ba/be in paediatric population: what may be extrapolated from findings in adults?
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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. - PowerPoint PPT PresentationTRANSCRIPT
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
AGAH Interactive WorkshopBonn, February 25-26, 2013
The world of biopharmaceutics
gut lumen bloodvessel tissueenterocytes
delivery
dissolveddrug
absorption absorption/distribution
substance separated
from product
impact of dosage form on drug absorption?
BA/BE:
biopharmaceutics(drug product)
pharmacokinetics(drug substance)
What is the rate determining process?
Drug absorption(penetration membrane)
Drug substance properties physicochemical properties e.g. affinity for transporters
BCS biowaiverpossible
Determinants for systemic exposure
Drug delivery (release from product)
Drug formulation properties dissolution in various media gastric residence and GI transit
Solubilityaccording BCS
Release characteristics
"high" "low" MR formIR form
significantimpact likely
impact lesscritical
formulationessential
Generally accepted: extrapolation of findings from healthy subjects … … to patient population … to elderly people between gender (females vs. males) from fasted to fed administration (in case of IR
forms)
The general concept of BA/BE
Understanding BA/BE surrogate parameter for efficacy and safety … … healthy subjects representative for therapeutic
conditions essential quality characteristics (batch-to-batch,
shelf-life)
… and what about paediatric population ??
Long development process
changes in drug disposition drug distribution (body water,
plasma protein binding) enzyme activity/hepatic
metabolism renal excretion & total
clearanceFocus on drug
absorption most essential for
BA/BE changes in GI tract …
… with potential impact pH in (empty) stomach
(HCl) gastric emptying/residence (small) intestinal transit secretion of bile salts
What is "special" in children?
(?)
Information on physiological changes … change in gastric pH…
Relevant changes in absorption?
impact of gastric emptying intestinal transit and bile secretion… rationale for differences in product BA? all information drug (substance) exposure related …
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 lack in published bioequivalence studies in paediatric
population … … however, might BE studies in children be
suggested/mandatory?
other routes of administration
Product development: entire BA programme in adults
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 optimisation of dosing schedule
Additional BA/BE studies in children?
Generic development of paediatric medicinal products
basis for MAA: BE assessment in adults
EMA Q&A document (PKWP, 2012)
Why studies in adults preferable? investigations in healthy subjects
possible(paediatric studies in Europe only in patients)
number of samples not limiting for profiling
advanced conditions to detect differences between formulations
Regulatory requirements
Areas/goals for intended extrapolation 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 diseases (of the different indications) commonly used concomitant medication(s)
Efficacy/safety extrapolation
Limitations of extrapolation PK-based approach insufficient, if …
… 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
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
Study design should be established based on knowledge from
adults PK characteristics (dose-/time-dependency; route of
elimination, …) route of administration & therapeutic index
specificities in paediatric population & patients 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
clinical conditions & development concept 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
PK surrogate for efficacy/safety
Drug substance characteristics
BCS Class-IV drug poor solubility in all media absolute BA: 64% mass-balance: 86% faeces, 2%
urine
Montelukast: chewing tablets
PK studies (one in adults, two in paediatric patients)
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 determination of dose normalized exposure comparison of results in adults and paediatric
patients comparison between dosage forms (FCT vs. chewable
tablet)
Okumu et al., Pharm. Res., 2008
Results dose proportionality
Study in children
Findings proportionality demonstrated for AUC and Cmax in
adults (CT)
Study in adults
Knorr et al., J. Clin. Pharmacol., 1999
FCT: significantly lower exposure (-17% AUC, -33% Cmax) suggested paediatric dose: 5 mg CT (= AUC 10 mg adults)
AIDS treatment: stavudine, lamivudine & nevirapine
well established in adults as FDC tablets (Thailand) no specific paediatric form, administered in
solution(s) goal: development of FDC chewable tablets (by
government)
Development chewable FDC tablets
Basis for approval m.d. (four weeks) BE study in paediatric patients
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
Plasma profiles (at steady state)
Study outcome
Stavudine Lamivudine Nevirapine
Pharmacokinetic results
Biopharmaceutics stavudine: BCS Class-I …
… biowaiver possible lamivudine: BCS Class-III
…… impact of excipients likely
nevirapine: BCS Class-II …… formulation determined BA
Vanprapar et al., Paediatr. Infect. Dis. J., 2010
Plasma profiles (at steady state)
Study outcome
Stavudine Lamivudine Nevirapine
Pharmacokinetic results Conclusions/
consequences study programme in
adults biowaiver for stavudine modification of
formulation … … adjusting total exposure?
MAA: substitution indication?
Bioavailability concept: entire investigational programme in adults assumption: findings transferable to paediatric
patients goals:
product development & optimisation of formulation candidate selection for further product development specification of administration conditions, e.g. food effect
Conclusions: extrapolation possible?
Bioequivalence BE assessment for generic MAA conducted in healthy
adultsPK extrapolation 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?
AGAH Interactive WorkshopBonn, February 25-26, 2013
Henning H. Blume, PhDSocraTec R&D, Oberursel/Germany
Concepts in Drug Research and [email protected]
Conventional concept/programme investigations during formulation development
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
BA/BE in formulation development
Additional studies needed for paediatric population?
characterisation of children-specific formulations, e.g. ODT
consideration of physiological specificities, e.g. 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?