Towards Quantitation of the Effects of Renal Impairment and Probenecid Inhibition on Kidney Uptake and Efflux Transporters, Using Physiologically Based Pharmacokinetic Modelling and Simulations
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Background and Objectives
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.
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 (Tup,b) and apical efflux transport (Teff,a) being specifically defined.
Results and Conclusion
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 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.
KeywordsRenal Impairment Cefuroxime Probenecid PBPK Modelling Severe Renal Impairment
Area under the concentration–time curve
Blood to plasma partition ratio
Transporter-mediated intrinsic clearance
In vivo clearance
Passive diffusion clearance
Renal clearance mediated by a transporter
Fraction available from dosage form
Fraction unbound in plasma
Glomerular filtration rate
Plasma unbound inhibitor concentration
First-order absorption rate constant
Reversible inhibition constant
Tissue-to-plasma partition coefficient
Organic anion transporter
Physiologically based pharmacokinetic modelling
Proximal tubular cells per gram kidney
Efflux transporter on apical membrane
Uptake transporter on basolateral membrane
Volume of distribution at steady state
The authors gratefully acknowledge Professor Amin Rostami-Hodjegan (from the University of Manchester, Manchester, UK) and Drs Sibylle Neuhoff and Masoud Jamei (from Simcyp Ltd, Sheffield, UK) for their scientific input. This research was supported by the US Food and Drug Administration’s (FDA’s) Medical Countermeasures initiative. Dr Vicky Hsu was supported in part by an appointment to the Research Participation Program at the Center for Drug Evaluation and Research, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the FDA. No official support or endorsement by the FDA or the Medical Products Agency is intended or should be inferred.
Conflicts of Interest
The authors have declared no conflict of interest.
Vicky Hsu, Manuela de L. T. Vieira and Ping Zhao designed the research, performed the research, analysed the data, contributed new reagents/analytical tools and participated in the writing of the manuscript. Lei Zhang, Jenny Huimin Zheng, Anna Nordmark, Eva Gil Berglund, Kathleen M. Giacomini and Shiew-Mei Huang analysed the data and participated in the writing of the manuscript. All authors read and approved the final manuscript.
- 1.Neuhoff S, Gaohua L, Burt H, Jamei M, Li L, Tucker GT, Rostami-Hodjegan A. Accounting for transporters in renal clearance: towards a mechanistic kidney model (Mech KiM). In: Steffanson B, Sugiyama Y, editors. Transporters in drug discovery, development, and use. New York: Springer; 2013 (in press).CrossRefGoogle Scholar
- 5.Jamei M, Dickinson GL, Rostami-Hodjegan A. A framework for assessing inter-individual variability in pharmacokinetics using virtual human populations and integrating general knowledge of physical chemistry, biology, anatomy, physiology and genetics: a tale of ‘bottom-up’ vs ‘top-down’ recognition of covariates. Drug Metab Pharmacokinet. 2009;24:53–75.CrossRefGoogle Scholar
- 7.Multiple ascending oral dose study of the pharmacokinetics, tolerability, and safety of the neuraminidase inhibitor Ro 64-0796 in subjects with renal impairment. Clinical Pharmacology and Biopharmaceutics Review from Drugs@FDA; 1999.Google Scholar
- 10.Chu XY, Bleasby K, Yabut J, Cai X, Chan GH, Hafey MJ, Xu S, Bergman AJ, Braun MP, Dean DC, Evers R. Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein. J Pharmacol Exp Ther. 2007;321:673–83.CrossRefGoogle Scholar
- 12.Hill G, Cihlar T, Oo C, Ho ES, Prior K, Wiltshire H, Barrett J, Liu B, Ward P. The anti-influenza drug oseltamivir exhibits low potential to induce pharmacokinetic drug interactions via renal secretion-correlation of in vivo and in vitro studies. Drug Metab Dispos. 2002;30:13–9.CrossRefGoogle Scholar
- 13.Cidofovir (US label); 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/1999/020638s003lbl.pdf.
- 14.Cidofovir (EMA summary for the public); 2013. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/000121/WC500052073.pdf.
- 15.Stuart & Ord. Kendall’s advanced theory of statistics, 6th ed. London: Arnold; 1998.Google Scholar
- 16.Zhao P, Vieira Mde L, Grillo JA, Song P, Wu TC, Zheng JH, Arya V, Berglund EG, Atkinson Jr AJ, Sugiyama Y, Pang KS, Reynolds KS, Abernethy DR, Zhang L, Lesko LJ, Huang SM. Evaluation of exposure change of nonrenally eliminated drugs in patients with chronic kidney disease using physiologically based pharmacokinetic modeling and simulation. J Clin Pharmacol. 2012;52:91S–108S.CrossRefGoogle Scholar
- 25.Hashimoto T, Narikawa S, Huang XL, Minematsu T, Usui T, Kamimura H, Endou H. Characterization of the renal tubular transport of zonampanel, a novel alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist, by human organic anion transporters. Drug Metab Dispos. 2004;32:1096–102.PubMedGoogle Scholar
- 29.Study of the pharmacokinetics and absolute bioavailability of the neuraminidase inhibitor Ro 64-0796/Ro 64-0802 (Protocol NP15719). Clinical Pharmacology and Biopharmaceutics Review from Drugs@FDA; 1999.Google Scholar
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