Safety and tolerability of lersivirine, a nonnucleoside reverse transcriptase inhibitor, during a 28-day, randomized, placebo-controlled, Phase I clinical study in healthy male volunteers

Davis, John D.; Hackman, Frances; Ndongo, Marie-Noella; Choo, HengWee; Lewis, Drew; Tawadrous, Margaret; Goodrich, James; Langdon, Grant

doi:10.1016/j.clinthera.2010.10.007

Cited by 7 publications

(5 citation statements)

References 12 publications

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“…Phase I clinical trials reported a satisfactory safety and tolerability profile for the drug following 28-day daily-dosing regimen [32]. As per two separate clinical trials, lersivirine dosing had no significant impact on pharmacokinetic profiles of co-administered drugs including integrase inhibitors or protease inhibitors [33,34].…”

Section: Non-nucleoside Reverse Transcriptase Inhibitorsmentioning

confidence: 99%

Investigational reverse transcriptase inhibitors for the treatment of HIV

Cory

Midde

Rao

et al. 2015

Expert Opinion on Investigational Drugs

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Introduction While considerable advances have been made in the development of antiretroviral agents, there is still work to be done. Reverse transcriptase inhibitors are important drugs for the treatment of HIV, and considerable research is currently ongoing to develop new agents and to modify currently existing agents. Areas covered Herein, the authors discuss both investigational nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), including agents that are in various stages of development. They also discuss novel formulations that are being investigated for currently available drugs, and discuss the advantages that these new formulations may provide. Expert opinion New formulations and co-formulations of currently existing antiretrovirals will represent an important area of development, as a means to improve adherence for HIV-positive individuals. New formulations will continue to be developed, with a focus on allowing for less-frequent administration, as well increasing drug concentrations at local sites such as vaginal tissue, rectal tissue and sites in the immune system.

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Section: Non-nucleoside Reverse Transcriptase Inhibitorsmentioning

confidence: 99%

Investigational reverse transcriptase inhibitors for the treatment of HIV

Cory

Midde

Rao

et al. 2015

Expert Opinion on Investigational Drugs

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“…In a phase IIa, dose‐ranging, randomized, double‐blind, placebo‐controlled monotherapy study in 48 asymptomatic HIV‐1 infected NNRTI‐naïve subjects, treatment with lersivirine for 7 days achieved mean viral RNA reductions of 1.7 log 10 copies ml −1 and 1.8 log 10 copies ml −1 after receiving 500 and 750 mg once daily, respectively, and 1.6 log 10 copies ml −1 after receiving 500 mg twice daily [4]. Common AEs observed for lersivirine at clinical doses include nausea, vomiting, headache, dizziness and abdominal pain [5, 6] with nausea and vomiting occurring at higher frequencies with higher clinical doses. This AE profile for lersivirine is based on emergent AEs observed at the current stage of development (phase IIb).…”

Section: Introductionmentioning

confidence: 99%

Effects of ketoconazole and valproic acid on the pharmacokinetics of the next generation NNRTI, lersivirine (UK‐453,061), in healthy adult subjects

Langdon

Davis

Layton

et al. 2012

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Lersivirine (UK-453,061) is predominantly cleared by glucuronidation (UGT2B7) and oxidation via cytochrome P450 (CYP) 3A4.• Lersivirine metabolism, and thus pharmacokinetics, may be affected by concomitant administration of drugs affecting CYP3A4 and UGT2B7.• Ketoconazole is a potent inhibitor of CYP3A4 and an inhibitor of UGT2B7. Valproic acid is a potent inhibitor of UGT2B7. WHAT THIS STUDY ADDS• Combined inhibition of CYP3A4 and UGT2B7 with ketoconazole increases the exposure of lersivirine, and may warrant lersivirine dose adjustment to compensate for this interaction.• Inhibition of UGT2B7 with valproic acid does not have a substantial effect on lersivirine pharmacokinetics. AIMSTo investigate the effect of inhibitors of cytochrome P450 (CYP) 3A4 and glucuronidation (UGT2B7) on the pharmacokinetics of lersivirine (UK-453,061), a next generation non-nucleoside reverse transcriptase inhibitor with a unique resistance profile, and to investigate the safety and tolerability of co-administration of lersivirine with these inhibitors. METHODSTwo open-label, randomized, placebo-controlled, crossover studies were conducted in healthy subjects. Study 1 investigated the effect of ketoconazole (400 mg once daily) on the pharmacokinetics of lersivirine (250 mg once daily). Subjects received ketoconazole 400 mg once daily or placebo on days 1-2 and received lersivirine 250 mg once daily and ketoconazole 400 mg once daily or placebo on days 3-9. Study 2 investigated the effect of valproic acid (VPA, sodium valproate, 1000 mg once daily) on the PK of lersivirine (500 mg once daily). On days 1-7, subjects received lersivirine 500 mg once daily plus either VPA 1000 mg or placebo. RESULTSCompared with lersivirine alone, co-administration with ketoconazole increased the lersivirine mean area under the curve (AUC(0,24 h)) and maximum plasma concentration (Cmax) by 82% (90% CI 74%, 91%) and 61% (90% CI 41%, 83%), respectively. VPA increased the mean lersivirine AUC(0,24 h) by 25% (90% CI 16%, 35%), with little effect on Cmax (2.5%, 90% CI -9%, 16%). There were no serious adverse events and no treatment-related discontinuations from either study. CONCLUSIONSInhibition of CYP3A4 and UGT2B7 by ketoconazole increased lersivirine exposure. Inhibition of UGT2B7-mediated glucuronidation by VPA had a modest effect on lersivirine exposure. Co-administration of lersivirine with either ketoconazole or VPA appeared to be well tolerated.

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“…Lersivirine is a second‐generation NNRTI undergoing clinical development for the treatment of HIV‐1. Lersivirine is structurally divergent from efavirenz and binds the RT enzyme in a novel way (Corbau et al, ; Davis et al, ). The potential for lersivirine to cause developmental toxicity and teratogenicity was evaluated in traditional embryo–fetal development (EFD) studies in mice and rabbits.…”

Section: Introductionmentioning

confidence: 99%

Developmental Toxicity Study of Lersivirine in Mice

Cappon

Bowman

Campion

et al. 2012

Birth Defects Research Pt B

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Lersivirine is a second-generation nonnucleoside reverse transcriptase inhibitor undergoing clinical development for the treatment of HIV-1. An embryo-fetal developmental toxicity study was performed to evaluate the maternal and developmental toxicity of lersivirine in pregnant mice. Mated Crl:CD1(ICR) mice were administered 0, 150, 350, and 500 mg/kg lersivirine once daily by oral gavage on gestation days 6 to 17, followed by cesarean section on gestation day 18. The first 2 days of dosing for the high-dose group were done at 250 mg/kg to allow induction of hepatic metabolizing enzymes, after which the dose was increased to 500 mg/kg/day. This dosing paradigm allowed for maintenance of exposure in the high-dose group despite the considerable autoinduction that occurs in rodents following lersivirine treatment. Lersivirine did not cause an increase in external, visceral, or skeletal malformations. Intrauterine growth retardation, demonstrated by reduced fetal body weights and increased variations associated with delayed skeletal ossification, was noted at 350 and 500 mg/kg/day. The results of these studies indicate that lersivirine is not teratogenic in mice.

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Safety and tolerability of lersivirine, a nonnucleoside reverse transcriptase inhibitor, during a 28-day, randomized, placebo-controlled, Phase I clinical study in healthy male volunteers

Cited by 7 publications

References 12 publications

Investigational reverse transcriptase inhibitors for the treatment of HIV

Investigational reverse transcriptase inhibitors for the treatment of HIV

Effects of ketoconazole and valproic acid on the pharmacokinetics of the next generation NNRTI, lersivirine (UK‐453,061), in healthy adult subjects

Developmental Toxicity Study of Lersivirine in Mice

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