Journal of clinical pharmacology
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The objectives of the analysis were to develop and verify a venetoclax physiologically based pharmacokinetic (PBPK) model to predict the effects of cytochrome P450 3A (CYP3A) inhibitors and inducers on the PK of venetoclax and inform dosing recommendations. A minimal PBPK model was developed based on prior in vitro and in vivo clinical data using a "middle-out" approach. The PBPK model was independently verified against clinical studies of the strong CYP3A inhibitor ketoconazole, the strong CYP3A inducer, multiple-dose rifampin, and the steady-state venetoclax PK in chronic lymphocytic leukemia (CLL) subjects by comparing predicted to observed ratios of the venetoclax maximum concentration (Cmax R) and area under the curve from time 0 to infinity (AUC∞ R) from these studies. ⋯ Model simulations indicated no effect of weak CYP3A inhibitors or inducers on Cmax or AUC∞ , while both moderate and strong CYP3A inducers were estimated to decrease venetoclax exposure. Moderate and strong CYP3A inhibitors were estimated to increase venetoclax AUC∞ , by 100% to 390% and 480% to 680%, respectively. The recommended venetoclax dose reductions of at least 50% and 75% when coadministered with moderate and strong CYP3A inhibitors, respectively, maintain venetoclax exposures between therapeutic and maximally administered safe doses.
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The optimal antibiotic prophylaxis dosing regimen of cefazolin for cesarean delivery (CD) in overweight and obese women is unknown. This study was done to compare the duration that cefazolin concentrations remain above the minimum inhibitory concentration (MIC) in adipose tissue (AT). Serum and AT concentrations from 3 previous studies in CD patients were comodeled using the nonparametric adaptive grid algorithm in Pmetrics. ⋯ Cefazolin achieved good penetration into AT. Because CD duration is commonly less than 1.5 hours, a 2-g dose has a high probability of providing AT concentrations above the target pathogens' MIC for overweight and obese females. A second dose may be considered for longer surgeries.