Presentation Abstract

Session: 161-Clinical Pharmacology of Antiviral and Anti-Tuberculosis Agents
Tuesday, Sep 11, 2012, 11:15 AM - 1:15 PM
Presentation Title: A-1250 - Pharmacokinetics of Cobicistat-Boosted Elvitegravir Administered in Combination with Methadone or Buprenorphine/Naloxone
Location: Halls A-C
Presentation Number: A-1250
Pres. Time: Tuesday, Sep 11, 2012, 11:15 AM - 1:15 PM
Category: A1
Keywords: elvitegravir; methadone; buprenorphine
Author(s): R. D. Bruce, MD - Professor 1, P. Winkle, MD - Professor 2, J. Custodio, PhD - Clinical Research 3, X. Yin, MD, PhD4, M. Rhee, MD - Clinical Research 3, J. Andrews, MSPH, CCRA5, B. P. Kearney, PharmD - Clinical Research 3, S. Ramanathan, PhD - Clinical Research3;
1Yale Univ., New Haven, CT, 2Anaheim Clinical Trials, Anaheim, CA, 3Gilead Clinical Res., Foster City, CA, 4Gilead Biometrics, Foster City, CA, 5Gilead Clinical Operations, Foster City, CA.
Financial Disclosures:  R. D. Bruce,
Gilead Sciences Role(s): Research Relationship.
P. Winkle,
Gilead Sciences Role(s): Research Relationship.
J. Custodio,
Gilead Sciences Role(s): Employee, Shareholder (excluding diversitied mutual funds).
M. Rhee,
Gilead Sciences Role(s): Employee, Shareholder (excluding diversitied mutual funds).
B. P. Kearney,
Gilead Sciences Role(s): Employee, Shareholder (excluding diversitied mutual funds).
S. Ramanathan,
Gilead Sciences Role(s): Employee, Shareholder (excluding diversitied mutual funds).
Abstract: Background: Elvitegravir (EVG) is an HIV strand transfer integrase inhibitor being developed for the treatment of HIV-1 infection as a component of a single tablet regimen containing cobicistat (COBI), emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) (QUAD STR). The present study evaluated the potential for drug interactions between COBI-boosted EVG (EVG/co) and methadone or buprenorphine/naloxone (BUP/NLX), commonly used opiates whose PK is unaffected by FTC or TDF. Methods: Subjects on a stable methadone (80 mg to 120 mg) (Cohort 1, n= 12) or BUP/NLX (16/4 mg to 24/6 mg) (Cohort 2, n=18) dose completed pharmacokinetic (PK) assessments after opiate dosing alone and 10-day coadministration with EVG/co; PK of study drugs and pharmacodynamic (PD) changes using withdrawal or overdose scales were determined. Safety was monitored throughout the study. Protocol-defined lack of opiate PK alteration boundaries for 90% confidence interval (90% CI) was 70-143% about the geometric mean ratio for coadministration vs alone dosing. Results: In Cohort 1 and 2, 11 of 12 and 17 of 18 subjects, respectively, provided PK data. With EVG/co, methadone PK was unaffected; BUP and nor-BUP exposures were modestly higher versus dosing alone (Table 1). No relevant changes in PD scales or opiate dose-adjustments were needed. EVG and COBI PK were comparable to historical data. Common adverse events (AE) in both cohorts included nausea (20%) and headache (19%); no study-drug related Grade 3 or 4 AEs or discontinuations were observed. Conclusions: Methadone PK was unaffected by EVG/co. Modest increases in BUP and nor-BUP exposures were observed without changes in PD, that are not considered clinically relevant or necessitate dose adjustments with QUAD STR.
Pharmacokinetics of COBI-boosted elvitegravir given with methadone or BUP/NLX
AUCtau (ng•hr/mL)Cmax (ng/mL)Ctrough (ng/mL)
GMR
(90% CI)
GMR
(90% CI)
GMR
(90% CI)
Methadone plus EVG/co (n = 11)
R-Methadone107 (96.1,119)101 (90.8,113)110 (94.8,128)
S-Methadone100 (89.4,112)95.9 (86.6,106)102 (89.2,117)
Buprenorphine/Naloxone plus EVG/co (n = 17)
Buprenorphine135 (118,155)112 (97.9,127)166 (143,193)
Norbuprenorphine142 (122,167)124 (103,149)157 (131,188)




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