Population pharmacokinetic analysis of DOVATO (DTG/3TC) as a fixed-dose combination (FDC), in antiretroviral therapy (ART)-naive HIV-1-infected adolescents, ≥12 to <18 years of age who weigh at least 25 kg
Yu-Wei Lin* (1), Muhammad Waqar Ashraf* (1), Isabelle Deprez (1), Hardik Chandasana (2), Rashmi Mehta (2), Mark Bush (3), Jon Collins (3), S.Y. Amy Cheung (1)
(1) Certara, Integrated Drug Development, Princeton, NJ, USA, (2) GlaxoSmithKline, Collegeville, Pennsylvania, USA, (3) ViiV Healthcare, Research Triangle Park, North Carolina, USA. *Contributed equally to this work
Introduction:
Dolutegravir (DTG) and lamivudine (3TC) fixed dose combination (FDC, 50/300 mg) is marketed as DOVATO which provides a novel, well-tolerated, 2-drug, first-line regimen for human immunodeficiency virus (HIV)-infected, treatment-naïve and -experienced virologically suppressed adults.
Objectives:
The goal of this analysis was to characterize the population pharmacokinetics (PopPK) of components of DOVATO in antiretroviral (ARV)-naive HIV-infected adolescents with screening plasma HIV-1 RNA between 1,000 and ≤500,000 c/mL. Additionally, covariates of interest were explored to understand their impact on PK of DTG and 3TC in adolescents.
Methodology:
Intensive and sparse concentration-dosing data from TANGO (adults) and DANCE (adolescents) studies were used to refine previously developed PopPK models for DTG and 3TC [1] using NONMEM 7.4.3. The refined PopPK models were used to simulate plasma PK profiles for DTG and 3TC in HIV -1 infected adult and adolescent subjects. Individual secondary PK parameters (AUC0-τ, Cmax,ss, and Cmin,ss) were derived and compared with PK parameters calculated using noncompartmental analysis.
Results:
DTG Modeling
Consistent with previous analyses, DTG PK in HIV-1-infected, treatment-naïve adolescents enrolled in DANCE (adolescents) were well described by a linear 1‑compartment model with first-order absorption and elimination. For a typical 77.2-kg, non-Hispanic or Latino, non-Black/African American or non-Asian individual with bilirubin of 8 µmol/L, the estimated typical (95% confidence interval [CI]) parameter values were: apparent clearance (CL/F) = 0.876 (0.841 – 0.911) L/h, apparent central volume of distribution (Vc/F) = 16.5 (15.7 – 17.2) L, and first-order absorption rate constant (Ka) = 2.13 (1.7 – 2.56) 1/h. IIV for CL/F and proportional error was relatively low (%CV = 26% and 26.9%, respectively). Weight, bilirubin, ethnicity, and race were significant determinants of CL/F, and weight was a determinant of Vc/F.
3TC Modeling
For 3TC, a 2-compartment model with linear first-order elimination and first-order absorption could adequately described the PK profile of 3TC in adult (TANGO) and adolescent (DANCE) subjects. The typical values (95% CI) of the CL/F, Vc/F, apparent intercompartmental clearance (Q/F), and Ka for a 77.2-kg individual with 99 mL/min/1.73 m2 eGFR were 21.1 (20.3, 21.8) L/h, 119 (110, 128) L, 3.33 (3.02, 3.64) L, and 2.22 (1.57, 2.86) 1/h, respectively. IIV was included for CL/F, Vc/F, and proportional residual error in the model and were estimated with %CV values of 27.6%, 43.7%, and 53.1%, respectively. The final model adequately describes the adult (TANGO) and adolescent (DANCE) data. Only eGFR and weight were included as covariates in the 3TC model, and their effect was not found to be clinically relevant in exposure analysis, with borderline significance for the Q1 and Q4 of eGFR distribution in the analysis dataset. Because clinical dosing of 3TC (50 to 300 mg) is critically attributed to a patient’s renal function according to current guidelines, the identification of eGFR as a significant covariate in this analysis poses no requirement for additional changes to the current dosing schemes.
Conclusion:
The findings are consistent with the conclusion of the previous analyses in HIV-infected, treatment-naïve, and virologically suppressed treatment-experienced adult subjects; the effects of identified covariates are small and not clinically relevant. The exposure of DOVATO FDC (DTG/3TC, 50/300 mg) following repeat oral administration are similar between adult and adolescent subjects. No further dose adjustment is therefore recommended for adolescent subjects as compared to the current labels for both DTG and 3TC.
References:
[1] ACoP13 (2022) PMX-318 [www.go-acop.org/?abstract=318] General Pharmacometrics e.g. popPK, PKPD, E-R, trial simulation, C-QT.