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Local and Systemic Pharmacokinetic Profile of Dapivirine Vaginal Ring-004 When Used Continuously Over Various Periods up to Twelve Weeks
Annalene M. Nel1, Wouter Haazen2, Marisa Russell1, Jeremy P. Nuttall3, Neliette Van Niekerk1, Nicoline Treijtel4
1 Clinical Affairs, International Partnership for Microbicides, Paarl, Western Cape, South Africa. 2 Clinical Pharmacology Unit Antwerpen, SGS Life Science Services, Antwerp, Belgium. 3 Product Development, International Partnership for Microbicides, Silver Spring, MD, United States. 4 Clinical Development, Kinesis Pharma BV, Breda, Netherlands.
Background: Dapivirine Vaginal Ring-004 (25 mg dapivirine) is a topical microbicide being evaluated for safety and efficacy in a Phase III clinical program. The pharmacokinetic (PK) profile of Ring-004 has been described for up to 35 days of continuous use. This trial investigated the PK of dapivirine from Ring-004 for continuous use up to 12 weeks.
Methods: An open-label, parallel group trial was conducted among 40 healthy, HIV-negative women, aged 18-40 years. Participants were divided into 5 groups of 8 women each: participants in Group A kept the ring inserted for 1 week, Group B for 2 weeks, Group C for 4 weeks, Group D for 8 weeks and Group E for 12 weeks. Dapivirine concentrations were determined in plasma and vaginal fluid (CVF) samples collected by tear test strip at the cervix, and residual dapivirine levels were assessed in used rings.
Results: Mean plasma dapivirine Cmax was similar across groups: 385 to 449 pg/mL. Median tmax was variable and ranged from 7 days to 17.5 days. Mean Cprior to ring removal was similar for rings inserted for 1, 2 or 4 weeks (329 to 379 pg/mL), and showed a pronounced decline for longer ring use: 228 pg/mL at Week 8; 156 pg/mL at Week 12. Maximum dapivirine CVF concentrations were achieved after approximately 1 week, displaying high inter- and intra-individual variability. Mean Cmax ranged between 48.2 and 61.3 µg/g across groups. Mean Cprior to ring removal was similar for rings inserted for 1 or 2 weeks (39.5 and 44.6 µg/g), and then declined with duration of ring use: 20.1 µg/g at Week 4; 17.2 µg/g at Week 8; 13.3 µg/g at Week 12. The lowest concentration observed (Week 12) was 1.1 µg/g, which was well above the in vitro IC99 in cervical tissue (3.3 ng/mL). Mean ring residual levels of dapivirine were 16.8, 21.6, 20.1, 17.0 and 15.0 mg for Groups A to E. In general, ring residual levels decreased with duration of ring use; results for Groups A and B should be interpreted with caution due to problems with validation of analytical results for these rings. No product-related SAEs occurred. Three AEs of vaginal discharge (Grade 1) and one AE of bacterial vaginitis (Grade 2) were reported as product-related.
Conclusions: Dapivirine ring residual levels, and plasma and CVF concentrations decreased with the duration of ring use for periods of greater than 4 weeks; mean CVF concentrations at 12 weeks were >4000 times above IC99. Ring-004, when worn continuously up to 12 weeks, was well tolerated with no safety concerns.