icon-folder.gif   Conference Reports for NATAP  
  11th International Workshop on Clinical Pharmacology of HIV Therapy
Sorrento, Italy
April 7-9, 2010
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Pharmacokinetic interaction study between TMC278, a next-generation NNRTI, and methadone
  Reported by Jules Levin
11th International Workshop on Clinical Pharmacology of HIV Therapy, Sorrento, Italy, 7-9 April 2010
HM Crauwels,1 RPG van Heeswijk,1 A Vandevoorde,1 DF McNeeley,2 A Buelens,1 K Boven,2 RMW Hoetelmans1 1Tibotec BVBA, Mechelen, Belgium; 2Tibotec Inc., Titusville, NJ, USA


TMC278 (rilpivirine) is a next-generation NNRTI with sustained efficacy and good tolerability through 96 weeks in antiretroviral (ARV)-na´ve, HIV-infected patients.1 TMC278 is currently being investigated in Phase III trials at a dose of 25 mg qd, in combination with a background regimen of two NRTIs. The current trial evaluated the effect of TMC278 on the pharmacokinetics and pharmacodynamics of methadone.
This was an open-label, single-sequence, add-on drug-drug interaction trial in 13 HIV-negative volunteers who were on stable methadone maintenance therapy. Volunteers received methadone (individualised stable methadone maintenance dose, between 60 mg and 150 mg qd) from Day -14 through Day 11, and TMC278 25 mg qd was added from Day 1 through Day 11. All intakes were witnessed, and all treatments were taken following breakfast. Pharmacokinetic (PK) profiles up to 24 hours after intake were determined on Day -1 (methadone alone) and on Day 11 (methadone + TMC278) for R- and S-methadone, and on Day 11 for TMC278. Plasma samples were analysed using validated liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) methods. PK parameters were calculated using non-compartmental analysis. The least square means (LSM) ratios (test/reference) and associated 90% confidence intervals (CI) were calculated based on log-transformed PK parameters. Pharmacodynamic assessments of symptoms of methadone withdrawal (Short Opiate Withdrawal Scale [SOWS], Desires for Drugs Questionnaire [DDQ], pupillometry) were performed on Day -7 and daily from Day -3 until Day 11, within 2 hours before the intake of methadone.
When TMC278 25 mg qd was added onto a stable methadone maintenance therapy, the mean minimum plasma concentration (Cmin), maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time of administration to 24-hours after dosing (AUC24h) of the biologically active R-isomer of methadone decreased by 22% (LSM ratio 0.78; 90% CI: 0.67-0.91), 14% (0.86; 0.78-0.95) and 16% (0.84; 0.74-0.95), respectively, as compared with administration of methadone alone. The mean Cmin, Cmax and AUC24h of the inactive S-methadone decreased by 21% (0.79; 0.67-0.92), 13% (0.87; 0.78-0.97) and 16% (0.84; 0.74-0.96), respectively. The AUC ratio for S-/R-methadone was similar during co-administration with TMC278 or when methadone was administered alone (1.01; 0.96-1.05). The exposure to TMC278 in the presence of methadone was within the expected range. During co-administration with TMC278, no clinically relevant changes in the pharmacodynamic assessments of methadone withdrawal symptoms (SOWS, DDQ scores, pupil dilation) were observed. Co-administration of methadone and TMC278 was generally safe and well tolerated. No grade 3 or 4 adverse events (AEs) and no serious AEs were reported. There were no discontinuations due to AEs.
No a-priori adjustment of the methadone dosage is required when initiating co-administration with TMC278. Clinical monitoring for withdrawal symptoms is, however, recommended, as methadone maintenance therapy may need to be adjusted in some patients.

1. Pozniak A, et al. AIDS 2010;24:55-65.
2. Azijn H, et al. AAC 2010;54:718-27.