Laishun Chen1, Ramesh Boinpally2, Nayra Gad3, William M Greenberg4, Julie Wangsa5, Antonia Periclou2, Parviz Ghahramani6. 1. Forest Research Institute, Inc., an affiliate of Actavis Inc., Harborside Financial Center, Plaza V, Jersey City, NJ, 07311, USA. laishun.chen@actavis.com. 2. Forest Research Institute, Inc., an affiliate of Actavis Inc., Harborside Financial Center, Plaza V, Jersey City, NJ, 07311, USA. 3. , Union City, NJ, USA. 4. Mental Health Association of Rockland County, Valley Cottage, NY, USA. 5. , Smithtown, NY, USA. 6. , Weehawken, NJ, USA.
Abstract
BACKGROUND AND OBJECTIVES:Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor with balanced potency for the reuptake inhibition of norepinephrine and serotonin, approved in the USA for the treatment of major depressive disorder (MDD) in adults. We conducted studies in healthy human subjects to investigate pharmacokinetic interactions when levomilnacipran extended-release (ER) is administered in combination with an inhibitor (ketoconazole), an inducer (carbamazepine), or a substrate (alprazolam) of cytochrome P450 (CYP) 3A4. METHODS: Randomised, open-label studies were conducted in healthy volunteers (n = 34 ketoconazole, n = 34 carbamazepine, n = 30 alprazolam) and pharmacokinetic parameters were determined when levomilnacipran was administered alone or together with the relevant study drug. RESULTS: Co-administration of ketoconazole with levomilnacipran ER increased levomilnacipran maximum concentration (C max) by 39% [90% confidence interval (CI) 31-47%] and area under the concentration-time curve (AUC) by 57% (90% CI 47-67%), whereas carbamazepine reduced the C max and AUC of levomilnacipran by 26% (90% CI 22-30%) and 29% (90% CI 26-32%), respectively. Levomilnacipran at steady state had no significant effect on the pharmacokinetics of a single 1 mg dose of alprazolam extended release (XR); neither did single-dose alprazolam XR affect the steady-state pharmacokinetics of levomilnacipran. No new safety concerns were noted in these studies. CONCLUSIONS: Based on these results, the levomilnacipran ER dose should not exceed 80 mg once daily when used with ketoconazole, compared to 120 mg once daily in the absence of ketoconazole. No dose adjustment for levomilnacipran is suggested when levomilnacipran ER is co-administered with carbamazepine or other CYP3A4 inducers. Co-administration with levomilnacipran of drugs metabolised by CYP3A4, such as alprazolam, requires no dose adjustment due to pharmacokinetic considerations.
RCT Entities:
BACKGROUND AND OBJECTIVES:Levomilnacipran is a serotonin and norepinephrine reuptake inhibitor with balanced potency for the reuptake inhibition of norepinephrine and serotonin, approved in the USA for the treatment of major depressive disorder (MDD) in adults. We conducted studies in healthy human subjects to investigate pharmacokinetic interactions when levomilnacipran extended-release (ER) is administered in combination with an inhibitor (ketoconazole), an inducer (carbamazepine), or a substrate (alprazolam) of cytochrome P450 (CYP) 3A4. METHODS: Randomised, open-label studies were conducted in healthy volunteers (n = 34 ketoconazole, n = 34 carbamazepine, n = 30 alprazolam) and pharmacokinetic parameters were determined when levomilnacipran was administered alone or together with the relevant study drug. RESULTS: Co-administration of ketoconazole with levomilnacipran ER increased levomilnacipran maximum concentration (C max) by 39% [90% confidence interval (CI) 31-47%] and area under the concentration-time curve (AUC) by 57% (90% CI 47-67%), whereas carbamazepine reduced the C max and AUC of levomilnacipran by 26% (90% CI 22-30%) and 29% (90% CI 26-32%), respectively. Levomilnacipran at steady state had no significant effect on the pharmacokinetics of a single 1 mg dose of alprazolam extended release (XR); neither did single-dose alprazolam XR affect the steady-state pharmacokinetics of levomilnacipran. No new safety concerns were noted in these studies. CONCLUSIONS: Based on these results, the levomilnacipran ER dose should not exceed 80 mg once daily when used with ketoconazole, compared to 120 mg once daily in the absence of ketoconazole. No dose adjustment for levomilnacipran is suggested when levomilnacipran ER is co-administered with carbamazepine or other CYP3A4 inducers. Co-administration with levomilnacipran of drugs metabolised by CYP3A4, such as alprazolam, requires no dose adjustment due to pharmacokinetic considerations.
Authors: Er-jia Wang; Karen Lew; Christopher N Casciano; Robert P Clement; William W Johnson Journal: Antimicrob Agents Chemother Date: 2002-01 Impact factor: 5.191
Authors: Darlene C Deecher; Chad E Beyer; Grace Johnston; Jenifer Bray; S Shah; M Abou-Gharbia; Terrance H Andree Journal: J Pharmacol Exp Ther Date: 2006-05-04 Impact factor: 4.030
Authors: A L Auclair; J C Martel; M B Assié; L Bardin; P Heusler; D Cussac; M Marien; A Newman-Tancredi; J A O'Connor; R Depoortère Journal: Neuropharmacology Date: 2013-03-13 Impact factor: 5.250
Authors: David Bakish; Anjana Bose; Carl Gommoll; Changzheng Chen; Rene Nunez; William M Greenberg; Michael Liebowitz; Arif Khan Journal: J Psychiatry Neurosci Date: 2014-01 Impact factor: 6.186
Authors: Angelo Sambunaris; Anjana Bose; Carl P Gommoll; Changzheng Chen; William M Greenberg; David V Sheehan Journal: J Clin Psychopharmacol Date: 2014-02 Impact factor: 3.153