Applications of Population Pharmacokinetic Modeling during Phase2B to Support the Clinical Development of Dolutegravir (DTG, S/GSK1349572)
Ivy Song (1), Jianping Zhang (1), Shuguang Chen (2), Steve Almond (3)
(1) Clinical Pharmacology Modeling & Simulation, (2) Discovery Biometrics, GlaxoSmithKline, RTP, NC, USA; (3) Statistics & Programming; GlaxoSmithKline, Mississauga, ON, Canada
Objectives: Population pharmacokinetic (PK) analysis performed in early and late stages of clinical development generally serves different purposes. Population PK analysis is routinely performed when data from Phase 3 become available with the purpose of evaluating the effects of various patient characteristics on the PK of the drug of interest, while analysis conducted in the early phases (Phase1-2) often have different utilities. DTG is a new integrase inhibitor currently in Phase 3 clinical development for the treatment of HIV infection. This abstract presents several applications of a population PK model of DTG developed during Phase 2B.
Methods: DTG plasma concentration-time data from two dose-ranging Phase 2 studies in HIV-infected subjects (n=164) were used to fit various base PK models using a mixed-effects modeling approach with the first-order conditional method (FOCE) of NONMEM. Covariates including age, weight, gender, race, liver functions, smoking status, and use of certain concurrent medications were evaluated.
Results: PK of DTG were best described by a 2-compartment linear model with first order absorption. The resulting population PK model was used to: (1) guide the design of optimal sparse PK sampling scheme in Phase 3 trials; (2) model the relationship between DTG PK exposure and changes in serum creatinine levels from baseline in response to a clinical finding in Phase 2b and to support the safety monitoring plan in Phase 3; (3) support sample size selected for a proposed pediatric study with PK evaluation as the primary objective; (4) to simulate DTG exposure with consideration of variability in comparison to target exposure(s) support dose selection for the proposed pediatric study.
Conclusions: Population PK analysis performed early in clinical development (prior to Phase 3) has broad applications. This approach in the development of DTG supported decision making for Phase 3, allowed for evaluation of exposure response relationships for safety, and informed study design for pediatric trials.References:
 CDC growth chart: United Status. 2000 http://www.cdc.gov/nchs/data/series/sr_11/sr11_246.pdf.