Post on 08-May-2018
Pharmaceutical Aspects
Mühlebach 1
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
Pharmaceutical Aspects:
Ocular Drugs and the Medication Process
Stefan Mühlebach, PhD, Hospital Pharmacist FPH Professor of Pharmacology and Hospital Pharmacy, University of Basel stefan.muehlebach@unibas.ch
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
Pharmaceutical Aspects
Mühlebach 2
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
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
Pharmaceutical Aspects
Mühlebach 3
Basic Science Course
Neuchâtel 2017
26.01.2017
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
Pharmaceutical Aspects
Mühlebach 4
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
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
Pharmaceutical Aspects
Mühlebach 5
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
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)
Pharmaceutical Aspects
Mühlebach 6
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
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)
Pharmaceutical Aspects
Mühlebach 7
Basic Science Course
Neuchâtel 2017
26.01.2017
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
Pharmaceutical Aspects
Mühlebach 8
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
• 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
Pharmaceutical Aspects
Mühlebach 9
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
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
Pharmaceutical Aspects
Mühlebach 10
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
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
Pharmaceutical Aspects
Mühlebach 11
Basic Science Course
Neuchâtel 2017
26.01.2017
Drug Delivery to the Eye
(Barriers)
Ocular Drug delivery AAPS J 2010;12(3):348-60
BRB
BAB
Aqueous humor
Pharmaceutical Aspects
Mühlebach 12
Basic Science Course
Neuchâtel 2017
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)
Pharmaceutical Aspects
Mühlebach 13
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
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
Pharmaceutical Aspects
Mühlebach 14
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
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←
→
Pharmaceutical Aspects
Mühlebach 15
Basic Science Course
Neuchâtel 2017
26.01.2017
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
Pharmaceutical Aspects
Mühlebach 16
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
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
Pharmaceutical Aspects
Mühlebach 17
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
Challenges in Health Care
• Steadily rising health care costs
• Inappropriate treatments (medication errors)
• DRG: differences in treatment types
(quality, competition)
Pharmaceutical Aspects
Mühlebach 18
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
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)
Pharmaceutical Aspects
Mühlebach 19
Basic Science Course
Neuchâtel 2017
26.01.2017
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
Pharmaceutical Aspects
Mühlebach 20
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
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
Pharmaceutical Aspects
Mühlebach 21
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
Administration of Topical Ophthalmics
Drops Ointments
Instilling an eye ointment into the
lower conjunctival sac.Use non-dominant hand to pull lower lid down.
Pharmaceutical Aspects
Mühlebach 22
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
The Nasolacrimal Drainage System
Capacity of the
lacrimal sac
20-30 µl
Compresse to
reduce outflow
(3-5 min)
Pharmaceutical Aspects
Mühlebach 23
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
Eye Drops Packaging (Mix-up?)
Pharmaceutical Aspects
Mühlebach 24
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
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
Pharmaceutical Aspects
Mühlebach 25
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
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
Pharmaceutical Aspects
Mühlebach 26
Basic Science Course
Neuchâtel 2017
26.01.2017
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
Pharmaceutical Aspects
Mühlebach 27
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
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.
Pharmaceutical Aspects
Mühlebach 28
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
Layout
• Drug development and drug authorization (off label)
• Ophthalmics: administration & formulation 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
Pharmaceutical Aspects
Mühlebach 29
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
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
Pharmaceutical Aspects
Mühlebach 30
Basic Science Course
Neuchâtel 2017
26.01.2017
Pharmaceutical Aspects
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