Low Darunavir and Etravirine Exposure When Used in Combination in HIV+ Children and Adolescents
Jennifer King*1, R Yogev2, A Wiznia3, R Hazra4, P Jean-Philippe5, B Graham6, P Britto7, E Acosta1, C Fletcher8, V Carey7, and IMPAACT P1058 Team
1Univ of Alabama at Birmingham, US; 2Children`s Memorial Hosp, Northwestern Univ, Feinberg Sch of Med, Chicago, IL, US; 3Jacobi Med Ctr, Bronx, NY, US; 4Natl Inst of Child Hlth and Human Devt, NIH, Bethesda, MD, US; 5Henry M Jackson Fndn for the Advancement of Military Med, NIH, Bethesda, MD, US; 6Frontier Sci and Tech Res Fndn, Amherst, NY, US; 7Harvard Sch of Publ Hlth, Boston, MA, US; and 8Univ of Nebraska Med Ctr, Omaha, US
Background: Twice-daily darunavir/ritonavir (DRV/r) 600/100 mg and etravirine (ETR) 200 mg, are commonly administered to HIV+ adults as part of their ART. Although weight-based dosing of DRV/r is available for patients ≥6 years, ETR dosing in the same population has not been well established. We report the pharmacokinetics of DRV and ETR in HIV+ children and adolescents.
Methods: HIV+ patients 6 to 20 years of age receiving DRV/r, dosed per body weight, and ETR 200 mg without any additional NNRTI or protease inhibitor (PI) were enrolled into an observational, intensive pharmacokinetic study. Patients reporting ≥2 missed doses in the 7 days preceding the pharmacokinetic analysis were excluded. Plasma samples were collected at 0, 1, 2, 4, 6, 8, and 12 hours post observed dosing. DRV and ETR plasma concentrations were determined using validated HPLC and UPLC methods, respectively. Statistical comparisons examined whether the 90% confidence intervals (90%CI) of the geometric mean for AUC and Cmin of DRV and ETR lie within the range of 0.5- to 2.0-fold of the target value obtained in adult studies demonstrating safety and efficacy. If the estimated 90%CI for AUC or Cmin fall entirely outside the target range, it is considered as evidence that dosing in the particular combination should be reevaluated.
Results: Data were collected from 37 subjects: 23 were male and 14 female, and median (range) age was 17 (6 to 20) years. DRV/r doses were: 375/100, n = 1; 400/100, n = 1; and 600/100, n = 35. All patients received ETR 200 mg twice daily. The AUC and Cmin 90%CI for both DRV and ETR contained values below the target lower limit. Results are reported below.
Conclusions: DRV and ETR exposure in patients 6 to 20 years of age is lower than in adults. Although the 90%CI for DRV AUC approaches the lower bound of the target range, the 90%CI for DRV Cmin falls well below the lower bound of the range. The 90%CI for ETR AUC and Cmin fall well below the lower bound of the target range. Determining the contribution of drug–drug interactions or age-related changes in pharmacokinetics to the lower exposure in this patient population and whether these lower exposures affect clinical response require further study.