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.

Changes in serum concentration of rilpivirine in an HIV-infected patient treated with a combination therapy of hemodialysis and peritoneal dialysis

“…RPV is the latest non-nucleoside reverse transcriptase inhibitor shown to be active against HIV-1, and although it is being used for HIV-infected patients with ESRD, no data were previously available describing its related pharmacokinetics and safety in this patient population. To the best of our knowledge, this is the first case RPV is > 99% bound to proteins within plasma and is minimally eliminated by the kidneys, with < 1% of the administered dose excreted in the urine [7,8]. In the case described here, plasma RPV concentration was maintained far above the level of the protein-bindingadjusted IC90 under the minimal ER of RPV during both hemodialysis and peritoneal dialysis.…”

“…The rebound phenomenon is attributed to returning of drug to the blood from the redistributed tissue and could cause elevation of drug during hemodialysis session even in the drugs with high-dialytic removal rate [11]. The distribution volume and protein-binding ratio of RPV are as high as 401 L [7] and 99.7%, respectively. The distribution volume of RPV may be further increased in this patient with hypoalbuminemia.…”

“…Renal excretion of RPV and DTG both having a lowmolecular weight is < 1% and their protein binding rates are 99.7% and 99.3%, respectively [6,7]. These findings suggest that removal of such drugs in plasma by hemodialysis and peritoneal dialysis may be small.…”

Stable HIV‐1 reservoirs on dolutegravir maintenance monotherapy: the MONODO study

“…Plasma DTG concentrations exceeded the protein‐adjusted IC90 of 64 ng/mL for all patients in our study . In the CSF, the median DTG concentration at week 24 was 9.7 ng/mlL (range 5.4–12.6 ng/mL).…”

Usefulness of therapeutic drug monitoring of rilpivirine and its relationship with virologic response and resistance in a cohort of naive and pretreated HIV‐infected patients

“…Population pharmacokinetic (Pop-PK) models developed in cohorts of unselected HIV-1-infected adult patients showed a moderate interpatient variability of RPV PK parameters but a lower apparent volume of distribution associated with a shorter terminal elimination half-life (t 1/2 ) than reported in the Summary of Product Characteristics. 11,12 This suggests that, in routine clinical practice, patients may be at greater risk of suboptimal exposure than expected, which may increase the risk of developing HIV-resistant variants as demonstrated in vitro and in vivo with other ARV treatments. 13,14 In phase III studies, a strong relationship between RPV trough plasma concentration (C trough ) and efficacy was established whatever the level of baseline VL (≤100,000 copies/mL or >100,000 copies/mL).…”