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Poly(ADP-ribose) polymerase (PARP) inhibitors have been developed to treat cancers associated with somatic BRCA mutations and germline genetic aberrations involved in the DNA damage response. The efficacy, tolerability, and pharmacokinetic/pharmacodynamic (PK/PD) profile of talazoparib, a potent small-molecule PARP inhibitor, was established in 4 clinical studies in cancer patients (2 phase 1 studies PRP-001 and PRP-002, the phase 2 ABRAZO trial, and the phase 3 EMBRACA trial). The current study aimed to describe the population PK of talazoparib and identify covariates that affect talazoparib PK in patients with advanced cancers using pooled data from these 4 studies. Talazoparib PK was well characterized by a 2-compartment model with first-order absorption and absorption lag time. Based on covariate analysis, no dose adjustment for talazoparib is required based on a patient's age, sex, baseline body weight, Asian race, the presence of mild renal or hepatic impairment, or use of acid-reducing agents. A reduced 0.75-mg daily dose is recommended for patients taking a potent P-glycoprotein inhibitor and those with moderate renal impairment. Insufficient data were available to establish dosing recommendations for patients with severe renal and moderate or severe hepatic impairment. The PK of a single 1-mg talazoparib capsule is comparable with 4 0.25-mg capsules. Talazoparib can be taken with or without food. These data provide support for dosing recommendations and labeling information for talazoparib., (© 2019, The American College of Clinical Pharmacology.)

In this open-label study (NCT02142920), we investigated the distribution, pharmacokinetics, and metabolism of the pan-class-I isoform phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor gedatolisib (PF-05212384), following a single intravenous administration in healthy male subjects. A single, 89-mg, intravenous dose of gedatolisib was associated with a favorable safety profile in the 6 healthy subjects evaluated. Peak plasma concentrations for unchanged gedatolisib and total radioactivity were observed at the end of the 30-minute infusion. The only observed drug-related material in plasma was the parent drug, gedatolisib. Terminal half-life for plasma gedatolisib was ∼37 hours. Following the dose, 66%-73% of drug-related material was recovered in the feces. Metabolism of gedatolisib was trace; only 1 oxidative metabolite, M5, was identified in feces (<1% of total dose). Identification of gedatolisib in feces suggests that biliary and/or intestinal secretion of unchanged parent drug significantly contributes to gedatolisib clearance., (© 2018, The American College of Clinical Pharmacology.)

A simple and sensitive method for the determination of nitrendipine in rat plasma was developed using high-performance liquid chromatography (HPLC). The procedure involves extraction of nitrendipine in dichloromethane/sodium hydroxide, followed by reversed phase HPLC using a Waters, Spherisorb ODS2 (250 x 4.6 mm, 5 microm) column and UV detection at 238 nm. The retention times of nitrendipine and internal standard (felodipine) were 5.0 min and 7.5 min, respectively. The calibration curves were linear over the range of 5 ng/mL (lower limit of quantification, LOQ) to 200 ng/mL for nitrendipine. The intra- and inter-day coefficients of variation for all criteria of validation were less than 15% over the linearity range. The sensitivity and precision of the method were within the accepted limits (< 15%) throughout the validation period. The present method was also successfully applied for the study of plasma pharmacokinetics of nitrendipine loaded solid lipid nanoparticles (SLN) in rats., ((c) 2007 John Wiley & Sons, Ltd.)