Bioequivalence and Food Effect Assessment of 2 Fixed-Dose Combination Formulations of Dolutegravir and Lamivudine

Abstract

This single-dose study evaluated the bioequivalence, food effect, and safety of 2 experimental, 2-drug, fixed-dose formulations of 50 mg dolutegravir and 300 mg lamivudine (formulation AH and formulation AK) as compared with coadministration of single-entity tablets of 50 mg dolutegravir and 300 mg lamivudine (reference). In fasted subjects, formulation AH lamivudine exposure was similar to the reference; however, dolutegravir exposure was consistently higher in formulation AH, with area under the concentration-time curve (AUC) and maximum concentration (C_max ) approximately 27% to 28% greater than reference. Formulation AK met bioequivalence standards to the reference for dolutegravir (AUC_0-∞ and C_max ) and lamivudine (AUC_0-∞ and AUC_0-t ) exposure; however, dolutegravir AUC_0-t and lamivudine C_max were approximately 16% and 32% higher than the reference, respectively. A high-fat meal increased dolutegravir AUC and C_max by up to 33% and 21%, respectively, and decreased lamivudine C_max by approximately 30%. Both test and reference formulations were well tolerated. The results support further development of formulation AK as a novel, 2-drug, fixed-dose combination tablet treatment for patients with HIV.

Keywords: HIV; bioequivalence; dolutegravir; lamivudine.

Figure 1

Study design for Study 204994 to assess the bioequivalence and food effect of 2 experimental formulations of fixed‐dose combination tablets (formulation AH, part 1, and AK, part 2) containing 50 mg dolutegravir and 300 mg lamivudine. Reference regimen administration was coadministration of individual, single‐entity tablets of 50 mg dolutegravir plus 300 mg lamivudine. Both parts of the study had equivalent designs: an open‐label, crossover design in which 76 subjects (planned) were randomized 1:1 to receive test or reference treatment in periods 1 and 2. In period 3, 16 subjects who had completed period 1 and period 2 also completed the food‐effect study, in which the test formulation was administered with a high‐fat meal. In part 1, subjects were administered formulation AH as the test drug. In part 2, a separate cohort of subjects received formulation AK.

Figure 2

Arithmetic mean (standard error of mean) plasma concentration‐time curves in the fasted state for the analytes dolutegravir and lamivudine after administration of formulation AH or reference (left) and formulation AK or reference (right), where the reference was coadministration of dolutegravir and lamivudine. Solid lines are given for the reference treatment, and dotted lines are given for formulation AH or AK. AH and AK respectively indicate formulations AH and AK; DTG, dolutegravir; 3TC, lamivudine.

Figure 3

Arithmetic mean (standard error of mean) plasma concentration‐time curves for the analytes dolutegravir and lamivudine after administration of formulation AH (left) or formulation AK (right) in the fed and fasted states. Solid lines are given for the treatment administered in the fasted state, and dotted lines are given for treatment administered in the fed state. AH and AK respectively indicate formulations AH and AK; DTG, dolutegravir; 3TC, lamivudine.