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1.
Eur J Clin Pharmacol ; 74(4): 473-481, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29374296

ABSTRACT

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.


Subject(s)
Anti-HIV Agents/pharmacokinetics , Emtricitabine, Rilpivirine, Tenofovir Drug Combination/pharmacokinetics , HIV Infections/drug therapy , HIV-1/drug effects , Models, Biological , Administration, Oral , Adult , Aged , Aged, 80 and over , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Area Under Curve , Chromatography, Liquid , Computer Simulation , Drug Dosage Calculations , Drug Monitoring/methods , Emtricitabine, Rilpivirine, Tenofovir Drug Combination/administration & dosage , Emtricitabine, Rilpivirine, Tenofovir Drug Combination/adverse effects , Female , France , HIV Infections/blood , HIV Infections/virology , HIV-1/pathogenicity , Half-Life , Humans , Male , Metabolic Clearance Rate , Middle Aged , Nonlinear Dynamics , Retrospective Studies , Software , Tablets , Tandem Mass Spectrometry , Young Adult
3.
Clin Infect Dis ; 61(8): 1336-41, 2015 Oct 15.
Article in English | MEDLINE | ID: mdl-26123937

ABSTRACT

BACKGROUND: Completion rates for human immunodeficiency virus (HIV) postexposure prophylaxis (PEP) are low. We investigated the adherence and safety of coformulated emtricitabine (FTC), rilpivirine (RPV), and tenofovir disoproxil fumarate (TDF) as a 3-drug, single-tablet regimen for PEP in men who have sex with men (MSM). METHODS: In an open-label, single-arm study at 2 public sexual health clinics and 2 hospital emergency departments in urban Australia, 100 HIV-uninfected MSM requiring 3-drug PEP received single-tablet FTC-RPV-TDF once daily for 28 days. The primary endpoint was premature PEP cessation or primary HIV infection through week 12. Additional endpoints were adherence (by self-report of doses missed or not ingested with a meal, by pill count, and by plasma concentrations of tenofovir and FTC at week 4); and safety (clinical and laboratory adverse events [AEs]). RESULTS: PEP completion was 92% (95% confidence interval, 85%-96%); premature cessation resulted from loss to follow-up (6%), AEs (1%), or study burden (1%). No participant was found to acquire HIV through week 12. Adherence was 98.6% (standard deviation [SD], 2.4) by pill count and 98.5% (SD, 2.7) by self-report; 86% reported taking all doses with food, and 88% of the subset tested had plasma tenofovir levels suggesting full adherence (>40 ng/mL). Eighty-eight participants experienced at least 1 clinical AE; 4 had grade 3 AEs or higher, possibly attributable to study drug. Fifty-six participants experienced at least 1 laboratory AE; 4 had AEs of grade 3 or higher, possibly attributable to study drug. CONCLUSIONS: A single-tablet regimen of FTC-RPV-TDF was well tolerated as once-daily PEP, with high levels of adherence and completion. CLINICAL TRIALS REGISTRATION: NCT01715636.


Subject(s)
Anti-HIV Agents/administration & dosage , Emtricitabine, Rilpivirine, Tenofovir Drug Combination/administration & dosage , HIV Infections/prevention & control , Homosexuality, Male , Post-Exposure Prophylaxis , Adult , Anti-HIV Agents/blood , Anti-HIV Agents/therapeutic use , Australia , Drug Administration Schedule , Emtricitabine, Rilpivirine, Tenofovir Drug Combination/blood , Emtricitabine, Rilpivirine, Tenofovir Drug Combination/therapeutic use , Humans , Male , Medication Adherence , Middle Aged , Tablets , Young Adult
5.
PLoS One ; 10(7): e0134430, 2015.
Article in English | MEDLINE | ID: mdl-26226257

ABSTRACT

OBJECTIVE: To assess, in a clinical cohort, the efficacy of switching treatment in virologically-suppressed patients to tenofovir/emtricitabine/rilpivirine as a single-tablet regimen (STR) using the PCR signal of the viral load (VL) assay and plasma drug determination (C24h). PATIENTS AND METHODS: An observational single-centre study enrolling patients with VL<50 copies/mL initiating rilpivirine-based STR. C24h and VL were performed until W48 and W96 of STR, respectively. PCRneg was defined as an undetected PCR signal. Medians (IQR) were presented. RESULTS: 116 patients were enrolled. At STR baseline, time since first antiretroviral therapy and time of virological suppression were 6 years (2-9) and 17 months (7-43), respectively. Before STR initiation, patients were receiving protease inhibitors and non-nucleoside reverse transcriptase inhibitors-based regimen in 44% and 47% of cases, respectively. Historical genotype showed virus resistant to one drug of the STR in 6 patients (5%). At W96, 17 (15%) discontinued STR due to adverse events. The proportion of patients maintaining VL <50 copies/mL on treatment was 98%, 99%, 100%, 100%, 100% and 100% at W12, W24, W36, W48, W72 and W96, respectively. Among them, 70%, 66%, 68%, 59%, 74%, 68% and 60% were PCRneg at baseline, W12, W24, W36, W48, W72 and W96, respectively. Median rilpivirine C24h was 91 ng/mL (57-141, n = 285), with 91% of rilpivirine C24h >50 ng/mL, the target effective concentration. CONCLUSIONS: In this clinical cohort of virologically-suppressed patients switching to a new STR, most subjects had adequate rilpivirine C24h and displayed a high level of virological suppression with no residual viremia until W96.


Subject(s)
Anti-HIV Agents/administration & dosage , Emtricitabine, Rilpivirine, Tenofovir Drug Combination/administration & dosage , Emtricitabine/administration & dosage , HIV Infections/drug therapy , Rilpivirine/administration & dosage , Tenofovir/administration & dosage , Viral Load/drug effects , Adult , Anti-HIV Agents/blood , Anti-HIV Agents/therapeutic use , Drug Combinations , Drug Substitution , Drug Therapy, Combination , Emtricitabine/blood , Emtricitabine/therapeutic use , Emtricitabine, Rilpivirine, Tenofovir Drug Combination/therapeutic use , Female , Follow-Up Studies , Humans , Male , Middle Aged , Rilpivirine/blood , Rilpivirine/therapeutic use , Tenofovir/blood , Tenofovir/therapeutic use
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