Towards Quantitation of the Effects of Renal Impairment and Probenecid Inhibition on Kidney Uptake and Efflux Transporters, Using Physiologically Based Pharmacokinetic Modelling and Simulations

Abstract

Background and ObjectivesThe kidney is a major drug-eliminating organ. Renal impairment or concomitant use of transporter inhibitors may decrease active secretion and increase exposure to a drug that is a substrate of kidney secretory transporters. However, prediction of the effects of patient factors on kidney transporters remains challenging because of the multiplicity of transporters and the lack of understanding of their abundance and specificity. The objective of this study was to use physiologically based pharmacokinetic (PBPK) modelling to evaluate the effects of patient factors on kidney transporters.MethodsModels for three renally cleared drugs (oseltamivir carboxylate, cidofovir and cefuroxime) were developed using a general PBPK platform, with the contributions of net basolateral uptake transport (Tup,b) and apical efflux transport (Teff,a) being specifically defined.Results and ConclusionWe demonstrated the practical use of PBPK models to: (1) define transporter-mediated renal secretion, using plasma and urine data; (2) inform a change in the system-dependent parameter (≥10-fold reduction in the functional ‘proximal tubule cells per gram kidney’) in severe renal impairment that is responsible for the decreased secretory transport activities of test drugs; (3) derive an in vivo, plasma unbound inhibition constant of Tup,b by probenecid (≤1 μM), based on observed drug interaction data; and (4) suggest a plausible mechanism of probenecid preferentially inhibiting Tup,b in order to alleviate cidofovir-induced nephrotoxicity.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-013-0117-y) contains supplementary material, which is available to authorized users.

Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation

“…Recent studies have reported static models (54,55) and a PBPK kidney model (14) for prediction of transporter mediated renal DDIs. By using the same transporter kinetics parameters as those reported for the PBPK models (18,39,40), area under the curve (AUC) ratios for renal transporter DDIs with five victim drugs were predicted well using the static model (54) (Fig. 3).…”

“…Studies reported to-date using PBPK models have mostly been limited to investigating impact of changes in GFR and plasma protein binding in renally impaired patients on the CL R (39,40,62). However, CL R may reduce linearly with GFR for many drugs, even when secretion or reabsorption contributes, in accordance with the intact nephron hypothesis (63,64).…”

“…abundances in human kidney and in vitro systems) are lacking, and therefore the proposed IVIVE approach is not currently feasible (1). Instead, empirical optimisation of transporter activities or REF/RAF parameters using clinical data has been applied to adequately describe clinically observed CL R (18,19,39) (Table I). In some instances, as illustrated in the case of veliparib, REF scaling was not necessary for successful IVIVE of CL R (40).…”

“…Full references are listed in the supplementary material concentrations for apical uptake transporters. Therefore in cases where there is simultaneous inhibition (or induction) of both uptake and efflux transporter (18,39,40), or renally formed metabolites are perpetrators (as proposed for DDI between non-steroidal anti-inflammatory drugs and methotrexate (57)), the PBPK approach would be favoured for DDI assessment.…”

“…diabetes mellitus, acute kidney disease, augmented renal clearance in critically ill, chronic kidney disease) to be investigated and better understood. Regulatory bodies appear open to the prospect of using of PBPK models for prediction of the effect of renal impairment and consideration of any dosage adjustment in this patient population (39,60).…”