Peginterferon Alfa-2a Does Not Alter the Pharmacokinetics of Methadone in Patients with Chronic Hepatitis C Undergoing Methadone Maintenance Therapy*

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LINICAL TRIALS

eginterferon alfa-2a does not alter theharmacokinetics of methadone in patientsith chronic hepatitis C undergoingethadone maintenance therapy

Objective: Our objective was to quantify the pharmacokinetics of methadone and the pharmacokinetics andpharmacodynamics of peginterferon alfa-2a (40 kd) in patients with chronic hepatitis C undergoing meth-adone maintenance therapy.Methods: Adults with chronic hepatitis C who had been receiving a consistent methadone maintenanceregimen for at least 3 months were eligible for this open-label, multicenter, nonrandomized drug interactionstudy. All patients received 180 �g subcutaneous peginterferon alfa-2a once weekly for 4 weeks and contin-ued their methadone regimen. Serial blood samples were collected at baseline and immediately before and forup to 168 hours after study drug administration for the purposes of quantifying methadone and peginter-feron alfa-2a serum concentrations, measuring serum 2�,5�-oligoadenylate synthetase activity, and determin-ing hepatitis C virus ribonucleic acid levels.Results: Twenty-four patients were enrolled. Methadone exposure, as measured by maximum serum concen-tration (Cmax) and area under the concentration-time curve (AUC) normalized to a 100-mg/d dose, after 4doses of peginterferon alfa-2a increased by 10% to 15% when compared with baseline. The week 4/baselineratio of the mean Cmax was 1.11 (90% confidence interval [CI], 1.02-1.22), and for AUC from time 0 to 24hours, the week 4/baseline ratio was 1.15 (90% CI, 1.08-1.23). The mean accumulation ratios (week 4/firstdose) for Cmax and AUC from time 0 to 168 hours of peginterferon alfa-2a were 2.1 and 2.3, respectively.Conclusions: Peginterferon alfa-2a does not appreciably alter the pharmacokinetics of methadone. (ClinPharmacol Ther 2005;77:214-24.)

Mark Sulkowski, MD, Teresa Wright, MD, Stephen Rossi, PharmD,Sanjeev Arora, MD, Matthew Lamb, PharmD, Ka Wang, PhD,Jean-Michel Gries, PhD, and Sreeni Yalamanchili, PharmD Baltimore, Md, San Francisco and
Thousand Oaks, Calif, Albuquerque, NM, and Nutley, NJ
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Injection drug use is the most common mode ofcquisition of new hepatitis C virus (HCV) infections inhe United States.1,2 Injection drug users (IDUs) are atigh risk of HCV infection because of the efficiencyith which the virus is parenterally transmitted. Indeed,

rom the Viral Hepatitis Center, Johns Hopkins University Schoolof Medicine, Baltimore; Gastrointestinal Section, VeteransAffairs Medical Center, University of California, San Fran-cisco, San Francisco; Science Center, University of New Mex-ico, Albuquerque; Roche, Nutley; and Amgen, Inc, ThousandOaks.

he study was sponsored by Roche, Nutley, NJ.
eceived for publication June 9, 2004; accepted Sept 16, 2004. d
14

ithin 1 year of needle use, approximately 77% ofntravenous drug users become infected with HCV3; inhose who have used injectable drugs for 10 years orore, the prevalence of HCV exposure is as high as

4%.4,5 Comprehensive strategies for the management

eprint requests: Mark Sulkowski, MD, Viral Hepatitis Center, JohnsHopkins Medical Institutions, 1830 E Monument St, Room 448,Baltimore, MD 21205.

-mail: [email protected]/$30.00opyright © 2005 by the American Society for Clinical Pharmacologyand Therapeutics.

oi:10.1016/j.clpt.2004.09.008

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CLINICAL PHARMACOLOGY & THERAPEUTICS2005;77(3):214-24 Peginterferon alfa-2a and methadone PK 215

f HCV infection must encompass IDUs. Methadoneaintenance programs are effective in diminishing opi-

id drug use and decreasing other high-risk behaviors;ccordingly, such drug treatment programs may serves an important link to provide IDUs with access toreatment for chronic hepatitis C.6

The combination of pegylated interferon plus ribavi-in, the treatment of choice in patients with chronicepatitis C,7 produces sustained virologic responses in2% to 63% of patients with HCV monoinfection and0% of patients with HCV/human immunodeficiencyirus coinfection.8-12 Until recently, methadone treat-ent has been a strict exclusion criterion in clinical

rials, and as a result, patients with hepatitis C who areeceiving methadone maintenance therapy have beendentified as an understudied population.13 Thus thistudy was designed to address this critical problem ofhronic hepatitis C in methadone recipients.

Because of the magnitude of the epidemic of hepa-itis C in IDUs, it is important to understand the clinicalmplications of the concomitant use of opiates (ie,ethadone) and anti-HCV therapies. Moreover, poten-

ial pharmacokinetic interactions between therapies forepatitis C and opiate agonists need to be investigatedo establish the safety of concurrent HCV and metha-one treatment.6

Methadone is a racemic mixture of which the-enantiomer is the active moiety.14-17 There is marked

nterindividual variability in the distribution and clear-nce of the drug that is derived from variability in thendividual serum concentrations of �1-acid glycopro-ein and cytochrome P450 (CYP) 3A4 activity.14,16,17

he stereoselective metabolism of methadone is medi-ted by CYP3A4, CYP2C8, and CYP2D6, and databtained in vitro and in vivo demonstrate that there isignificant potential for drug interactions with inhibi-ors of these CYP isozymes.18,19

Conventional interferon alfa has been shown to in-ibit various CYP isozymes including CYP3A4 andYP2D6.20-23 Moreover, some patients with chronicepatitis C have antibodies directed at CYP2D6,24,25

nd a study conducted during the first month of treat-ent with interferon alfa revealed an increase in the

ctivity of CYP3A4 and CYP2D6 in patients withhronic hepatitis C.26 It is, therefore, important to as-ess the potential for clinically significant CYP-ediated interactions in drugs that may be used by

atients with chronic hepatitis C who are candidates fornterferon-based therapy.

Methadone has been shown to have “anti-interferon”roperties in mice.27 Whether the reduction in serum
evels was related to decreased production or increased s
learance of endogenous interferon is another unre-olved but relevant question with potential implicationsor the treatment of chronic hepatitis C in patientsndergoing methadone maintenance therapy.The objective of this study was to quantitatively

valuate the effects of peginterferon alfa-2a on theharmacokinetics of methadone in patients withhronic hepatitis C who were receiving a stable meth-done maintenance regimen. The pharmacokinetics andharmacodynamics of peginterferon alfa-2a were alsouantified in these individuals.

ETHODSSubjects. Eligible subjects were aged 18 years or

reater; had evidence of HCV infection, defined as aositive anti-HCV antibody test result and either aositive radioimmunoblot assay for HCV or quantifi-ble HCV ribonucleic acid (RNA) in serum by poly-erase chain reaction (COBAS AMPLICOR HCVONITOR Test, v2.0; Roche Diagnostics, Basel, Swit-

erland) (limit of detection, �2000 IU/mL); and hadompensated liver disease. Women of childbearing po-ential were required to have a negative urine preg-ancy test result documented within 24 hours beforedministration of the first dose of peginterferon alfa-2a.

All participants had to have been receiving a consis-ent methadone maintenance regimen, in terms of theormulation, dose, and frequency of administration, fort least 3 months before study entry. No specific dose ofethadone was selected for the trial. Because alcohol

nfluences the disposition of methadone,28 patientsere not eligible if the dosage form of methadone

ncluded alcohol (ie, use of methadone tincture ornited States Pharmacopeia oral solution containing% alcohol was prohibited). Methadone diskettes, tab-ets, alcohol-free liquid concentrate, and powder werecceptable dosage forms.

Patients were excluded if they had a positive urinecreening result for drugs, except methadone, or evi-ence of excessive alcohol or drug use within 6 monthsf study entry. Drug use was defined as the use of drugsithout a documented indication, including amphet-

mines, barbiturates, benzodiazepines, cannabis, co-aine, or opiates other than methadone. A history ofevere psychiatric disease, including depression, waslso grounds for exclusion.

Patients coinfected with hepatitis A or B virus oruman immunodeficiency virus were also excluded, asere patients with evidence of severe or advanced liverisease of any etiology or other severe or chronic
ystemic disease.

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CLINICAL PHARMACOLOGY & THERAPEUTICS216 Sulkowski et al MARCH 2005

Prescription medications were allowed for the treat-ent of concurrent chronic conditions, provided that

he patient had been receiving a consistent regimen fort least 2 months and adjustments to the regimen wereot anticipated during the study and that the medicationas not a known inhibitor of CYP3A4 (ie, clarithro-ycin, erythromycin, fluconazole, fluoxetine, fluvox-

mine, itraconazole, ketoconazole, nefazodone, andmeprazole). Because methadone is a substrate ofYP3A4, consumption of grapefruit juice was prohib-

ted during the study. In addition to the above-entioned medications, the use of theophylline was

rohibited. With the exception of acetaminophen (INN,aracetamol), which could be used at a maximum dosef 4 g/d, the use of nonprescription medications wasrohibited for 2 weeks before and during the study.Female participants were required to use contracep-

ion throughout the study.Study design. Patients enrolled in this open-label,ulticenter, nonrandomized drug interaction study con-

inued their ongoing daily methadone maintenanceherapy regimen and received 180 �g subcutaneouseginterferon alfa-2a (40 kd) (Pegasys; Roche, Nutley,J) once weekly for 4 weeks. Patients fasted for 12ours before peginterferon alfa-2a administration dur-ng weeks 1 and 4. Caffeinated drinks were not allowedor 48 hours before or on study drug administrationays. Patients remained in the study clinic for 24 hoursfter peginterferon alfa-2a administration for bloodampling. The date and time of methadone administra-ion were recorded at baseline, on day 1 (week 1), andn day 22 (week 4). The date and time of administra-ion of all peginterferon alfa-2a doses and collection ofll blood samples were recorded.

Serial blood samples of 5 mL were collected ataseline (day 7) and during week 4 (day 22) at 0 hoursnd at 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours afterethadone administration for the purpose of quantitat-

ng methadone serum levels.Serial blood samples of 5 mL were collected during

eek 1 (day 1) and week 4 (day 22) before adminis-ration of peginterferon alfa-2a (0 hours) and at 3, 8, 24,8, 72, 84, 96, 120, 144, and 168 hours after adminis-ration for the purpose of quantitating peginterferonlfa-2a serum levels.

Blood samples (2 mL) were collected before meth-done administration at baseline (day 7); before pegin-erferon alfa-2a administration during weeks 1, 2, 3,nd 4; and before dosing and at 6, 12, 24, 36, 48, 72, 96,nd 168 hours after administration of peginterferonlfa-2a during week 1 for the purpose of quantifying
erum HCV RNA levels. Serial blood samples were b
lso collected before dosing and at 3, 8, 24, 48, 72, 84,6, 120, 144, and 168 hours after administration ofeginterferon alfa-2a at baseline (day 7) and duringeeks 1 and 4 for the purpose of measuring serum�,5�-oligoadenylate synthetase (2�,5�-OAS) activity, aidely used marker for interferon-induced antiviral ac-

ivity.Serum concentrations of methadone were quantified

y a validated gas chromatography–mass spectroscopyssay at PPD Development (Richmond, Va). Samplesere kept frozen until analyzed, at which time theyere thawed at room temperature in a water bath. Oneilliliter of sample and 100 �L of internal standard (50

g/mL methadone-d9) were placed in a silylated 16 �25–mm culture tube. After the mixture was allowed totand for 20 minutes, 4 mL of water and 2 mL of00-mmol/L phosphate buffer/methanol (80:20) weredded; the tube was blended in a vortex mixer and thenentrifuged at 3000 rpm for 5 minutes. The supernatantas decanted into a second silylated 16 � 125–mm

ulture tube. The sample was then placed on a solidhase extraction cartridge (Bond Elut Certify SPE col-mns, 130 mg, LRC [large reservoir cartridge], Variano. 1211-3050; Varian, Inc, Palo Alto, Calif ). The

artridge was then washed with 2 mL of water, 2 mL of00-mmol/L acetic acid, and then 3 mL 100% metha-ol. The columns were dried under vacuum for 5 min-tes before being eluted into silylated, conical centri-uge tubes with 3 mL of dichloromethane/isopropyllcohol/ammonium hydroxide (78:20:2). The eluateas then evaporated to dryness at 40°C or greater undergentle stream of nitrogen. Samples were reconstitutedith 25 �L of 10% N-methyl-N-trimethylsilyltriflu-roacetamide in toluene. Reconstituted samples weretored at �20°C until analysis. A 1.0-�L volume washen injected onto a DB-1 30-m � 0.32-mm inneriameter column (J&W Scientific, Folsom, Calif)ounted in a Varian 3400 gas chromatograph (Varian,

nc) coupled with a mass spectrometer. The carrier gasas helium, the injector temperature was 300°C, and

he instrument was programmed to increase the columnemperature from 165°C to 300°C at a rate of 20°C/in. The analytic range of the assay was 0.1 to 50

g/mL. Samples with concentrations greater than 50g/mL were diluted and reanalyzed. The coefficient ofariation for the assay ranged from 2.5% to 35.1%.Serum concentrations of peginterferon alfa-2a were

uantified by a validated enzyme-linked immunosor-ent assay at MDS Pharma Services (Montreal, Que-ec, Canada). In a 1-step immunoreaction, the pegin-erferon alfa-2a (40 kd) contained in the sample is
ound by the peroxidase-conjugated antibody. The as-

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ay is a quantitative sandwich enzyme immunoassayhich uses 2 monoclonal antibodies that recognizeifferent epitopes. It is not known whether the antibod-es bind to receptor-bound peginterferon alfa-2a (40d). One hundred microliters of substrate buffer and 50L of assay dilution buffer were added to all wells inicrotiter plates. A 50-�L aliquot of the standard or

tudy sample was then added, followed by 50 �L oferoxidase-conjugated solution. This complex bindsia the capture–anti–peginterferon alfa-2a (40 kd) an-ibody to the multiprotein layer–coated surface of theicrotiter plate. The plate is sealed and incubated at

oom temperature for 30 minutes with shaking at 150pm before incubation for 16 to 24 hours at 37°Cithout shaking. After incubation, the plate was shaken

t room temperature at 150 rpm for 60 minutes. Thelate was then washed 5 times with 300 �L of washuffer. Next, 200 �L of substrate solution (0.8 mL of.2% tetramethylbenzidine in acetone/ethanol/hydro-en peroxide [10:89:1]/22 mL substrate buffer, pH 4.1)as added to each well. This solution is converted by

he peroxidase to a colored product that can be deter-ined photometrically. The plates were sealed and

ncubated in the dark at room temperature for approx-mately 15 to 20 minutes with shaking at 150 rpm. Fiftyicroliters of 2N sulfuric acid was then added to stop

he reaction, and the plate was read within 15 minutesy use of a SpectraMax 340 PC microplate readerMolecular Devices Corporation, Sunnyvale, Calif) seto 450 to 650 nm. The concentration of the samples wasalculated by comparison with a standard curve. Thenalytic range of the assay was 350 to 3000 pg/mL.amples with concentrations greater than 3000 pg/mLere diluted and reanalyzed. The coefficient of varia-

ion for the assay ranged from 9.1% to 13.5%.HCV RNA levels in serum were determined with the

OBAS AMPLICOR HCV MONITOR Test, v2.0Roche Diagnostics, Basel, Switzerland). Serum 2�,5�-AS activity was determined with a commercially

vailable radioimmunoassay kit.After completion of the study, patients were allowed

o participate in an open-label continuation study witheginterferon alfa-2a and ribavirin combination ther-py. Patients who declined combination therapy wereollowed up for 4 weeks after administration of the lastose of peginterferon alfa-2a.The institutional review boards at each center ap-

roved the protocol. All patients provided informedritten consent before enrollment. The study was con-ucted in conformance with the principles of the Dec-
aration of Helsinki, the principles outlined in the f
uideline for Good Clinical Practice, and the laws andegulations of the United States.

Pharmacokinetic parameters. The following phar-acokinetic parameters were determined for peginter-

eron alfa-2a and methadone by use of noncompart-ental methods: observed maximum serum drug

oncentration (Cmax), time to Cmax (tmax), time of lastbserved serum concentration (tlast), area under theerum concentration–time curve (AUC) (AUC betweenime 0 and the time of the last observed serum concen-ration [AUC0-last], AUC from time 0 extrapolated tonfinity [AUC0-�], and AUC from time 0 to 24 hoursAUC0-24] for methadone and AUC from time 0 to 168ours [AUC0-168] for peginterferon alfa-2a). The totalpparent clearance (CLss/F) and apparent terminalhase volume of distribution (Vz/F) were calculated forethadone, and the accumulation ratio for week 4:1 for

max and AUC0-168 was calculated for peginterferonlfa-2a.

Pharmacokinetic characteristics of peginterferonlfa-2a and methadone were evaluated by model-ndependent analysis by use of WinNonlin Pro (version.0; Pharsight Corporation, Mountain View, Calif). Ac-ual sampling times rather than scheduled samplingimes were used in all analyses. For individual pegin-erferon alfa-2a profiles with measurable baseline con-entrations, all data for the subject were excluded if theaseline concentration exceeded 1000 pg/mL. If theaseline value was less than 1000 pg/mL, subsequentalues were adjusted for the baseline concentration byubtracting the baseline value from the measured value.fter adjustment, if the value was below the limit ofuantitation, it was excluded from the analysis.The slope of the terminal log-linear portion of each

eginterferon alfa-2a and methadone concentration-ime profile was determined by least squares linearegression. The log-linear trapezoidal method with ex-rapolation beyond the last experimental concentrationalue was used to determine AUC0-�.The total apparent clearance of methadone (CLss/F)

as calculated as Dose/AUC0-24; the apparent volumef distribution of methadone (Vz/F) was estimated asose/(Terminal slope � AUC0-�).Dose-normalized methadone pharmacokinetic pa-

ameters were used to compare the Cmax and AUC ofethadone at baseline and during week 4; the param-

ters were normalized to a 100-mg dose.Pharmacodynamic parameters. 2�,5�-OAS is an im-

ortant effector of interferon-induced antiviral effects,nd the serum activity of this enzyme is widely used asn indicator of interferon activity. Calculations of the
ollowing parameters were based on week-1 measure-

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ents of 2�,5�-OAS data: observed maximum activityOASmax), time to OASmax (tmax), observed last activityOASlast), time to OASlast (tlast), and area beneath theffect curve at the last time point (ABEClast).

Serum 2�,5�-OAS activity–time profiles were ana-yzed with noncompartmental methods by use of Win-onlin Pro (version 4.0). The log-linear trapezoidalethod was used to determine ABEClast. For individual

rofiles with measurable baseline 2�,5�-OAS activity,ubsequent values were adjusted for the baseline con-entration by subtracting the baseline value from theeasured value. After adjustment, if the value was

elow the limit of quantitation, it was excluded fromhe analysis.

Statistical analysis. No formal sample size calcula-ion was made. A planned enrollment of 24 patientsas established, with the expectation that 18 individu-

ls would complete the study.A 90% confidence interval (CI) for the true ratio of

eek 4 to baseline for the Cmax and AUC0-24 of meth-done and a 90% CI for the true difference betweeneans for the tmax of methadone were calculated. The

esidual mean square error from an ANOVA was useds the estimate of variance for the CI.

ESULTSA total of 24 patients were enrolled in the study, 22

f whom received 4 doses of peginterferon alfa-2a andompleted the pharmacokinetic portion of the study.ata from 2 patients who received only 3 doses ofeginterferon alfa-2a were excluded from the pharma-okinetic analyses. In addition, pharmacokinetic dataor peginterferon alfa-2a from 2 further patients werexcluded because of analytic artifacts. All patients werencluded in the safety analysis. The baseline character-stics of the patients are presented in Table I. The mean

able I. Baseline characteristics of 24 patientsnrolled in study

Characteristic No.

Male/female 15/9Race (white/black/other) 13/6/5Age (y) (median and range) 49.5 (33-61)Weight (kg) (median and range) 78.5 (52-129)Height (cm) (median and range) 170 (137-185)Body mass index (kg/m2) (median

and range)26.9 (19.1-48.9)

Methadone dose (mg/d) (medianand range)

95 (30-150)

ethadone dose at baseline was 88 mg/d. a

harmacokinetic resultsInfluence of peginterferon alfa-2a on pharmacoki-

etics of methadone. Methadone exposure after 4oses of peginterferon alfa-2a increased by 10% to 15%hen compared with baseline (Table II). However, the0% CIs for the ratio of the mean Cmax and AUC0-24 ataseline and during week 4 were 1.02 to 1.22 and 1.08o 1.23, respectively, which fell within the generallyccepted equivalence interval of 0.80 to 1.25, indicat-ng no significant effect of peginterferon alfa-2a on theharmacokinetics of methadone (Table II).Paired values for Cmax and AUC0-24 for methadone

re presented for each patient in Fig 1, A and B,espectively. Intersubject variabilities at baseline anduring week 4 were 36% and 34%, respectively, for

max and 28% and 33%, respectively, for AUC0-24. Ofhe patients, 8 of 22 (36%) and 16 of 21 (76%) hadigher individual Cmax and AUC0-24 values, respec-ively, during week 4 than at baseline.

The mean 24-hour serum concentration profile forethadone (normalized to a 100-mg dose) at baseline

ig 1. Individual dose-normalized maximum serum concen-ration (Cmax) (A) and area under concentration-time curverom time 0 to 24 hours (AUC0-24) (B) for methadone ataseline and during week 4.

nd during week 4 is presented in Fig 2. Methadone

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All patients continued to receive stable doses ofethadone throughout the study.Influence of methadone on pharmacokinetics of

eginterferon alfa-2a. Three patients had detectableredose concentrations of peginterferon alfa-2a, andubsequent determinations were adjusted before analy-is. The intersubject variability of Cmax was 38% andhat of AUC0-168 was 39% after the first dose of pegin-erferon alfa-2a, and it was 42% for both parametersuring week 4.Single- and multiple-dose pharmacokinetic data for

eginterferon alfa-2a in patients receiving methadoneaintenance therapy are presented in Table III. Theean accumulation ratios (week 4/first dose) for Cmax

able II. Methadone noncompartmental pharmacokine

Parameter

tmax (h) 2.Cmax (ng/mL)* 70AUClast (ng · h/mL)* 10,67AUC0-24 (ng · h/mL)*† 10,57CLss/F (L/h)† 1Vz/F (L)‡ 63Geometric least squares means

Cmax (ng/mL)Week 4/baseline (mean and 90% CI)

AUC0-24 (ng · h/mL)†Week 4/baseline (mean and 90% CI)

Values are given as mean SD with 95% CI, unless otherwise indicated.tmax, Time to maximum serum concentration; Cmax, maximum serum co

oncentration; AUC0-24, area under concentration-time curve from time 0 toonfidence interval.

*Individual parameter estimates were normalized to a 100-mg dose.†n � 21.‡n � 20.

able III. Single- and multiple-dose peginterferon alfatients receiving stable methadone maintenance thera

Parameter Firs

tmax (h) 84 Cmax (ng/mL) 14.4 tlast (h) 167 Clast (ng/mL) 9.9 AUClast (ng · h/mL) 1769 AUC0-168 (ng · h/mL) 1788 Accumulation ratio: Cmax

Accumulation ratio: AUC0-168

Values are given as mean SD with 95% CI.tlast, Time of last observed serum concentration; Clast, serum concentration fro

A, not applicable.

nd AUC0-168 were 2.1 (90% CI, 1.62-2.58) and 2.3 t

90% CI, 1.82-2.78), respectively. Values for peginter-eron alfa-2a during week 1 and week 4 reveal a generalncrease during the study (Fig 3).

harmacodynamic resultsMean 2�,5�-OAS activity at baseline and after the

rst (week 1) and last doses of peginterferon alfa-2aweek 4) are presented in Fig 4. A summary of 2�,5�-AS activity parameters is presented in Table IV. The

nduction of 2�,5�-OAS activity in methadone recipi-nts was similar to that previously reported in subjectsot receiving methadone maintenance therapy.Of 24 patients, 12 (50%) had either a greater than

-log10 decrease in serum HCV RNA levels or unde-ectable serum HCV RNA levels after 4 weeks of

ameters

(n � 22) Week 4 (n � 22)

(2.2-3.6) 2.6 1.0 (2.2-3.0)(595-807) 774 266 (663-885)4 (9428-11,914) 12,511 4300 (10,714-14,308)2 (9288-11,864) 12,576 4153 (10,841-14,311).9-12.2) 9 4 (7.3-10.7)(397-871) 616 574 (376-856)

56.7 731.3.02-1.22)063.9 11,602.3.08-1.23)

; AUClast, AUC between time 0 and the time of the last observed serumCLss/F, total apparent clearance; Vz/F, apparent volume of distribution; CI,

ncompartmental pharmacokinetic parameters in

� 22) Week 4 (n � 20)

98) 78 24 (67-89).1-16.7) 26.0 10.9 (21.2-30.8)9-169.1) 168 0.5 (167.8-168.2)-11.8) 15.9 6.3 (13.1-18.7)89-2049) 3459 1451 (2823-4095)95-2081) 3515 1463 (2874-4156)

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eek-4 responders, 8 had HCV RNA levels below theimit of quantitation of the assay by week 4.

afetyA total of 123 adverse events were reported by 20

Fig 2. Mean dose-normalized methadone seruweek 4 after 4 180-�g doses of peginterferon

Fig 3. Mean serum concentration of peginterfdose intervals.

atients (83%). The most common adverse events were �

hose typically associated with conventional interferonr pegylated interferon administration (ie, flulike symp-oms). Of the patients, 4 (17%) had a neutrophil countf less than 0.75 � 109/L at some point during the trialut no patient had a neutrophil count of less than 0.50

ntration (Conc) (SD) at baseline and during.

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ess than 50 � 109/L at some point during the trial buto patient had a platelet count of less than 20 � 109/L.here were no serious adverse events, and no patientsithdrew prematurely because of adverse events or

aboratory abnormalities. In addition, no subject hadlinical signs or symptoms of intoxication or with-rawal related to methadone.

ISCUSSIONThe results of our study demonstrate that peginter-

eron alfa-2a does not influence the pharmacokineticsf methadone to a clinically significant extent in pa-ients receiving ongoing methadone maintenance ther-py. Baseline pharmacokinetic and pharmacodynamicata for peginterferon alfa-2a in the absence of meth-done administration were not available for the patientsnrolled in our study; however, the pharmacokineticrofile of peginterferon alfa-2a in these individuals wasenerally similar to that observed previously in healthyolunteers and patients with chronic hepatitis C.29-32

The pharmacokinetic values for racemic methadoneeported in our study (normalized to 100 mg) compareell with those reported previously in opiate users

normalized to 10 mg14 or 70 mg16). It must be noted

Fig 4. Mean serum 2�,5�-oligoadenylate synthduring week 1, and during week 4.

hat we did not evaluate the pharmacokinetic properties i

f the active R-isomer of methadone, so it is not pos-ible to comment on the impact of peginterferon alfa-2an the pharmacokinetics of this entity. We also did notonitor �1-acid glycoprotein levels, which have an

nfluence on the plasma pharmacokinetics of the drug.15

As anticipated, the mean serum concentrations ofeginterferon alfa-2a were higher during week 4 thanuring week 1. This agent has a long elimination half-ife and, as a result, does not reach steady-state levelsntil 6 to 8 weeks after the initiation of weekly admin-

Table IV. Summary of baseline-adjusted2�,5�-oligoadenylate synthetase activity at week 1 (N� 24)

Parameter Mean

tmax (h) 98 49 (78-118)2�,5�-OASmax (nmol/L · h�1) 2.9 1.5 (2.3-3.5)tlast (h) 162 13 (157-167)2�,5�-OASlast (nmol/L · h�1) 2.1 1.2 (1.6-2.6)ABEClast (nmol/L) 253 139 (197-309)

Values are given as mean SD with 95% CI.2�,5�-OASmax, Observed maximum 2�,5�-oligoadenylate synthetase activity;

2�,5�-OASlast, observed last 2�,5�-oligoadenylate synthetase activity; ABEClast,area beneath effect curve at last time point.

AS) activity-time profiles (SD) at baseline,
etase (O
stration. The accumulation ratios (steady-state concen-

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ration/maximum concentration after 1 dose) reportedreviously have been approximately 2 to 3.29,32 Thusur finding of an accumulation ratio of approximately 2fter 4 weeks of weekly dosing is in line with ourxpectations.

The biologic response to peginterferon alfa-2a, asssessed by 2� 5�-OAS activity, was similar in patientseceiving ongoing methadone maintenance therapy inur study and in healthy subjects enrolled in previoustudies.31,33 The decrease in HCV RNA levels duringhe first 4 weeks of treatment with peginterferon alfa-2aas typical of that seen in chronic hepatitis C patientsho are not receiving methadone maintenance therapy,

nd one half of the patients had a substantial reductionn HCV RNA after only 4 doses of peginterferon alfa-a.34

Peginterferon alfa-2a monotherapy was well toler-ted during methadone maintenance therapy in patientsith chronic hepatitis C, and no serious adverse eventsere observed. The spectrum and frequency of adverse

vents were similar to those reported in patients withhronic hepatitis C who were not receiving methadonen a phase III trial,35 although it must be acknowledgedhat the patients in our trial were monitored for only 4eeks.There are several limitations to our study. As noted,

e evaluated patients during an abbreviated course ofreatment with peginterferon alfa-2a monotherapyather than for the full 48-week duration recommendedor the treatment of chronic hepatitis C at the time thetudy was planned. However, the 4-week treatmenteriod was sufficient to confirm whether peginterferonlfa-2a interfered with the pharmacokinetics of metha-one and to determine whether the pharmacodynamicsf peginterferon alfa-2a was impaired by methadone.hus, although the most important therapeutic endoint in patients with chronic hepatitis C is the eradi-ation of HCV infection, our study was not designedith sufficient statistical power to examine sustainedirologic response rates. In addition, it must be notedhat therapy for chronic hepatitis C has continued tovolve since our study was conceived, and the currentreatment of choice is the combination of pegylatednterferon plus ribavirin.7 Thus it remains to be deter-ined whether ribavirin has any influence on the phar-acokinetics of methadone.These limitations notwithstanding, our data provide

mportant information to clinicians treating the rela-ively large population of HCV-infected persons receiv-ng methadone maintenance therapy worldwide. De-pite the size of the population, patients with chronic
epatitis C who are receiving methadone maintenance r
herapy have been understudied, a problem that wasecognized by the US National Institutes of Healthonsensus Panel in their 2002 recommendations for theanagement of chronic hepatitis C.7 However, there is

ncreasing interest in the treatment of hepatitis C inethadone recipients, and recent studies have sug-

ested that sustained viral response rates in patientseceiving methadone maintenance therapy are similaro those observed in other HCV-infected patient popu-ations. For example, among patients included in aarge, retrospective, matched cohort study, Van Thiel etl36 reported that sustained virologic response ratesere similar in patients receiving methadone mainte-ance therapy and in patients without a history ofntravenous drug use after treatment with daily conven-ional interferon (33% and 37%, respectively). Interest-ngly, the researchers observed that the methadone doseas increased in some patients during treatment with

onventional interferon alfa. However, consistent withur findings, the authors reported that these increases inethadone dose generally represented the use of meth-

done to treat side effects of conventional interferonather than a response to clinical evidence of a phar-acokinetic interaction. Similarly, in an interim anal-

sis of 50 methadone maintenance patients treated withonventional interferon plus ribavirin, Sylvestre37 re-orted that the end-of-treatment response rate was sim-lar to that of patients without a history of injection drugse. It must be noted that we did not observe a similarncrease in methadone doses during our study. Amaller, prospective, open-label German study has alsoeported success in treating intravenous drug users en-olled in a detoxification program with conventionalnterferon-based therapy.38 Although preliminary, thesencouraging results suggest that patients with a recentistory of injection drug use, particularly those under-oing stable methadone maintenance therapy, can beuccessfully treated for hepatitis C with interferon-ased regimens.In conclusion, our data indicate that peginterferon

lfa-2a does not appreciably alter the pharmacokineticsf methadone. Thus concurrent treatment with metha-one is not a contraindication to therapy with peginter-eron alfa-2a for chronic hepatitis C. Although theecision to treat a patient who is using illicit drugshould be made by the patient after consulting with hisr her physician, this decision need not be influencedy the use of methadone maintenance therapy, and ariori adjustment of either the methadone or the pegin-erferon alfa-2a dose is not recommended in patients
eceiving stable methadone maintenance therapy who

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ndergo treatment for chronic hepatitis C with pegin-erferon alfa-2a–containing regimens.

Drs Sulkowski and Arora have received research grants fromoche. Dr Wright has no potential conflicts of interest. Dr Yalaman-hili is a former employee of Roche. Drs Rossi, Lamb, Wang, andries are currently employed by Roche.

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Documents

Peginterferon Alfa-2a Does Not Alter the Pharmacokinetics of Methadone in Patients with Chronic Hepatitis C Undergoing Methadone Maintenance Therapy*