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

Abstract

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.

Lipophilic nanocrystal prodrug-release defines the extended pharmacokinetic profiles of a year-long cabotegravir

“…CAB has more favorable PK properties than other INSTIs. This includes its long plasma half-life of 30-40 h 8 , fast oral absorption (t max = 1.5-2 h) 16 , near-complete oral bioavailability 16,22 , and low DDI potential due to its high membrane permeability and low affinity for CYP450 9,10 . In humans, CAB is primarily eliminated unchanged in feces (up to 50% unchanged and 10% unidentified metabolites) and as glucuronide metabolites in urine (27%) 16 .…”

Lipophilic Nanocrystal Prodrug-Release Defines the Extended Pharmacokinetic Profiles of a Year-Long Cabotegravir

“…CAB has more favorable PK properties then other INSTIs. This includes its long plasma half-life of 30-40 h 8 , fast oral absorption (t max = 1.5-2 h) 16 , near-complete oral bioavailability 16, 22 , and low DDI potential due to its high membrane permeability and low affinity for CYP450 9, 10 . In humans, CAB is primarily eliminated unchanged in feces (up to 50% unchanged and 10% unidentified metabolites) and as glucuronide metabolites in urine (27%) 16 .…”

A Phase I Study to Evaluate the Pharmacokinetics and Safety of Cabotegravir in Adults With Severe Renal Impairment and Healthy Matched Control Participants

“…Accuracy ranged from 14.8% to 8.0% bias. The complete analysis of cabotegravir with all the necessary parameters has been previously described …”

“…Cabotegravir is rapidly absorbed after oral administration and the previously reported geometric mean (95% confidence interval [CI]) of the area under the concentration‐time curve (AUC) was 146 (128–167) µg · h/mL with single‐dose administration of a 30‐mg tablet; it is slowly cleared with a long apparent terminal elimination half‐life (t 1/2 ) of 38.5 hours . Results from a recent food‐effect study revealed that both plasma cabotegravir AUC and maximum observed cabotegravir concentration (C max ) increase by 14% in the presence of a high‐fat meal . The PK parameters increased proportionally to dose from 5 to 30 mg but were less than proportional to dose from 30 to 60 mg .…”

“…Results from a recent food‐effect study revealed that both plasma cabotegravir AUC and maximum observed cabotegravir concentration (C max ) increase by 14% in the presence of a high‐fat meal . The PK parameters increased proportionally to dose from 5 to 30 mg but were less than proportional to dose from 30 to 60 mg . Cabotegravir LA exhibits absorption‐limited (flip‐flop) kinetics and has been detected in plasma up to 48 weeks at a concentration of approximately 0.1 µg/mL after a single 400‐mg intramuscular injection .…”