Effect of ribavirin on intracellular and plasma pharmacokinetics of nucleoside reverse transcriptase inhibitors in patients with human immunodeficiency virus-hepatitis C virus coinfection: results of a randomized clinical study.
The intracellular triphosphorylation and plasma pharmacokinetics of lamivudine (3TC), stavudine (d4T), and zidovudine (ZDV) were assessed in a pharmacokinetic substudy, in 56 human immunodeficiency virus-hepatitis C virus (HIV-HCV) coinfected patients receiving peginterferon alfa-2a (40KD) 180 microg/week plus either placebo or ribavirin (RBV) 800 mg/day in the AIDS PEGASYS Ribavirin International Coinfection Trial. There were no significant differences between patients treated with RBV and placebo in plasma pharmacokinetics parameters for the nucleoside reverse transcriptase inhibitors (NRTIs) at steady state (weeks 8 to 12): ratios of least squares mean of area under the plasma concentration-time curve (AUC(0-12 h)) were 1.17 (95% confidence interval, 0.91 to 1.51) for 3TC, 1.44 (95% confidence interval, 0.58 to 3.60) for d4T and 0.85 (95% confidence interval, 0.50 to 1.45) for ZDV, and ratios of least squares mean plasma C(max) were 1.33 (95% confidence interval, 0.99 to 1.78), 1.06 (95% confidence interval, 0.68 to 1.65), and 0.84 (95% confidence interval, 0.46 to 1.53), respectively. Concentrations of NRTI triphosphate (TP) metabolites in relation to those of the triphosphates of endogenous deoxythymidine-triphosphate (dTTP) and deoxcytidine-triphosphate (dCTP) were similar in the RBV and placebo groups. Differences (RBV to placebo) in least squares mean ratios of AUC(0-12 h) at steady state were 0.274 (95% confidence interval, -0.37 to 0.91) for 3TC-TP:dCTP, 0.009 (95% confidence interval, -0.06 to 0.08) for d4T-TP:dTTP, and -0.081 (95% confidence interval, -0.40 to 0.24) for ZDV-TP:dTTP. RBV did not adversely affect HIV-1 replication. In summary, RBV 800 mg/day administered in combination with peginterferon alfa-2a (40KD) does not significantly affect the intracellular phosphorylation or plasma pharmacokinetics of 3TC, d4T, and ZDV in HIV-HCV-coinfected patients.
Rodriguez-Torres
M
M
Fundacion de Investigación de Diego, Santurce, Puerto Rico. fdciondeinvest@aol.com
Torriani
F J
FJ
Soriano
V
V
Borucki
M J
MJ
Lissen
E
E
Sulkowski
M
M
Dieterich
D
D
Wang
K
K
Gries
J-M
JM
Hoggard
P G
PG
Back
D
D
D000328:Adult; D019540:Area Under Curve; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000150:complications* / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006526:Hepatitis C / Q000097:blood* / Q000150:complications / Q000188:drug therapy; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D019259:Lamivudine / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000493:pharmacokinetics; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018119:Stavudine / Q000097:blood / Q000493:pharmacokinetics; D013997:Time Factors; D015215:Zidovudine / Q000097:blood / Q000493:pharmacokinetics
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D011092:Polyethylene Glycols; D012254:Ribavirin; D015215:Zidovudine; D018119:Stavudine; C100416:peginterferon alfa-2a