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 (Cmax ) approximately 27% to 28% greater than reference. Formulation AK met bioequivalence standards to the reference for dolutegravir (AUC0-∞ and Cmax ) and lamivudine (AUC0-∞ and AUC0-t ) exposure; however, dolutegravir AUC0-t and lamivudine Cmax were approximately 16% and 32% higher than the reference, respectively. A high-fat meal increased dolutegravir AUC and Cmax by up to 33% and 21%, respectively, and decreased lamivudine Cmax 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.
Subject(s)
Fasting/metabolism , Food/adverse effects , HIV Infections/drug therapy , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Lamivudine/pharmacokinetics , Oxazines/pharmacokinetics , Piperazines/pharmacokinetics , Pyridones/pharmacokinetics , Administration, Oral , Adult , Area Under Curve , Body Mass Index , Drug Therapy, Combination , Female , HIV Infections/metabolism , HIV Integrase Inhibitors/administration & dosage , HIV Integrase Inhibitors/adverse effects , HIV Integrase Inhibitors/pharmacokinetics , HIV-1/drug effects , HIV-1/isolation & purification , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/adverse effects , Humans , Lamivudine/administration & dosage , Lamivudine/adverse effects , Male , Middle Aged , Oxazines/administration & dosage , Oxazines/adverse effects , Piperazines/administration & dosage , Piperazines/adverse effects , Pyridones/administration & dosage , Pyridones/adverse effects , Reverse Transcriptase Inhibitors/administration & dosage , Reverse Transcriptase Inhibitors/adverse effects , Reverse Transcriptase Inhibitors/pharmacokinetics , Safety , Therapeutic EquivalencyABSTRACT
A novel approach to high-throughput logP measurement based on liquid chromatography/ultraviolet/mass spectrometry (LC/UV/MS) is proposed. The logP value is determined by correlation with the logk value, where k is the capacity factor k = (t(r)-t(0))/t(0), with the logP value using a defined set of standards. Since the analyte retention time (t(r)) is determined from the appropriate extracted ion chromatogram (EIC), there are no interferences from impurities and this allows the pooling of multiple compounds into one injection. To ensure the accuracy and instrument robustness in a routine high-throughput environment, a simple and MS-friendly mobile phase consisting of 20 mM ammonium carbonate (pH 8.0) for basic compounds or 20 mM ammonium formate (pH 1.0) for acidic compounds, both in combination with methanol at a ratio of 45:55, is used. This approach has been successfully used on single as well as parallel multi-channel LC/UV/MS systems to screen small to large sets of lead compounds and their analogs. A high-throughput capability to analyze over 1000 compounds per day has been achieved.