Prequalification programme:
Priority essential medicines
Training Workshop for evaluators from National
Medicines Regulatory Authorities in the East African
Community:
Evaluation of quality and interchangeability
of medicinal products.
Dar Es Salaam
United Republic of Tanzania
10 – 14 September 2007
Evaluation of quality and interchangeability of medicinal products |
1 EAC/EC/WHO Training workshop / 10-14 September 2007
Training Workshop on
Evaluation of quality and interchangeability of medicinal products.
Complicated issues regarding bioequivalence
Presenter: Drs. J. Welink
Senior pharmacokineticist
Medicines Evaluation Board, NL
WHO adviser
E-mail: j.welink@cbg-meb.nl
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Bioequivalence
Bioequivalence:
Two medicinal products are bioequivalents if
they are pharmaceutical equivalents or alternatives
and if their bioavailabilities (rate and extent) after
administration in the same molar dose are similar
to such degree that their effects, with respect
to both efficacy and safety, will be
essential the same.
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Bioequivalence – single dose
Basic design considerations:
minimize variability not
attributable to formulations
minimize bias
goal: compare performance
2 formulations
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Bioequivalence – single dose
Golden standard study design:
single dose, two-period,
crossover
healthy volunteers
Reference (comparator)/
Test (generic)
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Bioequivalence – standard situation
Bioequivalence:
Linear pharmacokinetics
Non narrow therapeutic drug
Non highly variable drug
Decision based upon parent drug data
Decision based upon plasma concentrations
Stereochemistry not an issue
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Bioequivalence-non linear pharmacokinetics
Goal:
compare performance
2 formulations
select the strength with the
largest sensitivity to detect differences
in the two products
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Bioequivalence-non linear pharmacokinetics
Linear PK:
R T
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R T
Bioequivalence-non linear pharmacokinetics
AUC/Cmax increase less
than dose proportional
exception:
solubility!
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Bioequivalence-non linear pharmacokinetics
AUC/Cmax increase more
than dose proportional
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Bioequivalence-narrow therapeutic drugs
Narrow Therapeutic Index Drugs
 ‘Critical dose drugs’
– Small changes in dose may cause
• Serious therapeutic failure
• Serious adverse events
– Individual dose-titration needed (TDM)
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Bioequivalence-narrow therapeutic drug
Acceptance range for bioequivalence testing
 The 90%-CI should lie within the range of 0.8-1.25
• AUC-ratio
• Cmax-ratio
 In cases of NTI drugs the acceptance range may need to be
tightened (0.9 – 1.11)
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Bioequivalence-narrow therapeutic drug
NTI drugs –
Does a 90%-CI = 0.8-1.25 assure clinical interchangeability?
 Probably not!
If the BE study is repeated 10 times then 9 times out of 10
the average ratio would fall within 0.8-1.25
It does NOT mean that all the individuals will fall
within the acceptance range
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Bioequivalence-narrow therapeutic drug
 Bioequivalence in healthy volunteers does not
always assure therapeutic equivalence
– A high intra-individual variation in patients may lead to…
Bioinequivalence
Difference in efficacy
Need for dose-adjustments when switching
 Food interaction
– may be an additional problem..
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Bioequivalence-narrow therapeutic drug
Options:
 BE studies in (relevant) patients
– Less feasible
– Ethical considerations
 Narrowing the BE acceptance range
– 90%-CI = 0.9-1.11
 Additional requirements (ad hoc)
– Steady-State studies (serial Cthrough?)
– Fed/fasted state
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Bioequivalence-narrow therapeutic drug
The EU position
 The current BE guideline does not specifically
address NTI drugs
Narrowing of BE acceptance range allowed
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Bioequivalence-narrow therapeutic drug
The Canadian
position:
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Bioequivalence-narrow therapeutic drug
Canadian guidance for NTI drugs
 AUC: 90%-CI within 0.9-1.12
 Cmax: 90%-CI within 0.8-1.25
 Studies in both fasted and fed state
 Steady-state studies on a case-by-case basis
– Cmin: 90%-CI within 0.8-1.25
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Bioequivalence – highly variable drugs
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Bioequivalence – highly variable drugs
Highly variable drugs
What are HVD?
HVD drugs and products
How to establish BE HVD
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Bioequivalence – highly variable drugs
What are HVD?
HVD are medicinal products which show
high inter occasional variability: CV > 30%
Not the ANOVA CV!
Occasion 1
Occasion 2
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Bioequivalence – highly variable drugs
High Variable Drug
High variability caused by intrinsic intraindiviudual variability in the pharmacokinetic
response of the active compound
Furosemide (ng/ml)
HVD drugs and products
1200
1000
800
600
400
200
0
0
2
4
time (h)
High Variable Product
High variability caused by intra indiviudual
variability in the pharmacokinetic caused by
formulation effects
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Bioequivalence – highly variable drugs
How to establish HVD
CV=15%
Problem:
Difficult to establish bioequivalence with
normal acceptance criteria (90 % CI)
CV=30%
45%
N=88 subjects
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Bioequivalence-highly variable drugs
How to establish HVD
 Multiple dose (steady-state) studies
 Increase number of subjects
 Replicate design to determine intra-individual variability
 Scaling (not considered)
– proposal to scale the average BE criterion
 Widen goal post - 80-125 for both AUC and Cmax
– AUC - widen/narrow acceptance limits according to clinical considerations
(not HVD)
– Cmax - same as AUC, but wider for HVD (75-133)
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Bioequivalence – metabolite
Bioequivalence based on the metabolite
Reasons:

Parent = pro-drug

Analytical difficulties
–
–
too low concentration
unstable in matrix

Short elimination half-life parent drug

Metabolite contributes to the activity

Pharmacokinetics non-linear (parent + metab.)
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Bioequivalence – metabolite
FORMATION RATE-LIMITED METABOLISM (IV) (FRL)
ELIMINATION RATE-LIMITED METABOLISM (IV) (ERL)
100.0
CONC (ng/mL)
CONC (ng/mL)
100
10
1
0,1
0,01
10.0
1.0
0.1
0
5
10
15
20
25
30
TIME (HR)
Parent drug
0
5
10
15
20
TIME (HR)
Metabolite
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Parent drug
Metabolite
25
30
Bioequivalence – metabolite
Further considerations (1):
Metabolite data can only be used if the Applicant
presents convincing, state-of-the art arguments that
measurements of the parent compound are unreliable.
Cmax of the metabolite is less sensitive to differences in
the rate of absorption than Cmax of the parent drug.
when the rate of absorption is considered of clinical
importance, bioequivalence should, if possible, be
determined for Cmax of the parent compound, if necessary
at a higher dose.
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Bioequivalence – metabolite
Further considerations (2):
Metabolite is more reflective of metabolite formation,
distribution and elimination.
Bioequivalence based upon confidence interval
approach.
Measurement inactive metabolite can be rarily justified.
When using metabolite data as a substitute for parent
drug concentrations, the applicant should present data
supporting the view that the parent drug exposure will be
reflected by metabolite exposure dose.
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Bioequivalence – metabolite
Example:
TRANDOLAPRIL
TRANDOLAPRILAT
4
3,5
3
2,5
2
1,5
1
0,5
0
200
150
100
50
0
0
1
2
3
4
5
0
1
3
Dose
Dose (mg)
Cmax
2
AUC
From Lenfant et al, J Cardiovasc Pharmacol 1994, 23
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AUC0-96h
4
5
Bioequivalence – stereochemistry
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Bioequivalence-stereochemistry
Stereoselective assay
WHO:
- enantiomers different pharmacological/
metabolic profile
- systemic availability non-linear
FDA:
- enantiomers exhibit different PD
- enantiomers exhibit different PK
- primary efficacy/safety resides
with minor enantiomer
- non-linear absorption
EMEA: Not, in case of
- R and T contain same single enantiomer
- R and T contain racemate and
show linear PK
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Bioequivalence – urine data
Use of urine data in BE:
 only in exceptional case
 blood/plasma concentrations too low
 drug eliminated unchanged in urine
 absorption phase not good covered
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Bioequivalence – urine data
Use of urine data in BE:
input of data….
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Bioequivalence-urine data
i.v. input:
dAe/dt:
Clr:
- take care of sampling!!!
Clin. Pharm; 3th ed.
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Bioequivalence-urine data
Treatment
Ae
(=Cu x V)
2 main parameters
for BE
Ae
Rmax
Tmax
mean ± SD Test
210 ± 151
71 ± 46
1.02 ±0.53
mean ± SD Reference
201 ± 190
68 ± 55
1.01 ± 0.49
to 36h cumulative urinary excretion from time zero Ae(0-36h)
Rmax maximal rate of urine excretion
Tmaxtime of maximal urinary excretion
tTes vsReference
Ae36-0
Rmax
Ratio of least square means
115%
107%
106 –124%
92 – 122%
37%
41%
Rmax
(max. Ae/dt)
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90% CI
CVANOVA
End
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