Pharmacokinetic evaluation of the effects of ribavirin on zidovudine triphosphate formation: ACTG 5092s Study Team.
OBJECTIVE
Ribavirin (RBV) is used for the treatment of hepatitis C virus (HCV) infection in subjects with HIV-1 infection who may require antiretroviral treatment (ART) with nucleoside reverse transcriptase inhibitors including zidovudine (ZDV). We sought to investigate the potential antagonism between RBV and ZDV by evaluating the impact of RBV on the formation of intracellular ZDV triphosphate (TP) in HIV-infected patients receiving ZDV who were treated for HCV infection.


METHODS
Serial plasma and intracellular ZDV TP pharmacokinetics (PK) were determined in 14 subjects at entry (within 2 weeks prior to RBV administration) and at 8 weeks following initiation of RBV. Intracellular ZDV TP in peripheral blood mononuclear cells (PBMC) was quantified by a validated cartridge/liquid chromatography/tandem mass spectrometry method. PK exposure was estimated from the steady-state area under the concentration vs time curve (AUC(0-12 h)) in plasma and PBMC.


RESULTS
Ribavirin did not have a statistically significant impact on ZDV TP AUC(0-12 h), plasma ZDV AUC(0-12 h) or the ratio of ZDV TP AUC(0-12 h) to plasma ZDV AUC(0-12 h), although there was a trend towards an increase post-RBV ratio compared with pre-RBV. There was extensive variability in the ZDV TP AUC(0-12 h).


CONCLUSIONS
Ribavirin did not inhibit formation of ZDV TP in PBMC in 14 patients receiving ZDV as part of ART and RBV-based HCV therapy for 8 weeks. These results are consistent with those of a previously published limited study in seven subjects. These PK findings should be weighed carefully against emerging clinical reports of significant anaemia associated with combination ZDV and high-dose RBV therapy.
Aweeka
F T
FT
Drug Research Unit, University of California, San Francisco, CA 94143-0622, USA. faweeka@sfghsom.ucsf.edu
Kang
M
M
Yu
J-Y
JY
Lizak
P
P
Alston
B
B
Chung
R T
RT
D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects / Q000494:pharmacology; D019540:Area Under Curve; D004347:Drug Interactions; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D015497:HIV-1; D016174:Hepacivirus; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000378:metabolism* / Q000821:virology; D006801:Humans; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics; D012254:Ribavirin / Q000009:adverse effects / Q000494:pharmacology*; D015215:Zidovudine / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*
D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors; D012254:Ribavirin; D015215:Zidovudine