Population pharmacokinetic modeling and simulation to support qualification of pyridoxic acid as endogenous biomarker of OAT1/3 renal transporters

Abstract

Renal clearance of many drugs is mediated by renal organic anion transporters OAT1/3 and inhibition of these transporters may lead to drug-drug interactions (DDIs). Pyridoxic acid (PDA) and homovanillic acid (HVA) were indicated as potential biomarkers of OAT1/3. The objective of this study was to develop a population pharmacokinetic model for PDA and HVA to support biomarker qualification. Simultaneous fitting of biomarker plasma and urine data in the presence and absence of potent OAT1/3 inhibitor (probenecid, 500 mg every 6h) was performed. The impact of study design (multiple vs. single dose of OAT1/3 inhibitor) and ability to detect interactions in the presence of weak/moderate OAT1/3 inhibitors was investigated, together with corresponding power calculations. The population models developed successfully described biomarker baseline and PDA/HVA OAT1/3-mediated interaction data. No prominent effect of circadian rhythm on PDA and HVA individual baseline levels was evident. Renal elimination contributed >80% to total clearance of both endogenous biomarkers investigated. Estimated probenecid unbound in vivo OAT Ki was up to 6.4-fold lower than in vitro values obtained with PDA as a probe. The PDA model was successfully verified against independent literature-reported datasets. No significant difference in power of DDI detection was found between multiple and single dose study design when using the same total daily dose of 2000 mg probenecid. Model-based simulations and power calculations confirmed sensitivity and robustness of plasma PDA data to identify weak, moderate and strong OAT1/3 inhibitors in an adequately powered clinical study to support optimal design of prospective clinical OAT1/3 interaction studies.

Effect of Chronic Kidney Disease on the Renal Secretion via Organic Anion Transporters 1/3: Implications for Physiologically‐Based Pharmacokinetic Modeling and Dose Adjustment

“…29 The database also included 4-pyridoxic acid, proposed endogenous biomarker of OAT1/3-mediated DDI. 27,30 Considering complexities of CKD, this evaluation of disease-related changes in activity of OAT1/3 included substrates with representative range in plasma protein binding ( f u,p = 0.0026-1.0), extent of renal secretion and impact of CKD on plasma exposure (AUCR Severe-CKD = 1.64-11.62). Furthermore, analysis into the disease impact on active secretion accounted for observed CKD-associated changes in protein binding.…”

“…Seven drugs in the database are FDA recommended probes either for OAT1/3‐mediated clinical DDI evaluation (adefovir, ceftizoxime, famotidine, furosemide, ganciclovir, and oseltamivir carboxylate) or as in vitro OAT1/3 substrates (adefovir and tenofovir) 29 . The database also included 4‐pyridoxic acid, proposed endogenous biomarker of OAT1/3‐mediated DDI 27,30 . Considering complexities of CKD, this evaluation of disease‐related changes in activity of OAT1/3 included substrates with representative range in plasma protein binding ( f u,p = 0.0026–1.0), extent of renal secretion and impact of CKD on plasma exposure (AUCR Severe‐CKD = 1.64–11.62).…”

Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

“…The selectivity of PDA and homovanillic acid as OAT1 and OAT3 biomarkers in human was confirmed by assessing substrate potential of the compounds towards major renal and hepatic transporters 182 , 184 . A human popPK model has been developed, and the analysis supports qualification of PDA as endogenous biomarkers of OAT1 and OAT3 185 .…”

Effects and Mechanisms of Traditional Chinese Medicine and Related Active Constituents Treating Gout

“…Additionally, uric acid excretion is regulated by the kidneys and intestines, particularly through glomerular filtration, as well as active and passive reabsorption at the beginning and straight segments of the proximal tubule. Many transporters are involved in the filtration and reabsorption processes, namely, URAT1; GLUT9; OAT1, OAT2, and OAT3; and secretion transporter ABCG2 [17][18][19][20][21][22]. The expression and dysfunction of these transporters affect uric acid excretion.…”