Serum and Cellular Ribavirin Pharmacokinetic and Concentration-effect Analysis in HCV Patients Receiving Sofosbuvir Plus Ribavirin

Overview

Journal J Antimicrob Chemother

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2015 May 15

PMID 25971261

Citations 9

Authors

Joseph E Rower

Eric G Meissner

Leah C Jimmerson

Anu Osinusi

Zayani Sims

Tess Petersen

Lane R Bushman

Pamela Wolfe

John G McHutchison

Shyamasundaran Kottilil

Jennifer J Kiser

Affiliations

Soon will be listed here.

Abstract

Objectives: Ribavirin concentrations may impact hepatitis C virus (HCV) treatment outcome. We modelled ribavirin serum and intracellular ribavirin monophosphate (RBV-MP) and ribavirin triphosphate (RBV-TP) pharmacokinetics in red blood cells (RBC) using samples collected during the NIAID SPARE trial to explore associations with treatment outcome and the development of anaemia.

Patients And Methods: Individuals infected with HCV genotype 1 (GT1) received 400 mg of sofosbuvir and either low-dose or weight-based ribavirin as part of the NIAID SPARE trial. Concentrations were modelled using NONMEM and associated with treatment outcomes using unpaired t-tests or Pearson's rho correlations.

Results: Average day 14 RBV-MP concentrations were higher in subjects with haemoglobin nadir <10 g/dL relative to patients with haemoglobin nadir ≥10 g/dL (6.54 versus 4.48 pmol/10(6) cells; P = 0.02). Additionally, day 14 RBV-MP average concentrations trended towards being higher in subjects that achieved sustained virological response (SVR) as compared with patients who relapsed (4.97 versus 4.09 pmol/10(6) cells; P = 0.07). Receiver operating characteristic curves suggested day 14 RBV-MP concentration thresholds of 4.4 pmol/10(6) cells for SVR (P = 0.06) and 6.1 pmol/10(6) cells for haemoglobin nadir <10 versus ≥10 g/dL (P = 0.02), with sensitivity and specificity ≥60%. Dosing simulations showed that 800 mg of ribavirin once daily produced day 14 RBV-MP concentrations within the 4.4-6.1 pmol/10(6) cells range.

Conclusions: RBV-MP concentrations in RBC at day 14 were related to anaemia and SVR. A therapeutic range was identified for RBV-MP in persons with HCV GT1 disease receiving 24 weeks of sofosbuvir plus ribavirin, suggesting a potential pharmacological basis for individualized ribavirin dosing in IFN-free regimens.

Citing Articles

Effects of sofosbuvir-based hepatitis C treatment on the pharmacokinetics of tenofovir in HIV/HCV-coinfected individuals receiving tenofovir disoproxil fumarate.

MacBrayne C, Marks K, Fierer D, Naggie S, Chung R, Hughes M J Antimicrob Chemother. 2018; 73(8):2112-2119.

PMID: 29746648 PMC: 6054189. DOI: 10.1093/jac/dky146.

Sofosbuvir and Ribavirin Liver Pharmacokinetics in Patients Infected with Hepatitis C Virus.

Babusis D, Curry M, Kirby B, Park Y, Murakami E, Wang T Antimicrob Agents Chemother. 2018; 62(5).

PMID: 29439971 PMC: 5923114. DOI: 10.1128/AAC.02587-17.

Liver decompensation predicts ribavirin overexposure in hepatitis C virus patients treated with direct-acting antivirals.

Guardigni V, Badia L, Conti M, Rinaldi M, Mancini R, Viale P World J Hepatol. 2018; 9(34):1270-1277.

PMID: 29290908 PMC: 5740096. DOI: 10.4254/wjh.v9.i34.1270.

Sofosbuvir Plus Ribavirin Without Interferon for Treatment of Acute Hepatitis C Virus Infection in HIV-1-Infected Individuals: SWIFT-C.

Naggie S, Marks K, Hughes M, Fierer D, MacBrayne C, Kim A Clin Infect Dis. 2017; 64(8):1035-1042.

PMID: 28329053 PMC: 5850409. DOI: 10.1093/cid/cix025.

ITPA polymorphism effects on decrease of hemoglobin during sofosbuvir and ribavirin combination treatment for chronic hepatitis C.

Morio K, Imamura M, Kawakami Y, Nakahara T, Nagaoki Y, Kawaoka T J Gastroenterol. 2016; 52(6):746-753.

PMID: 27822709 DOI: 10.1007/s00535-016-1279-9.

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