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Effect of other medicinal products on the pharmacokinetics of dolutegravir and lamivudine: Dolutegravir is eliminated mainly through metabolism by uridine diphosphate glucuronosyl transferase (UGT) 1A1. Dolutegravir is also a substrate of UGT1A3, UGT1A9, CYP3A4, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). Co-administration of Dovato and other medicinal products that inhibit UGT1A1, UGT1A3, UGT1A9, CYP3A4, and/or P-gp may, therefore, increase dolutegravir plasma concentration. Medicinal products that induce those enzymes or transporters may decrease dolutegravir plasma concentration and reduce the therapeutic effect of dolutegravir.
The absorption of dolutegravir is reduced by certain metal cation-containing anti-acid substances and supplements (see Table 4).
Lamivudine is cleared renally. Active renal secretion of lamivudine in the urine is mediated through the OCT2 and multidrug and toxin extrusion transporters (MATE1 and MATE2-K). Trimethoprim (an inhibitor of these transporters) has been shown to increase lamivudine plasma concentrations, however the resulting increase was not clinically significant (see Table 4). Dolutegravir is an OCT2 and MATE1 inhibitor; however, lamivudine concentrations were similar with or without co-administration of dolutegravir based on a cross study analysis, indicating that dolutegravir has no relevant effect on lamivudine exposure in vivo. Lamivudine is also 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.
Although lamivudine is a substrate of BCRP and P-gp in vitro, given its high absolute bioavailability, (see Pharmacology: Pharmacokinetics under Actions), inhibitors of these efflux transporters are unlikely to result in a clinically relevant impact on lamivudine concentrations.
Effect of dolutegravir and lamivudine on the pharmacokinetics of other medicinal products: In vivo, dolutegravir did not have an effect on midazolam, a CYP3A4 probe. Based on in vivo and/or in vitro data, dolutegravir is not expected to affect the pharmacokinetics of medicinal products that are substrates of any major enzyme or transporter such as CYP3A4, CYP2C9 and P-gp (for more information see Pharmacology: Pharmacokinetics under Actions).
In vitro, dolutegravir inhibited the renal transporters OCT2 and MATE1. In vivo, a 10-14% decrease of creatinine clearance (secretory fraction is dependent on OCT2 and MATE1 transport) was observed in patients. In vivo, dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OCT2 and/or MATE1 (e.g. fampridine [also known as dalfampridine], metformin) (see Table 4 and Contraindications).
In vitro, dolutegravir inhibited the renal uptake organic anion transporters (OAT)1 and OAT3. Based on the lack of effect on the in vivo pharmacokinetics of the OAT substrate tenofovir, in vivo inhibition of OAT1 is unlikely. Inhibition of OAT3 has not been studied in vivo. Dolutegravir may increase plasma concentrations of medicinal products in which excretion is dependent upon OAT3.
In vitro, lamivudine was an inhibitor of OCT1 and OCT2; the clinical consequences are not known.
Established and theoretical interactions with selected antiretrovirals and non-antiretroviral medicinal products are listed in Table 4.
Interaction table: Interactions between dolutegravir, lamivudine and co-administered medical products are listed in Table 4 (increase is indicated as "↑", decrease as "↓", no change as "↔", area under the concentration versus time curve as "AUC", maximum observed concentration as "Cmax", concentration at end of dosing interval as "Cτ"). The table should not be considered exhaustive but is representative of the classes studied. (See Tables 4a, 4b and 4c.)
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