Predicting contributions of hepatic and renal organic cation transporters to the clinical pharmacokinetic cimetidine-metformin interaction using a mechanistic PBPK model

Abstract ID 94434 Poster Board 442 Metformin, a widely prescribed oral anti-diabetic drug, is eliminated unchanged from the body via renal excretion¹. Organic cation transporter (OCT) 2, an uptake transporter expressed on the basolateral membrane of renal proximal tubule cells, plays a critical role in the renal secretion of metformin². In addition, metformin exposure in the liver, the site of action, is governed by OCT1-mediated uptake at the basolateral (sinusoidal) membrane of hepatocytes². A clinical pharmacokinetic drug-drug interaction study was conducted in 16 healthy adults (8M, 8F) who were orally administered metformin (50 mg) as a dual OCT1/2 substrate alone (baseline) and with cimetidine (400 mg) as a dual OCT1/2 inhibitor. Plasma and urine samples were collected and analyzed for metformin and cimetidine concentrations using a validated LC/MS/MS method. Relative to baseline, metformin area under the plasma concentration-time curve (AUC0-24h), maximum plasma concentration (Cmax), and amount excreted unchanged in the urine were significantly increased (p< 0.05) by 27%, 37%, and 17%, respectively, in the presence of cimetidine. A small but significant decrease in metformin renal clearance (CLR) (8%, p=0.005) also was observed. Based on the higher changes in metformin AUC0-24h and Cmax compared to CLR, we hypothesized that the cimetidine-metformin interaction involves inhibition of both hepatic OCT1 and renal OCT2. Accordingly, we developed a physiologically based pharmacokinetic (PBPK) model using the Simcyp™ PBPK Simulator (V 22.0) to gain mechanistic insight into this interaction. Metformin hepatic OCT1 intrinsic clearance and renal OCT2 intrinsic clearance were optimized to reproduce the clinical data. Likewise, Ki values for OCT1 and OCT2 were adjusted to render the model sensitive to cimetidine inhibition. OCT2-mediated uptake was considered rate-limiting by arbitrarily increasing the renal apical efflux clearance of metformin. Unlike the established PBPK model for metformin that was based on the "electrochemical model"³, our model was mechanistic and captured comparable changes in AUC0-24h, Cmax, and CLR. The reported metformin liver-to-plasma concentration ratio of 4.3-fold⁴ at baseline also was captured, indicating a role for hepatic OCT1. This mechanistic PBPK model suggests that both hepatic OCT1 and renal OCT2 are implicated in the pharmacokinetic cimetidine-metformin interaction. The model could be used to predict the effect of increasing cimetidine doses, other dual OCT1/2 inhibitors, and genetic polymorphisms of OCT1/2 on systemic and liver tissue concentrations of metformin. References: Markowicz-Piasecka et al., 2017. Curr. Pharm. Des. 23, 2532-2550. Liang and Giacomini, 2017. J. Pharm. Sci. 106, 2245-2250. Burt et al., 2016. Eur.J. Pharm. Sci. 88, 70-82. Song., 2016. Diabetes care. 39, 187-189. This project was funded by the NIH/NICHD (R01 HD081299) and NIH/NCCIH (U54 AT008909).