dolutegravir does not affect methadone pharmacokinetics in opioid dependent hiv seronegative subjects

Drug and Alcohol Dependence 133 (2013) 781–784 Contents lists available at ScienceDirect Drug and Alcohol Dependence journal homepage: www.elsevier.com/locate/drugalcdep Short communication Dolutegravir does not affect methadone pharmacokinetics in opioid-dependent, HIV-seronegative subjects 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,∗ a GlaxoSmithKline, Moore Drive, Research Triangle Park, NC 27709, USA GlaxoSmithKline, 7333 Mississauga Road, Mississauga, ON, Canada L5N 6L4 c Shionogi & Co., Ltd., 1-8, Doshomachi 3-chome, Chuo-ku, Osaka 541-0045, Japan d INC Research, 720 King Street West, Toronto, ON, Canada M5V 2T3 b a r t i c l e i n f o Article history: Received May 2013 Received in revised form 13 August 2013 Accepted 14 August 2013 Available online 26 August 2013 Keywords: Dolutegravir Methadone Pharmacokinetics Drug interaction a b s t r a c t Background: Dolutegravir (DTG) is an investigational integrase inhibitor for treatment of HIV infection As intravenous drug use is a common risk factor for HIV, this study evaluated the effect of DTG on the pharmacokinetics (PK) of methadone Methods: This was an open-label, 2-period study in adult, opioid-dependent, HIV-seronegative subjects Subjects received their current individual methadone doses once daily for days (Period 1) followed by DTG 50 mg twice daily (BID) for days while continuing their stable methadone therapy (Period 2) Serial PK samples for R- and S-methadone were collected after each Period Pharmacodynamic (PD) measures and safety assessments were obtained throughout the study Non-compartmental PK analysis was performed, and geometric least-squares mean ratios and 90% confidence intervals were generated Results: Plasma exposures of total, R-, and S-methadone were not affected by co-administration of DTG Mean ratios for AUC were 0.98, 0.95, and 1.01 for total, R-, and S-methadone, respectively, alone compared with in combination with DTG No statistically significant differences were noted between the treatment periods in methadone PD measures The combination of DTG and methadone was well tolerated No deaths, serious adverse events, or grade 3/4 adverse events occurred No clinically significant changes in laboratory values, vital signs, or electrocardiograms were observed Conclusion: Co-administration of methadone with repeat doses of DTG 50 mg BID had no effect on total, R-, and S-methadone PK or on methadone-induced PD markers No dose adjustment in methadone is required when given in combination with DTG © 2013 Elsevier Ireland Ltd All rights reserved 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 complicated 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, including 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 likelihood 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 Methods ∗ Corresponding author Tel.: +1 919 483 2523; fax: +1 919 315 0151 E-mail address: stephen.c.piscitelli@gsk.com (S Piscitelli) 0376-8716/$ – see front matter © 2013 Elsevier Ireland Ltd All rights reserved http://dx.doi.org/10.1016/j.drugalcdep.2013.08.009 This was an open-label, study in adult subjects who were identified at local methadone clinics and referred to the clinical study site Subjects were required to be on a stable dose of methadone at least 14 days prior to the pre-screening visit and had to remain on the current dose for the duration of the study Written informed I Song et al / Drug and Alcohol Dependence 133 (2013) 781–784 consent was obtained from all subjects, and the study was approved by IRB Services, Ontario, Canada (ClinicalTrials.gov registry number NCT01467518) Subjects had a pre-screening visit within 30 days prior to the first dose of the study drug, treatment periods, and a follow-up visit to 14 days after the last dose Subjects received their individual doses of methadone once daily for days (Period 1) followed by DTG 50 mg BID for days to achieve steady-state while continuing on their stable methadone therapy (Period 2) Subjects were housed in the unit during treatment periods DTG has been administered as 50 mg QD or 50 mg BID in phase III trials However, the 50 mg twice daily regimen was selected in this study to maximize the chance of finding an interaction Adult male and female subjects who were HIV and hepatitis C virus seronegative, 18–65 years of age, and enrolled in a methadone maintenance program for at least 12 weeks were eligible The subject’s methadone dose had to have been unchanged for 14 days prior to the pre-screening visit and had to be ≤200 mg per day Subjects were judged to be healthy by physical exam, medical history, and laboratory testing (complete blood count, hepatic function, electrolytes, creatinine, BUN) Subjects were permitted to use concomitant medications that were considered medically necessary and were not expected to affect DTG pharmacokinetics (PK) Safety was assessed by adverse event (AE) reporting and by clinical and laboratory evaluations throughout the study and at follow-up Serial PK samples for R- and S-methadone were collected on Period Day and Period Day after an 8-h fast at pre-dose, and then 1, 2, 3, 4, 6, 8, 12, 16, and 24 h after dosing PK samples for DTG were collected pre-dose and then 1, 2, 3, 4, 6, 8, and 12 h after dosing The Opioid Symptom Questionnaire and pupillometry were employed as pharmacodynamic (PD) measures The summations were reported as the overall opiate agonist and withdrawal scores The questionnaire was administered on the PK days at the pre-dose and h post-dose time points in both Periods and A NeurOptics pupillometer (Irvine, CA, USA) was used to measure the mean pupil diameter for one eye Data from a series of frames were used in the calculation, and the final display showed the weighted average and standard deviation (SD) of the pupil size Measurements were collected under mesopic lighting conditions The right eye was used for all assessments If the right eye could not be scanned, the left eye was used Assessments were done on PK days at time points 0, 1, 3, 6, 12, and 24 h 2.1 Analytical methods Plasma DTG was extracted by protein precipitation with acetonitrile containing the internal standard [15N2H7] DTG, injected onto a 2.1 mm × 50 mm, 3.5-␮m XBridge C18 column (Waters Associates, Milford, MA, USA) and eluted with a mobile phase of 40% acetonitrile in aqueous 0.1% formic acid Plasma R- and Smethadone, and their internal standard, [2H9](±) methadone, were extracted by supported liquid extraction (ISOLUTE SLE+; Biotage, Uppsala, Sweden), injected onto a 2.0 mm × 50 mm, 5-␮m Chiral-AGP column (Chrom Tech, Apple Valley, MN, USA), and eluted with 12% isopropyl alcohol in 10 mM ammonium acetate The eluates for DTG, R-methadone, and S methadone were detected by a triple quadrupole API 4000 mass spectrometer (AB Sciex, Framingham, MA, USA) using the positive ion mode and multiple reaction monitoring Data acquisition and processing were performed with Analyst 1.4.2 software (AB Sciex) using the validated calibration ranges of 0.020–2 ␮g/mL for DTG, and 0.005–1 ␮g/mL for R- and S-methadone Total methadone concentrations were calculated by summation of the R- and Smethadone concentrations The bias from the analysis of these study QC samples was −5.1 to 4.8% for DTG, −3.3 to 0.9% for R-methadone, and 2.0 to 4.9% for S-methadone The precision for all analytes was ≤3.3% 2.2 Pharmacokinetic and statistical analyses A sample size of 12 to obtain 10 evaluable subjects was chosen based on an expected withdrawal rate of approximately 20% and the within-subject variability of methadone Non-compartmental PK analyses using WinNonlin, version 6.1 (Pharsight, Cary, NC, USA), were performed to determine parameters for methadone, methadone isomers, and DTG, including area under the concentration–time curve from time zero until the end of the dosage interval (AUC(0−␶) ), maximum R-Methadone Methadone Alone R-Methadone DTG + Methadone Mean plasma methadone concentration (ng/mL) 782 450 S-Methadone Methadone Alone 400 S-Methadone DTG + Methadone 350 Total Methadone Methadone Alone 300 Total Methadone DTG + Methadone 250 200 150 100 50 0 12 16 20 24 Hours Fig Mean concentration–time profiles of R-, S-, and total methadone alone and in combination with DTG DTG, dolutegravir concentration (Cmax ), and concentration at the end of the dosage interval (C␶ ) Logtransformed PK parameters of R-methadone, S-methadone, and total methadone were calculated using mixed linear effects model (SAS 9.1; Cary, NC, USA) considering treatment as a fixed effect and subjects as a random effect Geometric least-squares mean ratios for DTG plus methadone and methadone alone and associated 90% confidence intervals (CIs) were estimated Change from baseline in overall opiate agonist and withdrawal scores, change from baseline in minimum pupil diameter, and pupillometry area over the effect curve, calculated using a mixed linear effects models (SAS 9.1), were used to test within-subject differences across study days (effect of DTG) 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, 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 Exposures of total, Table Statistical summary of methadone pharmacokinetic parameters Ratio of GLS means (90% CI) Total methadone B vs A R-methadone B vs A S-methadone B vs A AUC(0−␶) Cmax C0 C␶ Cmin CL/F R-/S-methadone AUC ratio 0.98 (0.91, 1.06) 0.95 (0.89, 1.02) 1.01 (0.93, 1.09) 1.00 (0.94, 1.06) 0.97 (0.91, 1.03) 1.03 (0.97, 1.10) 0.97 (0.89, 1.05) 0.94 (0.87, 1.01) 1.00 (0.90, 1.10) 0.99 (0.91, 1.07) 0.95 (0.89, 1.02) 1.02 (0.93, 1.12) 0.98 (0.91, 1.06) 0.95 (0.89, 1.01) 1.01 (0.92, 1.12) 1.02 (0.95, 1.09) 1.05 (0.98, 1.12) 0.99 (0.92, 1.07) NA 0.94 (0.92, 0.97) NA Treatment A: Stable individual once-daily methadone dose Treatment B: DTG 50 mg BID × days + stable individual methadone dose BID, twice daily; CI, confidence interval; DTG, dolutegravir; GLS, geometric least-squares; PK, pharmacokinetic I Song et al / Drug and Alcohol Dependence 133 (2013) 781–784 R-, and S-methadone were not affected by co-administration of DTG 50 mg BID Geometric mean ratios were approximately 1.0, and all 90% CIs were within 0.8 and 1.25 for AUC, Cmax, and C␶ (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 parameters 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 significant 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 combination, 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 baseline 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 reference (combination minus methadone alone) included the value of zero 3.4 Safety There were no serious or grade 3/4 AEs The most commonly reported drug-related AEs were headache (27%) and fatigue (18%) All drug-related AEs were reported in subjects receiving DTG + methadone Two subjects experienced drug-related AEs that were moderate (grade 2) in intensity One subject experienced moderate dizziness Another subject experienced moderate headache, hematuria, and panic attack and was withdrawn from the study; the AE resolved after day The subject did not experience 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 electrocardiogram values or changes in vital signs were observed Discussion Methadone is administered as a chiral mixture of R and S isomers in which the opioid effect is primarily mediated through Rmethadone (Eap et al., 2002) The addition of DTG to individualized stable methadone therapy had no effect on total, R-, and Smethadone PK Additionally, the AUC ratios of R- and S-methadone showed no significant differences between the treatments, suggesting 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 783 et al., 2008; Crauwels et al., 2010; Van Heeswijk et al., 2011) The AUC difference between these isomers was approximately 10% The results of this study are consistent with previous data showing 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 programs 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 crossstudy 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 differences in exposure translate to clinically significant effects Two PD measurements were employed in this study, the Opioid Symptom 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 subjects 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 measurements, 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 statistical 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 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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. .. 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. .. Eap, C.B., Buclin, T., Baumann, P., 2002 Interindividual variability of the clinical pharmacokinetics of methadone: implications for the treatment of opioid dependence Clin Pharmacokinet 41, 1153–1193