PI-039 - APPLICATION OF POPULATION PHARMACOKINETIC AND PHARMACODYNAMIC MODELING TO SUPPORT DOSAGE REGIMEN OF FESOTERODINE IN PEDIATRICS WITH NEUROLOGICAL DETRUSOR OVERACTIVITY.

Y. Sano¹, S. Shoji¹, M. Shahin², A. Darekar³, B. Malhotra⁴; ¹Pfizer R&D Japan, Tokyo, Japan, ²Pfizer Global Research and Development, Groton, CT, USA, ³Pfizer, Walton Oaks, Tadworth, United Kingdom, ⁴Pfizer, New York, NY, USA.

Background: Fesoterodine is a muscarinic receptor antagonist approved for the treatment of overactive bladder (OAB) in adults and neurogenic detrusor overactivity (NDO) in pediatrics. This work aimed to characterize the population pharmacokinetics (PK) of 5-hydroxymethyl tolterodine (5-HMT); fesoterodine active metabolite, and its pharmacokinetic/pharmacodynamic (PK/PD) relationship in pediatrics with OAB or NDO following administration of fesoterodine.

Methods: 5-HMT plasma concentrations from 142 participants of age ≥ 6 years from 2 pediatric clinical trials were analyzed, and a non-linear mixed-effects model was developed. Weight-based simulations of 5-HMT exposure and maximum cystometric capacity (MCC) were conducted using the final models.

Results: A one-compartment model with first-order absorption and a lag time, which includes the effect of body weight, sex, CYP2D6 metabolizer and fesoterodine formulation on PK parameters, best described 5-HMT PK. An Emax model described the exposure-response relationship adequately. The median maximum concentration at steady-state for pediatrics weighing >25-35 kg and receiving 8 mg once daily (QD) was estimated to be 2.45 times greater than that in adults receiving 8 mg QD. Moving from a 25 kg threshold to a 35 kg threshold for 8 mg tablet QD dosing in pediatrics was accompanied by a decrease in 5-HMT exposure, to the point at which it was comparable to the range of exposure estimated in adults receiving the 8 mg tablet.

Conclusion: Population models were developed for 5-HMT and MCC in pediatrics of age > 6 years old for evaluating the impact of covariates. Weight-based simulation indicated that 4 mg tablet QD for pediatrics weighing >25-35 kg and 8 mg tablet QD for those weighing >35 kg provided similar exposures to those in adults following 8 mg tablet QD and adequate exposure-response.