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Effect of Dolutegravir and Lamivudine on the Pharmacokinetics of Other Agents: Dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of cytochrome P450 enzymes, uridine diphosphate glucuronosyl transferase (UGT), or the transporters P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), bile salt export pump (BSEP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, multidrug resistance-associated protein (MRP) 2 or MRP4.
In vitro, dolutegravir demonstrated no direct, or weak inhibition (IC50 >50 μM) of the enzymes cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1 or UGT2B7, or the transporters Pgp, BCRP, BSEP, OATP1B1, OATP1B3, OCT1, MRP2 or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6 or CYP3A4. In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on these data, dolutegravir is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or transporters (e.g., reverse transcriptase and protease inhibitors, abacavir, zidovudine, maraviroc, opioid analgesics, antidepressants, statins, azole antifungals, proton pump inhibitors, erectile dysfunction agents, aciclovir, valaciclovir, sitagliptin, adefovir).
In drug interaction studies, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following: tenofovir, ritonavir, methadone, efavirenz, lopinavir, atazanavir, darunavir, etravirine, fosamprenavir, rilpivirine, boceprevir, telaprevir, daclatasvir, and oral contraceptives containing norgestimate and ethinyl estradiol.
In vitro, dolutegravir inhibited the renal OCT2 (IC50 = 1.93 μM), multidrug and toxin extrusion transporter (MATE) 1 (IC50 = 6.34 μM) and MATE2-K (IC50 = 24.8 μM). Given dolutegravir's in vivo exposure, it has a low potential to affect the transport of MATE2-K substrates in vivo. In vivo dolutegravir increases plasma concentrations of drugs in which excretion is dependent upon OCT2 or MATE1 (for example dofetilide, pilsicainide, fampridine [also known as dalfampridine] or metformin) (see Tables 6a, 6b and 6c).
In vitro, dolutegravir inhibited the basolateral renal transporters: OAT1 (IC50 = 2.12 μM) and OAT3 (IC50 = 1.97 μM). However, dolutegravir had no notable effect on the pharmacokinetics in vivo of the OAT substrates tenofovir and para aminohippurate, and therefore has low propensity to cause drug interactions via inhibition of OAT transporters.
Lamivudine does not inhibit or induce CYP enzymes (such as CYP3A4, CYP2C9 or CYP2D6) and demonstrates no or weak inhibition of the drug transporters OATP1B1, OATP1B3, BCRP and Pgp, OCT3, MATE1 or MATE2-K. Lamivudine is therefore not expected to affect the plasma concentrations of drugs that are substrates of these enzymes or transporters.
Although lamivudine is an inhibitor of OCT1 and OCT2 in vitro, it has low potential to affect the plasma concentrations of substrates of these transporters at the therapeutic dose (300 mg)/exposure.
Effect of Other Agents on the Pharmacokinetics of Dolutegravir and Lamivudine: Dolutegravir is eliminated mainly through metabolism by UGT1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, Pgp, and BCRP; therefore drugs that induce those enzymes or transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir. Co-administration of dolutegravir and other drugs that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or Pgp may increase dolutegravir plasma concentration (see Tables 6a, 6b and 6c).
In vitro, dolutegravir is not a substrate of human organic anion transporting polypeptide (OATP)1B1, OATP1B3, or OCT1, therefore drugs that solely modulate these transporters are not expected to affect dolutegravir plasma concentration.
Rifampicin, carbamazepine, phenytoin, phenobarbital, St. John's wort, etravirine (without boosted protease inhibitors), efavirenz, nevirapine, or tipranavir/ritonavir each reduced the plasma concentrations of dolutegravir significantly, and require dolutegravir dose adjustment to 50 mg twice daily. A separate preparation of dolutegravir (TIVICAY) is available where a dose adjustment is required due to drug-drug interactions. An additional dose of 50 mg dolutegravir (TIVICAY) should be administered, approximately 12 hours after DOVATO. In these cases the physician should refer to the TIVICAY product information.
The likelihood of metabolic interactions with lamivudine is low due to limited metabolism and plasma protein binding, and almost complete renal clearance. Lamivudine is not significantly metabolised by CYP enzymes. Although lamivudine is a substrate of BCRP and Pgp in vitro, inhibitors of these efflux transporters are unlikely to affect the disposition of lamivudine due to its high bioavailability. Lamivudine is an in vitro substrate of MATE1, MATE2-K and OCT2. Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations however; the resulting increase was of such magnitude that a dose adjustment is not recommended as it is not expected to have clinical significance. Lamivudine is a substrate of the hepatic uptake transporter OCT1. As hepatic elimination plays a minor role in the clearance of lamivudine, drug interactions due to inhibition of OCT1 are unlikely to be of clinical significance.
Selected drug interactions are presented in Tables 6a, 6b, 6c and 7. Recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. DOVATO is not expected to be co-administered with other HIV-1 antiviral agents and information is provided for reference. (See Tables 6a, 6b, 6c and 7.)
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