Presentation on theme: "Henning H. Blume, PhD SocraTec R&D, Oberursel/Germany"— Presentation transcript:
1 BA/BE in paediatric population: what may be extrapolated from findings in adults? Henning H. Blume, PhDSocraTec R&D, Oberursel/GermanyConcepts in Drug Research and DevelopmentAGAH Interactive WorkshopBonn, February 25-26, 2013
2 The world of biopharmaceutics substance separated from productThe world of biopharmaceuticsgut lumenblood vesseltissueenterocytesdeliverydissolved drugabsorptionabsorption/distributionbiopharmaceutics (drug product)pharmacokinetics (drug substance)impact of dosage form on drug absorption? BA/BE:
3 Solubility according BCS Release characteristics Determinants for systemic exposureWhat is the rate determining process?Drug absorption (penetration membrane)Drug delivery (release from product)Drug substance propertiesphysicochemical propertiese.g. affinity for transportersDrug formulation propertiesdissolution in various mediagastric residence and GI transitSolubility according BCSRelease characteristics"high""low"IR formMR formBCS biowaiver possibleformulation essentialimpact less criticalsignificant impact likely
4 The general concept of BA/BE Understanding BA/BEsurrogate parameter for efficacy and safety …… healthy subjects representative for therapeutic conditionsessential quality characteristics (batch-to-batch, shelf-life)Generally accepted: extrapolation of findingsfrom healthy subjects …… to patient population… to elderly peoplebetween gender (females vs. males)from fasted to fed administration (in case of IR forms)… and what about paediatric population ??
5 What is "special" in children? Long development processchanges in drug dispositiondrug distribution (body water, plasma protein binding)enzyme activity/hepatic metabolismrenal excretion & total clearanceFocus on drug absorptionmost essential for BA/BEchanges in GI tract … … with potential impactpH in (empty) stomach (HCl)gastric emptying/residence(small) intestinal transitsecretion of bile salts
6 Relevant changes in absorption? Information on physiological changes …change in gastric pH…(?)impact of gastric emptyingintestinal 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 dosedata indicating differences between formulations not reportedlack 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 adultsin-vivo characterisation and optimisation of formulationcandidate selection, in particular specific forms for childrenadministration conditions: food effect, rationale for labellingcertain open issueoptimisation of dosing scheduleGeneric development of paediatric medicinal productsbasis for MAA: BE assessment in adultsEMA 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 profilingadvanced conditions to detect differences between formulations
9 Efficacy/safety extrapolation Areas/goals for intended extrapolationfrom adults to paediatric patientsbetween the different age groups in paediatric population: … normally from older to younger paediatric patientsbetween indications, as long as PK not affected bydiseases (of the different indications)commonly used concomitant medication(s)Limitations of extrapolationPK-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 efficacyif no such relationship PK/PD biomarkers might be used …… predictability value for paediatric population to be justified
11 PK surrogate for efficacy/safety Study designshould be established based on knowledge from adultsPK characteristics (dose-/time-dependency; route of elimination, …)route of administration & therapeutic indexspecificities in paediatric population & patientssparse sampling, small volumes (analytical sensitivity)necessity of multiple dosing, determination of active (!) metabolitescontrol group (established PK), historic comparison possibleExample: paediatric development of montelukastclinical conditions & development conceptasthma similar disease in adults and paediatric patients …… similar exposure should guarantee adequate efficacy & tolerabilitydose selection should be based on exposure comparison"chrono-adjusted" evening (QD) administration suggested
12 Montelukast: chewing tablets Drug substance characteristicsBCS Class-IV drugpoor solubility in all mediaabsolute BA: 64%mass-balance: 86% faeces, 2% urineOkumu et al., Pharm. Res., 2008PK studies (one in adults, two in paediatric patients)s.d. adults: 2, 5, 10 mg chewable tablets and 10 mg FCTs.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 proportionalitydetermination of dose normalized exposurecomparison of results in adults and paediatric patientscomparison between dosage forms (FCT vs. chewable tablet)
13 Results dose proportionality Study in adultsKnorr et al., J. Clin. Pharmacol., 1999Study in childrenFindingsproportionality 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)
14 Development chewable FDC tablets AIDS treatment: stavudine, lamivudine & nevirapinewell 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 approvalm.d. (four weeks) BE study in paediatric patientsfree combination (in solution) vs. FDC (7 mg/30 mg/50 mg), both BIDbody weight adjusted dosing (6-8 kg: 1 tablets; 8-16 kg: tablets; kg: tablets; kg: tablets)study in two stages (N=8/35) as tablets never dosed to humans beforesparse sampling (seven samples per twelve hours postdose)total and peak exposure, trough values
15 Study outcome Plasma profiles (at steady state) StavudineLamivudineNevirapineVanprapar et al., Paediatr. Infect. Dis. J., 2010Pharmacokinetic resultsBiopharmaceuticsstavudine: BCS Class-I … … biowaiver possiblelamivudine: BCS Class-III … … impact of excipients likelynevirapine: BCS Class-II … … formulation determined BA
16 Study outcome Plasma profiles (at steady state) StavudineLamivudineNevirapinePharmacokinetic resultsConclusions/consequencesstudy programme in adultsbiowaiver for stavudinemodification of formulation … … adjusting total exposure?MAA: substitution indication?
17 Conclusions: extrapolation possible? Bioavailabilityconcept: entire investigational programme in adultsassumption: findings transferable to paediatric patientsgoals:product development & optimisation of formulationcandidate selection for further product developmentspecification of administration conditions, e.g. food effectBioequivalenceBE assessment for generic MAA conducted in healthy adultsPK extrapolationassessment 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, PhDSocraTec R&D, Oberursel/GermanyConcepts in Drug Research and DevelopmentAGAH Interactive WorkshopBonn, February 25-26, 2013
19 BA/BE in formulation development Conventional concept/programmeinvestigations during formulation developmentassessment of total and peak exposure, characterisation of profilesselection 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 productgoal(s): appropriate quality, adequate efficacy, safetyAdditional studies needed for paediatric population?characterisation of children-specific formulations, e.g. ODTconsideration 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?