Development of 4‐Pyridoxic Acid PBPK Model to Support Biomarker‐Informed Evaluation of OAT1/3 Inhibition and Effect of Chronic Kidney Disease

Abstract

Monitoring endogenous biomarkers is increasingly used to evaluate transporter‐mediated drug‐drug interactions (DDIs) in early drug development and may be applied to elucidate changes in transporter activity in disease. 4‐pyridoxic acid (PDA) has been identified as the most sensitive plasma endogenous biomarker of renal organic anion transporters (OAT1/3). Increase in PDA baseline concentrations was observed after administration of probenecid, a strong clinical inhibitor of OAT1/3 and also in chronic kidney disease (CKD) patients. The aim of this study was to develop and verify a physiologically‐based pharmacokinetic (PBPK) model of PDA, to predict the magnitude of probenecid DDI and predict the CKD‐related changes in PDA baseline. PBPK model for PDA was first developed in healthy population, building on from previous population pharmacokinetic modelling, and incorporating a mechanistic kidney model to consider OAT1/3‐mediated renal secretion. Probenecid PBPK model was adapted from the Simcyp database and re‐verified to capture its dose‐dependent pharmacokinetics (n=9 studies). The PBPK model successfully predicted the PDA plasma concentrations, area under the curve and renal clearance in healthy subjects at baseline and after single/multiple probenecid doses. Prospective simulations in severe CKD predicted successfully the increase in PDA plasma concentration relative to healthy (within two‐fold of observed data) after accounting for 60% increase to fraction unbound in plasma and additional 50% decline in OAT1/3 activity beyond the decrease in glomerular filtration rate. The verified PDA PBPK model supports future robust evaluation of OAT1/3 DDI in drug development and increases our confidence in predicting exposure and renal secretion in CKD patients.

Utilising Endogenous Biomarkers in Drug Development to Streamline the Assessment of Drug–Drug Interactions Mediated by Renal Transporters: A Pharmaceutical Industry Perspective

“…The utility of NMN and creatinine as endogenous substrates for OCT2 and MATEs transporters was further evaluated in another DDI study by Müller et al, where metformin (10-mg and 500-mg doses) was administered with or without multiple doses of cimetidine, a strong OCT2 and MATE Table 2 In vitro and clinical studies investigating the effect of biomarkers on the renal drug transporters Adapted from Li et al [33] and Rodrigues [53] 6β-HC 6β-hydroxycortisol, AUC area under the plasma concentration-time curve, CL R renal clearance, HVA homovanillic acid, GCDCA-s glycochenodeoxycholic acid 3-O-sulphate, HEK human embryonic kidney, m 1 ↑AUC Pyrimethamine [21] ↓CL R NMN a OCT2, MATE1, MATE2-K HEK293 Yes [21,36] Trimethoprim [37] ↑AUC, ↓CL R Yes [34] Pyrimethamine [8,21,36] ↓CL R Dronedarone [40] ↓CL R PFE1, PFE2 [38] ↑AUC Abrocitinib [41] -Cimetidine [42] ↓CL R Bevurogant [43] -Creatinine a,b OCT2, MATE1, MATE2-K HEK293 Yes [21,35] Pyrimethamine [21,44] ↑AUC, ↓CL R Yes [45] Cimetidine [42] ↓CL R PDA a,b OAT1/OAT3 HEK293 Yes [29,46] Probenecid [17] ↑AUC, ↓CL R Yes [47,48] Pyrimethamine [21] ↑AUC, ↓CL R Probenecid 1000 mg [29] ↑AUC, ↓CL R HVA OAT1/OAT3 HEK293 Yes [29,46] Probenecid 500 mg qid [17] ↑AUC, ↓CL R Yes [47] Probenecid 1000 mg [29] ↑AUC, ↓CL R GCDCA-s a,b OAT3 HEK293 Yes [29] Probenecid [49] ↑AUC, ↓CL R Probenecid…”

“…In a similar way, PBPK models have been developed to evaluate endogenous biomarkers. Tan and colleagues developed a PBPK model of PDA in healthy volunteers, and then incorporated a mechanistic kidney model to consider OAT1/3-mediated renal secretion [ 48 ]. The model successfully predicted the PDA plasma concentrations, AUC and CL R in healthy volunteers (HVs) at baseline and following single or multiple doses of probenecid.…”