What are the pharmacokinetics of integrase strand-transfer inhibitors in antiretroviral therapy of HIV infection?

Updated: Apr 18, 2019
  • Author: R Chris Rathbun, PharmD, BCPS (AQ-ID), AAHIVP; Chief Editor: John Bartlett, MD  more...
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Raltegravir, dolutegravir, and bictegravir may be taken without regard for meals; whereas, elvitegravir should be taken with food to optimize its absorption.  All INSTIs are highly plasma protein bound (>98-99%) with the exception of raltegravir (83% bound to plasma proteins). [8]

Metabolism of raltegravir and dolutegravir occurs primarily through uridine diphosphate glucuronyl transferase 1A1 (UGT1A1). Bictegravir is metabolized equally through UGT1A1 and CYP3A4. Elvitegravir is primarily metabolized by CYP3A4 and secondarily through UGT1A1/UGT1A3. Elvitegravir is administered with cobicistat (150 mg) to reduce its first-pass metabolism and systemic clearance. [8, 84]

Dosage adjustment for INSTIs as individual components are not required in patients with renal or mild-to-moderate hepatic impairment; however, fixed dose combinations of INSTIs may not be recommended in some patients with renal insufficiency.  Use of dolutegravir/emtricitabine/abacavir (Triumeq) is not recommended in patients with creatinine clearances below 50 mL/min.  Initiation of elvitegravir in the fixed dose formulations elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild) and elvitegravir/cobicistat/emtricitabine/tenofovir AF (Genvoya) is not recommended in patients with creatinine clearances below 70 mL/min and 30 mL/min, respectively.  Bictegravir/emtricitabine/tenofovir AF (Biktarvy) is not recommended in patients with creatinine clearance below 30 mL/min. [8, 84]

Dolutegravir and bictegravir are inhibitors of organic cation transporter protein 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1). Dolutegravir also inhibits the breast cancer resistance protein (BCRP). Raltegravir and dolutegravir are substrates for p-glycoprotein. The pharmacokinetic booster, cobicistat, which is co-formulated with elvitegravir, is an inhibitor of p-glycoprotein, BCRP, MATE1, and organic anion transporters (OATP1B1, OATP1B35). [85, 84, 86, 87]

Raltegravir, dolutegravir, and bictegravir exhibit low potential to affect the metabolism of other drugs; however, other antiretroviral agents may alter the metabolism of these agents (see Drug Interactions with Antiretroviral Therapy or DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents).  Drug interactions between elvitegravir and other medications are more likely as a result of cobicistat coadministration.  Elvitegravir is also a modest inducer of CYP2C9, which may lead to drug-drug interactions with substrates (e.g., warfarin) of this isoenzyme. [88]

Antacids containing polyvalent cations and mineral supplements (e.g., iron) may decrease absorption of INSTIs by chelation reactions.  Raltegravir may be given with calcium carbonate antacids when administered twice daily (400 mg) but should not be coadministered when given once-daily (1200 mg) or with aluminum and magnesium hydroxide antacids. Elvitegravir- and bictegravir-containing regimens should be taken at least 2 hours before antacid administration.  Dolutegravir should be given at least 2 hours before or 6 hours after antacids with polyvalent cations.  When coadministration of mineral supplements is necessary, INSTIs should generally be given at least 2 hours before or 6 hours after the supplement.  Dolutegravir can be taken simultaneously with calcium and iron supplements if administered with food. No clinically significant decrease in INSTI absorption has been reported with gastric acid suppressants (proton pump inhibitors, H2 antagonists). [8]

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