Evaluation of Cytochrome P450 (CYP) 3A4-Based Interactions of Levomilnacipran with Ketoconazole, Carbamazepine or Alprazolam in Healthy Subjects

• Published in: Clinical drug investigation Vol. 35; no. 10; pp. 601 - 612
• Main Authors: Chen, Laishun, Boinpally, Ramesh, Gad, Nayra, Greenberg, William M., Wangsa, Julie, Periclou, Antonia, Ghahramani, Parviz
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.10.2015; Springer Nature B.V
• Subjects: Adolescent; Adult; Alprazolam - administration & dosage; Alprazolam - pharmacokinetics; Alprazolam - pharmacology; Area Under Curve; Carbamazepine - administration & dosage; Carbamazepine - pharmacology; Cyclopropanes - administration & dosage; Cyclopropanes - pharmacokinetics; Cyclopropanes - pharmacology; Cytochrome P-450 CYP3A Inducers - administration & dosage; Cytochrome P-450 CYP3A Inducers - pharmacology; Cytochrome P-450 CYP3A Inhibitors - administration & dosage; Cytochrome P-450 CYP3A Inhibitors - pharmacology; Delayed-Action Preparations - pharmacokinetics; Drug Interactions; Female; Healthy Volunteers; Humans; Internal Medicine; Ketoconazole - administration & dosage; Ketoconazole - pharmacology; Male; Medicine; Medicine & Public Health; Middle Aged; Original Research Article; Pharmacology/Toxicology; Pharmacotherapy; Young Adult; Suicidal Ideation; Ketoconazole; Carbamazepine; Major Depressive Disorder
• ISSN: 1173-2563; 1179-1918
• DOI: 10.1007/s40261-015-0318-2

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.