title: Population Pharmacokinetics and Pharmacogenetics Analysis of Rilpivirine in HIV-1-Infected Individuals.
abstract: Rilpivirine (RPV), the latest nonnucleoside reverse transcriptase inhibitor active against HIV-1, is prescribed in a standard dosage of 25 mg once a day in combination with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The aim of this observational study was to characterize the RPV pharmacokinetic profile, to quantify interpatient variability, and to identify potential factors that could influence drug exposure. RPV concentration data were collected from HIV-infected patients as part of routine therapeutic drug monitoring performed in our center (Laboratory of Clinical Pharmacology). A population pharmacokinetic analysis was performed with NONMEM by comparing various structural models. The influence of demographic and clinical covariates, as well as frequent genetic polymorphisms in 5 genes (CYP3A4*22, CYP3A5*3, CYP2C19*2, CYP2C19*17, UGT1A1*28, and UGT1A4*2), on RPV elimination was explored. A total of 325 plasma concentration measurements were obtained from 249 HIV-positive patients. Plasma concentrations ranged from 12 to 255 ng/ml. A one-compartment model with zero-order absorption best characterized RPV pharmacokinetics. The average RPV clearance (CL) was 11.7 liters/h, the average volume of distribution was 401 liters, and the mean absorption time was 4 h. The interinterindividual variability (IIV) for CL was estimated to be 33%. None of the available demographic or genetic covariates showed any influence on RPV pharmacokinetics, but 29% of the patients were predicted to present minimal concentrations below the recently identified target cutoff value of 50 ng/ml. The variability in RPV pharmacokinetics appears to be lower than that for most other antiretroviral drugs. However, under the standard regimen of 25 mg daily, a significant number of patients might be underdosed. It remains to be investigated whether the underexposure has an impact on the development of resistance while patients are on maintenance therapy.
authors: Innovation & Development, Laboratory of Clinical Pharmacology, Service of Biomedicine, University Hospital and University of Lausanne, Lausanne, Switzerland.|Division of Clinical Pharmacology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.
authors: Manel
authors: M
authors: Aouri
authors: Division of Clinical Pharmacology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.
authors: Catalina
authors: C
authors: Barcelo
authors: Division of Clinical Pharmacology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.|School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, Geneva, Switzerland.
authors: Monia
authors: M
authors: Guidi
authors: Division of Clinical Pharmacology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.|Institute of Microbiology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.
authors: Margalida
authors: M
authors: Rotger
authors: Division of Infectious Diseases, University Hospital Center, University of Lausanne, Lausanne, Switzerland.
authors: Matthias
authors: M
authors: Cavassini
authors: Division of Infectious Diseases, University Hospital and University of Bern, Bern, Switzerland.
authors: Cédric
authors: C
authors: Hizrel
authors: Division of Clinical Pharmacology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.
authors: Thierry
authors: T
authors: Buclin
authors: Innovation & Development, Laboratory of Clinical Pharmacology, Service of Biomedicine, University Hospital and University of Lausanne, Lausanne, Switzerland.
authors: Laurent A
authors: LA
authors: Decosterd
authors: Division of Clinical Pharmacology, University Hospital Center, University of Lausanne, Lausanne, Switzerland Chantal.Csajka@chuv.ch.|School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, Geneva, Switzerland.
authors: Chantal
authors: C
authors: Csajka
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D065731:Cytochrome P-450 CYP2C19 / Q000235:genetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000472:pathogenicity*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D000068696:Rilpivirine / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult; D000099148:UGT1A1 Enzyme
chemical_list: D019380:Anti-HIV Agents; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; D014453:Glucuronosyltransferase; D000068696:Rilpivirine; D000099148:UGT1A1 Enzyme; C019787:bilirubin glucuronoside glucuronosyltransferase
keywords: nonnucleoside reverse transcriptase; population pharmacokinetics; rilpivirine; therapeutic drug monitoring