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 Workshop Bonn, February 25-26, 2013

The world of biopharmaceutics substance separated from product The world of biopharmaceutics gut lumen blood vessel tissue enterocytes delivery dissolved drug absorption absorption/distribution biopharmaceutics (drug product) pharmacokinetics (drug substance) impact of dosage form on drug absorption?  BA/BE:

Solubility according BCS Release characteristics Determinants for systemic exposure What is the rate determining process? Drug absorption (penetration membrane) Drug delivery (release from product) Drug substance properties physicochemical properties e.g. affinity for transporters Drug formulation properties dissolution in various media gastric residence and GI transit Solubility according BCS 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 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 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 changes in drug disposition drug distribution (body water, plasma protein binding) enzyme activity/hepatic metabolism renal excretion & total clearance Focus 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

Relevant changes in absorption? Information on physiological changes … change in gastric pH… (?) 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

Additional BA/BE studies in children? 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 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

Efficacy/safety extrapolation 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) 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

PK surrogate for efficacy/safety 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

Montelukast: chewing tablets Drug substance characteristics BCS Class-IV drug poor solubility in all media absolute BA: 64% mass-balance: 86% faeces, 2% urine Okumu et al., Pharm. Res., 2008 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)

Results dose proportionality Study in adults Knorr et al., J. Clin. Pharmacol., 1999 Study in children Findings proportionality demonstrated for AUC and Cmax in adults (CT) FCT: significantly lower exposure (-17% AUC, -33% Cmax) suggested paediatric dose: 5 mg CT (= AUC 10 mg adults)

Development chewable FDC tablets 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) 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

Study outcome Plasma profiles (at steady state) Stavudine Lamivudine Nevirapine Vanprapar et al., Paediatr. Infect. Dis. J., 2010 Pharmacokinetic results Biopharmaceutics 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 Lamivudine Nevirapine Pharmacokinetic results Conclusions/consequences study programme in adults biowaiver for stavudine modification of formulation … … adjusting total exposure? MAA: substitution indication?

Conclusions: extrapolation possible? 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 Bioequivalence BE assessment for generic MAA conducted in healthy adults PK 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? Henning H. Blume, PhD SocraTec R&D, Oberursel/Germany Concepts in Drug Research and Development henning.blume@socratec-pharma.de AGAH Interactive Workshop Bonn, February 25-26, 2013

BA/BE in formulation development 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 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?