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Bictegravir Plus Tenofovir Alafenamide Nanoformulation as a Long-Acting Pre-Exposure Prophylaxis Regimen: Application of Modeling to Design Non-Human Primate Pharmacokinetic Experiments

ABSTRACT: Bictegravir (BIC) and tenofovir alafenamide fumarate (TAF), two potent anti-HIV drugs, had been nanoformulated (nBIC-TAF) to achieve once-a-month PrEP coverage. In-vivo mouse experiments for nBIC-TAF exhibited favorable subcutaneous (SC) pharmacokinetics. To probe the clinical suitability of the nBIC-TAF, as the next step, we intend to study nBIC-TAF in non-human primates (NHP), as the best preclinical model to foster clinical trials. Before entering an expensive NHP study, however, we seek to improve our a priori understanding about nBIC-TAF in higher species, having just mouse data. The mechanism-based pharmacokinetic modeling (MBPK) has been used as an appropriate method for pharmacokinetic modeling and interspecies scaling for nanoformulations. Via the use of MBPK, in this work, we created a model for nBIC-TAF able to predict plasma concentration-time curves in NHP. BIKTARVY is a daily oral combination of BIC, TAF, and emtricitabine (Gilead Science, CA), approved for HIV therapy. Using BIKTARVY equivalent dosages (from their NHP studies), we predicted that, following just one SC dose of nBIC-TAF in NHP, both BIC and tenofovir will have detectable and above in vitro efficacy levels for 28 days. Furthermore, the MBPK was able to provide a mechanistic explanation regarding the long-acting mechanism characterizing nBIC-TAF: nanoparticles stores in the SC space from which drugs slowly dissociate. Dissociated drugs in the SC space then buffer the plasma pool over time, yielding an extended-release effect in the plasma. Overall, we predicted for nBIC-TAF a promising long-acting pharmacokinetic in NHP, potentially usable as monthly PrEP. These results will help investigators to gain confidence for facing regulatory submissions at early stages.

SUBMITTER: Perazzolo S

PROVIDER: S-EPMC7775496 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:BackgroundBictegravir (B)/emtricitabine (F)/tenofovir alafenamide (TAF) is guideline-recommended treatment for human immunodeficiency virus type 1 (HIV-1). We evaluated whether people receiving dolutegravir (DTG) plus F/TAF or F/TDF (tenofovir disoproxil fumarate) with viral suppression can switch to B/F/TAF without compromising safety or efficacy, regardless of preexisting nucleoside reverse transcriptase inhibitor (NRTI) resistance.MethodsIn this multicenter, randomized, double-blinded, active-controlled, noninferiority trial, we enrolled adults who were virologically suppressed for ≥6 months before screening (with documented/suspected NRTI resistance) or ≥3 months before screening (with no documented/suspected NRTI resistance) on DTG plus either F/TDF or F/TAF. We randomly assigned (1:1) participants to switch to B/F/TAF or DTG + F/TAF once daily for 48 weeks, each with matching placebo. The primary endpoint was proportion of participants with plasma HIV-1 RNA ≥50 copies/mL at week 48 (snapshot algorithm); the prespecified noninferiority margin was 4%.ResultsFive hundred sixty-seven adults were randomized; 565 were treated (284 B/F/TAF, 281 DTG + F/TAF). At week 48, B/F/TAF was noninferior to DTG + F/TAF, as 0.4% (1/284) vs 1.1% (3/281) had HIV-1 RNA ≥50 copies/mL (difference, -0.7% [95.001% confidence interval {CI}, -2.8% to 1.0%]). There were no significant differences in efficacy among participants with suspected or confirmed prior NRTI resistance (n = 138). No participant had treatment-emergent drug resistance. Median weight change from baseline at week 48 was +1.3 kg (B/F/TAF) vs +1.1 kg (DTG + F/TAF) (P = .46). Weight change differed by baseline NRTIs (+2.2 kg [F/TDF] and +0.6 kg [F/TAF], P < .001), with no differences between B/F/TAF and DTG + F/TAF.ConclusionsThe single-tablet regimen B/F/TAF is a safe, effective option for people virologically suppressed on DTG plus either F/TDF or F/TAF, including in individuals with preexisting resistance to NRTIs.Clinical trials registrationNCT03110380.

Project description:BackgroundBictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a single-tablet regimen recommended for HIV-1 treatment. The safety and efficacy of B/F/TAF as initial therapy was established in two Phase 3 studies: 1489 (vs dolutegravir [DTG]/abacavir/lamivudine) and 1490 (vs DTG + F/TAF). After 144 weeks of randomized follow-up, an open-label extension evaluated B/F/TAF to 240 weeks.MethodsOf 634 participants randomized to B/F/TAF, 519 completed the double-blinded treatment, and 506/634 (80%) chose the 96-week open-label B/F/TAF extension, which was completed by 444/506 (88%) participants. Efficacy was based on the secondary outcome of the proportion of participants with HIV-1 RNA <50 copies/mL at Week 240 by missing = excluded and missing = failure methods. All 634 participants who were randomized to B/F/TAF and received at least one dose of B/F/TAF were included in efficacy and safety analyses. (Study 1489: ClinicalTrials.govNCT02607930; EudraCT 2015-004024-54. Study 1490: ClinicalTrials.govNCT02607956; EudraCT 2015-003988-10).FindingsOf those with available virologic data, 98.6% (95% CI [97.0%-99.5%], 426/432) maintained HIV-1 RNA <50 copies/mL at Week 240 (missing = excluded); when missing virologic data were considered as failure, 67.2% (95% CI [63.4%-70.8%], 426/634) maintained HIV-1 RNA <50 copies/mL. Mean (SD) change in CD4+ count from baseline was +338 (236.2) cells/μL. No treatment-emergent resistance to B/F/TAF was detected. Adverse events led to drug discontinuation in 1.6% (n = 10/634) of participants (n = 5 with events considered drug-related). No discontinuations were due to renal adverse events. Median (IQR) total cholesterol increased 21 (1,42) mg/dL from baseline; the change in total cholesterol:HDL was 0.1 (-0.5,0.6). Median (IQR) weight change from baseline was +6.1 kg (2.0, 11.7) at Week 240. In Study 1489, hip and spine bone mineral density mean percent changes from baseline were ≤0.6%.InterpretationThrough 5 years of follow-up, B/F/TAF maintained high rates of virologic suppression with no treatment-emergent resistance and rare drug discontinuations due to adverse events. These results demonstrate the durability and safety of B/F/TAF in people with HIV.FundingGilead Sciences.

Project description:Long-acting (LA) administration using a subcutaneous (s.c.) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological profiles, and overcome suboptimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-life. The aim of this study was to predict minimum TAF doses required to achieve concentrations effective for HIV preexposure prophylaxis (PrEP). Daily drug release requirements were then ascertained by averaging across the dosing interval. A TAF physiologically based pharmacokinetic (PBPK) model was developed and partially qualified against available oral single- and multiple-dose pharmacokinetics. The models were assumed to be qualified when simulated values were within 2-fold of the observed mean. TAF s.c. implants were simulated in five hundred individuals, reporting predicted TAF plasma and tenofovir (TFV) plasma concentrations for various release rates. Intracellular TFV diphosphate (TFV-DP) concentrations were also simulated in peripheral blood cells and cervical and rectal tissues. The minimum dose predicted to achieve intracellular TFV-DP levels above a target concentration of 48 fmol/106 cells for a month was identified. TAF, TFV, and TFV-DP concentrations for release rates between 1.0 and 1.6 mg/day were simulated. The PBPK model indicated that a minimum release of 1.4 mg/day TAF is necessary to achieve TFV-DP concentrations above the identified target in peripheral blood mononuclear cells (PBMCs). TFV-DP cervical and rectal tissue concentrations were predicted to be between 1.5 and 2.0 fmol/106 cells and 0.9 and 1.1 fmol/106 cells, respectively, for release rates between 1.3 and 1.6 mg/day. These simulations provide target minimum doses for LA TAF PrEP in humans. Based on the generated results, multiple implants delivering a total of 1.4 mg/day of TAF subcutaneously could provide protection levels for approximately 6 months to 1 year. This modeling may inform future design of s.c. implants to mitigate adherence issues for effective PrEP applications.

Project description:Abstract Background Switching to cabotegravir long-acting + rilpivirine long-acting (CAB LA + RPV LA) administered every month (Q1M) has demonstrated non-inferiority in viral suppression versus a range of standard of care (SoC) antiretroviral regimens, including tenofovir alafenamide based regimens, in two pivotal phase 3 clinical trials (ATLAS [NCT02951052] and FLAIR [NCT02938520]). Furthermore, CAB LA + RPV LA every 2 months (Q2M) has demonstrated non-inferiority in maintaining viral suppression compared with CAB LA + RPV LA Q1M in a phase 3b study (ATLAS-2M [NCT03299049]). As bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) was not widely used at study initiation, the regimen was not present in the SoC arms of ATLAS and FLAIR. The objective was to compare efficacy and safety of CAB LA + RPV LA Q2M to BIC/FTC/TAF using indirect treatment comparison. Methods Two switch studies appropriate for facilitating indirect comparison to BIC/FTC/TAF were identified via systematic literature review (Molina et al. 2018 [NCT02603120] and Sax et al. 2020 [NCT03110380]). Indirect comparison using a generalisation of Bucher’s methodology to calculate relative risk, odds ratio, and risk differences in efficacy (Week 48 HIV RNA < 50 c/mL and ≥50 c/mL per FDA Snapshot approach and CD4+ cell change from baseline) and safety (discontinuation due to adverse events [AEs] and overall and serious AEs excluding injection site reactions [ISRs]) was conducted. Results for CAB LA + RPV LA Q2M in ATLAS-2M participants with prior integrase inhibitor (INI) exposure, but without prior CAB exposure, were indirectly compared to those with prior INI use in ATLAS and FLAIR via the common CAB LA + RPV LA Q1M comparator and were then indirectly compared to BIC/FTC/TAF via the INI comparator (Figure 1). Results No statistically significant differences in virologic failure, virologic suppression, CD4+ cell change, discontinuations due to AEs, and non-ISR serious/non-serious AEs were found between CAB LA + RPV LA Q2M and BIC/FTC/TAF (Table 1). Conclusion Indirect treatment comparison indicated efficacy and safety of CAB LA + RPV LA Q2M is not different from BIC/FTC/TAF. These regimens will be further compared in a randomized head-to-head non-inferiority trial (SOLAR, NCT04542070). Disclosures Sonya J. Snedecor, PhD, ViiV Healthcare (Other Financial or Material Support, Author’s employer, OPEN Health received funding to execute this study) Melanie Schroeder, MSc, ViiV Healthcare (Employee) Nicolas Van de Velde, PhD, ViiV Healthcare (Employee)

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Bictegravir Plus Tenofovir Alafenamide Nanoformulation as a Long-Acting Pre-Exposure Prophylaxis Regimen: Application of Modeling to Design Non-Human Primate Pharmacokinetic Experiments

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