BA/BE in paediatric population: what may be extrapolated from findings in adults?

1. 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

2. substanceseparatedfrom product gut lumen bloodvessel tissue enterocytes delivery absorption absorption/distribution biopharmaceutics(drug product) pharmacokinetics(drug substance) BA/BE: impact of dosage form on drug absorption? The world of biopharmaceutics dissolveddrug

3. 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 Solubilityaccording BCS Release characteristics "high" "low" IR form MR form BCS biowaiverpossible formulationessential impact lesscritical significantimpact likely

4. … and what about paediatric population ?? 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)

5. 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 • Focuson 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

6. 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

7. 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 • 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 EMA Q&A document (PKWP, 2012)

8. Regulatory requirements

9. 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

10. 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

11. 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

12. 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)

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

14. 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

15. Study outcome Plasma profiles (at steady state) Stavudine Nevirapine Lamivudine Vanprapar et al., Paediatr. Infect. Dis. J., 2010 • Biopharmaceutics • stavudine: BCS Class-I …… biowaiver possible • lamivudine: BCS Class-III …… impact of excipients likely • nevirapine: BCS Class-II …… formulation determined BA Pharmacokinetic results

16. Study outcome Plasma profiles (at steady state) Stavudine Nevirapine Lamivudine Pharmacokinetic results • Conclusions/consequences • study programme in adults • biowaiver for stavudine • modification of formulation … … adjusting total exposure? • MAA: substitution indication?

17. 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

18. 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

19. 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?