Prediction for optimal dosage of pazopanib under various clinical situations using physiologically based pharmacokinetic modeling

Abstract

This study aimed to apply a physiologically based pharmacokinetic (PBPK) model to predict optimal dosing regimens of pazopanib (PAZ) for safe and effective administration when co-administered with CYP3A4 inhibitors, acid-reducing agents, food, and administered in patients with hepatic impairment. Here, we have successfully developed the population PBPK model and the predicted PK variables by this model matched well with the clinically observed data. Most ratios of prediction to observation were between 0.5 and 2.0. Suitable dosage modifications of PAZ have been identified using the PBPK simulations in various situations, i.e., 200 mg once daily (OD) or 100 mg twice daily (BID) when co-administered with the two CYP3A4 inhibitors, 200 mg BID when simultaneously administered with food or 800 mg OD when avoiding food uptake simultaneously. Additionally, the PBPK model also suggested that dosing does not need to be adjusted when co-administered with esomeprazole and administration in patients with wild hepatic impairment. Furthermore, the PBPK model also suggested that PAZ is not recommended to be administered in patients with severe hepatic impairment. In summary, the present PBPK model can determine the optimal dosing adjustment recommendations in multiple clinical uses, which cannot be achieved by only focusing on AUC linear change of PK.

Prediction for Plasma Trough Concentration and Optimal Dosing of Imatinib under Multiple Clinical Situations Using Physiologically Based Pharmacokinetic Modeling

“…Except for the three metabolizing enzymes, the reference concentrations of six transporters were not built into the PK-Sim expression database. The OCT1 expression was obtained from the paper . For OATP1A2, OATP1B3, OTCN2, ABCB1, and ABcg2, the reference concentration was calculated using the formula (transporter protein abundance × expressed organ weight)/liver volume.…”

“…The change in AGP level between different populations was described using the plasma protein scale factor (PPSF) in the PK-SIM. PPSF was estimated by PPSF = 1 f up + ( 1 − f up ) × AGP normalf where AGP f is the fractional value of the compared AGP level in healthy humans compared with AGP in CP and AP patients.…”

“… 28 The active uptake of IMA via OCT1 into cells was also depicted by Michaelis–Menten kinetics. The V max value for OCT1 in healthy humans was calculated as 128.1 pmol/min/pmol by V max (50.5 nmol/mg protein/10 min) in the paper 7 × protein expression (37.3 mg/g liver tissue) 30 × liver weight (1855.8 g for a 74.2 kg person) 31 × concentration (0.077 μM/L liver tissue) 32 × liver volume (mean 2.38L, built-in PK-Sim). Based on published studies, 7 V max for OTC in diseased cells is about 40% of that in healthy status.…”

“…The OCT1 expression was obtained from the paper. 32 For OATP1A2, 33 OATP1B3, 34 OTCN2, 35 ABCB1, 35 and ABcg2, 35 the reference concentration was calculated using the formula (transporter protein abundance × expressed organ weight)/liver volume.…”

“…PPSF was estimated by. 32 where AGP f is the fractional value of the compared AGP level in healthy humans compared with AGP in CP and AP patients. The renal clearance (CL R ) was estimated by the glomerular filtration rate (GFR) × f up method in PK-Sim.…”