Transcript BA/BE - challenges21Century

BA/BE in paediatric population:
what may be extrapolated from
findings in adults?
Henning H. Blume, PhD
SocraTec R&D, Oberursel/Germany
Concepts in Drug Research and Development
[email protected]
AGAH Interactive Workshop
Bonn, February 25-26, 2013
The world of biopharmaceutics
substance
separated
from product
gut lumen
enterocytes
blood
vessel
tissue
delivery
dissolved
drug
absorption
biopharmaceutics
(drug product)
absorption/distribution
pharmacokinetics
(drug substance)
 BA/BE: impact of dosage form on drug absorption?
Determinants for systemic exposure
What is the rate determining process?
Drug absorption
Drug delivery
(penetration membrane)
(release from product)
Drug substance properties
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physicochemical properties
e.g. affinity for transporters
Solubility
according BCS
Drug formulation properties
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dissolution in various media
gastric residence and GI transit
Release
characteristics
"high"
"low"
IR form
MR form
BCS biowaiver
possible
formulation
essential
impact less
critical
significant
impact likely
The general concept of BA/BE
Understanding BA/BE
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surrogate parameter for efficacy and safety …
… healthy subjects representative for therapeutic conditions
essential quality characteristics (batch-to-batch, shelf-life)
Generally accepted: extrapolation of findings
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from healthy subjects …
… to patient population
… to elderly people
between gender (females vs. males)
from fasted to fed administration (in case of IR forms)
… and what about paediatric population ??
What is "special" in children?
Long development process
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changes in drug disposition
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drug distribution (body water,
plasma protein binding)
enzyme activity/hepatic metabolism
renal excretion & total clearance
Focus on drug absorption
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most essential for BA/BE
changes in GI tract …
… with potential impact
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pH in (empty) stomach (HCl)
gastric emptying/residence
(small) intestinal transit
secretion of bile salts
Relevant changes in absorption?
Information on physiological changes …
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change in gastric pH…
impact of gastric emptying
intestinal transit and bile secretion
(?)
… rationale for differences in product BA?
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all information drug (substance) exposure related …
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improvement/reduction in pH-dependent solubility (e.g. in the stomach)
certain differences in exposure between children and adults possible …
… to be considered in definition of appropriate paediatric dose
data indicating differences between formulations not reported
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lack in published bioequivalence studies in paediatric population …
… however, might BE studies in children be suggested/mandatory?
other routes of administration
Additional BA/BE studies in children?
Product development: entire BA programme in adults
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in-vivo characterisation and optimisation of formulation
candidate selection, in particular specific forms for children
administration conditions: food effect, rationale for labelling
certain open issue
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optimisation of dosing schedule
Generic
development
of paediatric
medicinal products
Why
studies in adults
preferable?
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basis for
MAA: BE assessment
adults possible
investigations
in healthyinsubjects
(paediatric studies in Europe only in patients)
 number of samples not limiting for profiling
 advanced conditions to detect differences
between formulations
EMA Q&A document (PKWP, 2012)
Regulatory requirements
Efficacy/safety extrapolation
Areas/goals for intended extrapolation
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from adults to paediatric patients
between the different age groups in paediatric population:
… normally from older to younger paediatric patients
between indications, as long as PK not affected by
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diseases (of the different indications)
commonly used concomitant medication(s)
Limitations of extrapolation
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PK-based approach insufficient, if …
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…
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blood levels do not (or differently) correspond with efficacy
locally applied, locally acting drugs
other routes of administration, e.g. nasal, transdermal, …
novel indications (in paediatric patients, not in adults)
in such cases dose finding in paediatric patients necessary
PK approach for extrapolation
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similar exposure (adults/children)  produce similar efficacy
if no such relationship  PK/PD biomarkers might be used …
… predictability value for paediatric population to be justified
PK surrogate for efficacy/safety
Study design
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should be established based on knowledge from adults
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specificities in paediatric population & patients
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PK characteristics (dose-/time-dependency; route of elimination, …)
route of administration & therapeutic index
sparse sampling, small volumes (analytical sensitivity)
necessity of multiple dosing, determination of active (!) metabolites
control group (established PK), historic comparison possible
Example: paediatric development of montelukast
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clinical conditions & development concept
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asthma similar disease in adults and paediatric patients …
… similar exposure should guarantee adequate efficacy & tolerability
dose selection should be based on exposure comparison
"chrono-adjusted" evening (QD) administration suggested
Montelukast: chewing tablets
Drug substance characteristics
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Okumu et al., Pharm. Res., 2008
BCS Class-IV drug
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poor solubility in all media
absolute BA: 64%
mass-balance: 86% faeces, 2% urine
PK studies (one in adults, two in paediatric patients)
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s.d. adults: 2, 5, 10 mg chewable tablets and 10 mg FCT
s.d. paediatric patients: 6 and 10 mg FCT (multiples of 2 mg)
s.d./m.d. paediatric patients: 5 mg chewable tablet (15 days)
Assessment of dose proportionality
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determination of dose normalized exposure
comparison of results in adults and paediatric patients
comparison between dosage forms (FCT vs. chewable tablet)
Results dose proportionality
Study in adults
Knorr et al., J. Clin. Pharmacol., 1999
Study in children
Findings
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proportionality demonstrated for AUC and Cmax in adults (CT)
FCT: significantly lower exposure (-17% AUC, -33% Cmax)
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suggested paediatric dose: 5 mg CT (= AUC 10 mg adults)
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Development chewable FDC tablets
AIDS treatment: stavudine, lamivudine & nevirapine
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well established in adults as FDC tablets (Thailand)
no specific paediatric form, administered in solution(s)
goal: development of FDC chewable tablets (by government)
Basis for approval
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m.d. (four weeks) BE study in paediatric patients
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free combination (in solution) vs. FDC (7 mg/30 mg/50 mg), both BID
body weight adjusted dosing (6-8 kg: 1 tablets; 8-16 kg: 1.5-2 tablets;
16-23 kg: 2.5-3 tablets; 23-30 kg: 3.5-4 tablets)
study in two stages (N=8/35) as tablets never dosed to humans before
sparse sampling (seven samples per twelve hours postdose)
total and peak exposure, trough values
Study outcome
Plasma profiles (at steady state)
Stavudine
Pharmacokinetic results
Nevirapine
Lamivudine
Vanprapar et al., Paediatr. Infect. Dis. J., 2010
Biopharmaceutics
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stavudine: BCS Class-I …
… biowaiver possible
lamivudine: BCS Class-III …
… impact of excipients likely
nevirapine: BCS Class-II …
… formulation determined BA
Study outcome
Plasma profiles (at steady state)
Stavudine
Pharmacokinetic results
Lamivudine
Nevirapine
Conclusions/consequences
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study programme in adults
biowaiver for stavudine
modification of formulation …
… adjusting total exposure?
MAA: substitution indication?
Conclusions: extrapolation possible?
Bioavailability
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concept: entire investigational programme in adults
assumption: findings transferable to paediatric patients
goals:
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product development & optimisation of formulation
candidate selection for further product development
specification of administration conditions, e.g. food effect
Bioequivalence
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BE assessment for generic MAA conducted in healthy adults
PK extrapolation
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assessment of dose proportionality in healthy adults …
… exposure comparison between children and adults …
… in order to define efficacious dose for paediatric patients
BA/BE in paediatric population:
what may be extrapolated from
findings in adults?
Henning H. Blume, PhD
SocraTec R&D, Oberursel/Germany
Concepts in Drug Research and Development
[email protected]
AGAH Interactive Workshop
Bonn, February 25-26, 2013
BA/BE in formulation development
Conventional concept/programme
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investigations during formulation development
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assessment of total and peak exposure, characterisation of profiles
selection of development candidates (pilot studies)
determination of absorption from oral cavity (e.g. in case of ODT)
assessment of bioequivalence (generic MAA)
investigation of food interactions – drug substance and product
goal(s): appropriate quality, adequate efficacy, safety
Additional studies needed for paediatric population?
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characterisation of children-specific formulations, e.g. ODT
consideration of physiological specificities, e.g.
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changes in gastric pH  impact on drug dissolution/absorption?
maturation of bile secretion  impact on solubility, food-effects?
gastric emptying, intestinal transit  residence at absorption site?