PII-198 - CLINICAL PHARMACOLOGY CONSIDERATIONS IN EXTRAPOLATION OF EFFICACY AND SAFETY FROM ADULTS TO PEDIATRICS - LESSONS LEARNED FROM PEDIATRIC PROGRAMS OF DIRECT ORAL ANTICOAGULANTS.

P. Zou¹, T. Leil²; ¹Daiichi Sankyo, ²Daiichi Sankyo Inc..

Background: The aim of this presentation is to discuss major clinical pharmacology findings from the pediatric investigational programs (PIPs) of four direct oral anticoagulants (DOACs): dabigatran, apixaban, edoxaban, and rivaroxaban.

Methods: The pediatric clinical pharmacology data of apixaban, edoxaban, rivaroxaban, dabigatran was collected from published regulatory review documents and literature reports.

Results: The major lessons learned from these PIPs are listed below.
• For drugs undergoing substantial renal excretion (i.e., ≥ 50%), allometric scaling of CL/F from adults based on weight and age maturation may underestimate renal clearance in children. To improve first-in-child dose prediction, the renal and hepatic CL/F of these drugs in children may need to be estimated separately.
• For drugs (i.e., renally excreted drugs) with age-dependent CL/F in adults, pediatric CL/F should be scaled from young adults instead of whole adult population. If the efficacy and safety of the drug are well established in young adult patients, the drug exposure in young adults can be selected as the target exposure for pediatric dose selection
• The relative bioavailability of pediatric formulations versus adult formulation in children may be age- or dose-dependent. To improve the relative bioavailability estimation using PopPK modeling, children aged ≥ 8 years should be encouraged to switch between adult and pediatric formulations before sparse PK sampling visits.
• Pediatric exposure matching can be improved by increasing dosing frequency if Ctrough,ss or Cmax,ss is selected as the exposure matching metric.
• Regulatory flexibility has allowed different target exposure ranges for individual age groups if the exposure ranges are well justified.
• Regulatory flexibility has allowed the use of modeling and simulation post hoc to support pediatric dose adjustment and pediatric dose extrapolation to an unstudied sub-population.

Conclusion: The lessons learned from the PIPs of four DOACs are important not only for pediatric trial design for anticoagulants, but also useful for pediatric development of other renally excreted drugs.