A Compartmental Pharmacokinetic Evaluation of Long-Acting Rilpivirine in HIV-Negative Volunteers for Pre-Exposure Prophylaxis

Abstract

Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) refers to a strategy involving the use of antiretroviral (ARV) drugs to decrease the risk of HIV infection in uninfected individuals whose behavior would combine with local HIV prevalence to place them at high risk of infection. In 2012, the use of tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) in combination was approved by the US Food and Drug Administration for use as PrEP, based on the results of the iPrEx 1-3 study and Partners PrEP, 4 with the former showing a 44% reduction in the incidence of HIV transmission in men who have sex with men as compared with placebo treatment, when combined with a comprehensive package of prevention. Partners PrEP showed a 67-75% relative reduction in the incidence of HIV infection using TDF/FTC among heterosexual couples in sexual partnerships containing one seronegative partner.Although there is conceptual proof of PrEP in these specific contexts, recent negative results of two studies in women, FEMPrEP 5 and VOICE, 6 showed no evidence of benefit of daily oral TDF/FTC. These negative outcomes were later ascribed to suboptimal adherence to the dosing regimen, thus indicating the need for high motivation in order to attain prevention success. Therefore, durable adherence is critical for a successful long-term prevention strategy. 2,4,6 In addition, the potential for side effects and toxicities associated with the use of TDF/ FTC 2,7 remains a concern due to its widespread administration as HIV PrEP.An optimal PrEP therapy should be safe to administer and be readily distributed to the relevant target tissues in concentrations that are sufficient to provide protection against HIV infection. Ideally, PrEP agents should be characterized by convenient dosing and by routes of administration that do not depend on the recipient maintaining daily adherence to dosing.The nonnucleoside reverse-transcriptase inhibitor RPV is a diarylpyrimidine derivative that was approved by the Food and Drug Administration in 2011 for oral administration for the treatment of HIV infection in combination with other ARV drugs. 1,3 A parenteral formulation of rilpivirine (RPV-LA) with prolonged pharmacokinetic (PK) exposure is being developed, enabling improved adherence to ARV treatment over prolonged periods and having potential as an agent for HIV PrEP. 2,8,9 The potential advantages of a long-acting formulation include infrequent parenteral administration and a low potential for gastrointestinal side effects associated with lifelong oral ARV intake. Rilpivirine long-acting (RPV-LA) is a parenteral formulation enabling prolonged plasma exposure. We explored its multiple-compartment pharmacokinetics (PK) after a single dose, for pre-exposure prophylaxis. Sixty-six HIV-negative volunteers were enrolled: women received an intramuscular dose of 300, 600, or 1,200 mg, with plasma and genital levels measured to 84 days postdose; men receiving 600 mg had similar PK determined in plasma and rectum. Ex vivo antiviral activity of cervi...

Plasma Tenofovir, Emtricitabine, and Rilpivirine and Intracellular Tenofovir Diphosphate and Emtricitabine Triphosphate Pharmacokinetics following Drug Intake Cessation

“…Single-dose rilpivirine PK in plasma and in genital tracts of males (600 mg) and females (300, 600, and 1,200 mg) was assessed, and the drug was shown to persist for up to 84 days. The effect of rilpivirine concentrations in female genital tract fluid on HIV replication was also explored ex vivo (5). Studies to further evaluate long-acting rilpivirine as PrEP are planned (ClinicalTrials.gov identifier NCT02165202 [25]) or ongoing (ClinicalTrials.gov identifier NCT01656018 [26,27]).…”

“…Coformulated tenofovir DF-emtricitabine (Truvada; Gilead Sciences Ltd., London, United Kingdom) was approved by the U.S. Food and Drug Administration in 2012 for use as PrEP in high-risk individuals and in those engaging in sexual activity with HIV-infected partners (4). An intramuscularly administered, long-acting formulation of rilpivirine is also under investigation as a PrEP agent (5).…”

Pharmacokinetics of Injectable, Long-Acting Nevirapine for HIV Prophylaxis in Breastfeeding Infants

“…Parenteral administration of the integrase strand-transfer inhibitor GSK1265744 (GSK744) fully protected rhesus macaques against repeated low-dose intrarectal challenges of SHIV162P3 (30). Monthly or bimonthly injections of longacting nanoparticulate formulations of GSK744 and the non- nucleoside reverse transcriptase inhibitor rilpivirine (RPV) are being investigated clinically as possible regimens for HIV therapy (25,27,31). HIV prophylaxis using long-acting NVP formulations.…”

Advancements in nano-enabled therapeutics for neuroHIV management

“…This study is useful to decide the appropriate dose for HIV therapeutics. 8 In another study, the safety, tolerance, and pharmacokinetics of LA Rpv (TMC278, 300 mg/mL) formulation on administration, single and multiple intramuscular injection, in healthy volunteers were assessed by Verloes et al 9 The outcomes of this study suggested that a clinically relevant plasma concentration of Rpv could be optimized via tuning LA formulation. 9 Very recently, Margolis et al 10 presented a multicenter study based on long-acting ARV treatment enabling trial, for Phase IIb, using HIV-infected adults (.18 years old).…”

“…Thus, monthly and bimonthly oral administration in the form of tablet would be enough to control HIV infection. 7 The multi-component pharmacokinetic evaluation of LA Rpv, 300 mg, 600 mg, or 1,200 mg (for 84 days), in 66 HIV-negative volunteers for preexposure prophylaxis was performed by Jackson et al 8 The authors assessed ex vivo antiviral activity of cervicovaginal lavage and claimed that each Rpv dose exhibited effective therapeutic effect, lasting till 84 days, upon exposure to plasma and genital tract. This study is useful to decide the appropriate dose for HIV therapeutics.…”