Towards Quantitation of the Effects of Renal Impairment and Probenecid Inhibition on Kidney Uptake and Efflux Transporters, Using Physiologically Based Pharmacokinetic Modelling and Simulations
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 (T up,b) and apical efflux transport (T eff,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 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.
- 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).
- Varma MV, Feng B, Obach RS, Troutman MD, Chupka J, Miller HR, El-Kattan A. Physicochemical determinants of human renal clearance. J Med Chem. 2009;52:4844–52. CrossRef
- Rodgers T, Leahy D, Rowland M. Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. J Pharm Sci. 2005;94:1259–76. CrossRef
- Rodgers T, Rowland M. Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. J Pharm Sci. 2006;95:1238–57. CrossRef
- 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. CrossRef
- Rowland Yeo K, Aarabi M, Jamei M, Rostami-Hodjegan A. Modeling and predicting drug pharmacokinetics in patients with renal impairment. Expert Rev Clin Pharmacol. 2011;4:261–74. CrossRef
- 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.
- Bundtzen RW, Toothaker RD, Nielson OS, Madsen PO, Welling PG, Craig WA. Pharmacokinetics of cefuroxime in normal and impaired renal function: comparison of high-pressure liquid chromatography and microbiological assays. Antimicrob Agents Chemother. 1981;19:443–9. CrossRef
- Cundy KC. Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir. Clin Pharmacokinet. 1999;36:127–43. CrossRef
- 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. CrossRef
- Cutler MJ, Urguhart BL, Velenosi TJ, Meyer zu Schwabedissen HE, Dresser GK, Leake BF, Tirona RG, Kim RB, Freeman DJ. In vitro and in vivo assessment of renal drug transporters in the disposition of mesna and dimesna. J Clin Pharmacol. 2012;52:530–42. CrossRef
- 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. CrossRef
- Cidofovir (US label); 2013. http://www.accessdata.fda.gov/drugsatfda_docs/label/1999/020638s003lbl.pdf.
- 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.
- Stuart & Ord. Kendall’s advanced theory of statistics, 6th ed. London: Arnold; 1998.
- 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.
- Bohle A, Christ H, Grund KE, Mackensen S. The role of the interstitium of the renal cortex in renal disease. Contrib Nephrol. 1979;16:109–14.
- Dixon RJ, Young K, Brunskill NJ. Lysophosphatidic acid-induced calcium mobilization and proliferation in kidney proximal tubular cells. Am J Physiol. 1999;276:F191–8.
- Burton C, Harris KP. The role of proteinuria in the progression of chronic renal failure. Am J Kidney Dis. 1996;27:765–75. CrossRef
- Eddy AA. Interstitial nephritis induced by protein-overload proteinuria. Am J Pathol. 1989;135:719–33.
- Eddy AA, Giachelli CM. Renal expression of genes that promote interstitial inflammation and fibrosis in rats with protein-overload proteinuria. Kidney Int. 1995;47:1546–57. CrossRef
- Thomas ME, Schreiner GF. Contribution of proteinuria to progressive renal injury: consequences of tubular uptake of fatty acid bearing albumin. Am J Nephrol. 1993;13:385–98. CrossRef
- Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int. 2006;69:213–7. CrossRef
- Villar SR, Brandoni A, Anzai N, Endou H, Torres AM. Altered expression of rat renal cortical OAT1 and OAT3 in response to bilateral ureteral obstruction. Kidney Int. 2005;68:2704–13. CrossRef
- 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.
- Takeda M, Narikawa S, Hosoyamada M, Cha SH, Sekine T, Endou H. Characterization of organic anion transport inhibitors using cells stably expressing human anion transporters. Eur J Pharmacol. 2001;419:113–20. CrossRef
- Parrott N, Davies B, Hoffman G, Koerner A, Lave T, Prinssen E, Theogaraj E, Singer T. Development of a physiologically based model for oseltamivir and simulation of pharmacokinetics in neonates and infants. Clin Pharmacokinet. 2011;50:613–23. CrossRef
- Foord RD. Cefuroxime: human pharmacokinetics. Antimicrob Agents Chemother. 1976;9:741–7. CrossRef
- 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.
- Brody SR, Humphreys MH, Gambertoglio JG, Schoenfeld P, Cundy KC, Aweeka FT. Pharmacokinetics of cidofovir in renal insufficiency and in continuous ambulatory peritoneal dialysis or high-flux hemodialysis. Clin Pharmacol Ther. 1999;65:21–8.
- Garton AM, Rennie RP, Gilpin J, Marrelli M, Shafran SD. Comparison of dose doubling with probenecid for sustaining serum cefuroxime levels. J Antimicrob Chemother. 1997;40:903–6. CrossRef
- 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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- 1. 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
- 2. College of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- 3. Swedish Medical Products Agency, Uppsala, Sweden
- 4. Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California San Francisco, San Francisco, CA, USA