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Summary Background Long-acting injectable cabotegravir is a novel integrase inhibitor currently in advanced clinical development for HIV prevention and treatment. We aimed to assess the terminal phase pharmacokinetics and safety of long-acting injectable cabotegravir in participants included in the HPTN 077 trial. Methods HPTN 077 was a multicentre, double-blind, randomised, placebo-controlled phase 2a trial done at eight sites in Brazil, Malawi, South Africa, and the USA. Participants (aged 18–65 years), who were HIV-uninfected and at low-risk for HIV, were randomly assigned (3:1) to long-acting injectable cabotegravir (800 mg given three times at 12 week intervals or 600 mg given five times, administered at one 4 week interval, and every 8 weeks thereafter) or placebo. Participants were followed up to 76 weeks after final injection. In a prespecified analysis of secondary and exploratory outcomes, we assessed the safety, measured by the proportion of participants with grade 2 or worse adverse events, and pharmacokinetics, measured by apparent terminal phase half-life (t1/2app) and estimated time to lower limit of quantification (LLOQ) of long-acting injectable cabotegravir during the injection phase (defined as the time between first injection and 12 weeks or 8 weeks after the last injection in cohort 1 or cohort 2 respectively) and tail phase (defined as the time between final injection and 52–76 weeks post-final injection). Safety was analysed in all participants who received at least one injection. Pharmacokinetic analyses included all participants who had received at least one injection and had at least three cabotegravir measurements higher than the LLOQ after the final injection. Pharmacokinetic outcomes were estimated using non-compartmental methods. The trial is completed, and was registered with ClinicalTrials.gov , NCT02178800 . Findings Between Feb 9, 2015, and May 27, 2016, 177 participants (134 participants in the cabotegravir group [74 participants in cohort 1; 60 participants in cohort 2] and 43 participants in the placebo group [25 participants in cohort 1; 18 participants in cohort 2) were enrolled and received at least one injection and thus were included in the safety analysis. The incidence of grade 2 or worse adverse events was significantly lower during the tail phase than the injection phase (p Interpretation The clinical significance of the long pharmacokinetic tail of cabotegravir observed in female participants compared with male participants, and those with higher BMI compared with a lower BMI, need to be addressed in future trials. Funding National Institute of Allergy and Infectious Diseases.

Background: Long-acting injectable cabotegravir (CAB LA) is a novel integrase inhibitor in advanced clinical development for HIV treatment and HIV prevention. We investigated the terminal pharmacokinetics and safety of CAB LA after final injection as part of a Phase 2 study. Methods: We performed a randomized, double-blind placebo-controlled trial at 8 sites in the United States (US), sub-Saharan Africa, and Brazil. Participants, age 18-65, HIV-uninfected and at low-risk for HIV, were randomized 3:1 to CAB LA or placebo. Participants received CAB LA at one of two doses/intervals, which were aggregated for this analysis. The current analysis includes participants who received at least one injection and examines the tail phase (time from final injection to 52-76 weeks post-final injection). The outcomes were safety and pharmacokinetics. Safety was reported as incidence rates of grade 2 or higher adverse events. The apparent terminal phase half-life (t1/2app) and time to decay of CAB drug concentration to below the lower limit of quantification (LLOQ) were estimated using non-compartmental methods. Findings: Overall, 177 participants received at least one injection. Median age was 31 years, 66.1% were female, 69.5% were non-white, 52.5% were from the US. Rates of grade 2 or higher adverse events on CAB were higher in the injection phase compared to the tail phase. At one time point from 52-60 weeks and at 76 weeks after final injection, 22% and 13% of males, respectively, had detectable CAB concentrations; 63% and 48% of females had detectable CAB concentrations at those time points. The estimated median time from last injection to CAB concentration below the LLOQ was 43.7 (range 20-4-152.5) weeks for males and 67.3 (range 17.7-225.5) weeks for females. Terminal phase half-life was 33% longer for female sex at birth participants compared to male participants, and 31% longer for participants with body mass index (BMI) above vs. below the study median of 26. Interpretation: No new adverse events were observed with long-term follow-up. The long pharmacokinetic tail will need to be addressed in pivotal trials of treatment and prevention. Trial Registration: The trial was registered with ClinicalTrials.gov, number NCT02178800. This trial is completed. Funding Statement: National Institute of Allergy and Infectious Diseases (UM1AI068619, UM1AI068613, and, UM1AI068617) Declaration of Interests: RJL has received study medication, consulting fees and travel support from Gilead Sciences, and consulting fees and travel support from Merck, Inc. JJE is a consultant to Merck, Gilead Sciences, Janssen, and ViiV Healthcare; and he is an investigator on research contracts from ViiV Healthcare, Janssen, and Gilead Sciences. HD has received honoraria from Pfizer-South Africa, Novartis-South Africa, MSD-South Africa and Adcock Ingram for speaking engagements and has received travel support from Mylan-South Africa, Novartis-South Africa and Aspen-South Africa. AYL received research grants from NIH and has led studies in which study drug was donated by Gilead Sciences. MAM received grant support through the NIH and received grant support through ViiV/GSK on work external to this study. ARR and DM are paid employees of ViiV Healthcare. CWH has research contracts with NIH, ViiV/GlaxoSmithKline, Gilead Sciences, and Merck through Johns Hopkins. Ethics Approval Statement: Local institutional review boards or ethics committees at each participating site granted ethics and regulatory approvals of the protocol and all participants provided written informed consent.

As a step towards developing a light-controlled reversible binding switch based on photochromic bisbenzospiropyran for investigating intracellular calcium signaling, substituted bisbenzospiropyran and phenolic chelators were synthesized and examined for metal binding strength. The complexation of these compounds with alkaline earth and zinc ions in methanol and buffer was characterized using NMR and luminescence spectroscopy. An increased length of convergent ligands on the rigid scaffold maintained binding affinity for Ca(2+) but decreased selectivity for Ca(2+) over Mg(2+). Results indicate that at least three carboxylate ligands are required for significant binding, and increased length of the ligands will result in a fully water-soluble photoswitch that exhibits two states with approximately 300-fold difference in binding affinity for Ca(2+).