(0.82 to 1.10)
0.70
(0.57 to 0.87)
a Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir50 mg twice daily.
b Comparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir50 mg once daily.
Table 10. Effect of Sorbitol on the Pharmacokinetics of Lamivudine
Coadministered Drug and Dosea
Lamivudine Pharmacokinetic Parameters
(% Decreased)
Cmax AUC0-24 AUCinf
Sorbitol
(Excipient)
3.2 grams 28% 20% 14%
10.2 grams 52% 39% 32%
13.4 grams 55% 44% 36%
a Coadministered with a single dose of lamivudine 300 mg.
Cmax = Maximum concentration; AUC(0-24) = Area under the concentration-time curve integratedfrom time of administration to 24 hours; AUC(inf) = Area under the concentration-time curve fromthe time of administration to infinity.
No clinically significant differences in the pharmacokinetics of lamivudine were observed whencoadministered with trimethoprim (MATE1, MATE2-K, and OCT2 inhibitor)/sulfamethoxazole,interferon alfa, or ribavirin.
In Vitro Studies Where Drug Interaction Potential Was Not Further eva luated Clinically:
Dolutegravir: Dolutegravir does not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9,CYP2C19, CYP2D6, or CYP3A. Dolutegravir does not induce CYP1A2, CYP2B6, or CYP3A4.
Dolutegravir is a substrate of UGT1A3 and UGT1A9. Dolutegravir does not inhibit UGT1A1 orUGT2B7.
Dolutegravir is a substrate of BCRP and P-gp. Dolutegravir does not inhibit P-gp, BCRP, bilesalt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1,multidrug resistance protein (MRP)2, or MRP4. Dolutegravir is not a substrate of OATP1B1 orOATP1B3.
Lamivudine: Lamivudine is a substrate of P-gp and BCRP. Lamivudine does not inhibitOATP1B1/3, BCRP, P-gp, MATE1, MATE2-K, OCT1, OCT2, or OCT3.
12.4 Microbiology
Mechanism of Action
Dolutegravir: Dolutegravir inhibits HIV integrase by binding to the integrase active site andblocking the strand transfer step of retroviral DNA integration which is essential for the HIVreplication cycle. Strand transfer biochemical assays using purified recombinant HIV-1 integraseand pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.
Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly lamivudine isphosphorylated to its active 5-triphosphate metabolite, lamivudine triphosphate (3TC-TP). Theprincipal mode of action of 3TC-TP is inhibition of reverse transcriptase (RT) via DNA chaintermination after incorporation of the nucleotide analogue.
Antiviral Activity in Cell Culture
Dolutegravir: Dolutegravir exhibited antiviral activity against laboratory strains of wild-typeHIV-1 with mean concentrations of drug necessary to effect viral replication by 50 percent(EC50) values of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL) in peripheral blood mononuclearcells (PBMCs) and MT-4 cells.
Dolutegravir exhibited antiviral activity against 13 clinically diverse clade B isolates with amean EC50 value of 0.52 nM in a viral integrase susceptibility assay using the integrase codingregion from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against apanel of HIV-1 clinical isolates (3 in each group of M [clades A-G], and 3 in group O) with EC50values ranging from 0.02 nM to 2.14 nM for HIV-1. Dolutegravir EC50 values against three HIV-
2 clinical isolates in P |
