Tegrad Drug Interactions

Effect of Dolutegravir on the Pharmacokinetics of Other Agents: In vitro, dolutegravir inhibited the renal organic cation transporters, OCT2 (IC₅₀ = 1.93 μM) and multidrug and toxin extrusion transporter (MATE) 1 (IC₅₀ = 6.34 μM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide and metformin, Table 15) [see Contraindications, Established and Other Potentially Significant Drug Interactions as follows].
In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT) 1 (IC₅₀ = 2.12 μM) and OAT3 (IC₅₀ = 1.97 μM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3. In vitro, dolutegravir did not inhibit (IC₅₀ greater than 50 μM) the following: cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1), UGT2B7, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4. Based on these data and the results of drug interaction trials, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters.
In drug interaction trials, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following drugs: daclatasvir, tenofovir, methadone, midazolam, rilpivirine, and oral contraceptives containing norgestimate and ethinyl estradiol. Using cross-study comparisons to historical pharmacokinetic data for each interacting drug, dolutegravir did not appear to affect the pharmacokinetics of the following drugs: atazanavir, darunavir, efavirenz, etravirine, fosamprenavir, lopinavir, ritonavir, and boceprevir.
Effect of Other Agents on the Pharmacokinetics of Dolutegravir: Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir.
Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentration. Etravirine significantly reduced plasma concentrations of dolutegravir, but the effect of etravirine was mitigated by coadministration of lopinavir/ritonavir or darunavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir (Table 15) [see Established and Other Potentially Significant Drug Interactions as follows, Pharmacology under Actions].
In vitro, dolutegravir was not a substrate of OATP1B1, or OATP1B3.
Darunavir/ritonavir, lopinavir/ritonavir, rilpivirine, tenofovir, boceprevir, daclatasvir, prednisone, rifabutin, and omeprazole had no clinically significant effect on the pharmacokinetics of dolutegravir.
Established and Other Potentially Significant Drug Interactions: Table 15 provides clinical recommendations as a result of drug interactions with dolutegravir. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. [See Dosage & Administration, Pharmacology under Actions.] (See Table 15.)

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