Clinical Pharmacokinetics

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CLINICAL PHARMACOKINETICS

Presented By,NAUSHEEN FATHIMA

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CONTENTS Introduction Definition Altered Kinetics In Pregnancy Plasma Drug Monitoring During Pregnancy Points To Be Considered In Teratogenic Drug Selection Altered Pharmacokinetics In Children Issues In Therapeutics Factors To Be Considered When Selecting A Drug

Dosage Regimen Or Route Of Administration For A Child Patient

Monitoring References

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INTRODUCTIONClinical pharmacokinetic studies are

performed to examine the absorption, distribution, metabolism, and excretion of a drug under investigation (investigational drug and approved drug) in healthy volunteers and/or patients. Data obtained from such studies are useful for the design and conduct of subsequent clinical trials. They are also necessary for appropriate analysis and evaluation of the efficacy and safety data obtained in clinical trials for new drug development and in post-marketing clinical trials.

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DEFINITION

The application of pharmacokinetic principles in the dosage regimen design for the safe and effective management of illness in individual patient is called as clinical pharmacokinetics.

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ALTERED KINETICS IN PREGNANCY Two compartment model is the simplest model in

pregnant ladies (mother & fetus). But in practice, many compartments in mother & fetus

may present.(e.g. Placenta, amniotic fluid)DURING ABSORPTION:In Stomach: Acidic drugs in ionized form, so reaching of intestine is

delayed. Therefore, no change in extent of absorption but kinetic

of absorption is changed.

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In Intestine Though peristaltic movement is decreased, blood flow is more

which increase the rate of transport from mucosal side to serosal side. Therefore, no problem in absorption.

DURING DISTRIBUTION: Decrease in albumin concentration due to hemoglobin

dilution. In pregnancy: Though there is increased production on

proteins, decrease in amount of proteins occurs. This resembles hypo albuminemia.

Due to decrease in protein binding, increase in free drug concentration leads to increased therapeutic effect.

Also increase in elimination or metabolism and increase in volume of distribution.

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CLEARANCE Increase in renal plasma flow by 50-100%. Increase in GFR up to 70%. Increased levels of unbound drug in plasma. Hepatic clearance is variable. Progesterone increases intrinsic hepatic clearance

which leads to rapid metabolic degradation, especially of the more lipid soluble drugs.

Examples of such drugs include digoxin, gentamycin & cephalexin.

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PLASMA DRUG MONITORING DURING PREGNANCY

The physiological changes during pregnancy is longer (1 day-10 months) but return is very quick (5-7 weeks after parturition)

Monitoring is not useful in drugs used during childbirth.(1- stage:10 months,

2- stage: few hrs, 3- stage: few weeks).therefore 2nd stage is not very important.

Plasma levels of anticonvulsants may fall during 1st stage & 3rd stage because of

Increased intrinsic clearance and increased fluid volume. Therefore, dosage adjustment based on the free fraction

of the drug should be made.

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Monitoring every 4 weeks from onset of pregnancy till parturition & weekly after birth

For 2-3 weeks and then every two weeks until drug level stabilize is recommended.

Plasma lithium levels should be monitored every two weeks during three trimesters and every day after parturition until levels stabilize.

Digoxin is also needed monitoring. Serum concentration on antibiotics also needs

monitoring.

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POINTS TO BE CONSIDERED IN TERATOGENIC DRUG SELECTION

Teratogenecity: Birth defects in 2-4% of total birth. Of these, 65-70% with unknown cause, 25% due to

genetic defects, 3% due to chromosomal aberration and only 3% due to infections, drugs.

Pre-implantation (1-16 days): Complete damage of replacement of cell possible.

Organogenesis’s (17-56 days): Possibility of congenital malformation.

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ALTERED PHARMACOKINETICS IN CHILDREN Here, the organs are not matured. The development of organs continues until

at least to the age of 12 yrs. Pediatrics – branch of medicine dealing

with the development of disease and disorders in children.

Pediatric patients were always considered in the past for treatment as mini adults.

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SUBDIVISION IN CHILDREN Neonate: The first 30 days of life. Infant: From 1 month to 1 yr. Child: From 1yr to 12 yrs. Adolescent: From 12 yrs to 18 yrs.

General Consideration Infancy and childhood is a period of rapid growth and

development of organ systems and so careful administration of drugs should be ensured.

During the age of 1-12 yrs almost 60% drop in extra cellular volume.

Dosage is adjusted based on pharmacokinetic data of a given age group for the desired response. But considering each individuals drug handling capacity often the most rational approach.

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DURING ABSORPTION Until the 2nd yr of life, GI acid secretion is not

increased and it is comparable on a per kg basis to that observed in adult.

Gastric pH is neutral birth, so bioavailability of acid labile drug increase.(e.g. pencillin)

Intestinal peristalsis is lower until 1 yr. Drug absorbed by the oral route is erratic in the new

born baby of any gestation. Thus it is usual to give many drugs by the iv/im route

to ensure maximum bioavailability. Drugs that are not acid liable show oral bioavailability

equal to that of adults. (e.g. paracetamol, digoxin).

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DURING DISTRIBUTION Children’s total body water content is more and drugs that are

highly water soluble are absorbed faster. Total body water decreases throughout the first year and shift

from predominantly extra cellular to intra cellular fluid. Lipophilic drugs have a large Vd despite of lower adipose

tissue. (because of high affinity of these lipid site) Dosage adjustment has to be done to drugs that are highly

water soluble like gentamycin to avoid ADR. Large inter patient variability in Vd due to varied nature of

maturation. Albumin concentration remains comparable with adult but, α-

1 acid, glycoprotein concentration is low. Therefore protein binding of acidic drugs is more (due to

more albumin) and for the basis drugs it is less (due to less α-1 acid glycoprotein)

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DURING METABOLISM At birth majority of the metabolic enzyme systems are

either absent or present in considerably reduced amounts compared to adults.(exemption: sulfate conjugation is more)

Glucuronidation is very less. Therefore chloramphenicol is not bound extensively.

As there is no elemination (metabolism) accumulation of chloramphenicol occur which leads grow baby syndrome.

Caffeine in children may have half life of even 5 days. But in adults it is 4 hrs.

So drugs that are extensively metabolized by liver should be administered cautiously.(caffeine, lidocaine, chloramphenicol)

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DURING ELIMINATION Renal drug elimination is the primary route for

antimicrobial agents which are most commonly used drugs in children.(β-lactum antibodies, aminoglycosides)

Renal system undergoes active maturation during first 2 yrs of life. However, GFR may reach adult values in 2 months.

Inter individual variation is prominent (eg: gentamycin, ampicillin, frusemide)

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Issues In Therapeutics Sampling blood both difficult. Alternative source to be considered (saliva, urine) Estimation from urinary samples involve either

Amount remaining to be excreted technique.In (Acα – Ac) = In (Ke/ K.D) – Kt

Or

Excretion rate plotIn d/dt (Ac) = (In Ke.D) . Kt

Many drugs are often estimated by this method (paracetamol, gentamycin)

For drugs that achieve saturation kinetic rate of drug administration can be calculated using “Michaelis–Menten” equation.

D/t = Vmax +C/Km +C

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DOSAGE In selecting a method of dosage calculation

therapeutic index of the drug should be considered.

For a narrow therapeutic index drugs, dosing must be based on the calculated body surface area.

Dosage adjustments based on TDM and homograms in single and drug combination situation are possible. However wide variation in Vd and Cl exist.

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FACTORS TO BE CONSIDERED WHEN SELECTING A DRUG DOSAGE REGIMEN OR ROUTE OF ADMINISTRATION FOR A CHILD

PATIENT Age/ weight/ surface area. Dose / dose interval. Route of administration. Formulation / preparation. Interaction ADR Counseling and compliance aids.

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MONITORING Monitoring drug concentration from serum or

the biological fluids is useful if desired effect is not obtained.

Monitoring also helps to avoid ADR which may sometimes be fatal to the children.

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REFERENCES Milo Gibaldi, Biopharmaceutics and clinical

pharmacokinetics; page no: 154- 157. http://www.nihs.go.jp/phar/pdf/ClPkEng011122.pdf http://ajprd.com/downloadebooks_pdf/41.pdf