Physiologically Based Pharmacokinetic Modelling of Cytochrome P450 2C9-Related Tolbutamide Drug Interactions with Sulfaphenazole and Tasisulam

Background and Objectives: Cytochrome P450 2C9 (CYP2C9) is involved in the biotransformation of many commonly used drugs, and significant drug interactions have been reported for CYP2C9 substrates. Previously published physiologically based pharmacokinetic (PBPK) models of tolbutamide are based on an assumption that its metabolic clearance is exclusively through CYP2C9; however, many studies indicate that CYP2C9 metabolism is only responsible for 80–90% of the total clearance. Therefore, these models are not useful for predicting the magnitude of CYP2C9 drug–drug interactions (DDIs). This paper describes the development and verification of SimCYP-based PBPK models that accurately describe the human pharmacokinetics of tolbutamide when dosed alone or in combination with the CYP2C9 inhibitors sulfaphenazole and tasisulam. Methods: A PBPK model was optimized in SimCYP for tolbutamide as a CYP2C9 substrate, based on published in vitro and clinical data. This model was verified to replicate the magnitude of DDI reported with sulfaphenazole and was further applied to simulate the DDI with tasisulam, a small molecule investigated for the treatment of cancer. A clinical study (CT registration # NCT01185548) was conducted in patients with cancer to assess the pharmacokinetic interaction of tasisulum with tolbutamide. A PBPK model was built for tasisulam, and the clinical study design was replicated using the optimized tolbutamide model. Results: The optimized tolbutamide model accurately predicted the magnitude of tolbutamide AUC increase (5.3–6.2-fold) reported for sulfaphenazole. Furthermore, the PBPK simulations in a healthy volunteer population adequately predicted the increase in plasma exposure of tolbutamide in patients with cancer (predicted AUC ratio = 4.7–5.4; measured mean AUC ratio = 5.7). Conclusions: This optimized tolbutamide PBPK model was verified with two strong CYP2C9 inhibitors and can be applied to the prediction of CYP2C9 interactions for novel inhibitors. Furthermore, this work highlights the utility of mechanistic models in navigating the challenges in conducting clinical pharmacology studies in cancer patients

Accuracy of a novel approach to measuring arterial thermodilution cardiac output during intra-aortic counterpulsation

Objective: To assess the agreement between a novel approach of arterial and the pulmonary artery bolus thermodilution for measuring cardiac output in critically ill patients during aortic counterpulsation. Methods: Eighteen male patients aged 37-80years, undergoing preoperative insertion of an intra-aortic balloon pump (IABP) and elective coronary artery bypass grafting. A thin 1.3FG thermistor was introduced through the pressure lumen to the tip of an 8FG IABP catheter, and the pump rate was set at 1:1. After arrival in the intensive care unit cardiac output (CO) was measured under haemodynamic steady-state conditions hourly for 8-11h, and arterial bolus thermodilution (BCOiabp) and pulmonary artery bolus thermodilution (BCOpulm) were determined after the patients' admission to the intensive care unit. Results: A total of 198 data pairs were obtained: 177 with aortic counterpulsation and 21 without. During aortic counterpulsation, median CO was 6.8l/min for BCOiabp and 6.1l/min for BCOpulm, without aortic counterpulsation; corresponding values were 7.1l/min for BCOiabp and 6.5l/min for BCOpulm with aortic counterpulsation. Mean bias was +0.77l/min, limits of agreement ( ± 2SD) were -1.27/+2.81l/min, and mean error (2SD/[(BCOiabp+BCOpulm)/2] was 31.4%. Without aortic counterpulsation, corresponding values were +0.43l/min, -1.03/+1.87l/min, and 22.4%. Conclusions: Agreement between BCOiabp and BCOpulm was satisfactory for CO values between 2.0 and 10l/min only without aortic counterpulsation. BCOiabp CO measurements during aortic counterpulsation after coronary artery bypass grafting cannot be recommended at the present tim