Rabbit Anti-Human CYP3A4 (a.a. 26-503) Polyclonal antibody

Background Apalutamide is predominantly metabolized via cytochrome P450 (CYP) 2C8 and CYP3A4, whose contributions change due to autoinduction with repeated dosing. Objectives We aimed to predict CYP3A4 and CYP2C8 inhibitor/inducer effects on the steady-state pharmacokinetics of apalutamide and total potency-adjusted pharmacologically active moieties, and simulated drug-drug interaction (DDI) between single-dose and repeated-dose apalutamide coadministered with known inhibitors/inducers. Methods We applied physiologically based pharmacokinetic modeling for our predictions, and simulated DDI between single-dose and repeated-dose apalutamide 240 mg coadministered with ketoconazole, gemfibrozil, or rifampicin. Results The estimated contribution of CYP2C8 and CYP3A4 to apalutamide metabolism is 58% and 13%, respectively, after single dosing, and 40% and 37%, respectively, at steady-state. Apalutamide exposure is predicted to increase with ketoconazole (maximum observed concentration at steady-state [C-max,C-ss] 38%, area under the plasma concentration-time curve at steady-state [AUC(ss)] 51% [pharmacologically active moieties, C-max,C-ss 23%, AUC(ss) 28%]) and gemfibrozil (C-max,C-ss 32%, AUC(ss) 44% [pharmacologically active moieties, C-max,C-ss 19%, AUC(ss) 23%]). Rifampicin exposure is predicted to decrease apalutamide (C-max,C-ss 25%, AUC(ss) 34% [pharmacologically active moieties, C-max,C-ss 15%, AUC(ss) 19%]). Conclusions Based on our simulations, no major changes in the pharmacokinetics of apalutamide or pharmacologically active moieties are expected with strong CYP3A4/CYP2C8 inhibitors/inducers. This observation supports the existing recommendations that no dose adjustments are needed during coadministration of apalutamide and the known inhibitors or inducers of CYP2C8 or CYP3A4.

Background: The impact of major liver resection (LR) on the detoxifying function of the remaining liver tissue as represented by CYP3A activity has yet to be assessed. Therefore, this study evaluates the changes in CYP3A activity between preoperative values and after liver resection. Material and methods: To determine CYP3A activity, midazolam (MDZ) was used as a marker substance, 3 lig were applied intravenously one day before surgery and on the 3rd day after surgery. Subsequently blood was withdrawn at 0, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3, 4 and 6 h post application of the study drug. Plasma MDZ and 1-OH-MDZ concentration was assessed using a LC-MS/MS method. Volumetric analysis of the resected liver was done by syngo.CT liver analysis software (Siemens Healthineers) using preoperative multidetector computed tomography. Results: N = 13 (8 male/5 female) patients were included in this study and received preoperative evaluation, 11 patients were studied also after liver resection. The mean age was 62 (+/- 15.3) years with a mean BMI of 23.6 +/- 4.8 kg/m(2). No patient suffered from acute liver dysfunction postoperatively. None of the pharmacokinetic parameters assessed were significantly altered by liver resection. CYP3A activity over time was not significantly reduced by major liver resection. Conclusion: This study gives first time data on the impact of major liver resection on CYP3A activity. It was shown that MDZ clearance representing in vivo CYP3A activity is not altered by major liver resection. This suggests no dose adjustment of commonly applied drugs which are CYP3A substrates needs to be carried out.