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

henning.blume@socratec-pharma.de

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 Developmenthenning.blume@socratec-pharma.de

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?