Disposition and metabolism of cabotegravir: a comparison of biotransformation and excretion between different species and routes of administration in humans

Bowers, Gary; Culp, Amanda; Reese, Melinda J.; Tabolt, Glenn; Moss, Lee; Piscitelli, Stephen C.; Huynh, Phuong Tu; Wagner, David S.; Ford, Susan L.; Gould, Elizabeth; Pan, Rennan; Lou, Yu; Margolis, David; Spreen, William

doi:10.3109/00498254.2015.1060372

Cited by 44 publications

(61 citation statements)

References 20 publications

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“…Cabotegravir is primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT) 1A1 with a minor contribution by UGT 1A9 6. At clinically relevant concentrations, CAB does not inhibit or induce the major cytochrome P450 (CYP) or UGT enzymes in vitro and had no significant effect on the pharmacokinetics (PK) of midazolam, a sensitive CYP3A4 probe substrate 7.…”

Section: Introductionmentioning

confidence: 99%

Lack of effect of oral cabotegravir on the pharmacokinetics of a levonorgestrel/ethinyl oestradiol‐containing oral contraceptive in healthy adult women

Trezza¹,

Ford

Gould

et al. 2017

Brit J Clinical Pharma

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AimsThis study aimed to investigate whether cabotegravir (CAB), an integrase inhibitor in development for treatment and prevention of human immunodeficiency virus‐1, influences the pharmacokinetics (PK) of a levonorgestrel (LNG) and ethinyl oestradiol (EO)–containing oral contraceptive (OC) in healthy women.MethodsIn this open‐label, fixed‐sequence crossover study, healthy female subjects received LNG 0.15 mg/EO 0.03 mg tablet once daily Days 1–10 alone and with oral CAB 30 mg once daily Days 11–21. At the end of each treatment period, subjects underwent predose sampling for concentrations of follicle‐stimulating hormone, luteinizing hormone, and progesterone and serial PK sampling for plasma LNG, EO, and CAB concentrations.ResultsTwenty women were enrolled, and 19 completed the study. One subject was withdrawn due to an adverse event unrelated to study medications. Geometric least squares mean ratios (90% confidence interval) of LNG + CAB vs. LNG alone for LNG area under the plasma concentration–time curve over the dosing interval of duration τ and maximum observed plasma concentration were 1.12 (1.07–1.18) and 1.05 (0.96–1.15), respectively. Geometric least squares mean ratio (90% confidence interval) of EO + CAB vs. EO alone for EO area under the plasma concentration–time curve over the dosing interval of duration τ and maximum observed plasma concentration were 1.02 (0.97–1.08) and 0.92 (0.83–1.03), respectively. Steady‐state CAB PK parameters were comparable to historical values. There was no apparent difference in mean luteinizing hormone, follicle‐stimulating hormone, and progesterone concentrations between periods. No clinically significant trends in laboratory values, vital signs, or electrocardiography values were observed.ConclusionsRepeat doses of oral CAB had no significant effect on LNG/EO PK or pharmacodynamics, which supports CAB coadministration with LNG/EO OCs in clinical practice.

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Section: Introductionmentioning

confidence: 99%

Lack of effect of oral cabotegravir on the pharmacokinetics of a levonorgestrel/ethinyl oestradiol‐containing oral contraceptive in healthy adult women

Trezza¹,

Ford

Gould

et al. 2017

Brit J Clinical Pharma

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“…It is a class 2 compound (Biopharmaceutics Drug Disposition Classification System) exhibiting high passive permeability and low solubility . Cabotegravir is primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT)1A1 with a minor contribution by UGT1A9 to form glucuronic acid conjugates . The primary metabolite, M1, and unchanged cabotegravir are both excreted in bile.…”

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confidence: 99%

“…8 Cabotegravir is primarily metabolized by uridine diphosphate glucuronosyltransferase (UGT)1A1 with a minor contribution by UGT1A9 to form glucuronic acid conjugates. 9 The primary metabolite, M1, and unchanged cabotegravir are both excreted in bile. Due high intrinsic membrane permeability, the impact of efflux transporters on intestinal absorption of cabotegravir is minimal.…”

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Effect of a High‐Fat Meal on the Pharmacokinetics of the HIV Integrase Inhibitor Cabotegravir

Patel

Ford

Lou

et al. 2018

Clinical Pharm in Drug Dev

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Cabotegravir is an integrase inhibitor in clinical development for the treatment and prevention of HIV infection using oral tablets for short-term, lead-in use before subsequent administration of a long-acting injectable formulation. This phase 1, single-center, randomized, 2 × 2 crossover study evaluated the effect of a high-fat meal on the pharmacokinetics (PK) of oral cabotegravir. Healthy adults received oral cabotegravir 30 mg as a single dose on 2 separate occasions, either after fasting or following a high-fat meal (∼53% fat, ∼870 kcal). Safety evaluations and serial PK samples were collected, and a mixed-effects model was used to determine within-participant treatment comparison of noncompartmental PK parameters. Twenty-four patients were enrolled and had a mean body mass index of 25.6 kg/m ; 67% were male. Compared with the fasting state, coadministration of cabotegravir with a high-fat meal increased plasma cabotegravir area under the concentration-time curve and maximal drug concentration, each by 14%. The slight 14% to 17% increase in exposure associated with a high-fat, high-calorie meal was not considered clinically significant. No grade 3/4 adverse events (AEs), drug-related AEs, or AEs leading to discontinuation were reported.

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“…Cabotegravir is metabolized via UDP-glucuronosyltransferase (UGT) 1A1, with a secondary contribution from UGT1A9 to inactive glucuronide metabolites. 6 The primary metabolite of cabotegravir (M1) is an ether glucuronide excreted predominantly in urine. In vitro, cabotegravir has not been shown to inhibit or induce UGT and cytochrome P450 (CYP) enzymes.…”

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“…8 Overall, cabotegravir has a favorable drug interaction profile and is expected to have few clinically significant drug interactions. 6 In accordance with the International Conference on Harmonization (ICH) recommendations for new agents, 9 supratherapeutic doses of INSTIs have been examined for their potential to affect cardiac repolarization and have not been shown to have significant effects on the QTc interval. 10,11 In nonclinical studies, no effects of cabotegravir on cardiac conduction have been observed.…”

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Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects

Lou¹,

Buchanan²,

Chen

et al. 2016

Clinical Pharm in Drug Dev

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A randomized, partial‐blind, repeat‐dose, 3‐period crossover study (NCT02027454) assessed the effect of cabotegravir on QT interval in healthy subjects. To achieve a supratherapeutic dose, each subject received cabotegravir 150 mg (30 mg × 5 tablets) every 12 hours for a total of 3 doses over 2 days, matching placebo (every 12 hours) over 2 days, or a single open‐label 400‐mg dose of the positive control moxifloxacin, with a 21‐day washout between treatments. Blood samples for pharmacokinetic analyses were collected up to 24 hours after the third dose on day 2. QT interval data were obtained by continuous Holter monitoring for approximately 24 hours at baseline (day ‐1) and from 2 hours before to 24 hours after the third dose on day 2. Plasma cabotegravir exposure was approximately 3‐fold above clinically relevant doses. After 3 doses of 150 mg of cabotegravir administered every 12 hours, all upper limits of 2‐sided 90% confidence intervals for ΔΔQTcF (difference in time‐matched change from baseline for QTcF between cabotegravir and placebo) were <10 milliseconds. There was no relationship between cabotegravir plasma concentrations and ΔΔQTcF. No subject receiving cabotegravir had a QTcF value > 450 milliseconds. There were no serious or grade 3 or 4 adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiogram results. These data demonstrate that cabotegravir at a supratherapeutic dose had no effect on cardiac repolarization.

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Disposition and metabolism of cabotegravir: a comparison of biotransformation and excretion between different species and routes of administration in humans

Cited by 44 publications

References 20 publications

Lack of effect of oral cabotegravir on the pharmacokinetics of a levonorgestrel/ethinyl oestradiol‐containing oral contraceptive in healthy adult women

Lack of effect of oral cabotegravir on the pharmacokinetics of a levonorgestrel/ethinyl oestradiol‐containing oral contraceptive in healthy adult women

Effect of a High‐Fat Meal on the Pharmacokinetics of the HIV Integrase Inhibitor Cabotegravir

Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects

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