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
AGAH Interactive Workshop
Bonn, February 25-26, 2013

2. 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:

3. 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

4. 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 ??

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
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

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
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

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
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)

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: tablets; kg: tablets; kg: 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
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

16. 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?

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
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?