Drug interaction profile of the HIV integrase inhibitor cabotegravir: assessment from in vitro studies and a clinical investigation with midazolam

1. Cabotegravir (CAB; GSK1265744) is a potent HIV integrase inhibitor in clinical development as an oral lead-in tablet and long-acting injectable for the treatment and prevention of HIV infection. 2. This work investigated if CAB was a substrate for efflux transporters, the potential for CAB to int...

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Bibliographic Details
Published in:Xenobiotica 2016-05, Vol.46 (5), p.445-456
Main Authors: Reese, Melinda J., Bowers, Gary D., Humphreys, Joan E., Gould, Elizabeth P., Ford, Susan L., Webster, Lindsey O., Polli, Joseph W.
Format: Article
Language:English
Subjects:
Administration, Oral
Adolescent
Adult
Aged
Animals
Anti-HIV Agents - administration & dosage
Anti-HIV Agents - pharmacokinetics
Area Under Curve
ATP-Binding Cassette Transporters - metabolism
BCRP
Cytochrome P-450 CYP3A - chemistry
Cytochrome P450
Dogs
Dose-Response Relationship, Drug
Drug Interactions
drug metabolism
Female
Hepatocytes - drug effects
HIV Infections - drug therapy
HIV Integrase Inhibitors - chemistry
Humans
infections disease
Inhibitory Concentration 50
Madin Darby Canine Kidney Cells
Male
Midazolam - administration & dosage
Midazolam - pharmacokinetics
Middle Aged
OAT
Organic Anion Transport Protein 1 - antagonists & inhibitors
Organic Anion Transporters - metabolism
Organic Anion Transporters, Sodium-Independent - antagonists & inhibitors
P-glycoprotein
Pyridones - administration & dosage
Pyridones - pharmacokinetics
transporters
Young Adult
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Summary:1. Cabotegravir (CAB; GSK1265744) is a potent HIV integrase inhibitor in clinical development as an oral lead-in tablet and long-acting injectable for the treatment and prevention of HIV infection. 2. This work investigated if CAB was a substrate for efflux transporters, the potential for CAB to interact with drug-metabolizing enzymes and transporters to cause clinical drug interactions, and the effect of CAB on the pharmacokinetics of midazolam, a CYP3A4 probe substrate, in humans. 3. CAB is a substrate for Pgp and BCRP; however, its high intrinsic membrane permeability limits the impact of these transporters on its intestinal absorption. 4. At clinically relevant concentrations, CAB did not inhibit or induce any of the CYP or UGT enzymes evaluated in vitro and had no effect on the clinical pharmacokinetics of midazolam. 5. CAB is an inhibitor of OAT1 (IC 50 0.81 µM) and OAT3 (IC 50 0.41 µM) but did not or only weakly inhibited Pgp, BCRP, MRP2, MRP4, MATE1, MATE2-K, OATP1B1, OATP1B3, OCT1, OCT2 or BSEP. 6. Based on regulatory guidelines and quantitative extrapolations, CAB has a low propensity to cause clinically significant drug interactions, except for coadministration with OAT1 or OAT3 substrates.
ISSN:0049-8254
1366-5928
DOI:10.3109/00498254.2015.1081993