Exploring the Impact of Pharmacological Target-Mediated Low Plasma Exposure in Lead Compound Selection in Drug Discovery - A Modeling Approach.

Small-molecule drug development faces the challenge of low success rate. In this paper, we propose one potential cause that may occur in the preclinical phase and has rarely been brought up before - the neglected target-mediated low plasma exposure, and the subsequent lead compound mis-selection due to conventional pharmacokinetic criteria requiring sufficient plasma exposure and desired half-life. To evaluate the concept of target-mediate low plasma exposure, we established a minimal physiologically-based pharmacokinetic (mPBPK) model to evaluate the concentration-time profiles of a group of virtual lead series analogs in plasma and in tissues with and without pharmacological target expression. Simulation results demonstrated that the candidate with the highest target binding has the lowest plasma exposure due to target-mediated tissue retention. The traditional PK criteria, such as the requirement of sufficient plasma exposure and desired half-life, may potentially result in lead compound mis-selection by discarding the appropriate and best candidate(s). The mPBPK model was partially validated using 4 tyrosine kinase inhibitors based on our in-house PK and tissue distribution data obtained in animals. The association rate constant (K_ass) was estimated to be 49.8 h^-1, 31.4 h^-1, 8.58 h^-1, and 1.91 h^-1 for afatinib, dasatinib, gefitinib, and sorafenib, respectively. Among these four model drugs, a strong correlation was observed between their K_ass values and AUC_{high-perfused tissue} /AUC_plasma ratios, a metric of tissue retention. Our mPBPK modeling and simulation results indicated that the concept of target-mediated low plasma exposure should be kept in mind during the lead compound selection process.