Ribavirin plasma concentration measurements in patients with hepatitis C: early ribavirin concentrations predict steady-state concentrations.

BACKGROUND: Ribavirin is an essential component in the treatment of chronic hepatitis C (HCV) infection. Although ribavirin dose is weight-based, data in the literature suggest large between-patient variability in plasma ribavirin concentrations. Recent studies indicate that higher ribavirin exposure results in higher sustained viral response rates. Monitoring ribavirin concentration is suggested in the literature, but it is unclear at what time point during treatment plasma ribavirin concentrations should be monitored. AIM: To investigate the association between early plasma ribavirin concentrations and ribavirin dosing with steady-state (Css) concentration and the between- and within-patient variability in plasma ribavirin concentration in clinical practice. METHODS: We performed a prospective observational cohort study in patients with HCV who received pegylated interferon in combination with oral weight-based ribavirin (12-15 mg/kg) twice daily. Trough plasma ribavirin concentrations at Weeks 1, 2, 4, 8, 12, 16, 20, and 24 were studied using a validated high-performance liquid chromatography assay. RESULTS: In total, 53 patients (37 male, 16 female) with a mean age of 51 years (range, 26-68 years) were included and 209 samples were collected. There was a significant correlation between Week 2 as well as Week 4 and plasma ribavirin Css (r = 0.589 and r = 0.714, P < 0.05, respectively). Ribavirin Css was reached at Week 8 of HCV treatment. There was no correlation between dose in mg/kg and Css (r = 0.181, P = 0.263). The between- and within-patient coefficients of variation of plasma ribavirin concentrations at Week 8 and beyond were 43% and 13%, respectively. CONCLUSION: In HCV-infected patients, ribavirin steady-state concentrations can be predicted by measurement of concentrations made early after the start of therapy.

The effect of raltegravir on the glucuronidation of lamotrigine.

The authors studied the effect of raltegravir on the pharmacokinetics of the antiepileptic agent lamotrigine. Twelve healthy volunteers (group A) received 400 mg raltegravir twice daily from days 1 to 5. On day 4, a single dose of 100 mg lamotrigine was administered. After a washout period, participants received a second single dose of 100 mg of lamotrigine but now without raltegravir (day 32). In group B, 12 participants received the same treatment as in group A but in reverse order. On days 4 and 32, 48-hour pharmacokinetic curves were drawn. Geometric mean ratios (+90% confidence intervals [CIs]) of lamotrigine area under the plasma concentration-time curve (AUC(0-->48)) and peak plasma concentration (C(max)) for raltegravir + lamotrigine versus lamotrigine alone were 0.99 (0.96-1.01) and 0.94 (0.89-0.99), respectively. The mean ratio of the AUC(0-->48) of lamotrigine-2N-glucuronide to lamotrigine was similar when lamotrigine was taken alone (0.35) or when taken with raltegravir (0.36). Raltegravir does not influence the glucuronidation of lamotrigine.

Interaction study of the combined use of paroxetine and fosamprenavir-ritonavir in healthy subjects.

Human immunodeficiency virus-infected patients have an increased risk for depression. Despite the high potential for drug-drug interactions, limited data on the combined use of antidepressants and antiretrovirals are available. Theoretically, ritonavir-boosted protease inhibitors may inhibit CYP2D6-mediated metabolism of paroxetine. We wanted to determine the effect of fosamprenavir-ritonavir on paroxetine pharmacokinetics and vice versa and to evaluate the safety of the combination. Group A started with 20 mg paroxetine every day for 10 days; after a wash-out period of 16 days, subjects received paroxetine (20 mg every day) plus fosamprenavir-ritonavir (700/100 mg twice a day) from days 28 to 37. Group B received the regimens in reverse order. On days 10 and 37, pharmacokinetic curves were recorded. Twenty-six healthy subjects (18 females, 8 males) were included. Median (range) age and weight were 44.4 (18.2 to 64.3) years and 68.8 (51.0 to 89.4) kg. Three subjects were excluded (two because of adverse events; one for nonadherence). Addition of fosamprenavir-ritonavir to paroxetine resulted in a significant decrease in paroxetine exposure: the geometric mean ratios (90% confidence intervals) of paroxetine plus fosamprenavir-ritonavir to paroxetine alone were 0.45 (0.41 to 0.49) for the area under the concentration-time curve from 0 to 24 h (AUC(0-24)), 0.49 (0.45 to 0.53) for the maximum concentration of the drug in plasma (C(max)), and 0.75 (0.71 to 0.80) for the apparent elimination half-life (t(1/2)). The free fraction of paroxetine showed a median (interquartile range) increase of 30% (18 to 42%) after the addition of fosamprenavir-ritonavir. The AUC(0-12), C(max), C(min), and t(1/2) of amprenavir and ritonavir were similar to those of historical controls. No serious adverse events occurred. Fosamprenavir-ritonavir reduced total paroxetine exposure by 55%. This is partly explained by protein displacement of paroxetine. We think that this interaction is clinically relevant and that titration to a higher dose of paroxetine may be necessary to accomplish the needed antidepressant effect.