Population Pharmacokinetics of Lopinavir in Severely Malnourished HIV-infected Children and the Effect on Treatment Outcomes
Year: 2017
Type: article
Abstract: BACKGROUND: In developing countries, malnutrition remains a common clinical syndrome at antiretroviral treatment (ART) initiation. Physiologic changes because of malnutrition and during nutritional recovery could affect the pharmacokinetics of antiretroviral drugs. METHODS: HIV-infected children admitted with severe acute malnutrition were randomized to early or delayed initiation of lopinavir (LPV)/ritonavir, abacavir and lamivudine using World Health Organization weight band dosage charts. LPV concentrations were measured on day 1 and day 14. Thereafter, patients were followed-up to week 48. The population pharmacokinetics of LPV was described using NONMEM v7.3. Covariates were screened to assess their influence on the pharmacokinetics of LPV, and the relationship between pharmacokinetic variability and treatment outcomes were assessed. RESULTS: Five hundred and two LPV concentrations were collected from 62 pediatric patients 0.1-3.9 years of age (median: 0.9 years). Rifampin-based antituberculosis treatment and "super-boosted" LPV/ritonavir were prescribed in 20 patients. LPV disposition was well described by a one-compartment model with first-order elimination. Neither randomization to early or delayed ART, tuberculosis comedications nor anthropometrical measurements explained the pharmcokinetic variability. Allometrically scaled fat-free mass influenced apparent clearance (CL/F) and volume of distribution (Vd/F). Pharmacokinetic exposure did not correlate with virologic outcomes or death at 12 or 48 weeks. CONCLUSIONS: LPV pharmacokinetics was influenced by fat-free mass and not by timing of ART initiation or tuberculosis comedication in severely malnourished HIV-infected children. LPV pharmacokinetics was found to be highly variable and bioavailability greatly reduced, resulting in a high CL estimate in this population. The role of LPV dose adjustment should be further evaluated in severely malnourished children initiating ART.
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Statistical and Data Management Center for the AIDS Clinical Trials Group, International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group, Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections, AIDS Clinical Trial Group Laboratory Center, Statistical and Data Management Center (SDMC), Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG), IMPAACT Leadership Group
OpenAlex ID: W2775699062