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Background Critical drug-drug interactions (DDI) and hepatotoxicity complicate concurrent use of rifampicin and protease inhibitors. We investigated whether dose escalation of atazanavir/ritonavir could safely overcome the DDI with rifampicin. Methods DERIVE (NCT04121195, EDCTP) was a dose-escalation trial in people with human immunodeficiency virus (HIV) on atazanavir/ritonavir-based antiretroviral therapy (ART) in Uganda. Four intensive pharmacokinetic (PK) visits were performed: PK1 300/100 mg OD (baseline); PK2 300/100 mg OD with rifampicin 600 mg; PK3 300/100 mg twice a day (BID) with rifampicin 600 mg OD; PK4 300/100 mg BID with rifampicin 1200 mg OD. Dolutegravir 50 mg BID throughout the study period ensured participants remained protected from subtherapeutic atazanavir concentrations. The data were interpreted with noncompartmental analysis. The target minimum concentration was atazanavir's protein-adjusted IC90 (PA-IC90), 0.014 mg/L. Results We enrolled 26 participants (23 female) with median (range) age 44 (28–61) years and weight 67 (50–75) kg. Compared with PK1, atazanavir Ctau, and AUC were significantly reduced at PK2 by 96% and 85%, respectively. The escalation to BID dosing (PK3) reduced this difference in Ctau, and AUC24 to 18% lower and 8% higher, respectively. Comparable exposures were maintained with double doses of rifampicin. Lowest Ctau during PK1, PK3, and PK4 were 12.7-, 4.8-, and 8.6-fold higher than PA-IC90, respectively, whereas 65% of PK2 Ctau were below the limit of quantification (0.03 mg/L), hence likely below PA-IC90. No participant developed significant elevation of liver enzymes, reported a serious adverse event (SAE) or experienced rebound viraemia. Conclusions Twice daily atazanavir/ritonavir during rifampicin co-administration was well tolerated and achieved plasma concentrations above the target. Clinical Trials Registration NCT04121195. Registered on 09 October 2019, https://clinicaltrials.gov/ct2/show/NCT04121195. [ABSTRACT FROM AUTHOR]

Microarray patches (MAPs) are currently under investigation as a self-administered, pain-free alternative used to achieve long-acting (LA) drug delivery. Cabotegravir is a potent antiretroviral that has demonstrated superior results over current pre-exposure prophylaxis (PrEP) regimens. This study aimed to apply physiologically based pharmacokinetic (PBPK) modelling to describe the pharmacokinetics of the dissolving bilayer MAP platform and predict the optimal dosing strategies for a once-weekly cabotegravir MAP. A mathematical description of a MAP was implemented into a PBPK model, and empirical models were utilised for parameter estimation. The intradermal PBPK model was verified against previously published in vivo rat data for intramuscular (IM) and MAP administration, and in vivo human data for the IM administration of LA cabotegravir. The verified model was utilised for the prediction of 300 mg, 150 mg and 75 mg once-weekly MAP administration in humans. Cabotegravir plasma concentrations >4 × protein-adjusted 90% inhibitory concentration (PA-IC90) (0.664 µg/mL) and >8 × PA-IC90 (1.33 µg/mL) were set as targets. The 75 mg, 150 mg and 300 mg once-weekly cabotegravir MAP regimens were predicted to sustain plasma concentrations >4 × PA-IC90, while the 300 mg and 150 mg regimens achieved plasma concentrations >8 × PA-IC90. These data demonstrate the potential for a once-weekly cabotegravir MAP using practical patch sizes for humans and inform the further development of cabotegravir MAPs for HIV PrEP. [ABSTRACT FROM AUTHOR]

Developing long-acting products and formulations for infectious diseases is a nontrivial undertaking that is frequently classified as high risk and low reward by the pharmaceutical industry. The Long-Acting/Extended Release Antiretroviral Research Resource Program (LEAP) was founded in 2015 with the support of the National Institutes of Health to encourage, promote, and accelerate the development of such products. Assessment methodology for any new proposal brought to this group is part of a framework—the LEAP Process—that includes a landscape analysis of what is currently available in the public domain. This is followed by in silico modeling and simulation offered as a service to the relevant scientific community. A variety of preclinical and clinical outcome metrics are applied to each new agent as part of a continuous feedback loop to improve product characteristics. This allows us to catalog knowledge gaps and barriers that can be addressed by engaged stakeholders. Results are communicated in scientific articles, reviews, and position papers. This undertaking serves to de-risk discovery, development, and implementation by bridging the gaps between academic, regulatory, and industrial investigators, and by engaging those in the community who will be the eventual users of these medicines. The LEAP Process has supported formulations now approved for human immunodeficiency virus, as well as products in clinical and preclinical development for tuberculosis and hepatitis viruses B and C. [ABSTRACT FROM AUTHOR]

Background: Pharmacokinetic data are lacking for progestin-releasing subdermal contraceptive implants when used with either rilpivirine- or darunavir/ritonavir-based ART.Objectives: To characterize the pharmacokinetics of etonogestrel or levonorgestrel implants when administered with these ART regimens over 48 weeks.Patients and Methods: Two separate, parallel, three-group, non-randomized, pharmacokinetic studies evaluated either etonogestrel or levonorgestrel in women receiving rilpivirine- or darunavir-based ART compared with women without HIV (control group). Participants on ART were switched to rilpivirine-based ART with a run-in period of 6 weeks or darunavir-based ART with a run-in of 2 weeks prior to implant insertion. Plasma was collected on Day 0, and 1, 4, 12, 24, 36 and 48 weeks post-insertion. Plasma progestin concentrations were compared between ART and control groups by geometric mean ratio (GMR) and 90% CI.Results: At the primary endpoint of Week 24, progestin concentrations were similar between the rilpivirine and control groups [etonogestrel: 1.18 (0.99-1.37); levonorgestrel: 1.16 (0.97-1.33)]. At Week 24, progestin exposure was higher in the darunavir groups compared with the control group [etonogestrel: 2.56 (1.69-3.28); levonorgestrel: 1.89 (1.38-2.29)]. Results remained consistent through to Week 48. No differences in etonogestrel-related adverse events were observed, but both ART groups experienced more menstrual abnormalities versus the control group with levonorgestrel.Conclusions: Etonogestrel and levonorgestrel concentrations were not altered by rilpivirine-based ART. Although progestin concentrations were higher in the ART groups containing ritonavir-boosted darunavir, no implant-related serious adverse events were observed. Both progestin-releasing implants are an appropriate contraceptive option with either rilpivirine- or darunavir/ritonavir-based ART. [ABSTRACT FROM AUTHOR]

Despite the advancement of antiretroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV), drug–drug interactions (DDIs) remain a relevant clinical issue for people living with HIV receiving ART. Antiretroviral (ARV) drugs can be victims and perpetrators of DDIs, and a detailed investigation during drug discovery and development is required to determine whether dose adjustments are necessary or coadministrations are contraindicated. Maintaining therapeutic ARV plasma concentrations is essential for successful ART, and changes resulting from potential DDIs could lead to toxicity, treatment failure, or the emergence of ARV‐resistant HIV. The challenges surrounding DDI management are complex in special populations of people living with HIV, and often lack evidence‐based guidance as a result of their underrepresentation in clinical investigations. Specifically, the prevalence of hepatic and renal impairment in people living with HIV are between five and 10 times greater than in people who are HIV‐negative, with each condition constituting approximately 15% of non‐AIDS‐related mortality. Therapeutic strategies tend to revolve around the treatment of risk factors that lead to hepatic and renal impairment, such as hepatitis C, hepatitis B, hypertension, hyperlipidemia, and diabetes. These strategies result in a diverse range of potential DDIs with ART. The purpose of this review was 2‐fold. First, to summarize current pharmacokinetic DDIs and their mechanisms between ARVs and co‐medications used for the prevention and treatment of hepatic and renal impairment in people living with HIV. Second, to identify existing knowledge gaps surrounding DDIs related to these special populations and suggest areas and techniques to focus upon in future research efforts. [ABSTRACT FROM AUTHOR]