TULBPE026 - Poster Exhibition
Population pharmacokinetics of etravirine in HIV-1-infected treatment-experienced children and adolescents (6-17 years): week 24 primary analysis of the phase II PIANO trial
T. Kakuda1, B. Green2, G. Morrish2, A. Brochot3, S. Nijs4, P. Vis5
1Tibotec, Inc., Clinical Pharmacology, Titusville, United States, 2Model Answers Pty Ltd, Brisbane, Australia, 3Janssen Research & Development, Advanced Modeling & Simulation, Beerse, Belgium, 4Tibotec BVBA, Biostatistics, Beerse, Belgium, 5Tibotec BVBA, Advanced Modeling & Simulation, Beerse, Belgium
Background: The ongoing PIANO study (TMC125-C213; NCT00665847) is investigating the safety, efficacy and pharmacokinetics of etravirine 5.2mg/kg BID (maximum dose 200mg BID) in HIV-1-infected children/adolescents aged 6-17 years over 48 weeks. Population pharmacokinetic model development and pharmacokinetic results are presented.
Methods: A population pharmacokinetic model for etravirine was developed for pediatric use based on a previously developed model in adults and used to determine etravirine AUC12h and C0h for all subjects at Week 24 (primary analysis).
Sparse samples were collected at Weeks 4, 8, 12, 24 and 48; at Week 24, two samples were collected, a trough and sample >1 hour after etravirine intake. Etravirine plasma concentrations were measured using a validated HPLC-MS/MS assay. NONMEM VI and R were used for model development and analysis.
Results: The population pharmacokinetic model consisted of a sequential zero- (D1) and first-order (KA) absorption with lag-time (ALAG1) and one-compartment disposition. An effect of weight on volume of distribution (V/F) and clearance (CL/F) was included. The estimates for ALAG1, D1, KA, V/F and CL/F were: 0.328 h, 2.24 h, 0.89 h-1, 573 L and 45.9 L/h respectively. Inter-individual variability was included on KA and CL/F. Parameters for the pediatric model were similar to the adult model.
476 etravirine plasma concentration-time data were available from 101 subjects. The overall mean (SD) AUC12h and C0h were 5236 (4314) ng?h/mL and 347 (342) ng/mL, respectively. The mean AUC12h and C0h in adults are 5506 ng?h/mL and 393 ng/mL, respectively.
Conclusions: The population pharmacokinetic model developed adequately describes etravirine pharmacokinetics in the pediatric population. Etravirine 5.2mg/kg BID in children and adolescents (6-17 years) provides comparable exposure to adults receiving 200mg BID.
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