Single- and Multiple-Dose Pharmacokinetics of Darunavir Plus Ritonavir and Etravirine in Semen and Rectal Tissue of HIV-Negative Men

Abstract

Background Antiretroviral therapy (ART) has become a central component of combination HIV prevention efforts. Defining the individual exposure of commercially available ART in genital secretions and vulnerable mucosal tissues is paramount to designing future prevention interventions. Methods A pharmacokinetic study was performed in 12 HIV-negative men receiving darunavir 600mg, ritonavir 100mg, and etravirine 200mg orally twice daily for 8 days. Seven blood plasma (BP) samples were collected over 12 hours on Day 1 (PK1) and Days 7 and 8 (PK2). One rectal tissue (RT)sample from each subject was collected during PK1 and PK2. During PK1, two seminal plasma (SP)samples were collected from each subject. During PK2, six SP samples were collected from each subject over 2 days. Results Antiretrovirals were detected in SP and RT within 1 hour after a single dose. Over PK1 and PK2, SP exposures were lower than BP by 80–92% (DRV), 89–95% (RTV), 83–88% (ETR). However, protein binding in SP (14% for darunavir, 70% for ritonavir, and 97% for etravirine) was lower than in BP. RT AUCs were higher than BP by 39 to 155-fold for darunavir, 12 to 61-fold for ritonavir, and 20 to 40-fold for etravirine. Conclusions Lower SP protein binding resulted in higher pharmacologically active darunavir and etravirine concentrations compared to BP. High RT concentrations may also be favorable for suppressing viral replication in the gastrointestinal mucosa. The high protein-unbound exposures in SP and total exposures in RT support further investigations of darunavir+ritonavir and etravirine in secondary prevention.

HIV-1-RNA Decay and Dolutegravir Concentrations in Semen of Patients Starting a First Antiretroviral Regimen

“…Because of lower drug binding protein concentrations in SP than in BP [20,22], protein binding of certain ARV drugs has been found to be lower in SP [23]. Unbound DTG C 24h was measured in 13 of 15 participants.…”

Pharmacokinetics of Antiretrovirals in Genital Secretions and Anatomic Sites of HIV Transmission: Implications for HIV Prevention

“…The reduced penetration of these compounds into the MGT is likely influenced by their high affinity for plasma proteins. Despite low total concentrations of darunavir, ritonavir, etravirine, and efavirenz in the seminal plasma, these drugs demonstrate free drug exposures similar to or greater than those reported in the blood plasma [77, 127]. For example, the protein-free AUC 12h for etravirine was nearly 5-fold higher in the SP than in BP.…”

“…Darunavir, ritonavir, and etravirine colorectal tissue pharmacokinetics have also been measured in healthy volunteers after both single and multiple doses [77]. After 7 days of repeat dosing, ritonavir, darunavir, and etravirine colorectal exposure was ~13-fold, ~ 3-fold, ~ 7-fold higher than blood plasma respectively.…”

Pharmacokinetics of antiretrovirals in mucosal tissue

“…Following a single dose, darunavir and ritonavir were rapidly detected (within 1 hour), reaching peak concentrations by 5 hours. (57) Under steady state conditions, the rectal tissue:blood plasma AUC 0-12hour ratio was ∼2.7 for darunavir and 27 for ritonavir. (57)…”

“…A separate study in 12 HIV-negative men determined that after a single dose of etravirine, rectal tissue exposure was ∼15-fold higher than blood plasma: with repeated dosing, rectal tissue exposure was ∼9-fold higher. (57)…”