Atazanavir plasma concentrations are impaired in HIV-1-infected adults simultaneously taking a methadone oral solution in a once-daily observed therapy setting

Abstract

Objective The human immundeficiency virus (HIV) protease inhibitor atazanavir is often used in once-daily observed therapy of methadone substituted former opiate drug users. We performed a matched-pairs analysis on 24 patients (12 men/women) taking atazanavir/ritonavir 300/100 mg daily plus reverse transcriptase inhibitors, with (n=12) or without (n=12) methadone co-administration. Methods Twenty-four-hour pharmacokinetic profiles of atazanavir/ritonavir were assessed at steady-state and measured by liquid chromatography-tandem mass spectrometry. The geometric mean (GM, t test) minimum and maximum plasma drug concentrations (C min , C max ), area under the concentration-time curve (AUC), and total clearance (CL total ) were compared between the groups of pairs, which were matched for age, sex, weight, and ethnicity. Results The GM [90% confidence interval (CI)] of the atazanavir C min , C max , and AUC of patients taking the methadone oral solution at doses of 20-175 mg/day simultaneously with antiretroviral therapy were impaired compared to patients not taking methadone oral solution: C min =315 (range 197-448) vs. 519 (279-793) ng/mL [GM ratio (GMR)=0.61, p=0.229]; C max =1714 (1238-2262) vs. 3190 (2412-4076) ng/mL (GMR=0.54, p=0.018); AUC=21,987 (15,870-29,327) vs. 35,572 (26,211-46,728) ng h/mL (GMR=0.62, p=0.074). Methadone dose, which is proportional to the amount of methadone oral solution (10 mg/mL), was significantly correlated to atazanavir C max (r 2 =0.40, p=0.001) and AUC (r 2 =0.32, p=0.006). Ritonavir pharmacokinetics was similar between the groups with C min , C max , and AUC GMR of 1.01, 0.80, and 0.96, respectively. Conclusion The partial decrease in atazanavir plasma concentrations in patients concomitantly taking racemic methadone oral solution in this daily observed therapy setting deserves further attention, and therapeutic drug monitoring should be considered.

Pharmacokinetic interactions of CEP-1347 and atazanavir in HIV-infected patients

“…ATV and RTV pharmacokinetic parameters obtained in this study in the presence of CEP-1347 were comparable to values that have been previously reported. The estimated mean clearance of atazanavir (12.0 and 9.3 L/h for visits 1 and 2) in the present study was higher than that previously reported in patients (8.5 L/h) (Haberl et al 2010), although a population analysis reported 12.9 L/h in patients given ATV/r at 300/100 mg/day, similar to our present study (Colombo et al 2006). For mean AUC0-24 and C max , estimates ranging from 40.2 to 49.6 h μg/mL and 4.0 to 4.5 μg/mL, respectively, were consistent with literature (Wang et al 2011).…”

Predictors of the change in bilirubin levels over twelve weeks of treatment with atazanavir

“…There are 2 plausible explanations: intravenous drug use history and/ or methadone use are surrogate markers for hepatitis C seropositivity in this cohort or methadone co-administration affects plasma concentrations of ATV. The latter is supported by a pharmacokinetic study of the co-administration of methadone and ATV that demonstrated significantly lower maximum concentrations (Cmax) of plasma ATV in those on concomitant methadone [10]. However, in this previous study, despite lower ATV levels, there was no difference in the therapeutic efficacy of ATV.…”

Drug–drug interactions and clinical considerations with co-administration of antiretrovirals and psychotropic drugs

“…When administered unboosted, atazanavir has no effect on CYP 2B6 and as expected no significant effect on methadone concentrations 223 . Of interest, 1 study did note decreased concentrations of atazanavir when co-administered with methadone compared to patients not receiving methadone, though the effect was only statistically significant for Cmax, and an increase in virologic failure was not observed 224 . The authors proposed that this result may be specific to the oral solution of methadone formulated in Germany, which is particularly viscous and may more readily complex with atazanavir to impair its absorption.…”

“…223 Of interest, 1 study did note decreased concentrations of atazanavir when co-administered with methadone compared to patients not receiving methadone, though the effect was only statistically significant for Cmax, and an increase in virologic failure was not observed. 224 The authors proposed that this result may be specific to the oral solution of methadone formulated in Germany, which is particularly viscous and may more readily complex with atazanavir to impair its absorption. In another real-world survey and pharmacokinetic study of patients with HIV receiving atazanavir-or lopinavirbased regimens, the patients who were also receiving methadone had lower troughs of atazanavir and lopinavir than their counterparts.…”