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

Hsu V, de L T Vieira M, Zhao P, Zhang L, Zheng JH, Nordmark A, Berglund EG, Giacomini KM, Huang SM - Clin Pharmacokinet (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

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.

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.

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.

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Evaluation of the effects of theoretical changes in the number of proximal tubular cells per gram kidney (PTCPGK) on plasma exposure changes (AUCR, severe renal impairment versus normal renal function) in severe renal impairment. The dashed lines represent the simulated AUCR, and the solid lines ± shade represent observed the mean ± SD AUCR. The tested PTCPGK values ranged from 0.1 to 60 million proximal tubular cells per gram of kidney. a Oseltamivir carboxylate: 100 mg oral multiple dose (single dose on day 1, twice daily on days 2–5, single dose on day 6) in subjects with severe renal impairment and healthy subjects [7]. b Cidofovir: 0.5 mg/kg intravenous infusion over 1 h in subjects with severe renal impairment and healthy subjects [9, 30] (note: in both simulated and observed studies, cidofovir was co-administered with oral probenecid to reduce nephrotoxicity). c Cefuroxime: 750 mg intravenous bolus dose over 2 min in subjects with severe renal impairment and healthy subjects [8]
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Fig2: Evaluation of the effects of theoretical changes in the number of proximal tubular cells per gram kidney (PTCPGK) on plasma exposure changes (AUCR, severe renal impairment versus normal renal function) in severe renal impairment. The dashed lines represent the simulated AUCR, and the solid lines ± shade represent observed the mean ± SD AUCR. The tested PTCPGK values ranged from 0.1 to 60 million proximal tubular cells per gram of kidney. a Oseltamivir carboxylate: 100 mg oral multiple dose (single dose on day 1, twice daily on days 2–5, single dose on day 6) in subjects with severe renal impairment and healthy subjects [7]. b Cidofovir: 0.5 mg/kg intravenous infusion over 1 h in subjects with severe renal impairment and healthy subjects [9, 30] (note: in both simulated and observed studies, cidofovir was co-administered with oral probenecid to reduce nephrotoxicity). c Cefuroxime: 750 mg intravenous bolus dose over 2 min in subjects with severe renal impairment and healthy subjects [8]

Mentions: Initially, when the PBPK drug models only considered GFR changes in subjects with severe renal impairment (CLCR <30 mL/min, software ‘RenalGFR_less_30’ population), the plasma AUCRRI/Normal values were only predicted to be 3 to 5.5-fold, considerably lower than mean AUCR values of 7.5, 9.8 and 13-fold observed for cidofovir, cefuroxime and oseltamivir carboxylate, respectively. In order to reflect the effect of severe renal impairment on active transport processes, a sensitivity analysis of PTCPGK, a system-dependent parameter, was performed in subjects with severe renal impairment. The predicted AUCRRI/Normal values for each compound were plotted against PTCPGK values ranging from 0.1 × 106 to the default 60 million PTCPGK [1] and compared with the observed AUCR values (Fig. 2).Fig. 2


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

Hsu V, de L T Vieira M, Zhao P, Zhang L, Zheng JH, Nordmark A, Berglund EG, Giacomini KM, Huang SM - Clin Pharmacokinet (2014)

Evaluation of the effects of theoretical changes in the number of proximal tubular cells per gram kidney (PTCPGK) on plasma exposure changes (AUCR, severe renal impairment versus normal renal function) in severe renal impairment. The dashed lines represent the simulated AUCR, and the solid lines ± shade represent observed the mean ± SD AUCR. The tested PTCPGK values ranged from 0.1 to 60 million proximal tubular cells per gram of kidney. a Oseltamivir carboxylate: 100 mg oral multiple dose (single dose on day 1, twice daily on days 2–5, single dose on day 6) in subjects with severe renal impairment and healthy subjects [7]. b Cidofovir: 0.5 mg/kg intravenous infusion over 1 h in subjects with severe renal impairment and healthy subjects [9, 30] (note: in both simulated and observed studies, cidofovir was co-administered with oral probenecid to reduce nephrotoxicity). c Cefuroxime: 750 mg intravenous bolus dose over 2 min in subjects with severe renal impairment and healthy subjects [8]
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3927056&req=5

Fig2: Evaluation of the effects of theoretical changes in the number of proximal tubular cells per gram kidney (PTCPGK) on plasma exposure changes (AUCR, severe renal impairment versus normal renal function) in severe renal impairment. The dashed lines represent the simulated AUCR, and the solid lines ± shade represent observed the mean ± SD AUCR. The tested PTCPGK values ranged from 0.1 to 60 million proximal tubular cells per gram of kidney. a Oseltamivir carboxylate: 100 mg oral multiple dose (single dose on day 1, twice daily on days 2–5, single dose on day 6) in subjects with severe renal impairment and healthy subjects [7]. b Cidofovir: 0.5 mg/kg intravenous infusion over 1 h in subjects with severe renal impairment and healthy subjects [9, 30] (note: in both simulated and observed studies, cidofovir was co-administered with oral probenecid to reduce nephrotoxicity). c Cefuroxime: 750 mg intravenous bolus dose over 2 min in subjects with severe renal impairment and healthy subjects [8]
Mentions: Initially, when the PBPK drug models only considered GFR changes in subjects with severe renal impairment (CLCR <30 mL/min, software ‘RenalGFR_less_30’ population), the plasma AUCRRI/Normal values were only predicted to be 3 to 5.5-fold, considerably lower than mean AUCR values of 7.5, 9.8 and 13-fold observed for cidofovir, cefuroxime and oseltamivir carboxylate, respectively. In order to reflect the effect of severe renal impairment on active transport processes, a sensitivity analysis of PTCPGK, a system-dependent parameter, was performed in subjects with severe renal impairment. The predicted AUCRRI/Normal values for each compound were plotted against PTCPGK values ranging from 0.1 × 106 to the default 60 million PTCPGK [1] and compared with the observed AUCR values (Fig. 2).Fig. 2

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

ABSTRACT

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.

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.

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.

Show MeSH
Related in: MedlinePlus