 a total of99 trials carried out in the developing world wereidentified with a specific focus on antiparasitic andanti-infective drugs However no details were pre-sented on the type of medication studied or age groupinvolved (Nor Aripin et al 2010a)

We performed a systematic review on PubMed(httpwwwncbinlmnihgovpubmed) and theCochrane Central Register of Controlled ClinicalTrials (httponlinelibrarywileycomocochranecochrane_clcentral_articles_fshtml) In order tomaximise sensitivity and specificity (Kastner et al2006) we used the following age-specific MeSHterms lsquochildrsquo lsquoadolescentrsquo or lsquoinfantrsquo in combinationwith lsquoclinical trialrsquo and lsquoantiparasitic agentrsquo For thesearch on PK studies the same age-specific MeSHterms were employed but in combination withlsquopharmacokineticsrsquo Our searches were temporallyrestricted (from 2000 to the end of August 2010)while there was no language restriction Abstracts ofthe retrieved publications were analysed adheringto a standard protocol developed by the authorsStudies had to pass the following inclusion criteria(1) study population of children or adolescents(age418 years) (2) trials investigating drug efficacy(eg no vaccination or supplements) and (3) studyperformed on any parasitic disease The followinginformation was retrieved from each study thatmet our inclusion criteria (i) year of publication(ii) parasite studied (iii) study setting and country

1622Jennifer Keiser Katrin Ingram and Juumlrg Utzinger


(iv) sample size (v) age and age group of studypopulation (vi) methodological quality of trial and(vii) type of medication used (eg substance prep-aration and Anatomical Therapeutical Chemical(ATC) classification system see Glossary)

Number of studies identified and age groups

A total of 1025 articles were identified Based on theabstracts 756 studies were excluded and full-textcopies were obtained from 269 articles The threemain reasons for exclusion were (1) study populationconsisting of children and adult patients (44) (2)entire study population aged 18 years and above(24) and (3) trials investigating diagnostic tests orfocusing on health management issues (13)Additional exclusion criteria are summarised inFig 1In four out of five trials (80) both infants and

children (113 trials) or children only (102 trials) wereincluded The remaining 20 of the trials involvedthe following age classes (1) children and adolescents(34 trials) (2) infants (15 trials) (3) infants children

and adolescents (four trials) and (4) adolescents(one trial) More than 90 of the trials enrolledchildren (93middot7) while only 39 trials includedadolescents The number of participants per trialranged from 10 to 4906 One third of all trialsrecruited between 101 and 250 participants Table 1shows the frequency of trials stratified by differentsample sizes

Outcomes from temporal and geographical analyses

Our temporal analysis revealed that the number ofpaediatric drug trials steadily increased between 2000(only two trials) and 2004 (37 trials) decreased inthe following 2 years (25 and 23 studies in 2005 and2006 respectively) and subsequently varied between27 and 36 per year In 2010 until the end of August2010 a total of eight trials were identified forantiparasitic drugs in paediatrics (Fig 2)The studies examined were carried out in 61

countries More than a third of the trials (38middot7)were conducted in only five countries Thailand(24 trials) Nigeria (21 trials) United Republic of

57 abstracts identified on paediatric PK

trials Excluded (n=40)

Adults (n=29) Mixed age (n=10) No drug supplement (eg vaccines) (n=1)

1025 abstracts identified on

paediatric clinical trials

269 studies included in analyses


Excluded (n=756)

Mixed age (n=330) Adults (n=180) Health management diagnostics (n=98) Lab value (eg haematocrit) (n=42) Drug resistance mutation (n=38) No drug (eg vaccines) (n=38) No clinical trial (n=20) No parasitic disease (n=10)

Fig 1 Flow chart of study selection for systematic review of clinical trials and PK studies with antiparasitic drugs inchildren covering a period of 10 years and 8 months until the end of August 2010

Table 1 Number of paediatric patients involvedin clinical drug trials and pharmacokinetic (PK)studies identified through a systematic reviewcovering a 10-year period until the end ofAugust 2010

Sample size (n)

Clinical drugtrials PK studies

No No

450 32 11middot9 11 64middot751ndash100 40 14middot9 3 17middot6101ndash250 89 33middot1 2 11middot8251ndash500 48 17middot8 0 0501ndash1000 32 11middot9 1 5middot91001ndash2500 26 9middot7 0 02501ndash5000 2 0middot7 0 0

Total 269 100 17 100

40

30

20

10

0

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2

17

29

36 37

2523

36

2729

8

Fig 2 Temporal analysis of paediatric drug trialsidentified through a systematic review covering a 10-yearperiod until August 2010 ( indicates that in 2010 onlythe first 8 months were analysed)



Tanzania (21 trials) Uganda (20 trials) and Ghana(18 trials) Interestingly almost three-quarter ofthe trials were implemented in Africa (72middot7)The respective percentage of trials carried out inAsia South America North America Australia andEurope was 16middot8 3middot6 3middot3 2middot0 and 1middot6respectively (Fig 3)

Drugs investigated

Ninety-three percent of the drug trials that weidentified through our systematic review investigatedantiparasitic medications The remainder of thestudies (7) examined drugs of the following ATCclasses alimentary tract and metabolism blood andblood forming organs dermatologicals systemichormonal preparations anti-infectives for systemicuse antineoplastic and immunomodulating agentsmusculo-skeletal system CNS and respiratory sys-tem Less than a third (29) of all included studieswere classified as randomised controlled trials

Fig 4 shows that most of the antiparasitic drugsstudied were antimalarials (82middot6) followed bytherapies for gastrointestinal nematodes (9middot8)amoebiasis and other intestinal protozoal infections(3middot7) schistosomiasis (2middot9) and agents againstleishmaniasis and trypanosomiasis (1middot0) A closerinspection of the drugs studied showed that sulpha-doxine-pyrimethamine (SP) was the most frequentlytrialled medication (20 of all studies) which isexplained by the use of SP as part of malaria controlwith a strategy termed intermittent preventivetherapy in infants (IPTi) and children (IPTc) (seeGlossary) (Aponte et al 2009 Gosling et al 2010)Other frequently used antimalarials in the paediatricpopulation identified through our systematic reviewwere amodiaquine and artesunate (both 15) andchloroquine (10) Albendazole was the most com-monly studied anthelminthic drug (5 of all trials)

PK studies

Fifty-seven studies were retrieved after systemati-cally searching for PK investigations of antiparasiticdrugs in paediatrics covering a period of 10 years and8 months until the end of August 2010 Forty studieswere excluded when applying our selection criteria(study participants aged 518 years or studiesincluding both adults and children (n = 39) onetrial investigated a supplement rather than a drug)

The sample size of the 17 included studies rangedfrom as few as 10 individuals to 899 subjects(Table 1) Two-third of the trials (n = 11) recruited10 to 50 participants while only one trial had asample size of more than 250 individuals The mostcommonly studied age group were children 10 trialswere performed exclusively with children and fivestudies included both children and infants The age

groups of solely infants and adolescents in combi-nation with children were only represented in a singlestudy each PK parameters of antimalarial drugs werestudied in 15 of the 17 trials The remaining two PKstudies investigated anthelminthics and a neoplasticagent for leishmaniasis The antimalarial drugsartesunate and quinine were investigated most often(each drug in 29 of the PK studies identified) Withregard to anthelminthic drugs albendazole andpraziquantel were the only compounds subjected toPK investigations in the paediatric population

DRUG FORMULATIONS

General considerations

Although there is a pressing need for developing newantiparasitics very few drugs have been marked-approved in recent years For example while 11 newantimalarials have been marketed between 2000 and2009 no new drugs have been approved in any of theother parasitic disease categories over the same period(Cohen et al 2010) Given the paucity of clinicaltrials in paediatrics focusing on diseases other thanmalaria it is conceivable that only very few if anydrugs for other parasitic diseases will be forthcomingin the near future However drugs can be consider-ably optimised when new drug formulations aredeveloped (Kayser et al 2003)

Desired criteria for drug formulations include(1) good bioavailability (2) safe excipients andingredients (3) dose uniformity (4) ease and safetyof administration and (5) socio-cultural acceptability(Breitkreutz and Boos 2007) Based on factors suchas solubility and taste of the compound formulationdevelopment can be a time consuming and techni-cally challenging task and the financial implicationsare considerable (Milne 2009) Yet an acceptableformulation is particularly important for childrenIndeed one of the key issues in the development ofpaediatric drugs is the selection of the most appro-priate dosage form in relation to age Numerous drug

Fig 3 Geographic location of paediatric drug trials ()identified through a systematic review covering a periodof 10 years and 8 months until the end of August 2010



administration routes are available such asperoral nasal parenteral topical rectal or buccal(Breitkreutz et al 2007) Matrixes combining differ-ent paediatric age groups routes of administrationand dosage forms have therefore been developedto assist in selecting the ideal formulation (seefor example httpwwwemaeuropaeudocsen_GBdocument_libraryScientific_guideline200909WC500003782pdf and Breitkreutz (2009)) Aslightly simplified matrix for oral routes of drugadministration using lsquotraffic light coloursrsquo is depictedin Fig 5 Ideal recommended and desired dosageforms are shown using green colour less preferredbut probable applicable dosage forms are markedwith orange colour and not applicable oral dosageforms are depicted in red For example solid dosageforms might pose problems to small children as they

have difficulties swallowing tablets It follows thattablets and capsules are not recommended for infantsand toddlers and applicable but not preferred forpreschool-aged childrenClearly oral drug administration is the predomi-

nant route in paediatric patients and different oraldosage forms (eg solutions syrups powder gran-ules and effervescent tablets) have been developedHowever in particular when drugs are not licensedfor children (ie off-label use) suitable liquid formsare often not available Inert ingredients must beselected very carefully as children might have adversereactions to colourings flavouring or preservativeswhich are commonly used in adult formulations(Milne 2009) Taste is a particularly crucial issue toascertain high compliance in children For example asurvey carried out in theUS interviewing 500 parents

Antimalarials

Antinematodals

Agents against amoebiasis andother intestinal protozoal diseases

Antitrematodals

Agents againstleishmaniasistrypanosomiasis

Key

102937

98

826

Fig 4 Drug classes investigated () in a systematic review covering a period of 10 years and 8 months until the end ofAugust 2010

Solutiondrops

Emulsionsuspension

Effervescentdosage forms

Powdersmultiparticulates

Tablets

Capsules

Orodispersabledosage forms

Chewable tablets

Dosage form Pretermnewborns

Termnewborninfants

Infantsandtoddlers

Pre-schoolchildren

Children Ado-lescents

Fig 5 Matrix combining different dosage forms for oral routes of drug administration for different paediatricage groups



and caretakers has shown that taste was among two-third of the children a reason for non-compliance(Milne and Bruss 2008 Milne 2009)

Anthelminthic drug formulations

Table 2 shows the most important anthelminthicdrugs currently employed within the frame of

preventive chemotherapy programmes includingthe most common formulations (WHO 2006 Hotezet al 2007) Importantly these anthelminthics havebecome the drugs of choice against schistosomiasisfood-borne trematodiases and soil-transmittedhelminthiases the latter including strongyloidiasisIndeed millions of people are given one or several ofthese drugs each year particularly school-aged

Table 2 Available drug formulations their producers recommended dosages and paediatric use for drugsused for the treatment of schistosomiasis food-borne trematodiases soil-transmitted helminthiasesand strongyloidiasis

Infection Drug Formulation Producer(s) Recommended dosage Paediatric use

Schistosomiasisand food-bornetrematodiases

Praziquantel Tablet600mg

Four large scaleproducers MerckShin PoongEIPICO Cipla

40mgkg once(schistosomiasis)multiple doses(schedule dependingon trematode food-borne trematodiases)

Experience inchildrenbelow 4 yearsis limited

Praziquantel Syrup120mgml(Epiquantel)

EIPICO

Fascioliasis Triclabendazole Tablet250mg

Novartis 10mgkg once (20mgkg in the case oftreatment failures)

No experiencein childrenbelow 6 years

Soil-transmittedhelminthiases

Albendazole Chewabletablet 200and 400mg

GlaxoSmithKlinemany genericproducers

400mg once forindividuals aged2 years and abovesingle 200mg oncefor individuals aged1ndash2 years

No experiencein childrenbelow 1 year

Suspension100mg5ml

20ml once forindividuals aged2 years and above10ml once forindividuals aged1ndash2 years

Mebendazole Chewabletablet 100and 500mg

JanssenPharmaceuticamany genericproducers

500mg once 100mgtwice a day for 3 days


Suspension100mg5ml

25ml once 5 ml twice aday for 3 days

Levamisole Tablet 50 and150mg

ICIPharmaceuticalsmany genericproducers

2middot5 mgkg once No experiencein childrenbelow 1 year

Suspension40mg5ml

Generic producers (eg EIPICO)

2middot5 mgkg once

Pyrantel pamoate Chewabletablet250mg

Pfizer 10mgkg once 10mgkg for 3 days forindividuals aged 1 yearand above


Suspension50mgml

Pfizer 1ml for every 5 kgof body weight

Strongyloidiasis Ivermectin Tablet 3 and6mg

200 μgkg single dose15 kg and above

Safety andefficacy inindividualsweighing lessthan 15 kghave not beenestablished

Albendazole See above See above Multiple doses(eg 400mg twicedaily for 3 days) ages2 years and above

See above



children (WHO 2008b 2010bc Fenwick et al 2009)Manufacturers and recommended dosages both foradults and the paediatric population are presented Inthe remainder of this section we highlight short-comings linked to drug formulations available formajor helminthiases such as dosing accuracy lack ofPK investigations unknown bioavailability for ex-temporaneous preparation and indeed lack of suitableformulations for small children

Praziquantel

In 2008 17middot5 million individuals were treated withpraziquantel in the frame of preventive chemother-apy programmes against schistosomiasis (WHO2010b) It is conceivable that several more millionpeople were administered praziquantel facilitated bylocal regional and national control efforts purchasefrom pharmaceutical stores distributed by non-governmental organisations and aid workers butthese data were not reported to WHO However tensof millions of individuals particularly school-agedchildren at-risk of schistosomiasis in Africa still lackaccess to praziquantel (Utzinger et al 2009 Hotezet al 2010 WHO 2010b) There is a paucity of dataregarding the number of people at risk of food-bornetrematodiases who have been treated with praziquan-tel in the frame of preventive chemotherapyAt present praziquantel is recommended for

individuals aged 4 years and above (WHO 2002aBiltricide package insert) Praziquantel tablets(600 mg) are large bitter in taste and the rec-ommended dosage for preventive chemotherapy is40mgkg administered in a single oral dose (Hotezet al 2007 Meyer et al 2009) Praziquantel tabletsare often split into two or even four parts However ithas been shown that the weight of split tablets rangesfrom 50ndash150 of the desired weight of the half-tabletweight and even the use of tablet cutters do notimprove accuracy (Standing and Tuleu 2005)Furthermore although crushing of praziquanteltablets has been recommended by the manufacturer(package leaflet httpwwwmerckcom) and indeedemployed in recent studies with preschool-agedchildren infected with schistosomes (Odogwu et al2006 Betson et al 2010 Garba et al 2010) thebioavailability of the crushed formulation mightdiffer from the original tablet form To our knowl-edge the bioequivalence of praziquantel adminis-tered as crushed tablets versus tablets swallowedas a whole remains to be investigated For examplea recent study which compared PK parameters oftelithromycin administered either as whole tablets orcrushed (and offered with nutritional supplementdrink) found that both methods of administrationwere bioequivalent Hence crushing of telithromy-cin could be a viable method of administration forpatients unable to swallow whole tablets (Lippertet al 2005) However it should be kept in mind that

it is difficult to mask the bitter taste of crushedtablets Infants and children react unfavourably tobitter tastes and the more bitter the drug the morelikely it will be rejected (Mennella and Beauchamp2008 Schwartz et al 2009) Since praziquantel ismarketed as racemate and the antischistosomalactivity is stereoselective new efforts are underwayto develop a low-cost chemical synthesis for the activeenantiomer L-praziquantel (Meyer et al 2009) Ofnote L-praziquantel is less bitter than racemicpraziquantel (Meyer et al 2009) and one study inthe Peoplersquos Republic of China reported less adverseevents of L-praziquantel compared to the racemate(Wu et al 1991)A praziquantel syrup formulation is available

(Doenhoff et al 2009) However it is not commonlyused and not knownwhether bioequivalence has beenthoroughly studied In addition it is not knownwhich excipients which are required for doseuniformity stability or taste (Standing and Tuleu2005) are present A detailed summary of excipientstheir technological function and adverse events hasbeen provided by Pifferi and Restani (2003)Finally there is a need to study the safety dose-

response and PK of praziquantel thoroughly inchildren below the age of 4 years because recentstudies in different epidemiological studies docu-mented that schistosomiasis can occur in infants andpreschool-aged children hence well before the ageof 4 years (Mafiana et al 2003 Bosompem et al2004 Odogwu et al 2006 Stothard and Gabrielli2007 Betson et al 2010 Garba et al 2010 Sousa-Figueiredo et al 2010b Stothard et al 2011)Preschool-aged children are presently not targetedin schistosomiasis preventive chemotherapy cam-paigns However it has been emphasised that pre-school children do not only play a role in local diseasetransmission but importantly active infections ac-quired at early ages might aggravate the clinicalsignificance of the disease in later-life (see Stothardet al in this special issue) First trials have beencarried out treating preschool children with half orthree quarters of a tablet depending on height usingan extended dose pole (Sousa-Figueiredo et al2010ab) However as highlighted in the presentmanuscript a century ago it was recognised byDr Jacobi that children and infants are not miniaturemen and women requiring just reduced doses(Kearns et al 2003) Rather than using an empiricalapproach and applying weight-based calculations tothe adult dose there is a need for in-depth studieswith praziquantel including PK to determine theproper formulations and doses in paediatric patients

Triclabendazole

Similar to praziquantel triclabendazole is currentlynot registered for use in young children (lt6 years ofage) but off-label use in this age group has been



reported (WHO 2007b) Triclabendazole is thecurrent drug of choice against fascioliasis (Keiseret al 2005 Fairweather 2009 Keiser and Utzinger2010) and we strongly recommend that availabledata of the safety and efficacy of triclabendazole inpreschool-aged children be scrutinized We antici-pate that the evidence-base is currently insufficientand hence additional clinical trials are warranted tofill existing gaps Furthermore an appropriatetriclabendazole formulation for young childrenmight be considered However it is unlikely thatprogress in this field will be made in the near futuregiven the fact that fascioliasis is one of the mostneglected tropical disease and triclabendazole iscurrently registered in only four countries (Keiseret al 2005)

Albendazole mebendazole levamisole andpyrantel pamoate

The main drugs used for the treatment of soil-transmitted helminthiases are albendazole meben-dazole levamisole and pyrantel pamoate (Bethonyet al 2006 Keiser and Utzinger 2008) Clearly theformer two ndash the benzimidazoles albendazole andmebendazole ndash are the most widely used drugs withinthe frame of preventive chemotherapy campaigns(WHO 2006 Hotez et al 2007) At the momentall four drugs are recommended for children aged12months and above There are currently insufficientdata on safety and efficacy for use in younger childrenwhich is a problem as infections are often acquiredby infants before they reach 12 months (WHO2002a Montresor et al 2003) It is interesting to notethat for the two widely used benzimidazoles no age-specific dosing regimens exist For example a 1-year-old child (approximately 10 kg) receives the same500mg mebendazole dose than an 80 kg adultIndeed dosage adaptations based on weight orbody surface area (Kearns et al 2003) have not beensuggested for the benzimidazoles in children To ourknowledge PK studies with these drugs have neitherbeen undertaken in infants nor in children We andothers have highlighted that the majority of anthel-minthics currently used for preventive chemotherapyhave been developed in veterinary parasitology andhence were not sufficiently optimised for treatinghuman helminth infections (Geary et al 2010 Keiserand Utzinger 2010)

Albendazole mebendazole levamisole and pyran-tel pamoate are available as liquid formulationswhich are obviously most appropriate for paediatricpatients (Table 2) Typical target dose volumes forpaediatric liquid formulations are lt5ml for childrenunder the age of 5 years and lt10ml for children aged5 years and above (European Medicines Agency2006) However themore pleasant the formulation ofthe medicinal product tastes the higher the dose

volume which will be tolerated by the child Forexample 20ml of an albendazole suspension arerequired to achieve a total dose of 400mg Howeverin large-scale drug administration programmes liq-uid formulations of albendazole mebendazole orlevamisole and pyrantel pamoate are rarely usedAlbendazole mebendazole and pyrantel pamoate arealso available as chewable tablets Although the useof chewable tablets is officially recommended forchildren aged above 6 years a systematic review onthe safety of chewable tablets for children in the USconcluded that chewable tablets were a safe and welltolerated alternative to traditional paediatric formu-lations (Michele et al 2002) Tragically in 2007 inEthiopia four children below the age of 3 years diedfrom choking on chewable albendazole tablets duringa deworming campaign (WHO 2007a) Reasons forthe widespread use of tablets in preventive che-motherapy campaigns are the higher cost of thesuspension compared to tablets difficulties of trans-port and storage due to the larger volume of the liquidformulation stability issues and the difficulties inhandling the liquid formulation Hence additionalresources for implementation of liquid formulationswould be required Moreover medication errorscommonly occur with liquid formulations It hasbeen shown for example that poor dose uniformityis achieved using spoons and dosing cups hencedropper tubes or syringes are recommended(Breitkreutz and Boos 2007)

Ivermectin

Ivermectin the current drug of choice for strongy-loidiasis is marketed as 3mg and 6mg scored tabletsIvermectin was approved for human use in 1988 andis widely used to control and eliminate filarialinfections usually in combination with albendazole(Fox 2006 Taylor et al 2010) Ivermectin is labelledfor children weighting more than 15 kg since thedrug might cross the poorly-developed blood brainbarrier in infants resulting in possible neurotoxicevents (Fox 2006) There is a need to study the safetyof ivermectin in infants in greater detail In additionto our knowledge liquid formulations are notavailable hence preschool-aged children are routi-nely treated with tablets which is not the preferreddosage form for this age group (European MedicinesAgency 2006)

IMPLICATIONS FOR CONTROL

In the mid-1980s a paradigm shift occurred in theglobal strategy against schistosomiasis and othermajor helminth infections ie transmission controlwas gradually replaced by morbidity control Theadvent of safe anthelminthic drugs that showed highefficacy at single oral doses both in terms of curerate and egg reduction rate and hence morbidity



reduction was at the root of this shift (WHO 1985)Once the price of anthelminthics plummeted (egterming out of patents or pharmaceutical companiesproviding anthelminthic drugs free of charge)repeated large-scale administration to at-risk popu-lations became feasible In May 2001 World HealthAssembly (WHA) resolution 54middot19 was endorsedurging member states to regularly treat at least 75of school-aged children at risk of schistosomiasisand soil-transmitted helminthiases with praziquanteland albendazolemebendazole respectively (WHO2002b) Major progress has been made over the pastdecade and in 2006 the first African countriesreached the 75 target of administering benzimi-dazoles to school-aged children at risk of soil-transmitted helminthiasis (WHO 2008b 2010cSavioli et al 2009)With regard to schistosomiasis however only half

a dozen countries in sub-Saharan Africa have (re-)established national schistosomiasis control pro-grammes (Fenwick et al 2009) Hence only a smallfraction of school-aged children at-risk of morbiditydue to schistosomiasis are regularly given praziquan-tel (Hotez et al 2010 WHO 2010b) In view ofrecent reports from different epidemiological settingsdocumenting S haematobium and S mansoni single

and even mixed species infections among preschool-aged children (Mafiana et al 2003 Bosompem et al2004 Odogwu et al 2006 Stothard and Gabrielli2007 Betson et al 2010 Garba et al 2010 Sousa-Figueiredo et al 2010b Stothard et al 2011) thequestion has arisen whether preventive chemother-apy should be extended to this age groupWe welcome this discussion and an informal

consultation held at WHO headquarters in Genevain September 2010 We offer the following points forconsideration with Fig 6 serving as a conceptualframework Fig 6A depicts a typical age-prevalencecurve of schistosomiasis clearly documenting thatschool-aged children are at highest risk of egg-patentinfection and high infection intensity (Jordan andWebbe 1969) Let us first focus on school-agedchildren (age 5ndash19 years) The mean prevalence inthis age group based on detection of S mansoni eggsin stool samples is approximately 40 Concur-rently the egg-patent prevalence of S mansoni inpreschool-aged children (age 0ndash4 years) is approxi-mately 10 or one-fourth of their older counterpartsOf note immunodiagnostic markers particularlyantigens in urine can be detected earlier than eggsin stool and hence the respective prevalence based onantigens might be higher than that determined by egg

70

60

50

40

30

20

10

00-4 lt9 lt14 lt19 lt29 lt39 lt49 50

250

200

150

100

50

0

of subjects mean epg

AGE

gt1000

gt350

gt100

gt0epgmean

S mansoni Hookworm Co-infection

No-infection


No-infection

80

40

20

20

10

5

20

10

5

4

1

025

64

81

9025

80

40

20

64

16

4

4

36

64

A

B

C

Fig 6 Conceptual framework summarising the age-prevalence curve of schistosomiasis (a) and hypothetical scenarios ofS mansoni-hookworm co-infection in highly endemic (b) and low endemic (c) settings



patency (Stothard et al 2011) Notwithstanding theshortcoming of egg patency at early age let us assumea similar age-pattern of S mansoni and hookworminfection

Fig 6B shows three hypothetical scenarios withschool-aged children at risk of a S mansoni infectiona hookworm infection and a S mansoni-hookwormco-infection In an epidemiological setting whereboth infections are highly endemic and no controlmeasures in place ie 80 of school-aged childreninfected with either parasite the likelihood of a co-infection is 64 under the assumption of randomparasite distribution We argue that such settings arerare to find in contemporary Africa Suppose thatcontrol efforts have been launched and infectionprevalences dropped by 50 for each parasite Thelikelihood of a co-infection has now been reduced to16 Concurrently 36 of the school-aged childrenare free of both S mansoni and hookworm infectionNow let us suppose that preventive chemotherapy iscontinued and the prevalence of either parasiteinfection further reduced to 20 each (Fig 6C)The likelihood of a co-infection has further droppedto 4 whereas two-third of the school-aged childrenare helminth-free Next let us focus on preschool-aged children where the prevalence of each parasiteis one-fourth of the prevalence in their oldercounterparts In the latter setting less than 1 ofpreschool-aged children are co-infected whereasmore than 90 show no infection at all Canpreventive chemotherapy using both praziquanteland a benzimidazole which have yet to be properlytested in children below the age of 4 years be justifiedin such a setting There is a pressing need foradditional studies including risk-benefit analysesFor example the risk of not treating the preschool-aged population in terms of potential morbidityshould be determined and compared to the risk ofadministering two drugs that lack child-friendlyformulations and detailed information on efficacysafety and PK in this age group We conjecture thatnew research is urgently required to resolve theseissues before extension of preventive chemotherapyto preschool-aged children

CONCLUDING REMARKS AND RESEARCH NEEDS

Infectious diseases continue to be a leading cause ofmorbidity and mortality in children particularly inlow-income countries As we have shown there is apaucity of studies assessing the safety and efficacy ofantiparasitic drugs in children Moreover PK inves-tigations and studies in infants and adolescents withantiparasitics are a totally neglected research areaThough sometimes difficult to put into practice PKstudies should also assess the impact of the parasiticinfection on the disposition kinetics of the drughence ideally be carried out in healthy and diseasedchildren For example it has been demonstrated that

PK parameters were altered in patients infected withthe liver fluke Opisthorchis viverrini (Na Bangchanget al 1993) Similarly in many disease areas noprogress has been made with tailored drug formu-lations for children Hence off-label use empiricaldose adaptations and formulation tampering are stillthe rule rather than the exception

The forging of new alliances and public-privatepartnerships between academia pharmaceuticalcompanies and philanthropic organisations (eg Billamp Melinda Gates Foundation) hold promise to fillthe current gaps for optimising current antiparasiticdrugs and developing the next generation of anti-parasitic drugs (Moran 2005 Nwaka and Hudson2006 Keiser and Utzinger 2007 Moran et al2009) The Medicines for Malaria Venture (MMV)and the Drugs for Neglected Disease initiative(DNDi) can serve as useful role models (seeGlossary)

ACKNOWLEDGEMENTS

We are grateful to DrsMark Booth and J Russell Stothardfor their kind invitation to present the current paper atthe autumn 2010 symposium hosted by the British Societyfor Parasitology (BSP) and co-organised by the RoyalSociety of Tropical Medicine and Hygiene (RSTMH)Mark and Russrsquo leadership in putting together thisimportant and enjoyable event including entertainmentat the conference dinner on September 23 2010 was muchappreciated JKeiser andK Ingram acknowledge financialsupport from the Swiss National Science Foundation(project no PPOOAndash114941) and the Science andTechnology Programme Switzerland-Russia

REFERENCES

Aponte J J Schellenberg D Egan A Breckenridge ACarneiro I Critchley J Danquah I Dodoo A Kobbe RLell B May J Premji Z Sanz S Sevene E Soulaymani-Becheikh R Winstanley P Adjei S Anemana SChandramohan D Issifou S Mockenhaupt F Owusu-Agyei SGreenwood B Grobusch M P Kremsner P G Macete EMshinda H Newman R D Slutsker L Tanner M Alonso Pand Menendez C (2009) Efficacy and safety of intermittent preventivetreatment with sulfadoxine-pyrimethamine for malaria in African infants apooled analysis of six randomised placebo-controlled trials Lancet 3741533ndash1542Barsch M and Otte A (2010) The legal standards for the radioactive ornon radioactive drugs research and approval in the European Communityand in Germany after the thalidomide catastrophe Hellenic Journal ofNuclear Medicine 13 45ndash51Bethony J Brooker S Albonico M Geiger SM Loukas ADiemert D and Hotez P J (2006) Soil-transmitted helminth infec-tions ascariasis trichuriasis and hookworm Lancet 367 1521ndash1532Betson M Sousa-Figueiredo J C Rowell C Kabatereine N Band Stothard J R (2010) Intestinal schistosomiasis in mothers and youngchildren in Uganda investigation of field-applicable markers of bowelmorbidity American Journal of Tropical Medicine and Hygiene 83 1048ndash1055Black R E Cousens S Johnson H L Lawn J E Rudan IBassani D G Jha P Campbell H Fischer Walker CCibulskis R Eisele T Liu L Mathers C Child HealthEpidemiology Reference Group of WHO and UNICEF (2010)Global regional and national causes of child mortality in 2008 a systematicanalysis Lancet 375 1969ndash1987Boots I Sukhai R N Klein R H Holl R A Wit J MCohen A F and Burggraaf J (2007) Stimulation programs for pediatric



drug research ndash do children really benefit European Journal of Pediatrics166 849ndash855Bosompem KM Bentum I A Otchere J Anyan WKBrown C A Osada Y Takeo S Kojima S and Ohta N (2004)Infant schistosomiasis in Ghana a survey in an irrigation communityTropical Medicine and International Health 9 917ndash922Breitkreutz J (2009) Dosage forms for children After the EU ReformPharmazie unserer Zeit 38 30ndash37Breitkreutz J and Boos J (2007) Paediatric and geriatric drug deliveryExpert Opinion on Drug Delivery 4 37ndash45Breitkreutz J Tuleu C and Solomonidou D (2007) Paediatricformulations InGuide to Paediatric Clinical Research (ed Rose K and vanden Anker J N) pp 65ndash77 Karger BaselChoonara I (2009) Ethical and safety aspects of clinical trials in neonatesEarly Human Development 85 S19ndash20Cohen J Dibner M S and Wilson A (2010) Development of andaccess to products for neglected diseases PLoS One 5 e10610Conroy SMcIntyre J Choonara I and Stephenson T (2000) Drugtrials in children problems and the way forward British Journal ClinicalPharmacology 49 93ndash97Doenhoff M J Hagan P Cioli D Southgate V Pica-Mattoccia L Botros S Coles G Tchuem Tchuenteacute L AMbaye A and Engels D (2009) Praziquantel its use in control ofschistosomiasis in sub-Saharan Africa and current research needsParasitology 136 1825ndash1835European Medicines Agency (2006) Reflection paper formulationsof choice for the paediatric population European Medicines AgencyLondonFairweather I (2009) Triclabendazole progress report 2005ndash2009 anadvancement of learning Journal of Helminthology 83 139ndash150Fenwick A Webster J P Bosque-Oliva E Blair LFleming FM Zhang Y Garba A Stothard J RGabrielli A F Clements A C A Kabatereine N B Toure SDembele R Nyandindi U Mwansa J and Koukounari A (2009)The Schistosomiasis Control Initiative (SCI) rationale development andimplementation from 2002ndash2008 Parasitology 136 1719ndash1730Fox LM (2006) Ivermectin uses and impact 20 years onCurrent Opinionin Infectious Diseases 19 588ndash593Garba A Barkire N Djibo A Lamine M S Sofo BGouvras A N Bosque-Oliva E Webster J P Stothard J RUtzinger J and Fenwick A (2010) Schistosomiasis in infants andpreschool-aged children infection in a single Schistosoma haematobiumand a mixed S haematobium-S mansoni foci of Niger Acta Tropica 115212ndash219Geary T G Woo K McCarthy J S Mackenzie C D Horton JPrichard R K de Silva N R Olliaro P L Lazdins-Helds J KEngels D A and Bundy D A (2010) Unresolved issues in anthelminticpharmacology for helminthiases of humans International Journal forParasitology 40 1ndash13Gosling R D Cairns M E Chico RM and Chandramohan D(2010) Intermittent preventive treatment against malaria an updateExpertReviews of Anti-Infective Therapy 8 589ndash606Hotez P J Engels D Fenwick A and Savioli L (2010) Africa isdesperate for praziquantel Lancet 376 496ndash498Hotez P J Molyneux D H Fenwick A Kumaresan J EhrlichSachs S Sachs J D and Savioli L (2007) Control of neglected tropicaldiseases New England Journal of Medicine 357 1018ndash1027Howie R C (2011) Blood sample volumes in child health research reviewof safe limits Bulletin of the World Health Organization 89 46ndash53Jordan P and Webbe G (1969) Human Schistosomiasis WilliamHeinemann Medical Books Ltd LondonKastner M Wilczynski N L Walker-Dilks C McKibbon K Aand Haynes B (2006) Age-specific search strategies for Medline Journalof Medical Internet Research 8 e25Kayser O Olbrich C Croft S L and Kiderlen A F (2003)Formulation and biopharmaceutical issues in the development of drugdelivery systems for antiparasitic drugs Parasitology Research 90 (Suppl 2)S63ndashS70Kearns G L Abdel-Rahman SM Alander SW Blowey D LLeeder J S and Kauffman R E (2003) Developmentalpharmacology ndash drug disposition action and therapy in infants andchildren New England Journal of Medicine 349 1157ndash1167Keiser J Engels D Buumlscher G and Utzinger J (2005)Triclabendazole for the treatment of fascioliasis and paragonimiasisExpert Opinion on Investigational Drugs 14 1513ndash1526Keiser J and Utzinger J (2007) Advances in the discovery anddevelopment of trematocidal drugs Expert Opinion on Drug Discovery 2(Suppl 1) S9ndashS23

Keiser J and Utzinger J (2008) Efficacy of current drugs against soil-transmitted helminth infections systematic review and meta-analysisJAMA 299 1937ndash1948Keiser J and Utzinger J (2010) The drugs we have and the drugs weneed against major helminth infections Advances in Parasitology 73 197ndash230Kuepfer I and Burri C (2009) Reflections on clinical research in sub-Saharan Africa International Journal for Parasitology 39 947ndash954Lippert C Gbenado S Qiu C Lavin B and Kovacs S J (2005)The bioequivalence of telithromycin administered orally as crushedtablets versus tablets swallowed whole Journal of Clinical Pharmacology45 1025ndash1031Lunn P G and Northrop-Clewes C A (1993) The impact ofgastrointestinal parasites on protein-energymalnutrition inmanProceedingsof the Nutrition Society 52 101ndash111Macleod S (2010) Therapeutic drug monitoring in paediatrics how dochildren differ Therapeutic Drug Monitoring 32 253ndash256Mafiana C F Ekpo U F andOjo D A (2003) Urinary schistosomiasisin preschool children in settlements around Oyan Reservoir in Ogun StateNigeria implications for control Tropical Medicine and InternationalHealth 8 78ndash82Mellin GW and Katzenstein M (1962) The saga of thalidomideNeuropathy to embryopathy with case reports of congenital anomaliesNew England Journal of Medicine 267 1238ndash1244Mennella J A and Beauchamp G K (2008) Optimizing oralmedications for children Clinical Therapy 30 2120ndash2132Meyer T Sekljic H Fuchs S Bothe H Schollmeyer D andMiculka C (2009) Taste a new incentive to switch to (R)-praziquantel inschistosomiasis treatment PLoS Neglected Tropical Diseases 3 e357Michele TM Knorr B Vadas E B and Reiss T F (2002) Safety ofchewable tablets for children Journal of Asthma 39 391ndash403Milne C P (2009) Pharmaceutical economics and applications topediatrics business case development In Pediatric Drug DevelopmentConcepts and Applications (ed Mulberg A E Silber S A and van denAnker J N) pp 39ndash57 John Wiley amp Sons HobokenMilne C P and Bruss J B (2008) The economics of paediatricformulation development for off-patent drugs Clinical Therapy 30 2133ndash2145Montresor A Awasthi S and Crompton DW T (2003) Use ofbenzimidazoles in children younger than 24 months for the treatment ofsoil-transmitted helminthiasis Acta Tropica 86 223ndash232Moran M (2005) A breakthrough in RampD for neglected diseases newways to get the drugs we need PLoS Medicine 2 e302Moran M Guzman J Ropars A L McDonald A Jameson NOmune B Ryan S and Wu L (2009) Neglected diseaseresearch and development how much are we really spending PLoSMedicine 6 e30Na Bangchang K Karbwang J Pungpak S Radomyos B andBunnag D (1993) Pharmacokinetics of praziquantel in patients withopisthorchiasis Southeast Asian Journal of Tropical Medicine and PublicHealth 24 717ndash723Nor Aripin K N B Choonara I and Sammons HM (2010b) Asystematic review of paediatric randomised controlled drug trials publishedin 2007 Archives of Disease in Childhood 95 469ndash473Nor Aripin K N B Sammons HM and Choonara I (2010a)Published paediatric randomized drug trials in developing countries 1996ndash2002 Paediatric Drugs 12 99ndash103Nwaka S and Hudson A (2006) Innovative lead discovery strategiesfor tropical diseases Nature Reviews Drug Discovery 5 941ndash955Odogwu S E Ramamurthy N K Kabatereine N B Kazibwe FTukahebwa E Webster J P Fenwick A and Stothard J R(2006) Schistosoma mansoni in infants (aged lt3 years) along the Ugandanshoreline of Lake Victoria Annals of Tropical Medicine and Parasitology100 315ndash326Pandolfini C and Bonati M (2005) A literature review on off-label druguse in children European Journal of Pediatrics 164 552ndash558Pifferi G andRestani P (2003) The safety of pharmaceutical excipientsFarmaco 58 541ndash550Rakhmanina N Y and van den Anker J N (2009) Developmentalpharmacology issues neonates infants and children In Pediatric DrugDevelopment Concepts and Applications (ed Mulberg A E Silber S Aand van den Anker J N) pp 231ndash242 John Wiley amp Sons HobokenRose K (2009) European perspective In Pediatric Drug DevelopmentConcepts and Applications (ed Mulberg A E Silber S A and van denAnker J N) pp 137ndash152 John Wiley amp Sons HobokenSammons HM and Choonara I (2005) Clinical trials of medicationin children 1996ndash2002 European Journal of Clinical Pharmacology 61165ndash167



Savioli L Gabrielli A F Montresor A Chitsulo L and Engels D(2009) Schistosomiasis control in Africa 8 years after World HealthAssembly Resolution 54middot19 Parasitology 136 1677ndash1681Schachter A D and Ramoni M F (2007) Paediatric drug develop-ment Nature Reviews Drug Discovery 6 429ndash430Schwartz C Issanchou S and Nicklaus S (2009) Developmentalchanges in the acceptance of the five basic tastes in the first year of lifeBritish Journal of Nutrition 102 1375ndash1385Sousa-Figueiredo J C Day M Betson M Kabatereine N B andStothard J R (2010a) An inclusive dose pole for treatment ofschistosomiasis in infants and preschool children with praziquantelTransaction of the Royal Society of Tropical Medicine and Hygiene 104740ndash742Sousa-Figueiredo J C Pleasant J Day M Betson MRollinson D Montresor A Kazibwe F Kabatereine N B andStothard J R (2010b) Treatment of intestinal schistosomiasis in Ugandanpreschool children best diagnosis treatment efficacy and side-effects and anextended praziquantel dosing pole International Health 2 103ndash113Standing J F and Tuleu C (2005) Paediatric formulations ndash getting tothe heart of the problem International Journal of Pharmacy 300 56ndash66Stothard J R and Gabrielli A F (2007) Schistosomiasis in Africaninfants and preschool children to treat or not to treatTrends in Parasitology23 83ndash86Stothard J R Sousa-Figuereido J C Betson M Adriko MArinaitwe M Rowell C Besiyge F and Kabatereine N B(2011) Schistosoma mansoni infections in young children when areschistosome antigens in urine eggs in stool and antibodies to eggs firstdetectable PLoS Neglected Tropical Diseases 5 e938Stoumltter H (2007) Paediatric drug development ndash historical background ofregulatory initiatives In Guide to Paediatric Clinical Research (ed Rose Kand van den Anker J N) pp 25ndash32 Karger BaselStrolin Benedetti M Whomsley R and Baltes E L (2005)Differences in absorption distribution metabolism and excretion ofxenobiotics between the paediatric and adult populations Expert Opinionon Drug Metabolism and Toxicology 1 447ndash471Taylor M J Hoerauf A and Bockarie M (2010) Lymphatic filariasisand onchocerciasis Lancet 376 1175ndash1185United Nations (2009) World Population Prospects The 2008 RevisionUnited Nations Department of Economic and Social Affairs PopulationDivision New YorkUtzinger J Raso G Brooker S de Savigny D Tanner MOslashrnbjerg N Singer B H and NrsquoGoran E K (2009) Schistosomiasisand neglected tropical diseases towards integrated and sustainable controland a word of caution Parasitology 136 1859ndash1874WHO (1985) The control of schistosomiasis report of a WHO expertcommittee WHO Technical Report Series 728 1ndash113WHO (2002a) Report of the WHO Informal Consultation on the Use ofPraziquantel during PregnancyLactation and AlbendazoleMebendazole inChildren under 24 Months World Health Organization GenevaWHO (2002b) Prevention and control of schistosomiasis and soil-transmitted helminthiasis report of a WHO expert committee WHOTechnical Report Series 912 1ndash57WHO (2006) Preventive Chemotherapy in Human HelminthiasisCoordinated Use of Anthelminthic Drugs in Control Interventions AManual for Health Professionals and Programme Managers World HealthOrganization GenevaWHO (2007a) Promoting Safety of Medicines for Children World HealthOrganization GenevaWHO (2007b) The Selection and Use of Essential Medicines World HealthInstitution GenevaWHO (2008a) The Global Burden of Disease 2004 Update World HealthOrganization GenevaWHO (2008b) Soil-transmitted helminthiasis Progress report on numberof children treated with anthelminthic drugs an update towards the 2010global target Weekly Epidemiological Records 82 237ndash252WHO (2010a)Working to Overcome the Global Impact of Neglected TropicalDiseases First WHO Report on Neglected Tropical Diseases World HealthOrganization GenevaWHO (2010b) SchistosomiasisWeekly Epidemiological Records 85 158ndash164

WHO (2010c) Soil-transmitted helminthiasis Weekly EpidemiologicalRecords 85 141ndash147Wu MH Wei C C Xu Z Y Yuan H C Lian WN Yang Q JChenM JiangQWWang C Z Zhang S J Liu Z DWei RMYuan S J Hu L S andWu Z S (1991) Comparison of the therapeuticefficacy and side effects of a single dose of levo-praziquantel with mixedisomer praziquantel in 278 cases of schistosomiasis japonica AmericanJournal Tropical Medicine and Hygiene 45 345ndash349

GLOSSARY

ADMET Absorption distribution metabolismexcretion and toxicity

ATC Anatomical Therapeutical Chemical classifi-cation system

BPCA Best Pharmaceuticals for Children Act (2002)DALY Disability-adjusted life year is a compositemeasure to estimate the burden of disease or injuryexpressed as the number of years lost due to ill-health disability or premature death

DNDi Drugs for Neglected Diseases initiative is acollaborative not-for-profit drug research anddevelopment organisation founded in 2003 basedin Geneva Switzerland that aims to improve thequality of life and the health of people sufferingfrom neglected diseases by using an alternativemodel to develop drugs for these diseases and byensuring equitable access to new and field-relevanthealth tools (httpwwwdndiorg)

FDA US Food and Drug Administration (httpwwwfdagov)

FDAMA FDA Modernization Act (1998)IPT Intermittent preventive therapy is a publichealth intervention aimed at treating and pre-venting malaria episodes in infants (IPTi) children(IPTc) and pregnant women (IPTp) The inter-vention builds on two tested malaria controlstrategies namely (1) to clear existing parasites(treatment effect seen inmass drug administrations)and (2) to prevent new infections (prophylaxis)

MMV Medicines for Malaria Venture is a not-for-profit public-private partnership established in1999 based in Geneva Switzerland that aims toreduce the burden of malaria in disease-endemiccountries by discovering developing and facilitat-ing delivery of new effective and affordable anti-malarial drugs (httpwwwmmvorg)

Off-label Use for this populationage class notmentioned in the label

Preventive (anthelminthic) chemotherapy Useof (anthelminthic) drugs either alone or in combi-nation as a public health tool against (helminth)infections



patients should be given medicines that have beenappropriately evaluated for their userdquo (httpwwwfdagov) We pose the question whether antiparasiticdrugs have been adequately evaluated prior to widerapplication in paediatric populations Indeed ad-dressing this question served as the main motivationfor the current paper which forms part of a specialissue of Parasitology pertaining to ldquoProgress in Pae-diatric Parasitologyrdquo (see Stothard and Booth edi-torial in this special issue)We first provide a short historical background on

paediatric drug development and highlight practicalethical and economic issues We then juxtapose thelatest United Nations (UN) population figuresand disease burden estimates in the lowest incomecountries To strengthen the current evidence-base ofantiparasitic drugs in the paediatric population weperformed a systematic review using two readilyavailable electronic databases We examined the typeof drugs investigated the age of the study partici-pants and performed a temporal and geographicalanalysis of studies meeting our inclusion criteriaPaediatric pharmacokinetic (PK) studies were alsoexaminedWith an emphasis on anthelminthic drugswe critically reviewed available drug formulationsFinally in the current era of lsquopreventive (anthel-minthic) chemotherapyrsquo (see Glossary) that is theregular administration of antiparasitic drugs to entireat-risk populations (WHO 2006 2010a) we discussimplications for control programmes that aim atincluding also preschool-aged children


Regulatory ethical commercial and economic issues

Regulatory efforts to protect children from harm-ful medications began in the mid-20th century inresponse to serious adverse events such as limbmalformations caused by thalidomide (Barsch andOtte 2010) Indeed thalidomide (Conterganreg)which had been used as a treatment for recurringmorning sickness in pregnant women during the1950s and the early 1960s caused peripheral neuritisand malformations eg phocomelia in babies ofmothers who had taken thalidomide over the courseof their pregnancies (Stoumltter 2007 Barsch and Otte2010) Once the evidence of these serious adverseevents of thalidomide had been established throughcase-control studies the medication was withdrawnfrom the market (Mellin and Katzenstein 1962)As a consequence many drugs received marketingauthorisation for use in adults only However anincrease in off-label use (see Glossary) was sub-sequently observed amounting to 80 in paediatricpatients (Pandolfini and Bonati 2005 Stoumltter 2007)Bearing the aforementioned dilemmas in mind

over the past two decades regulations have beenenacted upon and incentives created first in the US

(eg Food and Drug Administration ModernizationAct (FDAMA) instigated in 1998 and Best Pharma-ceuticals for Children Act (BPCA) put forth in 2002see Glossary) and second by a number of EU pae-diatric guidelines (Rose 2009) The purpose of theseregulations was to improve paediatric drug develop-ment particularly in terms of safety (Schachter andRamoni 2007 Macleod 2010) It is clear that theseinitiatives and regulations have changed the land-scape for paediatric drug development For examplethere are recent signs of enhanced research activitiesgoing hand-in-hand with clinical trials on the efficacyand safety of drugs in children including PK studiesand the development of drug formulations that aresuitable for the paediatric population (Macleod2010)Nonetheless there are a number of challenges

regarding clinical trials in children Ethical issuesinclude the complexity to obtain written informedconsent from parents and legal guardians as well asassents from participating children (Kuepfer andBurri 2009) Furthermore the level of invasivenessshould be kept as little as possible and hence thenumber of blood samples and the amount of bloodtaken in PK studies should be minimised (Howie2011) Scientific issues comprise for example thenecessity to stratify the patient population into dif-ferent age groups or the need to develop microassaysto analyse small amounts of biological samples thatare typically obtained from paediatric populations(Conroy et al 2000 WHO 2007a Choonara 2009)Finally there are commercial and economic issues

as the market for paediatric medicines is small com-pared to the adult population (estimated to be lessthan 10 of the total prescription drug market(Milne 2009)) and hence lacks attractiveness forthe international pharmaceutical industry Whileblockbusters mainly address highly prevalent chronicdiseases children often experience acute illnessesand the chronic conditions that do exist in the pae-diatric population are mostly rare disorders (WHO2007b Milne and Bruss 2008)


DEMOGRAPHY AND DISEASE BURDEN

In the US since the FDAMA institutionalised anincentive of a 6-monthpatent extension for previouslyapproved drugs in July 1998 a total of 173 drugs weregranted paediatric exclusivity (httpwwwfdagovdownloadsDrugsDevelopmentApprovalProcessDevelopmentResourcesUCM223058pdf) Thesedevelopments it was claimed showed the achieve-ments made by FDAMA for the paediatric popu-lation However it should be noted that most of thesepatent extensions were for drugs targeting the centralnervous system (CNS) (eg anti-depressants) cardi-ovascular system (eg ACE inhibitors) alimentarytract and metabolism (eg anti-diabetic drugs) and





























Excluded (n=756)




Sample size (n)


No No


Total 269 100 17 100

40

30

20

10

0

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2

17

29

36 37

2523

36

2729

8





Drugs investigated



PK studies




DRUG FORMULATIONS










Antimalarials

Antinematodals


Antitrematodals


Key

102937

98

826


Solutiondrops

Emulsionsuspension



Tablets

Capsules


Chewable tablets


Termnewborninfants

Infantsandtoddlers

Pre-schoolchildren

















EIPICO









Suspension100mg5ml






Suspension100mg5ml





Suspension40mg5ml


2middot5 mgkg once




Suspension50mgml






See above




Praziquantel






Triclabendazole









Ivermectin










70

60

50

40

30

20

10

00-4 lt9 lt14 lt19 lt29 lt39 lt49 50

250

200

150

100

50

0


AGE

gt1000

gt350

gt100

gt0epgmean


No-infection


No-infection

80

40

20

20

10

5

20

10

5

4

1

025

64

81

9025

80

40

20

64

16

4

4

36

64

A

B

C










ACKNOWLEDGEMENTS


REFERENCES










GLOSSARY






































Excluded (n=756)




Sample size (n)


No No


Total 269 100 17 100

40

30

20

10

0

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2

17

29

36 37

2523

36

2729

8





Drugs investigated



PK studies




DRUG FORMULATIONS










Antimalarials

Antinematodals


Antitrematodals


Key

102937

98

826


Solutiondrops

Emulsionsuspension



Tablets

Capsules


Chewable tablets


Termnewborninfants

Infantsandtoddlers

Pre-schoolchildren

















EIPICO









Suspension100mg5ml






Suspension100mg5ml





Suspension40mg5ml


2middot5 mgkg once




Suspension50mgml






See above




Praziquantel






Triclabendazole









Ivermectin










70

60

50

40

30

20

10

00-4 lt9 lt14 lt19 lt29 lt39 lt49 50

250

200

150

100

50

0


AGE

gt1000

gt350

gt100

gt0epgmean


No-infection


No-infection

80

40

20

20

10

5

20

10

5

4

1

025

64

81

9025

80

40

20

64

16

4

4

36

64

A

B

C










ACKNOWLEDGEMENTS


REFERENCES










GLOSSARY



























Excluded (n=756)




Sample size (n)


No No


Total 269 100 17 100

40

30

20

10

0

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2

17

29

36 37

2523

36

2729

8





Drugs investigated



PK studies




DRUG FORMULATIONS










Antimalarials

Antinematodals


Antitrematodals


Key

102937

98

826


Solutiondrops

Emulsionsuspension



Tablets

Capsules


Chewable tablets


Termnewborninfants

Infantsandtoddlers

Pre-schoolchildren

















EIPICO









Suspension100mg5ml






Suspension100mg5ml





Suspension40mg5ml


2middot5 mgkg once




Suspension50mgml






See above




Praziquantel






Triclabendazole









Ivermectin










70

60

50

40

30

20

10

00-4 lt9 lt14 lt19 lt29 lt39 lt49 50

250

200

150

100

50

0


AGE

gt1000

gt350

gt100

gt0epgmean


No-infection


No-infection

80

40

20

20

10

5

20

10

5

4

1

025

64

81

9025

80

40

20

64

16

4

4

36

64

A

B

C










ACKNOWLEDGEMENTS


REFERENCES










GLOSSARY













Drugs investigated



PK studies




DRUG FORMULATIONS










Antimalarials

Antinematodals


Antitrematodals


Key

102937

98

826


Solutiondrops

Emulsionsuspension



Tablets

Capsules


Chewable tablets


Termnewborninfants

Infantsandtoddlers

Pre-schoolchildren

















EIPICO









Suspension100mg5ml






Suspension100mg5ml





Suspension40mg5ml


2middot5 mgkg once




Suspension50mgml






See above




Praziquantel






Triclabendazole









Ivermectin










70

60

50

40

30

20

10

00-4 lt9 lt14 lt19 lt29 lt39 lt49 50

250

200

150

100

50

0


AGE

gt1000

gt350

gt100

gt0epgmean


No-infection


No-infection

80

40

20

20

10

5

20

10

5

4

1

025

64

81

9025

80

40

20

64

16

4

4

36

64

A

B

C










ACKNOWLEDGEMENTS


REFERENCES










GLOSSARY















Antimalarials

Antinematodals


Antitrematodals


Key

102937

98

826


Solutiondrops

Emulsionsuspension



Tablets

Capsules


Chewable tablets


Termnewborninfants

Infantsandtoddlers

Pre-schoolchildren

















EIPICO









Suspension100mg5ml






Suspension100mg5ml





Suspension40mg5ml


2middot5 mgkg once




Suspension50mgml






See above




Praziquantel






Triclabendazole









Ivermectin










70

60

50

40

30

20

10

00-4 lt9 lt14 lt19 lt29 lt39 lt49 50

250

200

150

100

50

0


AGE

gt1000

gt350

gt100

gt0epgmean


No-infection


No-infection

80

40

20

20

10

5

20

10

5

4

1

025

64

81

9025

80

40

20

64

16

4

4

36

64

A

B

C










ACKNOWLEDGEMENTS


REFERENCES










GLOSSARY
























EIPICO









Suspension100mg5ml






Suspension100mg5ml





Suspension40mg5ml


2middot5 mgkg once




Suspension50mgml






See above




Praziquantel






Triclabendazole









Ivermectin










70

60

50

40

30

20

10

00-4 lt9 lt14 lt19 lt29 lt39 lt49 50

250

200

150

100

50

0


AGE

gt1000

gt350

gt100

gt0epgmean


No-infection


No-infection

80

40

20

20

10

5

20

10

5

4

1

025

64

81

9025

80

40

20

64

16

4

4

36

64

A

B

C










ACKNOWLEDGEMENTS


REFERENCES










GLOSSARY













Praziquantel






Triclabendazole









Ivermectin










70

60

50

40

30

20

10

00-4 lt9 lt14 lt19 lt29 lt39 lt49 50

250

200

150

100

50

0


AGE

gt1000

gt350

gt100

gt0epgmean


No-infection


No-infection

80

40

20

20

10

5

20

10

5

4

1

025

64

81

9025

80

40

20

64

16

4

4

36

64

A

B

C










ACKNOWLEDGEMENTS


REFERENCES










GLOSSARY

















Ivermectin










70

60

50

40

30

20

10

00-4 lt9 lt14 lt19 lt29 lt39 lt49 50

250

200

150

100

50

0


AGE

gt1000

gt350

gt100

gt0epgmean


No-infection


No-infection

80

40

20

20

10

5

20

10

5

4

1

025

64

81

9025

80

40

20

64

16

4

4

36

64

A

B

C










ACKNOWLEDGEMENTS


REFERENCES










GLOSSARY
















70

60

50

40

30

20

10

00-4 lt9 lt14 lt19 lt29 lt39 lt49 50

250

200

150

100

50

0


AGE

gt1000

gt350

gt100

gt0epgmean


No-infection


No-infection

80

40

20

20

10

5

20

10

5

4

1

025

64

81

9025

80

40

20

64

16

4

4

36

64

A

B

C










ACKNOWLEDGEMENTS


REFERENCES










GLOSSARY


















ACKNOWLEDGEMENTS


REFERENCES










GLOSSARY


















GLOSSARY














GLOSSARY












Antiparasitic drugs for paediatrics: systematic review ... · Antiparasitic drugs for paediatrics: systematic review, formulations, pharmacokinetics, safety, eﬃcacy and implications

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