Safety and pharmacokinetics of islatravir subdermal implant for HIV-1 pre-exposure prophylaxis: a randomized, placebo-controlled phase 1 trial

Matthews, Randolph P.; Patel, Malini; Barrett, Stephanie E.; Haspeslagh, Liesbeth; Reynders, Tom; Zhang, Saijuan; Rottey, Sylvie; Goodey, Adrian; Vargo, Ryan; Grobler, Jay A.; Stoch, S. Aubrey; Iwamoto, Marian

doi:10.1038/s41591-021-01479-3

Cited by 49 publications

(58 citation statements)

References 33 publications

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“…The most frequently reported adverse event was implant-site reactions associated with insertion or removal including induration, hematoma, pain, erythema, and pruritus. The adverse effects of this treatment were consistent with those observed in other implant types, including the etonogestrel contraceptive implants [26 ▪▪ ]. A phase 3 study is currently underway to better understand the safety profile of the drug.…”

Section: Safetysupporting

confidence: 68%

“…This reversible phosphorylation/dephosphorylation recycling results in intracellular persistence of ISL-TP with a prolonged half-life of 118–171 h in healthy adults after a single dose [19]. The long intracellular half-life potentially supports ISL-based flexible and extended dosing regimens for the treatment and prevention of HIV [26 ▪▪ ]. Recycling of ISL to and from its triphosphate form also results in a dose-dependent apparent terminal half-life of 16.5 h for a 10 mg weekly dose and up to 78.14 h for a 30 mg weekly dose, as computed through noncompartmental analysis [19].…”

Section: Pharmacokineticsmentioning

confidence: 99%

“…Implantable ISL formulations are under development and have shown potential for PrEP. Following implant placement, plasma ISL concentrations rose rapidly, peaking after 2 h and intracellular ISL-TP concentrations reaching the pharmacokinetic threshold for antiviral effect after 1 h [26 ▪▪ ]. A next-generation implant formulation is predicted to provide efficacious ISL-TP concentrations for at least 1 year [34 ▪▪ ].…”

Section: Islatravir In Hiv Prophylaxismentioning

confidence: 99%

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Role of islatravir in HIV treatment and prevention: an update

Derbalah

Karpick

Maize

et al. 2022

Current Opinion in HIV and AIDS

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Purpose of reviewTo summarize recent updates on the potential role of islatravir for HIV treatment and prevention. Recent findingsIslatravir is an investigational antiretroviral agent with unique pharmacologic properties that facilitate flexible dosing regimens. Islatravir has demonstrated potent antiviral activity and a high barrier to resistance when combined with doravirine and lamivudine. A simplified two-drug HIV treatment regimen of islatravir combined with doravirine has also demonstrated comparable efficacy to standard of care threedrug regimens. The long half-life and high potency of islatravir's active metabolite may support its use as a long-acting option for HIV preexposure prophylaxis (PrEP). A once monthly oral dose of islatravir maintains effective concentrations of its active metabolite over the entire dosing interval. Furthermore, an investigational implantable formulation has been projected to provide efficacious concentrations for at least a year and exhibits comparable distribution into vaginal and rectal tissues making it a promising PrEP option for male and female individuals. Islatravir has minimal risks of drug interactions as it is not a substrate, inducer, or inhibitor of major drug metabolizers and transporters. Finally, clinical trials demonstrate islatravir's favorable safety profile revealing only mild and transient adverse events.

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Section: Safetysupporting

confidence: 68%

Section: Pharmacokineticsmentioning

confidence: 99%

Section: Islatravir In Hiv Prophylaxismentioning

confidence: 99%

See 1 more Smart Citation

Role of islatravir in HIV treatment and prevention: an update

Derbalah

Karpick

Maize

et al. 2022

Current Opinion in HIV and AIDS

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“…The study also employs a double‐blind, double placebo design and is end‐point driven. ISL is further being developed as an implant, based on the implantable contraceptive device containing etonogestrel, with the first pharmacokinetic study results released in 2019 [ 45 ]. This option offers the benefit of reversibility of removal, unlike the depot injectables and could last up to a year, it also has potential for MPT use.…”

Section: Discussionmentioning

confidence: 99%

HIV prevention: better choice for better coverage

2022

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Introduction: Antiretroviral-based pre-exposure prophylaxis (PrEP) is today an established, effective and safe method of HIV prevention used in multiple countries worldwide by a broad range of populations at risk of HIV infection. Biomedical innovations are critical in supporting the primary prevention of HIV; however, their potential can only be maximized if end-user challenges are recognized, described and used to develop next-generation models. Discussion: First-generation PrEP, a daily oral pill, is highly efficacious, discreet and affords users the ability to commence and conclude treatment rapidly. However, consistent daily adherence and persistence is challenging, especially among younger populations, due in part to side effects, the risk of stock-outs and a lack of pill storage options. Second-generation PrEP, longer acting agents that require less frequent dosing, could overcome such challenges. Agents that have shown efficacy in clinical trials include a monthly vaginal ring and PrEP injectables to be administered every 8 weeks, while products in development include 6 monthly injectables, oral therapy that uses monthly rather than daily pills, implants and the potential for long-acting passive immunization. Conclusions: Second-generation PrEP agents will have the potential to offer improved adherence and less frequent reminders once they have undergone further development and the delivery systems that will best support them have been established. In order to pursue global UNAIDS targets of reducing new HIV infections to fewer than 500,000 annually by 2025, and to ensure that all people have access to prevention options that meet their specific prevention needs, both early and nextgeneration PrEP options are needed.

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“…Both implants maintained intracellular isaltravir-triphosphate (ISL-TP) concentrations above the antiviral target of 0.05 pmol/10 6 cells for the full 12 weekS duration of insertion. Overall tolerability of the implants was good, although about half the recipients of the 62 mg implant reported induration and erythema at the insertion site for at least 30 days after placement [27 ▪ ]. Modeling studies based on these data indicate that intracellular ISL-TP concentrations would remain at or above the target for at least 16 months with the 54 mg product, raising the possibility of a once-yearly implant for PrEP.…”

Section: Long-acting Antiretroviral Approaches In Preclinical and Cli...mentioning

confidence: 93%

The future of long-acting agents for preexposure prophylaxis

Flexner

2022

Current Opinion in HIV and AIDS

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Purpose of reviewThe main reason for the failure of oral preexposure prophylaxis (PrEP) regimens for HIV is poor adherence. Intramuscular cabotegravir was recently approved for PrEP, and a number of other long-acting antiretroviral formulations and products are currently in clinical development. This includes subcutaneous and intravenous injections, implants, and microarray (microneedle) patches, as well as extended duration oral drugs. The success and future uptake of these products will depend on a variety of factors. Recent findingsLong-acting delivery of antiretroviral agents for PrEP confers significant advantages over short-acting oral delivery. This is exemplified by the superior efficacy of intramuscular cabotegravir given every eight weeks as compared to daily oral co-formulated tenofovir disoproxil fumarate and emtricitabine. There is also evidence for PrEP efficacy for a broadly neutralizing monoclonal antibody given intravenously every eight weeks. One of the leading candidates for long-acting PrEP, islatravir, was being studied as a monthly oral drug or a nonerodable subcutaneous implant inserted for up to 12 months. However, clinical studies of this agent were put on hold in late 2021 because of unanticipated lymphopenia.

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Safety and pharmacokinetics of islatravir subdermal implant for HIV-1 pre-exposure prophylaxis: a randomized, placebo-controlled phase 1 trial

Cited by 49 publications

References 33 publications

Role of islatravir in HIV treatment and prevention: an update

Role of islatravir in HIV treatment and prevention: an update

HIV prevention: better choice for better coverage

The future of long-acting agents for preexposure prophylaxis

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