Pharmaceutical Aspects: Ocular Drugs and the … · Pharmaceutical Aspects: Ocular Drugs and the Medication Process Stefan Mühlebach, PhD, ... (Authorization relies on a dossier

Pharmaceutical Aspects

Mühlebach 1

Basic Science Course

Neuchâtel 2017

26.01.2017


Pharmaceutical Aspects:

Ocular Drugs and the Medication Process

Stefan Mühlebach, PhD, Hospital Pharmacist FPH Professor of Pharmacology and Hospital Pharmacy, University of Basel [email protected]

https://pharma.unibas.ch/research-groups/people/profile/person/muehlebach/?tx_x4epersdb_pi1%5BoriginPageID%5D=44842&cHash=42bcfbe93a4ca4a20bc6e61d8e5cea1a

Director and Lead Regulatory Science NBCDs, Vifor Pharma Ltd (Switzerland)

Head Health Care Products at the Federal Office for National Economic Supply


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Individualized Pharmacotherapy:Genomics → Proteomics → Metabolomics

Variability, interactions

Gene-mediated enzyme profile

cytochrom P450 enzymes

Cyp2D6 polymorphism:

(codeine demethylation)

(Protein) Biomarkers

Distinct proteins are made under

distinct (cell) conditions

mRNA → proteins →post-translational modifications

e.g. IL-6, IL-8 analysis in CVD

Matrix-assisted laser desorption/ionization

Disease diagnostics

Fingerprints of small

molecule (profile) for

individual cellular processes

GLC-MS instrumentation

Urine / blood analysis:

toxicity,

functional genomics,

nutrigenomics

Individual metabolism


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Aim of a Pharmacotherapy:

(Cost-)Effective and Safe

Multifaceted / multidisciplinary approach

within each discipline

• Correct diagnosis of the ophthalmic disease in the patient’s life

context (medical)

• Upon pharmacotherapy: appropriate ophthalmic drug and drug

formulation (pharmaceutical)

• Ensure the necessary ophthalmic drug delivery– Focus drug: appropriate product selection

– Focus patient: Compliance, medication error

• Consider regulatory, legal, cost and ME aspects of drug use


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Layout

• Drug development and drug authorization (off label)

• Ophthalmics: formulation & administration

challenges

• Medication errors: from drug prescribing to drug use

• Measures to eliminate ME or improve the ME rate

• Physician’s and pharmacist’s responsibilities in the

medication process


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From an API to a Drug Product (Active Pharmaceutical Ingredient)

Pharmacological active compound(physicochemical, biological, preclinical and clinical characterization)

Embedded in an appropriate formulation(API + excipients to get a stable formulation with sufficient bioavailability)

Authorized (reimbursed) drug/medicinal product(Authorization relies on a dossier (drug profile, labels), REMS, PMS)

(Product launch, reimbursement / prizing, supply)


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Manufacture of Medicinal ProductsGMP (Good Manufacturing Practice):

Internationally defined standards for pharmaceutical manufacturing

according to the Pharmaceutical Inspection Convention (PIC) and

EU (pharmacopoeial quality requirements)

Industrial large scale production

Preparation in

small quantities

(individual,

extemporaneous

preparation)


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Three Drug Classes

Adapted from:http://www.gabionline.net/Biosimilars/Research/Small-molecule-versus-biological-drugs.

Borchard et al. Reg Tox Pharmacol 2012;64:2

SMALL MOLECULE DRUGS BIOLOGICSNON-BIOLOGICAL

(NANOMEDICINES)

Size Low molecular (<500 Da) High molecular (5-900 kDa) High molecular (10-1000nm)

Structure

Simple, well defined,

independent of manufacturing

process

Complex (modifications, surface, mixtures),

defined by manufacturing process.

Not to be fully characterized by physicochemical means

Manufacturing Chemical synthesisProduced by living cells or

organisms (bio source) Synthetic, (nano)technologies

Stability High Low, sensitive to external conditions

Immunogenic No Yes Yes/no

Follow-on versions Identical (the same) Similar

GENERICS BIOSIMILARS (NANO-)SIMILARS


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• NBCD products are used to treat a variety of serious medical conditions

including cancer, auto-immune diseases, infectious diseases, anemia, and more.

Doxil®

Cancer

Doxorubicin liposomes

Janssen

NBCDs in Therapy

Venofer®

Iron deficiency (Anemia)

Iron sucrose

Vifor Pharma

Copaxone®

Multiple sclerosis

Glatiramer acetate

Teva Pharmaceuticals

Restasis®

Chronic dry eye disease

Cyclosporine ophthalmic emulsion

Allergan

Renvela®

Control of phosphorus levels (chronic kidney disease)

Sanofi


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Authorization

(licensed, in- and off-label)

Authorized (in label)

• Indication(s)

• Doses

• Precautions

• Contraindications

off label*:• Indication

• Population groups (children, elderly!)

• Dosing

• Administration

• Pharmaceutical aspects (expiry, solvents, formulation)

*off label indication (responsibility!)

upon clinical need / rational behind

no authorized MP available

Adapted from: Mühlebach S. Der Weg des Medikaments vom Molekül zum zugelassenen Präparat.

Swiss Med Forum 2008;8(50):973–977

https://compendium.ch/home/de


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Layout



challenges




medication process


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Drug Delivery to the Eye

(Barriers)

Ocular Drug delivery AAPS J 2010;12(3):348-60

BRB

BAB

Aqueous humor


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26.01.2017 http://www.ahaf.org/glaucoma/about/Anatomy Eye.htm

anterior chamber

(aqueous humor)

cornea

ciliar muscle

posterior chamber

vitrous humor

Ocular Administration upon Cornea(<5% reaches intraocular tissues)


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Corneal Bioavailability : Reducing factors upon local application

• Tear production (volume per time)

Tear drainage

• Non-productive absorption

(trabecular, conjunctival; ADR)

Others: - release / elimination

- binding

- degradation

Important: timedrug presence x concentration


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Drug Distribution: Lipophilicity and pK

R-N-H R-N + H Corneal fluid←→

+ +

Pro-drugs: Dipivefrin (epinephrine ester)

Lipophilicity↑ 600 x

Dosage↓ 1/20 - 1/10 (ADR!)

+R-N-H R-N Stroma←

→

+R-N-H R-N Anterior chamber←

→


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Eye Preparations:

Proper Topical ApplicationIntraocular bioavailability < 5%

High clearance by tears and mechanical eyelid wiping

Lacrimal system Surface Permeability

Capacity 30µl Cornea 1 Cornea 1

MG < 500

Lipophilic

Production 1.2µl

(basal/min)

Lacrymal system 3

Transit time 0.5-12min

(nasopharynx)

Conjunctiva 17 Conjunctiva 100-1000

MG< 25‘000

Active transport


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Layout



challenges




medication process


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Challenges in Health Care

• Steadily rising health care costs

• Inappropriate treatments (medication errors)

• DRG: differences in treatment types

(quality, competition)


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Adverse Events

(ADE)

ADE: “Injury resulting from a medical

intervention timely related to a drug”. (Bates DW, JAMA 1995;274:29)

Cost per ADE (≈ 5000 CHF)Bates DW JAMA 1997;

Cullen DJ Crit Care Med 1997

in contrast to ADR not necessarily drug-caused

Potential Complications

Medication Errors

(ME)

(Drug) Treatment & Complications

(ADE)

American Society of Health System Pharmacists 1999

Adverse Reactions

(ADR)


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Medication Errors: Where they OccurManual

Prescribing

*49%

Transcription / Documentation

11%

Dispensation

14%

26%Administration

*The rates correlated to avoidable ADE and ME with potential ADE.

From: Bates et al., JAMA 1995, 274

© Patientensicherheit Schweiz


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Incidence of Prescribing Errors

in an Eye Hospital• Overall 144/1952 (8%) prescription

sheets had errors.

• 7% of the total errors were errors of

prescription writing

• 1% were drug errors (dose, route,

frequency).

• The majority of errors were made by

junior doctors and no drug errors

were made by senior doctors.

• The outpatients department had by

far the highest prevalence of errors

K Mandal and SG Fraser, BMC Ophthalmol. 2005;5:4

A&E: accident and emergency

OPD: outpatients department


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Administration of Topical Ophthalmics

Drops Ointments

Instilling an eye ointment into the

lower conjunctival sac.Use non-dominant hand to pull lower lid down.


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The Nasolacrimal Drainage System

Capacity of the

lacrimal sac

20-30 µl

Compresse to

reduce outflow

(3-5 min)


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Eye Drops Packaging (Mix-up?)


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Risks in Preparation and Administration of Injectable Medicines

• Incomplete and ambiguous prescription administer 1 ampoule

• Complex preparation procedure before use vacuum

• Lack of essential technical information

• Absence of multidisciplinary procedures / support

• Selection of wrong drug or diluent

• Use of drug, diluent or infusion after exp. date

• Calculation errors 1%=10 mg/ml

• Incompatibility heparin!

• Administration to wrong patient

• Administration of wrong route

• Unsafe handling or inappropriate aseptic non-touch technique

• Health and safety risks to operator or environment

• Variable knowledge, training and competence among health care staff

From: HPE Clinical Pharmacy Europe - Number 7 - Summer 2007


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Layout



challenges




medication process


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Trends ADE over Time:

Process not controlled; no improvement despite awareness

Author Country Year Harms

Kohn et al. Institute of Medicine

USA 1999 3-16%

Landrigan CP et al.NEJM 2010; 363: 2124-2134

USA 2002-2007 no reduction

Classen DC. et al.Health Aff 2011; 30:581-589

USA 2008 33%

Baines RJ. et al.JQSHC 2013, 22: 290-298

NL 2004-2008 4,1% to 6,2%

Adapted slide by courtesy from Prof. D. Conen, President of the Swiss patient safety foundation


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Patients Adherence to 1x Travatan®

Travoprost (PG F20 analogue)

• Patients:

196/282 (70%) pat. with electronic dosing aid

evaluated for 8 w period (medical history).

Instruction and free medication.

• Result:

mean adherence rate 0.71 ± 0.24 (0.02-0.97)

75% < 0.556;

poor corr. between pat. & physician estimate

• Conclusions:

nearly 45% of pat < 75% adherence

CO Okeke et al. Ophthalmology 2009;116:191-199.


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Layout


• Ophthalmics: administration & formulation challenges




medication process


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Drug Prescribing and Dispensing

LThP § 26 Prescription and dispensation of drugs

1 When prescribing and dispensing drugs the accepted rules of the medical and pharmaceutical sciences have to respected.

Federal Law on Therapeutic Products 2002 (SR 812.21)

Physician’s responsibility

Diagnosis

Therapeutic decision

Prescription

Pharmacist’s responsibility

Procurement

Dispensing

Instruction on correct use


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Medication necessary?

Which therapeutic class?cost effectiveness

Which pharmacologically active

compound?

Which patient?ADE

Psyche / mind

Compliance

Which product?Drug formulation

cost, paid by health insurance?

Efficient and Safe Therapy


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Actions to Improve Patient Safety

Instituting processes to ensure “the five rights of patient safety”:

• right patient

• right drug

• right time

• right dose

• right route of delivery

Pharmaceutical Aspects: Ocular Drugs and the … · Pharmaceutical Aspects: Ocular Drugs and the Medication Process Stefan Mühlebach, PhD, ... (Authorization relies on a dossier

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