DOVATO

), metformin) or MATE1 (see Table 6). 97 M). Based upon the dolutegravir unbound plasma concentration, in silico modelling, and no notable effect on the pharmacokinetics in vivo of the OAT substrates tenofovir and para-aminohippurate, dolutegravir has low propensity to cause drug interactions via inhibition of OAT transporters.

Lamivudine In vitro, lamivudine does not inhibit or induce CYP enzymes (such as CYP 3A4, CYP 2C9 or CYP 2D6). Lamivudine demonstrates no or weak inhibition of the drug transporters organic anion transporter 1B1 (OATP1B1), OATP1B3, breast cancer resistance protein (BCRP) or P-glycoprotein (Pgp), multidrug and toxin extrusion protein 1 (MATE1), MATE2-K or organic cation transporter 3 (OCT3).

Lamivudine is therefore not expected to affect the plasma concentrations of drugs that are substrates of these enzymes or drug transporters. Lamivudine is an inhibitor of OCT1 and OCT2 in vitro with IC50 values of 17 and 33 μM, respectively, however lamivudine has low potential to affect the plasma concentrations of OCT1 and OCT2 substrates at therapeutic drug exposures (up to 300 mg).

Effect of Other Agents on the Pharmacokinetics of Dolutegravir or Lamivudine Dolutegravir Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, Pgp and BCRP in vitro; therefore drugs that induce those enzymes and 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 Table 6). In vitro, dolutegravir is not a substrate of human organic anion transporting polypeptide (OATP)1B1, OATP1B3, or OCT1.

DOVATO, dolutegravir sodium and lamivudine Page 18 of 46 Protected B / Protégé B Coadministration of dolutegravir with polyvalent cation-containing products may lead to decreased adsorption of dolutegravir. Lamivudine Lamivudine is a substrate of MATE1, MATE2-K and OCT2 in vitro.

Trimethoprim (an inhibitor of these drug transporters) has been shown to increase lamivudine plasma concentrations, however this interaction is not considered clinically significant as no dose adjustment of lamivudine is needed. 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. Lamivudine is a substrate of Pgp and BCRP, however due to its high bioavailability it is unlikely that these transporters play a significant role in the absorption of lamivudine.

Therefore, co-administration of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine. Lamivudine is predominantly eliminated by active organic cationic secretion.