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Variant Inosine Triphosphatase Phenotypes Are Associated With Increased Ribavirin Triphosphate Levels
Leah C Jimmerson1, Thomas J Urban2, Aimee Truesdale3
1Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado.
Journal of Clinical Pharmacology
|June 29, 2016
Summary
Lower inosine triphosphatase (ITPA) enzyme activity in patients treated for hepatitis C virus (HCV) with ribavirin (RBV) is linked to higher RBV triphosphate (RBV-TP) levels in red blood cells (RBCs). This contradicts the idea that lower RBV-TP protects against RBV-induced anemia.
Area of Science:
- Pharmacogenomics
- Hepatology
- Hematology
Background:
- Individuals with lower inosine triphosphatase (ITPA) enzyme activity show reduced risk of hemolytic anemia during hepatitis C virus (HCV) treatment with ribavirin (RBV).
- ITPA's role in purine degradation and RBV's nature as a purine analog suggest ITPA activity might influence intracellular RBV concentrations.
Purpose of the Study:
- To assess the association between ITPA activity phenotype and red blood cell (RBC) concentrations of RBV triphosphate (RBV-TP) during HCV treatment.
Main Methods:
- Quantified RBV-TP in RBCs of 177 HCV-infected individuals undergoing RBV-containing treatment.
- Categorized participants into ITPA activity groups: 100%, 60%, 30%, and ≤10%.
Main Results:
- RBV-TP concentrations were approximately 2-fold higher in patients with ≤30% ITPA activity compared to those with 100% activity (P < .0001).
- Despite higher RBV-TP levels, individuals with lower ITPA activity experienced significantly less hemoglobin drop, indicating less anemia.
- Mean hemoglobin drop was -2.20 g/dL for 100% ITPA activity vs. -0.70 g/dL for ≤10% activity (P = .06).
Conclusions:
- Higher RBV-TP concentrations in RBCs of ITPA variants were unexpectedly observed.
- This finding refutes the hypothesis that lower RBV-TP levels explain the reduced risk of RBV-induced anemia in ITPA activity-deficient individuals.
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