No statistically signif-icant difference P > 0.10 was noted between subjects receiving methadone alone and subjects receiving DTG + methadone for change from baseline in overall opiate
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j o u r n a l h o m e p a g e : w w w e l s e v i e r c o m / l o c a t e / d r u g a l c d e p
Short communication
Ivy Song a , Stephen Mark b , Shuguang Chen a , Paul Savina a , Toshihiro Wajima c ,
Amanda Peppercorn a , Urmilla Bala d , Pierre Geoffroy d , Stephen Piscitelli a,∗
Available online 26 August 2013
Keywords:
Dolutegravir
Methadone
Pharmacokinetics
Background:Dolutegravir(DTG)isaninvestigationalintegraseinhibitorfortreatmentofHIVinfection
AsintravenousdruguseisacommonriskfactorforHIV,thisstudyevaluatedtheeffectofDTGonthe pharmacokinetics(PK)ofmethadone
Methods:Thiswasanopen-label,2-periodstudyinadult,opioid-dependent,HIV-seronegativesubjects Subjectsreceivedtheircurrentindividualmethadonedosesoncedailyfor3days(Period1)followed
byDTG50mgtwicedaily(BID)for5dayswhilecontinuingtheirstablemethadonetherapy(Period 2).SerialPKsamplesforR-andS-methadonewerecollectedaftereachPeriod.Pharmacodynamic(PD) measuresandsafetyassessmentswereobtainedthroughoutthestudy.Non-compartmentalPKanalysis wasperformed,andgeometricleast-squaresmeanratiosand90%confidenceintervalsweregenerated Results:Plasmaexposuresoftotal,R-,andS-methadonewerenotaffectedbyco-administrationofDTG MeanratiosforAUCwere0.98,0.95,and1.01fortotal,R-,andS-methadone,respectively,alonecompared withincombinationwithDTG.Nostatisticallysignificantdifferenceswerenotedbetweenthe2treatment periodsinmethadonePDmeasures.ThecombinationofDTGandmethadonewaswelltolerated.No deaths,seriousadverseevents,orgrade3/4adverseeventsoccurred.Noclinicallysignificantchangesin laboratoryvalues,vitalsigns,orelectrocardiogramswereobserved
Conclusion:Co-administrationofmethadonewithrepeatdosesofDTG50mgBIDhadnoeffectontotal, R-,andS-methadonePKoronmethadone-inducedPDmarkers.Nodoseadjustmentinmethadoneis requiredwhengivenincombinationwithDTG
© 2013 Elsevier Ireland Ltd All rights reserved
1 Introduction
Intravenous drug use remains a significant risk factor for HIV
infection (Lansky et al., 2010) As such, methadone is commonly
given for the treatment of opioid dependence in combination with
antiretroviral drugs However, co-administration is often
compli-cated by drug interactions between HIV treatments and methadone
(Kharasch et al., 2009; Stocker et al., 2004; McCance-Katz et al.,
2003) Antiretrovirals without significant drug interactions may be
advantageous in this population.
Dolutegravir (DTG) is an integrase inhibitor with demonstrated
activity in HIV-infected patients (Raffi et al., 2013; Eron et al., 2013).
DTG is primarily metabolized via UDP-glucuronosyltransferase
(UGT) 1A1 with a minor component of CYP3A4 It demonstrates minimal or no direct inhibition of various CYP isozymes, UGTs, and transporters and is not a metabolic inducer (Reese et al., 2013) Methadone is metabolized by multiple isozymes, includ-ing CYP2B6, CYP2D6, and CYP2C19, while CYP3A4 also plays a role (Shiran et al., 2009).
Despite the low potential for an interaction, there is a high like-lihood for combination use, warranting an evaluation of DTG to alter plasma concentrations of methadone Also, since methadone demonstrates no inhibition or induction effects on UGTs or CYPs, this study only evaluated the effect of DTG on methadone and not vice versa.
2 Methods
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Hours
R-Methadone Methadone Alone R-Methadone DTG + Methadone S-Methadone Methadone Alone S-Methadone DTG + Methadone Total Methadone Methadone Alone Total Methadone DTG + Methadone
3 Results
3.1 Demographics Twelve subjects were enrolled and 11 completed the study One subject was withdrawn due to an AE The mean age was 34.5 years (SD, 6.11) A similar number of males and females were enrolled (6 male, 5 female) All subjects were white Methadone doses ranged from 16 to 150 mg.
3.2 Pharmacokinetics Plasma PK profiles of R-, S-, and total methadone alone and
in combination with DTG are shown in Fig 1 Exposures of total,
Table 1
RatioofGLSmeans(90%CI)
AUCratio Totalmethadone
BvsA
0.98 (0.91,1.06)
1.00 (0.94,1.06)
0.97 (0.89,1.05)
0.99 (0.91,1.07)
0.98 (0.91,1.06)
1.02 (0.95,1.09)
NA R-methadone
BvsA
0.95 (0.89,1.02)
0.97 (0.91,1.03)
0.94 (0.87,1.01)
0.95 (0.89,1.02)
0.95 (0.89,1.01)
1.05 (0.98,1.12)
0.94 (0.92,0.97) S-methadone
BvsA
1.01 (0.93,1.09)
1.03 (0.97,1.10)
1.00 (0.90,1.10)
1.02 (0.93,1.12)
1.01 (0.92,1.12)
0.99 (0.92,1.07)
NA TreatmentA:Stableindividualonce-dailymethadonedose.TreatmentB:DTG50mgBID×5days+stableindividualmethadonedose.BID,twicedaily;CI,confidenceinterval;
Trang 3R-, and S-methadone were not affected by co-administration of
( Table 1) The ratio of R-/S-methadone when methadone was given
with DTG compared with methadone alone was 0.94, suggesting
that co-administration with DTG did not affect the proportion of
each isomer Geometric mean (coefficient of variation) PK
param-eters of DTG were 44.3 (37) g h/mL for AUC(0−), 4.88 (35) g/mL
for Cmax, and 2.63 (37) g/mL for C.
3.3 Pharmacodynamics
3.3.1 Opiate agonist and withdrawal scores No statistically
signif-icant difference (P > 0.10) was noted between subjects receiving
methadone alone and subjects receiving DTG + methadone for
change from baseline in overall opiate agonist and withdrawal
scores The change from baseline in overall opiate agonist score
was 4.52 for methadone alone and 4.48 for the combination, with a
mean difference (combination minus methadone alone) in change
from baseline of −0.05 (SD, 31.0; 90% CI for the mean difference,
−58.69 to 58.59) The change from baseline in overall withdrawal
score was -56.3 for methadone alone and −40.8 for the
combina-tion, with a mean difference (combination minus methadone alone)
in change from baseline of 15.6 (SD, 12.1; 90% CI for the mean
difference, −6.77 to 37.9).
3.3.2 Pupillometry No significant difference in change from
base-line in pupillometry scores was noted between subjects receiving
methadone compared with DTG + methadone The change from
baseline in minimum pupil diameter was −1.47 for methadone
alone and −1.48 for the combination (point estimate −0.01; 90%
CI, −0.30 to 0.28) No significant difference in pupillometry area
over the effect curve was also noted between subjects receiving
methadone compared with DTG + methadone At all time points
evaluated, 90% CIs around the point estimate of test minus
refer-ence (combination minus methadone alone) included the value of
zero.
3.4 Safety
There were no serious or grade 3/4 AEs The most
com-monly reported drug-related AEs were headache (27%) and fatigue
(18%) All drug-related AEs were reported in subjects
receiv-ing DTG + methadone Two subjects experienced drug-related AEs
that were moderate (grade 2) in intensity One subject
experi-enced moderate dizziness Another subject experienced moderate
headache, hematuria, and panic attack and was withdrawn from
the study; the AE resolved after 1 day The subject did not
expe-rience any pain with the hematuria and was referred for an
ultrasound and to a urologist No treatment-related or clinically
significant trends in hematology or clinical chemistry values were
observed in the study No clinically significant abnormal
electro-cardiogram values or changes in vital signs were observed.
4 Discussion
Methadone is administered as a chiral mixture of R and S
isomers in which the opioid effect is primarily mediated through
R-methadone (Eap et al., 2002) The addition of DTG to individualized
stable methadone therapy had no effect on total, R-, and
S-methadone PK Additionally, the AUC ratios of R- and S-methadone
showed no significant differences between the 2 treatments,
sug-gesting an absence of a stereo-specific effect of DTG These results
were consistent with previous studies, which showed slightly
lower R-methadone compared with S-methadone exposures (Cao
et al., 2008; Crauwels et al., 2010; Van Heeswijk et al., 2011) The AUC difference between these 2 isomers was approximately 10% The results of this study are consistent with previous data show-ing DTG does not affect other drugs that are metabolized by CYP3A, such as midazolam and oral contraceptives (Song et al., 2013; Min
et al., 2011) These negative findings are important for clinicians to guide dosing of DTG in subjects in methadone maintenance pro-grams.
DTG PK parameters observed in this study were comparable to other DTG PK studies in which DTG was administered BID (Dooley
et al., 2013; Koteff et al., 2013) Given the limitations of a cross-study comparison, there did not appear to be a significant effect of methadone on DTG PK An additional limitation of the study was the small sample size However, the low to moderate variability of methadone and cross-over design of the study support the findings.
PD measurements were incorporated in the event that DTG significantly altered the PK of methadone Even in the presence
of PK differences, PD evaluations can determine whether differ-ences in exposure translate to clinically significant effects Two
PD measurements were employed in this study, the Opioid Symp-tom Questionnaire and pupillometry Overall, co-administration of repeat doses of DTG had no effect on the PD parameters There were no statistically significant differences noted between sub-jects receiving methadone alone and subjects receiving DTG plus methadone for change from baseline in overall opiate agonist and withdrawal scores No significant differences were also noted between treatment periods in pupillometry scores.
No differences were observed in either PK or PD measure-ments, demonstrating the lack of interaction between DTG and methadone These data demonstrate that no dose adjustments in methadone are required when DTG is co-administered.
Role of funding source
Funding for this study was provided by ViiV Healthcare and was involved in the design of the study and review of the manuscript The writing of the manuscript and the decision to submit the paper for publication was the responsibility of the authors.
Contributors
SP, IS, SC, and SM designed the study and wrote the protocol with input from UB and PG SP and PS managed the literature searches and summaries of previous related work SC undertook the statis-tical analysis, and SP wrote the first draft of the manuscript IS,
SM, SC, PS, TW, AP, UB, PG, and SP participated in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication All authors contributed to and have approved the final manuscript.
Conflict of interest
IS, SM, SC, PS, AP, and SP are employees of GlaxoSmithKline and have stock ownership TW is an employee of Shionogi & Co., Ltd UB and PG have no actual or potential conflicts of interest.
Acknowledgements
The authors wish to acknowledge the following individual for editorial assistance during the development of this manuscript: Gina Uhlenbrauck.
References
Trang 4Pharmacokineticsandpharmacodynamicsofmethadone enantiomersafter
coadministrationwithfosamprenavir-ritonavirinopioid-dependentsubjects
Pharmacotherapy28,863–874
Next-GenerationNNRTI,andMethadone.In:Presentedatthe11thInternational
WorkshoponClinicalPharmacologyofHIVTherapy,Sorrento,Italy,7–9April
theHIVintegraseinhibitordolutegravirgiventwicedailywithrifampinoronce
dailywithrifabutin:resultsofaphase1studyamonghealthysubjects.J.Acquir
ImmuneDefic.Syndr.62,21–27
clini-calpharmacokineticsofmethadone:implicationsforthetreatmentofopioid
dependence.Clin.Pharmacokinet.41,1153–1193
treatment-experiencedsubjectswithraltegravir-resistantHIVtype1infection:
24-weekresultsoftheVIKINGstudy.J.Infect.Dis.207,740–748
Methadonemetabolismandclearanceareinducedbynelfinavirdespite
inhi-bitionofcytochromeP4503A(CYP3A) activity.DrugAlcoholDepend.101,
158–168
renalfunctionviameasurementofiohexolandpara-aminohippurateclearance
inhealthysubjects.Br.J.Clin.Pharmacol.75,990–996
Epi-demiologyofHIVintheUnitedStates.J.Acquir.ImmuneDefic.Syndr.55(suppl
2),S64–S68
inhibitorlopinavir-ritonavirmayproduceopiatewithdrawalin
methadone-maintainedpatients.Clin.Infect.Dis.37,476–482
activ-ity,safety,andpharmacokinetics/pharmacodynamicsofdolutegraviras10-day monotherapyinHIV-1-infectedadults.AIDS25,1737–1745
raltegravirinantiretroviral-naiveadultswithHIV-1infection:48weekresults fromtherandomised,double-blind,non-inferioritySPRING-2study.Lancet381, 735–743
intotherolesofdrugtransportersandmetabolizingenzymesinthedisposition anddruginteractionsofdolutegravir,aHIVintegraseinhibitor.DrugMetab Dispos.41,353–361
CYP1A2andotherpotentialcovariatestothedispositionofmethadonein patientsundergoingmethadonemaintenancetreatment.Br.J.Clin.Pharmacol
67,29–37
Dolutegravirhasnoeffectonthepharmacokineticsofmethadoneororal contra-ceptiveswithnorgestimateandethinylestradiol.In:AbstractJ-102Presented
atthe20thConferenceonRetrovirusesandOpportunisticInfections,Atlanta,
GA,March3–6,pp.3–6
signif-icantlyreducesthelevelsofracemicmethadoneand(R)-methadoneinhuman immunodeficiencyvirus-infectedpatients.Antimicrob.AgentsChemother.48, 4148–4153
inter-actionbetweenmethadoneandtheinvestigationalHCVproteaseinhibitor telaprevir.J.Hepatol.54(suppl.1),S491–S492