The effect of mild to moderate renal impairment on the pharmacokinetics of the nucleoside analog hepatitis C virus polymerase inhibitor mericitabine

Joshua Haznedar, Sebastian Moreira, Thomas Marbury, Richard Robson, William Smith, Rohit Kulkarni, Marie L. Munson, James A. Thommes, Annabelle Lemenuel-Diot, Carla Washington, Patrick Smith, Ya Chi Chen

Research output: Contribution to journalArticle

Abstract

Clinical Development Phases I-III Regulatory, Quality, Manufacturing Mericitabine is the prodrug of RO4995855, a selective inhibitor of the hepatitis C virus (HCV) NS5B polymerase. This study assessed the effect of renal impairment on RO4995855 pharmacokinetics. In this open-label study, HCV-negative volunteers (18-75 years) with normal renal function (NRF: creatinine clearance [CLCR] >80?mL/min, n?=?10) or stable renal impairment (mild: CLCR 50-80?mL/min, n?=?10; moderate: CLCR 30-49?mL/min, n?=?10) received oral mericitabine 1000?mg twice daily (BID) (500?mg BID for moderate renal impairment) for 5 days. Primary outcome measures were renal clearance, maximum plasma concentration (Cmax), and area under the concentration-time curve (0-12?h) (AUC0-12) for RO4995855. Renal clearance decreased as renal function decreased. Relative to subjects with NRF, the geometric mean ratios (GMR) for AUC0-12 and Cmax in mild renal impairment subjects were 1.45 (90% confidence interval [CI], 1.26-1.66) and 1.14 (1.02-1.28), respectively. For moderate renal impairment subjects, the dose-normalized GMR for AUC0-12 and Cmax relative to NRF subjects were 2.51 (90% CI, 2.19-2.88) and 1.76 (1.56-1.97), respectively. Renal clearance of RO4995855 declined in subjects with mild/moderate renal impairment following mericitabine. Dose adjustment of mericitabine may be required in patients with moderate renal impairment.

Original languageEnglish (US)
Pages (from-to)107-113
Number of pages7
JournalDrug Development Research
Volume75
Issue number2
DOIs
StatePublished - Jan 1 2014

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2'-fluoro-2'-methyl-3',5'-diisobutyryldeoxycytidine
Nucleosides
Hepacivirus
Pharmacokinetics
Kidney
Confidence Intervals

All Science Journal Classification (ASJC) codes

  • Drug Discovery

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The effect of mild to moderate renal impairment on the pharmacokinetics of the nucleoside analog hepatitis C virus polymerase inhibitor mericitabine. / Haznedar, Joshua; Moreira, Sebastian; Marbury, Thomas; Robson, Richard; Smith, William; Kulkarni, Rohit; Munson, Marie L.; Thommes, James A.; Lemenuel-Diot, Annabelle; Washington, Carla; Smith, Patrick; Chen, Ya Chi.

In: Drug Development Research, Vol. 75, No. 2, 01.01.2014, p. 107-113.

Research output: Contribution to journalArticle

Haznedar, J, Moreira, S, Marbury, T, Robson, R, Smith, W, Kulkarni, R, Munson, ML, Thommes, JA, Lemenuel-Diot, A, Washington, C, Smith, P & Chen, YC 2014, 'The effect of mild to moderate renal impairment on the pharmacokinetics of the nucleoside analog hepatitis C virus polymerase inhibitor mericitabine', Drug Development Research, vol. 75, no. 2, pp. 107-113. https://doi.org/10.1002/ddr.21166
Haznedar, Joshua ; Moreira, Sebastian ; Marbury, Thomas ; Robson, Richard ; Smith, William ; Kulkarni, Rohit ; Munson, Marie L. ; Thommes, James A. ; Lemenuel-Diot, Annabelle ; Washington, Carla ; Smith, Patrick ; Chen, Ya Chi. / The effect of mild to moderate renal impairment on the pharmacokinetics of the nucleoside analog hepatitis C virus polymerase inhibitor mericitabine. In: Drug Development Research. 2014 ; Vol. 75, No. 2. pp. 107-113.
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abstract = "Clinical Development Phases I-III Regulatory, Quality, Manufacturing Mericitabine is the prodrug of RO4995855, a selective inhibitor of the hepatitis C virus (HCV) NS5B polymerase. This study assessed the effect of renal impairment on RO4995855 pharmacokinetics. In this open-label study, HCV-negative volunteers (18-75 years) with normal renal function (NRF: creatinine clearance [CLCR] >80?mL/min, n?=?10) or stable renal impairment (mild: CLCR 50-80?mL/min, n?=?10; moderate: CLCR 30-49?mL/min, n?=?10) received oral mericitabine 1000?mg twice daily (BID) (500?mg BID for moderate renal impairment) for 5 days. Primary outcome measures were renal clearance, maximum plasma concentration (Cmax), and area under the concentration-time curve (0-12?h) (AUC0-12) for RO4995855. Renal clearance decreased as renal function decreased. Relative to subjects with NRF, the geometric mean ratios (GMR) for AUC0-12 and Cmax in mild renal impairment subjects were 1.45 (90{\%} confidence interval [CI], 1.26-1.66) and 1.14 (1.02-1.28), respectively. For moderate renal impairment subjects, the dose-normalized GMR for AUC0-12 and Cmax relative to NRF subjects were 2.51 (90{\%} CI, 2.19-2.88) and 1.76 (1.56-1.97), respectively. Renal clearance of RO4995855 declined in subjects with mild/moderate renal impairment following mericitabine. Dose adjustment of mericitabine may be required in patients with moderate renal impairment.",
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AU - Robson, Richard

AU - Smith, William

AU - Kulkarni, Rohit

AU - Munson, Marie L.

AU - Thommes, James A.

AU - Lemenuel-Diot, Annabelle

AU - Washington, Carla

AU - Smith, Patrick

AU - Chen, Ya Chi

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N2 - Clinical Development Phases I-III Regulatory, Quality, Manufacturing Mericitabine is the prodrug of RO4995855, a selective inhibitor of the hepatitis C virus (HCV) NS5B polymerase. This study assessed the effect of renal impairment on RO4995855 pharmacokinetics. In this open-label study, HCV-negative volunteers (18-75 years) with normal renal function (NRF: creatinine clearance [CLCR] >80?mL/min, n?=?10) or stable renal impairment (mild: CLCR 50-80?mL/min, n?=?10; moderate: CLCR 30-49?mL/min, n?=?10) received oral mericitabine 1000?mg twice daily (BID) (500?mg BID for moderate renal impairment) for 5 days. Primary outcome measures were renal clearance, maximum plasma concentration (Cmax), and area under the concentration-time curve (0-12?h) (AUC0-12) for RO4995855. Renal clearance decreased as renal function decreased. Relative to subjects with NRF, the geometric mean ratios (GMR) for AUC0-12 and Cmax in mild renal impairment subjects were 1.45 (90% confidence interval [CI], 1.26-1.66) and 1.14 (1.02-1.28), respectively. For moderate renal impairment subjects, the dose-normalized GMR for AUC0-12 and Cmax relative to NRF subjects were 2.51 (90% CI, 2.19-2.88) and 1.76 (1.56-1.97), respectively. Renal clearance of RO4995855 declined in subjects with mild/moderate renal impairment following mericitabine. Dose adjustment of mericitabine may be required in patients with moderate renal impairment.

AB - Clinical Development Phases I-III Regulatory, Quality, Manufacturing Mericitabine is the prodrug of RO4995855, a selective inhibitor of the hepatitis C virus (HCV) NS5B polymerase. This study assessed the effect of renal impairment on RO4995855 pharmacokinetics. In this open-label study, HCV-negative volunteers (18-75 years) with normal renal function (NRF: creatinine clearance [CLCR] >80?mL/min, n?=?10) or stable renal impairment (mild: CLCR 50-80?mL/min, n?=?10; moderate: CLCR 30-49?mL/min, n?=?10) received oral mericitabine 1000?mg twice daily (BID) (500?mg BID for moderate renal impairment) for 5 days. Primary outcome measures were renal clearance, maximum plasma concentration (Cmax), and area under the concentration-time curve (0-12?h) (AUC0-12) for RO4995855. Renal clearance decreased as renal function decreased. Relative to subjects with NRF, the geometric mean ratios (GMR) for AUC0-12 and Cmax in mild renal impairment subjects were 1.45 (90% confidence interval [CI], 1.26-1.66) and 1.14 (1.02-1.28), respectively. For moderate renal impairment subjects, the dose-normalized GMR for AUC0-12 and Cmax relative to NRF subjects were 2.51 (90% CI, 2.19-2.88) and 1.76 (1.56-1.97), respectively. Renal clearance of RO4995855 declined in subjects with mild/moderate renal impairment following mericitabine. Dose adjustment of mericitabine may be required in patients with moderate renal impairment.

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