| |
Reyataz & Methadone: no drug interaction observed
|
| |
| |
"Lack of an effect of atazanavir on steady-state pharmacokinetics of methadone in patients chronically treated for opiate addiction"
AIDS: Volume 19(15) 14 October 2005 p 1635-1641
Friedland, Geralda; Andrews, Lauriea; Schreibman, Tanyaa; Agarwala, Sangeetac; Daley, Leitha; Child, Michaelc; Shi, Juliab; Wang, Yonghuac; O'Mara, Edwardc,*
From the aAIDS Program, Yale School of Medicine
bAPT Foundation Drug Treatment Program, New Haven Connecticut
cBristol-Myers Squibb Company, Princeton, New Jersey, USA.
Sponsorship: This study was supported by Bristol Myers Squibb Company and in part by a General Clinical Research Center grant from the National Center of Research Resources, National Institute of Health (Grant M01-RR00125) awarded to Yale University, School of Medicine.
"....Once-a-day dosing may be of particular benefit for HIV-infected drug users....The results indicate that coadministration of a standard clinical dosage of atazanavir and methadone does not significantly affect methadone levels.... pKa data from the present atazanavir study were compared with steady-state data from non-matched healthy and HIV-infected historical controls; this indicated that atazanavir concentrations were not affected by methadone..... atazanavir at a dose of 400 mg....in concert with once-a-day dosing and favorable side effect profile make it an excellent choice for protease inhibitor-naive HIV-infected patients on chronic methadone treatment and requiring antiretroviral therapy....
..... While some in vivo studies have shown ritonavir to lead to a decrease in the AUC and C max of methadone], a more recent study has demonstrated no significant effect on methadone metabolism when low-dose ritonavir and methadone are coadministered to subjects on chronic methadone therapy... a formal pharmacokinetic study of this (atazanavir+low-dose ritonavir) combination is currently under consideration."
AUTHOR DISCUSSION
The current study was undertaken to provide data on the administration of atazanavir to an important section of the HIV-positive population: opiate abusers on methadone therapy. The results indicate that coadministration of a standard clinical dosage of atazanavir and methadone does not significantly affect methadone levels. In particular, the AUC, C min and C max of the active (R)-isomer were not significantly altered; the 90% CI values for dose-normalized AUC, C max and C min ratios of geometric means met the no-effect criteria for bioequivalence (within the range 0.80-1.25) [25]. Likewise, for total methadone, the 90% CI values for dose-normalized AUC and C min ratios of geometric means met the no-effect criteria. The concentrations of inactive (S)-methadone were modestly decreased. Further, pK a data from the present atazanavir study were compared with steady-state data from non-matched healthy and HIV-infected historical controls [24]; this indicated that atazanavir concentrations were not affected by methadone.
These data are of importance in the current usage of antiretroviral therapy, particularly among drug users. Simplification of regimens in highly active antiretroviral therapy (HAART) has been an important recent therapeutic development. Most regimens now require only dosing only twice a day and agents and regimens requiring only once daily dosage are increasingly available [26,27]. Once-a-day dosing may be of particular benefit for HIV-infected drug users receiving HAART both in and out of drug treatment and is an important advantage of atazanavir therapy [20].
The potential consequences of unsuspected and clinically significant drug interactions between methadone and antiretroviral agents are of substantial concern [28]. The production of opiate-withdrawal syndromes or other drug toxicities can lead to non adherence to antiretroviral regimens, with the risk of treatment failure and selection of drug-resistant HIV strains. Increased abuse of other illicit substances may also occur and represent additional risks to patients. Conversely, the effect of methadone on antiretroviral drugs could lead to increased toxicities or to decreased efficacy.
Methadone is a chiral compound, administered in the United States as a 50:50 racemate of the (R)-and (S)-isomers. The opiate activity resides within the (R)-isomer [4,5]. The pharmacokinetics of each of the isomers has been shown to be linear over the range 7.5-130 mg/day and hence can be normalized to a median or unit dose in a population for pharmacokinetic/statistical evaluation. With a terminal half-life of 24-36 h, it requires about 5 days at the same dose to achieve steady-state levels [29].
Methadone is considered to be a substrate for multiple cytochrome P450 isoforms, mainly CYP3A4, but also CYP2B6 and CYP2D6. Therefore, there is a potential for pharmacological interactions between methadone and protease inhibitors, which affect and are affected by the cytochrome P450 pathway. Prior protease inhibitor and methadone interaction studies have included ritonavir, saquinavir, indinavir, nelfinavir, amprenavir and lopinavir/ritonavir and have shown varying results. Gerber et al. [14] reported that methadone-stabilized subjects exhibited a 32% decrease in AUC for the (R)-isomer of methadone and a 40% decrease in the AUC of the (S)-isomer after concomitant dosing of ritonavir/saquinavir and methadone. There was no reported evidence of withdrawal symptoms associated with this decrease. While some in vivo studies have shown ritonavir to lead to a decrease in the AUC and C max of methadone [13], a more recent study has demonstrated no significant effect on methadone metabolism when low-dose ritonavir and methadone are coadministered to subjects on chronic methadone therapy [19]. When the protease inhibitor indinavir was coadministered with methadone, the AUC of methadone was not affected, although the indinavir C max was decreased, while the C min was increased [30]. Several studies with nelfinavir and methadone have noted decreased methadone levels, [16,17,18], but apart from a single reported case [16], there have been no reports of clinically apparent opiate withdrawal symptoms. Coadministration of methadone and amprenavir has resulted in a decrease in the levels of both amprenavir and methadone [15,31]. Recent labeling changes to the amprenavir product information have suggested that this agent should not be used in patients receiving methadone because of the potential reductions in plasma concentrations of amprenavir [32].
Finally, a recent study showed that the administration of lopinavir/ritonavir was associated with significantly reduced methadone concentrations and opiate withdrawal symptoms [19]. Previous studies [33,34] documented decreased methadone levels but did not detect withdrawal symptoms. Prudence dictates that treatment with lopinavir/ritonavir in patients receiving methadone requires careful clinical monitoring for opiate withdrawal and may require increased methadone dosages in some patients.
No prior studies exist examining the effect of atazanavir on methadone levels. Atazanavir is pharmacologically similar to indinavir, an acid salt protease inhibitor, and does not induce metabolic enzymes [29,35], in contrast to known inducers such as nelfinavir or lopinavir. We hypothesized that atazanavir would not have a clinically significant induction effect on methadone exposure but, as a moderate inhibitor of CYP3A4, could result in decreased methadone metabolism, increased methadone exposure, and clinical excess. Previous experience and studies have indicated that formal pharmacological studies are required to define the absence or presence of interactions between methadone and antiretroviral drugs, and the nature of any such interactions [27]. This present study confirms that atazanavir does not induce methadone metabolism and also indicates a lack of inhibition.
A potential limitation of this study is that the subjects were not necessarily representative of the HIV-infected intravenous drug-using population as they were selected because of a relatively stable lifestyle and healthy physiological state. However, the patients studied are representative of the in-treatment population of intravenous drug users likely to be receiving both methadone and atazanavir. In addition, our subjects were HIV negative, and it is possible, though unlikely, that the drug interactions might be different in HIV-infected patients. Finally, current atazanavir usage is often combined with low-dose ritonavir to provide pharmacological boosting. Although it is unlikely that this would alter the study results, as a previous study has demonstrated no effect of ritonavir on methadone metabolism [19], a formal pharmacokinetic study of this combination is currently under consideration.
In conclusion, this study indicates an absence of clinically important pharmacokinetic interactions between atazanavir and methadone and the lack of symptoms of opiate withdrawal or excess. Exposures to the active (R)-isomer were not significantly affected and exposures to the inactive (S)-isomer and total methadone were minimally affected by coadministration with atazanavir. Atazanavir exposures were within the range observed in historic controls. Dosage adjustment is, therefore, not recommended when atazanavir at a dose of 400 mg is coadministered with methadone. These pharmacological properties of atazanavir in concert with once-a-day dosing and favorable side effect profile make it an excellent choice for protease inhibitor-naive HIV-infected patients on chronic methadone treatment and requiring antiretroviral therapy.
Abstract
Background: Effective antiretroviral treatment of opiate-addicted drug users with HIV infection often requires concomitant substance abuse treatment, commonly with methadone. Pharmacological interactions between antiretroviral drugs and methadone may result in opiate withdrawal or increased side effects.
Objectives: To determine if atazanavir, a once-daily protease inhibitor and moderate inhibitor of P450 CYP3A4, exhibited pharmacokinetic interactions with (R)-methadone.
Methods: Methadone pharmacokinetic parameters were measured in 16 patients on chronic methadone therapy prior to and after 14 days of daily administration of atazanavir. Steady-state pharmacokinetic values for total, (R)- (active) and (S)- (inactive) isomers of methadone were derived from plasma concentrations versus time data. Symptoms of opiate withdrawal and excess were monitored.
Results: For the active isomer (R)-methadone, the ratio of geometric means for coadministration with atazanavir relative to methadone alone were 1.03 [90% confidence interval (CI), 0.95-1.10] for the area under the concentration-time curve (AUC), 0.91 (90% CI, 0.84-1.00) for plasma maximal concentration and 1.11 (90% CI, 1.02-1.20) for plasma trough concentration. Confidence intervals for all three were within the no-effect or bioequivalence range of 0.80-1.25 for (R)-methadone. Inactive (S)-methadone was modestly reduced during atazanavir coadministration. Clinically relevant symptoms of opiate withdrawal or excess were not detected. Exposures to atazanavir were within range of previously reported values.
Conclusions: No clinically relevant pharmacokinetic interactions were found between atazanavir and methadone. Dosage adjustment need not be recommended for either methadone or atazanavir when co-administered to patients treated for opiate abuse and HIV disease.
Introduction
Intravenous drug use is the second most common mode of HIV transmission in the United States and Europe and is responsible for a major portion of HIV transmission in Asia, Eastern Europe, and Latin America [1]. A large and increasing number of intravenous drug users with HIV require care and treatment with antiretroviral therapy. Successful medical management of opiate-addicted drug users with HIV disease often requires treatment of both substance abuse, most commonly with methadone, and HIV disease [2,3].
Methadone occurs as a chiral compound with pharmacologically active, (R), and inactive, (S), isomers [4,5] and is a substrate for multiple cytochrome P450 isoforms, including CYP3A4 [6]. Concomitant administration of antiretroviral drugs with methadone has resulted in altered pharmacological disposition of some nucleoside reverse transcriptase inhibitor drugs [7-9]. The non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine have been shown to alter methadone disposition, with resultant reduced methadone exposure and well-documented and frequent opiate withdrawal symptoms [10-12]. The protease inhibitors have also been associated with reduction in methadone exposure and opiate withdrawal symptoms, but less commonly or predictably [13-19]. These pharmacological interactions may diminish the effectiveness of either or both therapies.
Atazanavir is a highly selective inhibitor of the HIV protease enzyme with favorable oral bioavailability and clinical profile [20]. It is administered as two 200 mg capsules, once daily, and rapidly and durably suppresses HIV viral load. Atazanavir does not result in clinically relevant elevations in serum lipids. Resistance (uniquely characterized by the I150L mutation) is uncommonly observed. Atazanavir is a moderate inhibitor of CYP3A4; therefore, potential drug-drug interactions between atazanavir and methadone must be considered when it is used in patients chronically treated with methadone.
The current study was undertaken with the following objectives. First, the study assessed the effect of atazanavir on the steady-state pharmacokinetics of the active (R)-isomer of methadone in subjects chronically treated with racemic methadone. Second, the effect of atazanavir on the steady-state pharmacokinetics of (S)-methadone and on total methadone was examined. Third, the steady-state pharmacokinetics of atazanavir in subjects chronically treated with methadone were compared with those from historic controls not treated with methadone. Finally, the safety and tolerability of coadministered atazanavir and racemic methadone was examined.
Methods
Subjects
HIV-negative volunteers who had long-term opiate dependency and were receiving a stable dose of methadone were recruited from the APT Foundation Drug Treatment Program, New Haven, Connecticut. The study was approved by the Yale University School of Medicine Human Investigation Committee. All subjects provided written informed consent prior to study entry and were compensated monetarily for their time and effort in participating in the study.
Men and women between 18 and 50 years of age who were taking a stable dose of methadone for at least 3 weeks prior to screening and with a body mass index of 18-30 kg/m2 were eligible for this study. Nursing mothers and pregnant women were excluded. Women of child-rearing potential were required to be on an acceptable non-hormonal method of contraception for at least 1 month prior to dosing. Other exclusion criteria included history or evidence of any significant acute or chronic medical illness that would interfere with the conduct or interpretation of the study. Examples of such criteria included major surgery, known or suspected HIV infection, and known active drug or alcohol abuse. In addition, patients with elevated bilirubin levels (total bilirubin > 20 mg/l), elevated aspartate and alanine transaminases (≥ 3x upper limit of normal) second- or third-degree atrioventricular block or prolonged QTc interval (> 450 ms) were excluded from the study. Any subjects with known prior exposure to atazanavir or the use of any agent known to induce or inhibit drug-metabolizing enzymes were also excluded.
Study design
The study was designed as a multiple-dose, open-label, sequential, non-randomized pharmacokinetic interaction study. After meeting eligibility requirements, subjects were admitted to the General Clinical Research Center at Yale New Haven Hospital the evening prior to dosing. On study day 1, after a 10 h fast, subjects received their usual dose of methadone as an oral solution within 5 min subsequent to completion of a light meal. Subjects then underwent full pharmacokinetic sampling to determine methadone disposition. Atazanavir (400 mg) and methadone were then coadministered for 14 days (study days 2-15). Methadone and atazanavir were given with a snack at the subjects' regular methadone program visits on study days 2-14. On day 15, methadone and atazanavir were administered in the General Clinical Research Center, where pharmacokinetic sampling for atazanavir and methadone disposition were carried out. Screening for opiate withdrawal or excess was carried out on a daily basis before each dosing using a standardized and validated instrument for opiate withdrawal [21] and a consensus questionnaire for opiate excess. Medical history, physical examination, 12-lead electrocardiogram, and laboratory data, including complete blood count, chemistry, renal function, glucose, triacylglycerols, cholesterol, liver function tests, hepatitis panel, serum chorionic gonadotropin, urine toxicology, ethanol breathalyzer, urinalysis and HIV testing, were collected on all patients at baseline and at the conclusion of the study.
Drug measurements
Blood samples for methadone pharmacokinetic analysis were collected following the methadone dose on day 1 and for methadone and atazanavir pharmacokinetic analysis on day 15. Blood samples were collected at before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, and 24 h after dosing on days 1 and 15. In addition, trough concentrations (C min) of atazanavir and methadone were obtained on days 7 and 13. Liquid chromatography/tandem mass spectrometry was used to measure (R)- and (S)-methadone and atazanavir [22,23]. Total methadone was calculated as the sum of (R)- and (S)-methadone. The standard curve range was 5.00-1000 ng/ml for (R)- and (S)-methadone and 1.00-1000 ng/ml for atazanavir.
Steady-state pharmacokinetic values for total methadone and the (R)- and (S)-isomers and for atazanavir were derived from plasma versus time data. Plasma concentration-time (AUC) data were analyzed by a non-compartmental method. Pharmacokinetic parameters measured for methadone on days 1 and 15 and atazanavir on day 15 were maximum plasma concentration (C max), time of maximum plasma concentration on study days (t max), C min, AUC [at the end of the dosing interval (tau)] and apparent oral clearance (CLT/F). The pharmacokinetics of the isomers of methadone have been shown to be linear over the range 7.5-130 mg/day and hence pharmacokinetic parameters can be normalized to a per milligram dose in a population for pharmacokinetic/statistical evaluation.
Safety assessments
Safety assessments were based on medical review of adverse event reports and the results of vital sign measurements, electrocardiograms, physical examinations, and clinical laboratory tests. Opiate withdrawal and excess screening questionnaires were reviewed on a daily basis.
Data analysis
Frequency distributions of gender and race were derived. Summary statistics for age, body weight, height and body mass index were calculated. For dose-normalized C max, AUC (tau), and C min values of total methadone and of (R)- and (S)-methadone, 90% confidence intervals (CI) for the study day 15 to study day 1 ratios of population geometric means were calculated from the results of general linear model analysis on log10 values. The factor in the model was study day, with subject as a random effect. Summary statistics for each pharmacokinetic parameter were recorded by study day, for each analyte. Geometric means and coefficients of variation were calculated for C max, AUC (tau), and C min. Medians, minima, and maxima were calculated for t max, and mean and SD values were calculated for the half-life and CLT/F. In addition, the steady-state pharmacokinetics of atazanavir in subjects were descriptively compared with those from historic controls with and without HIV disease and not treated with methadone [24].
Results
Demography
Of the 18 enrolled patients, 11 were male, 14 Caucasian, and 4 Black; mean age was 41 years (range, 31-57). Weight ranged from 59.9 to 117.9 kg, with a mean of 78.6 kg (SD, 13.8). Body mass index was 20.1-36.4 kg/m2 with a mean of 27.1 kg/m2 (SD, 3.9). Two patients did not complete the study; one was found to have non-methadone opiate metabolites during the study and a second patient left the study before completing the second pharmacokinetic analysis and was lost to follow-up.
Pharmacokinetics
Table 1 shows the pharmacokinetic parameters of total, (R)-, and (S)-methadone for the 16 patients who completing the study and the ratio of dose-normalized adjusted geometric means and 90% CI values for AUC, C max and C min during atazanavir coadministration relative to administration of methadone alone. Figure 1 shows the plasma concentration-time profiles for total, (R)-, (S)-methadone for these patients. On coadministration with atazanavir, exposures to the active (R)-isomer, the inactive (S)- isomer, and total methadone did not differ significantly from those with methadone alone. For (R)-methadone, the AUC and C min increased by 3% and 11%, respectively, and C max decreased by 9%. For (S)-methadone, the AUC, C max and C min decreased by 15, 21 and 10%, respectively, and for total methadone AUC and C max decreased by 6 and 15%, respectively, and C min increased by 2%. For (R)-methadone, the ratio of geometric means for coadministration with atazanavir relative to methadone alone were 1.03 (90% CI, 0.95-1.10) for AUC, 0.91 (90% CI, 0.84-1.00) for C max and 1.11 (90% CI, 1.02-1.20) for C min. Confidence intervals for AUC, C max and C min were within the no-effect or bioequivalence range of 0.80-1.25 for (R)-methadone [25]. The inactive (S)-methadone was modestly reduced during atazanavir coadministration; the geometric mean ratios for AUC, C max and C min were 0.85 (90% CI, 0.79-0.93), 0.79 (90% CI, 0.72-0.88) and 0.90 (90% CI, 0.81-1.01), respectively. For total methadone, geometric mean ratios for AUC, C max and C min were 0.94, 0.85 and 1.02. Table 2 shows the pharmacokinetic parameters for atazanavir when administered with methadone. These were within the range of values reported previously for healthy and HIV-infected subjects [24]. In the current study, the geometric mean AUC (tau) value for atazanavir was 20237 ng/ml per h [range, 8558-70 114; percentage coefficient of variation (CV%), 65]. In previous studies, the geometric mean atazanavir AUC (tau) value was 28 132 ng/ml per h (range, 14 756-46 532; CV%, 28) in healthy subjects and 14 874 ng/ml per h; (range, 3009-75 882; CV%, 91) in HIV-infected patients.
Safety measurements
Clinically relevant signs and symptoms of opiate withdrawal or excess were not detected. No instances of death, serious adverse events, or discontinuations because of adverse events were observed. Laboratory parameters remained within study-defined baseline limits through the course of study. Five subjects were noted to have elevated grade 2 or 3 bilirubin at day 7 or at discharge, consistent with bilirubin levels following administration of atazanavir in other healthy populations and patients with HIV disease and with the known mechanism of reversible inhibition of UDP glycosyltransferase 1 by atazanavir [20].
|
|
| |
| |
|
|
|
