Moclobemide monotherapy vs. combined therapy with valproic acid or carbamazepine in depressive patients: a pharmacokinetic interaction study

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Moclobemide (MCB) undergoes extensive both presystemic and systemic metabolism that can be affected by concomitant drugs. • Valproic acid (VPA) and carbamazepine (CBZ) have been found to interact with psychotropic medications of all classes and many other drugs; VPA acts as a broad-spectrum inhibitor, and CBZ as a potent inducer of a variety of drug-metabolizing enzymes. • There have been no previous studies designed to investigate a potential pharmacokinetic (PK) interaction between MCB and VPA or CBZ; however, these agents are likely to be used concomitantly for the treatment of depressive disorders. WHAT THIS STUDY ADDS • VPA does not significantly affect PK or metabolism of MCB at steady state. • CBZ significantly decreases MCB exposure. This effect is time-dependent, being more pronounced after 3-5 weeks of co-administration. AIM To assess the impact of valproic acid (VPA) and carbamazepine (CBZ) on moclobemide (MCB) pharmacokinetics (PK) and metabolism at steady state in depressive patients. METHODS Twenty-one inpatients with recurrent endogenous depression received MCB (150 mg t.i.d.), either as monotherapy or in combination with VPA (500 mg b.i.d.) or CBZ (200 mg b.i.d.) in a nonrandomized manner. Steady-state plasma PK parameters of MCB and its two metabolites, Ro 12-8095 and Ro 12-5637, were derived. Clinical assessments of treatment efficacy were performed weekly using standard depression rating scales. RESULTS CBZ, but not VPA, was associated with decreases in the MCB AUC by 35% [from 7.794 to 5.038 mg h l-1 ; 95% confidence interval (CI)-4.84863,-0.66194; P = 0.01] and Cmax by 28% (from 1.911 to 1.383 mg l-1 ; 95% CI-0.98197,-0.07518; P < 0.05), and an increase in its oral clearance by 41% (from 0.323 to 0.454 l h-1 kg-1 ; 95% CI 0.00086, 0.26171; P < 0.05) after 4 weeks of co-administration. MCB through concentrations were also decreased, on average by 41% (from 0.950 to 0.559 mg l-1 ; 95% CI-0.77479,-0.03301; P < 0.05). However, the efficacy in this group of patients was not inferior to the controls, for several possible reasons. Overall tolerability of all study medications was good. CONCLUSIONS VPA does not significantly affect PK or metabolism of MCB, whereas CBZ time-dependently decreases MCB exposure, probably by inducing metabolism of MCB and its major plasma metabolite. The actual clinical relevance of the observed MCB-CBZ PK interaction needs to be further evaluated in a more comprehensive study.

Evaluation of Single-Point Sampling Strategies for the Estimation of Moclobemide Exposure in Depressive Patients

“…Better predictive performance of plasma concentrations at earlier time points in the elimination phase (such as C 3 ) compared with the later ones (C 5 and C 6 ) might have been a consequence of a complex PK interaction between MCB and CBZ (CBZ probably affects both MCB absorption and elimination and also induces further metabolism of MCB major plasma metabolite). 24 The process of identifying sparse data points to predict AUC is essentially a variable selection problem, with the variables being the drug concentrations at the various time points. Although fitting more variables into a model will typically allow for a better prediction of AUC, improving the prediction has to be traded off against the desirability of using as few time points as possible.…”

“…This investigation was a continuation of our recently published PK interaction study and was performed in the same patient population. 24 A total of 21 hospitalized patients with recurrent depressive disorder were included in the study. Patients received MCB (150 mg 3 times daily at intervals of 6, 6, and 12 hours), either as monotherapy (n = 7) or in combination with a single mood stabilizer, valproic acid (VPA) (500 mg twice daily; n = 7) or carbamazepine (CBZ) (200 mg twice daily; n = 7).…”

Serotonergic antidepressants as predictors of depressive disorders treatment

“…Their pharmacological action takes place in serotonin transporter on presynaptic membrane of serotonergic neurons (SERT), blocking the reuptake of serotonin in presynaptic neuron and increasing the amount of available serotonin in the synaptic cleft and on postsynaptic receptors. Antidepressive action is explained by monoamine hypothesis on etiopathogenesis of depression, which is basically a change of number or sensitivity of serotonin receptors on the neuronal membranes, impaired synthesis of key cell-survival proteins and disorder of gene expression [1].…”