Evaluation of the effect of UGT1A1 polymorphisms on the pharmacokinetics of oral and long-acting injectable cabotegravir.
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ABSTRACT:
SUBMITTER: Patel P
PROVIDER: S-EPMC7366207 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
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Evaluation of the effect of UGT1A1 polymorphisms on the pharmacokinetics of oral and long-acting injectable cabotegravir.
Patel Parul P Xue Zhengyu Z King Karen S KS Parham Laura L Ford Susan S Lou Yu Y Bakshi Kalpana K KK Sutton Kenneth K Margolis David D Hughes Arlene R AR Spreen William R WR
The Journal of antimicrobial chemotherapy 20200801 8
<h4>Background</h4>Cabotegravir is an HIV integrase inhibitor in clinical development with both oral and long-acting (LA) injectable formulations. Cabotegravir is primarily metabolized by uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A1, a known polymorphic enzyme with functional variants that can affect drug metabolism and exposure.<h4>Objectives</h4>To investigate the pharmacogenetic effects of the reduced-function alleles UGT1A1*6, UGT1A1*28 and/or UGT1A1*37 on steady-state pharmacokine ...[more]
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Project description:Purpose of reviewThis review highlights the development of long-acting injectable cabotegravir (CAB LA) for HIV preexposure prophylaxis (PrEP), with a focus on phase 2 studies and later development.Recent findingsEarly studies of CAB LA for HIV prevention offered promising pharmacokinetic data and paved the way for phase 2 studies, which have now been completed. On the basis of phase 2 data, dosing of CAB LA at 8-week intervals consistently delivers target trough concentrations in both men and women. Recent studies have shown no required dose adjustments for hepatic or renal disease and minimal drug--drug interactions. Additionally, injectable PrEP is desired by potential PrEP candidates. Still, gaps in knowledge remain with respect to implementation and delivery, the clinical significance of the pharmacologic tail, and dosing in key populations. Phase 3 trials are underway that are anticipated to inform some of these questions and provide efficacy and safety data to support regulatory submissions for CAB LA as a potential PrEP agent.SummaryRecent studies have defined an appropriate CAB LA dosing interval and offered insight into its safety profile. Phase 3 studies will provide much-anticipated efficacy data. If efficacious, CAB LA may provide a desirable PrEP option for those who face challenges to daily pill adherence. A more complete understanding of how to best integrate LA PrEP into service delivery models will be critical for success.
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Project description:AimsCabotegravir is an integrase strand transfer inhibitor in clinical development as long-acting (LA) injectable HIV preexposure prophylaxis.MethodsThis phase I study assessed pharmacokinetics of cabotegravir in plasma and anatomical sites associated with sexual HIV-1 transmission after repeated oral and single intramuscular (IM) LA dosing in healthy adults. Following a 28-day oral lead-in period of cabotegravir 30 mg and a washout period of 14-42 days, participants were administered a single ultrasound-guided gluteal IM cabotegravir LA 600-mg injection. The study objective was to characterize cabotegravir concentrations in plasma, cervical, vaginal and rectal tissues, and cervicovaginal and rectal fluids and up to Week 12 after IM injection.ResultsNineteen participants enrolled and 16 completed the study through Week 52. Cabotegravir was detected in plasma and all tissues and fluids. Median plasma cabotegravir concentrations exceeded the in vitro protein-adjusted 90% maximal inhibitory concentration through Week 12. Median tissue- and fluid-to-plasma cabotegravir concentration ratios across all visits were 0.32 for rectal fluid and 0.08-0.16 for other tissues and fluids. Adjusted R2 coefficients between cabotegravir concentrations in plasma and cervical, vaginal and rectal tissues were 0.78, 0.79 and 0.90, respectively. Injection-site reactions were common (88% of participants) and were mostly grade 1 in intensity (82%). Two participants reported 11 non-drug-related serious adverse events.ConclusionConcentrations of cabotegravir in tissues and fluids were proportional to plasma over time, with strong correlations between tissue and plasma concentrations. Cabotegravir LA tissue-to-plasma ratios may be important for understanding its use as preexposure prophylaxis.
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Project description:BackgroundThe use of a combination of the integrase inhibitor, cabotegravir, and the non-nucleoside reverse transcriptase inhibitor, rilpivirine, in a long-acting injectable form is being considered as an antiretroviral treatment option for people with HIV in sub-Saharan Africa. We aimed to model the effects of injectable cabotegravir-rilpivirine to help to inform its potential effectiveness and cost-effectiveness under different possible policies for its introduction.MethodsWe used an existing individual-based model of HIV to predict the effects of introducing monthly injections of cabotegravir-rilpivirine for people with HIV in low-income settings in sub-Saharan Africa. We evaluated policies in the context of 1000 setting scenarios that reflected characteristics of HIV epidemics and programmes in sub-Saharan Africa. We compared three policies for introduction of injectable cabotegravir-rilpivirine with continued use of dolutegravir-based oral regimens for: all individuals on antiretroviral therapy (ART); individuals with a recently measured viral load of more than 1000 copies per mL (signifying poor adherence to oral drugs, and often associated with drug resistance); and individuals with a recently measured viral load of less than 1000 copies per mL (a group with a lower prevalence of pre-existing drug resistance). We also did cost-effectiveness analysis, taking a health system perspective over a 10 year period, with 3% discounting of disability-adjusted life-years (DALYs) and costs. A cost-effectiveness threshold of US$500 per DALY averted was used to establish if a policy was cost-effective.FindingsIn our model, all policies involving the introduction of injectable cabotegravir-rilpivirine were predicted to lead to an increased proportion of people with HIV on ART, increased viral load suppression, and decreased AIDS-related mortality, with lesser benefits in people with a recently measured viral load of less than 1000 copies per mL. Its introduction is also predicted to lead to increases in resistance to integrase inhibitors and non-nucleoside reverse transcriptase inhibitors if introduced in all people with HIV on ART or in those with a recently measured viral load of less than 1000 copies per mL, but to a lesser extent if introduced in people with more than 1000 copies per mL due to concentration of its use in people less adherent to oral therapy. Consistent with the effect on AIDS-related mortality, all approaches to the introduction of injectable cabotegravir-rilpivirine are predicted to avert DALYs. Assuming a cost of $120 per person per year, use of this regimen in people with a recently measured viral load of more than 1000 copies per mL was borderline cost-effective (median cost per DALY averted across setting scenarios $404). The other approaches considered for its use are unlikely to be cost-effective unless the cost per year of injectable cabotegravir-rilpivirine is considerably reduced.InterpretationOur modelling suggests that injectable cabotegravir-rilpivirine offers potential benefits; however, to be a cost-effective option, its introduction might need to be carefully targeted to individuals with HIV who might otherwise have suboptimal adherence to ART. As data accumulate from trials and implementation studies, such findings can be incorporated into the model to better inform on the full consequences of policy alternatives.FundingBill & Melinda Gates Foundation, including through the HIV Modelling Consortium (OPP1191655).
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