Teodora Pene Dumitrescu, Hardik Chandasana, Rajendra Singh
GlaxoSmithKline
Objectives: DOVATO is a once-daily complete oral regimen approved for use in therapy-naïve adults (US) and for the treatment of HIV-1 infection in adults and adolescents (EU). The aim of this analysis was to characterize the population pharmacokinetics of DTG and 3TC and identify important determinants of variability based on data from a Phase 3 study in virologically-suppressed, HIV-1 infected adults switching to DOVATO.
Methods: The population PK analyses included 362 subjects who were 20 to 74 years old, weighted 50 to 153 kg and predominantly male (93.1%) and that contributed a total of 2629 and 2611 DTG and 3TC samples, respectively. The dataset included intensive PK samples collected in fasted state at week 4 at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 10 and 24 hours post-dose in a subset of 30 subjects and sparse PK collected without regard to food in most subjects at week 4 (pre-dose and 1 hour post-dose), week 8 and week 12 interchangeably at either 1 to 4 or 4 to 12 hours post-dose, and weeks 24, 36 and 48 at pre-dose. The First-Order Conditional Estimation with Interaction estimation method was used with NONMEM (version 7.3). Covariate data included patient demographics (age, weight, gender, race, ethnicity, body mass index, body surface area), alanine aminotransferase, aspartate aminotransferase, serum albumin, bilirubin, creatinine clearance, estimated glomerular filtration rate (eGFR), smoking, prandial status, concurrent medications, and HBV/HCV co-infection. Covariate evaluation was performed using forward selection (p<0.01) followed by backward elimination procedure (p<0.001).
Results: A 1-compartment model with first-order absorption and elimination parameterized by apparent oral clearance (CL/F), apparent volume of distribution (V/F), absorption rate constant (Ka) was selected as the base model for DTG. The residual error was described using a proportional error model. Covariate search yielded body weight, bilirubin, and ethnicity as predictors of CL/F and weight was predictive for V/F. However, their effects on DTG steady-state exposure parameters [maximum concentration (Cmax) and area under the concentration-time curve (AUC)] were small (<20%) and not clinically relevant. The estimates of CL/F, V/F and Ka were 0.858 L/hr, 16.7 L and 2.15 h-1, respectively. The interindividual variability (IIV) on CL/F and proportional error were 26.6% and 24.2%, respectively. IIV on V/F and Ka could not be estimated. All parameters were estimated with good precision (relative standard error [RSE] <30%).
A 2-compartment model with first-order absorption and elimination parameterized by CL/F, apparent intercompartmental clearance (Q/F), apparent central volume of distribution (V2/F), apparent peripheral volume of distribution (V3/F) and Ka was selected as the base model for 3TC. To stabilize the model, V3/F was fixed to V2/F. The residual error was described using a proportional error model. Body weight was incorporated in the base model using fixed allometric exponents of 0.75 on CL/F and Q/F and unity on V2/F. Covariate search yielded eGFR and race as predictors of CL/F, however, their effects on 3TC steady-state Cmax and AUC were small (<20%) and not clinically relevant. The estimated parameter values were CL/F=19.6 L/h, Q/F=2.97 L/h, V2/F=V3/F=105 L and Ka=2.30 h-1. IIV on CL/F, V2/F and proportional error were 30.4%, 41.4% and 24.2%, respectively. IIV on Q/F and Ka could not be estimated. All parameters were estimated with good precision (RSE <33%).
Conclusions: The proposed models were able to characterize the PK of DTG and 3TC in virologically-suppressed, HIV-1 infected adults switching to DOVATO. The effects of body weight, bilirubin and ethnicity on CL/F and of body weight on V/F of DTG were small and not clinically relevant over the range of values observed in this study. Similarly, the effects of eGFR and race on CL/F of 3TC were small and not clinically significant. Therefore, no dose adjustments are recommended based on these analyses. The results support the proposed once-daily regimen for DOVATO.
Reference: PAGE () Abstr 9338 [www.page-meeting.org/?abstract=9338]
Poster: Drug/Disease Modelling - Other Topics