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 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 (IC50 0.81 µM) and OAT3 (IC50 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.
a Drug Metabolism and Pharmacokinetics, GlaxoSmithKline , Research Triangle Park , NC , USA and.
Melinda J
MJ
Reese
a Drug Metabolism and Pharmacokinetics, GlaxoSmithKline , Research Triangle Park , NC , USA and.
Gary D
GD
Bowers
a Drug Metabolism and Pharmacokinetics, GlaxoSmithKline , Research Triangle Park , NC , USA and.
Joan E
JE
Humphreys
b Clinical Platforms and Sciences, GlaxoSmithKline , RTP , NC , USA.
Elizabeth P
EP
Gould
b Clinical Platforms and Sciences, GlaxoSmithKline , RTP , NC , USA.
Susan L
SL
Ford
a Drug Metabolism and Pharmacokinetics, GlaxoSmithKline , Research Triangle Park , NC , USA and.
Lindsey O
LO
Webster
a Drug Metabolism and Pharmacokinetics, GlaxoSmithKline , Research Triangle Park , NC , USA and.
Joseph W
JW
Polli
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D019428:HIV Integrase Inhibitors / Q000737:chemistry*; D022781:Hepatocytes / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008874:Midazolam / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008875:Middle Aged; D027362:Organic Anion Transport Protein 1 / Q000037:antagonists & inhibitors; D027361:Organic Anion Transporters / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors; D011728:Pyridones / Q000008:administration & dosage* / Q000493:pharmacokinetics; D055815:Young Adult; D054659:Diketopiperazines
D018528:ATP-Binding Cassette Transporters; D019380:Anti-HIV Agents; D051544:Cytochrome P-450 CYP3A; D019428:HIV Integrase Inhibitors; D008874:Midazolam; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D011728:Pyridones; C114338:organic anion transport protein 3; C584914:cabotegravir; D054659:Diketopiperazines
BCRP; Cytochrome P450; OAT; P-glycoprotein; drug metabolism; infections disease; transporters