Revisiting Nonlinear Bosentan Pharmacokinetics by Physiologically Based Pharmacokinetic Modeling: Target Binding, Albeit Not a Major Contributor to Nonlinearity, Can Offer Prediction of Target Occupancy.

Satoshi Koyama,Kota Toshimoto,Wooin Lee,Yasunori Aoki,Yuichi Sugiyama

doi:10.1124/dmd.120.000023

Abstract

Bosentan is a high-affinity antagonist of endothelin receptors and one of the earliest examples for target-mediated drug disposition [a type of nonlinear pharmacokinetics (PKs) caused by saturable target binding]. The previous physiologically based PK (PBPK) modeling indicated that the nonlinear PKs of bosentan was explainable by considering saturable hepatic uptake. However, it remained unexamined to what extent the saturable target binding contributes to the nonlinear PKs of bosentan. Here, we developed a PBPK model incorporating saturable target binding and hepatic uptake and analyzed the clinical bosentan PK data using the cluster Gauss-Newton method (CGNM). The PBPK model without target binding fell short in capturing the bosentan concentrations below 100 nM, based on the PK profiles and the goodness-of-fit plot. Both global and local identifiability analyses (using the CGNM and Fisher information matrix, respectively) informed that the target binding parameters were identifiable only if the observations from the lowest dose (10 mg) were included. By analyzing blood PK profiles alone, the PBPK model with target binding yielded practically identifiable target binding parameters and predicted the maximum target occupancies of 0.6-0.8 at clinical bosentan doses. Our results indicate that target binding, albeit not a major contributor to the nonlinear bosentan PKs, may offer a prediction of target occupancy from blood PK profiles alone and potential guidance on achieving optimal efficacy outcomes, under the condition when the high-affinity drug target is responsible for the efficacy of interest and when the dose ranges cover varying degrees of target binding. SIGNIFICANCE STATEMENT: By incorporating saturable target binding, our physiologically based pharmacokinetic (PBPK) model predicted in vivo target occupancy of bosentan based only on the blood concentration-time profiles obtained from a wide range of doses. Our analysis highlights the potential utility of PBPK models that incorporate target binding in predicting target occupancy in vivo.

Highlights

Bosentan (Tracleer), an endothelin receptor antagonist, is used for the treatment of pulmonary arterial hypertension
Building upon the previous physiologically based PK (PBPK) model incorporating saturable hepatic uptake (Sato et al, 2018), we constructed a PBPK model of bosentan that incorporated saturable target binding and hepatic uptake and assessed the performance of the PBPK model in capturing the clinical PKs of bosentan
Our results indicated that target binding is not a major contributor to the nonlinear bosentan PKs

Summary

Introduction

Bosentan (Tracleer), an endothelin receptor antagonist, is used for the treatment of pulmonary arterial hypertension. Bosentan displays nonlinear pharmacokinetics (PKs), and it was one of the earliest examples that initiated the concept of target-mediated. Drug disposition (TMDD, a type of nonlinear PK caused by high-affinity binding of a drug to its pharmacological target) (Mager and Jusko, 2001). When 10–750 mg bosentan doses were administered intravenously to healthy volunteers, its systemic clearance and volume of distribution at steady state decreased with escalating doses (Weber et al, 1996). When bosentan was administered orally to healthy volunteers, the dosenormalized Cmax values of bosentan were comparable for doses up to 600 mg, but decreased at doses above 600 mg, suggesting that the dissolution rate limited absorption from an aqueous suspension of bosentan (Weber et al, 1996). Bosentan is metabolized mainly by cytochrome P450s 3A4 and 2C9 and

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