Development and application of a PBPK modeling strategy to support antimalarial drug development.

As part of a collaboration between Medicines for Malaria Venture (MMV), Certara UK and Monash University, physiologically-based pharmacokinetic (PBPK) models were developed for 20 antimalarials, using data obtained from standardized in vitro assays and clinical studies within the literature. The models have been applied within antimalarial drug development at MMV for more than 5 years. During this time, a strategy for their impactful use has evolved.

Metabolism and pharmacokinetics of vitamin D in patients with cystic fibrosis.

Patients with cystic fibrosis (CF) commonly have lower circulating concentrations of 25-hydroxyvitamin D (25(OH)D) than healthy populations. We comprehensively compared measures of vitamin D metabolism among individuals with CF and healthy control subjects. In a cross-sectional study, serum from participants with CF (N = 83) and frequency-matched healthy control subjects by age and race (N = 82) were analyzed for: 25(OH)D and 25(OH)D, 1α,25-dihydroxyvitamins D and D (1α,25(OH)D and 1α,25(OH)D), 24,25-dihydroxyvitamin D (24,25(OH)D), 4β,25-dihydroxyvitamin D (4β,25(OH)D), 25-hydroxyvitamin D-3-sulfate (25(OH)D-S), and 25-hydroxyvitamin D-3-glucuronide (25(OH)D-G).

Simultaneous quantification of 25-hydroxyvitamin D-3-sulfate and 25-hydroxyvitamin D-3-glucuronide in human serum and plasma using liquid chromatography-tandem mass spectrometry coupled with DAPTAD-derivatization.

25-hydroxyvitamin D-3-sulfate (25-OHD-S) and 25-hydroxyvitamin D-3-glucuronide (25-OHD-G) are major conjugative metabolites of vitamin D found in the systemic circulation and potentially important reservoirs for 25-hydroxyvitamin D. Simultaneous and accurate quantification of these metabolites could advance assessment of the impact of vitamin D on health and disease. In this study, a highly sensitive and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous quantification of 25-OHD-S and 25-OHD-G in human serum or plasma.

Pregnancy Increases the Renal Secretion of N-methylnicotinamide, an Endogenous Probe for Renal Cation Transporters, in Patients Prescribed Metformin.

N-methylnicotinamide (1-NMN) has been investigated as an endogenous probe for the renal transporter activity of organic cation transporter 2 (OCT2) and multidrug and toxin extrusion proteins 1 and 2-K (MATE1 and MATE2-K). As pregnancy increased the renal secretion of metformin, a substrate for OCT2, MATE1, and MATE2-K, we hypothesized that the renal secretion of 1-NMN would be similarly affected. Blood and urine samples collected from women prescribed metformin for type 2 diabetes, gestational diabetes, and polycystic ovarian syndrome during early, mid, and late pregnancy ( = 34 visits) and postpartum ( = 14 visits) were analyzed for 1-NMN using liquid chromatography-mass spectrometry.