TY - JOUR T1 - Mechanistic PBPK Modeling of Urine pH Effect on Renal and Systemic Disposition of Methamphetamine and Amphetamine JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.120.264994 SP - jpet.120.264994 AU - Weize Huang AU - Lindsay C Czuba AU - Nina Isoherranen Y1 - 2020/01/01 UR - http://jpet.aspetjournals.org/content/early/2020/03/20/jpet.120.264994.abstract N2 - The effect of urine pH on renal drug excretion and systemic drug disposition has been observed for many drugs. When urine pH is altered, tubular drug ionization, passive reabsorption, renal clearance, and systemic exposure may all change dramatically, raising clinically significant concerns. Surprisingly, the urine pH effect on drug disposition is not routinely explored in humans, and regulatory agencies have neither developed guidance on this issue nor required industry to conduct pertinent human trials. In this study, we hypothesized that PBPK modeling can be used as a cost-effective method to examine potential urine pH effect on drug and metabolite disposition. Our previously developed and verified mechanistic kidney model was integrated with a full body PBPK model to simulate renal clearance and systemic AUC with varying urine pH statuses, using methamphetamine and amphetamine as model compounds. We first developed and verified drug models for methamphetamine and amphetamine under normal urine pH condition (absolute-average-fold-error (AAFE) < 1.25 at study level). Then, acidic and alkaline urine scenarios were simulated. Our simulation results show that the renal excretion and plasma concentration-time profiles for methamphetamine and amphetamine could be recapitulated under different urine pH (AAFE < 2 at individual level). The methamphetamine-amphetamine parent-metabolite full body PBPK model also successfully simulated amphetamine plasma concentration-time profile (AAFE < 1.25 at study level) and amphetamine/methamphetamine urinary concentration ratio (AAFE < 2 at individual level) after dosing methamphetamine. This demonstrates that our mechanistic PBPK model can predict urine pH effect on systemic and urinary disposition of drugs and metabolites.SIGNIFICANCE STATEMENT Our study shows that integrating mechanistic kidney model with full body PBPK model can predict the magnitude of alteration in renal excretion and systemic AUC of drugs when urine pH is changed. This provides a cost-effective method to evaluate the likelihood of renal and systemic disposition changes due to varying urine pH. This is important as multiple drugs and diseases can alter urine pH, leading to quantitatively and clinically significant changes in drug and metabolite disposition that may require adjustment of therapy. ER -