Population pharmacokinetics of Rilpivirine in HIV-1-infected patients treated with the single-tablet regimen rilpivirine/tenofovir/emtricitabine

• Published in: European journal of clinical pharmacology 2018-04, Vol.74 (4), p.473-481
• Main Authors: Néant, Nadège, Gattacceca, Florence, Lê, Minh Patrick, Yazdanpanah, Yazdan, Dhiver, Catherine, Bregigeon, Sylvie, Mokhtari, Saadia, Peytavin, Gilles, Tamalet, Catherine, Descamps, Diane, Lacarelle, Bruno, Solas, Caroline
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Aged; Aged, 80 and over; Anti-HIV Agents - administration & dosage; Anti-HIV Agents - adverse effects; Anti-HIV Agents - pharmacokinetics; Antiretroviral drugs; Area Under Curve; Biomedical and Life Sciences; Biomedicine; Chromatography, Liquid; Computer Simulation; Data processing; Drug Dosage Calculations; Drug Monitoring - methods; Emtricitabine; Emtricitabine, Rilpivirine, Tenofovir Drug Combination - administration & dosage; Emtricitabine, Rilpivirine, Tenofovir Drug Combination - adverse effects; Emtricitabine, Rilpivirine, Tenofovir Drug Combination - pharmacokinetics; Female; France; Graphical methods; Half-Life; HIV; HIV Infections - blood; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - drug effects; HIV-1 - pathogenicity; Human immunodeficiency virus; Humans; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Nonlinear Dynamics; Parameter estimation; Pharmacokinetics; Pharmacokinetics and Disposition; Pharmacology/Toxicology; Population; Retrospective Studies; Software; Tablets; Tandem Mass Spectrometry; Tenofovir; Therapeutic drug monitoring; Variability; Young Adult
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-017-2405-1

Purpose Rilpivirine, prescribed for the treatment of HIV infection, presents an important inter-individual pharmacokinetic variability. We aimed to determine population pharmacokinetic parameters of rilpivirine in adult HIV-infected patients and quantify their inter-individual variability. Methods We conducted a multicenter, retrospective, and observational study in patients treated with the once-daily rilpivirine/tenofovir disoproxil fumarate/emtricitabine regimen. As part of routine therapeutic drug monitoring, rilpivirine concentrations were measured by UPLC-MS/MS. Population pharmacokinetic analysis was performed using NONMEM software. Once the compartmental and random effects models were selected, covariates were tested to explain the inter-individual variability in pharmacokinetic parameters. The final model qualification was performed by both statistical and graphical methods. Results We included 379 patients, resulting in the analysis of 779 rilpivirine plasma concentrations. Of the observed trough individual plasma concentrations, 24.4% were below the 50 ng/ml minimal effective concentration. A one-compartment model with first-order absorption best described the data. The estimated fixed effect for plasma apparent clearance and distribution volume were 9 L/h and 321 L, respectively, resulting in a half-life of 25.2 h. The common inter-individual variability for both parameters was 34.1% at both the first and the second occasions. The inter-individual variability of clearance was 30.3%. Conclusions Our results showed a terminal half-life lower than reported and a high proportion of patients with suboptimal rilpivirine concentrations, which highlights the interest of using therapeutic drug monitoring in clinical practice. The population analysis performed with data from “real-life” conditions resulted in reliable post hoc estimates of pharmacokinetic parameters, suitable for individualization of dosing regimen.