Towards quantitation of the effects of renal impairment and probenecid inhibition on kidney uptake and efflux transporters, using physiologically based pharmacokinetic modelling and simulations.
OBJECTIVE
The 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.


METHODS
Models 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 (T up,b) and apical efflux transport (T eff,a) being specifically defined.


CONCLUSIONS
We 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 T up,b by probenecid (≤1 μM), based on observed drug interaction data; and (4) suggest a plausible mechanism of probenecid preferentially inhibiting T up,b in order to alleviate cidofovir-induced nephrotoxicity.
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
Vicky
V
Hsu
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.|College of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Manuela
M
de L T Vieira
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA. ping.zhao@fda.hhs.gov.
Ping
P
Zhao
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
Lei
L
Zhang
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
Jenny Huimin
JH
Zheng
Swedish Medical Products Agency, Uppsala, Sweden.
Anna
A
Nordmark
Swedish Medical Products Agency, Uppsala, Sweden.
Eva Gil
EG
Berglund
Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, San Francisco, CA, USA.
Kathleen M
KM
Giacomini
Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993, USA.
Shiew-Mei
SM
Huang
D000818:Animals; D003198:Computer Simulation; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007674:Kidney Diseases / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D011339:Probenecid / Q000037:antagonists & inhibitors*; D012076:Renal Agents / Q000037:antagonists & inhibitors*
D026901:Membrane Transport Proteins; D004364:Pharmaceutical Preparations; D012076:Renal Agents; D011339:Probenecid