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

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2009
1247.pdf (743.1Kb)
Authors
Rakić-Ignjatović, Anita
Miljković, Branislava
Todorović, Dejan
Timotijević, Ivana
Pokrajac, Milena
Article (Published version)
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Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT center dot Moclobemide (MCB) undergoes extensive both presystemic and systemic metabolism that can be affected by concomitant drugs. center dot 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. center dot 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 center dot VPA does not significantly affect PK or metabolism of MCB at steady state. center dot CBZ significantly decreases MCB exposure. This effect is time-dependent, being more pronounced after 3-5 weeks of co-administration. To assess the impact of valproic acid (VPA) and carbamazepine (CBZ) o...n moclobemide (MCB) pharmacokinetics (PK) and metabolism at steady state in depressive patients. 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. 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 C-max by 28% (from 1.911 to 1.383 mg l(-1); 95% CI -0.98197, -0.07518; P lt 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 lt 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 lt 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. 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.

Keywords:
carbamazepine / depression / interaction / moclobemide / pharmacokinetics / valproic acid
Source:
British Journal of Clinical Pharmacology, 2009, 67, 2, 199-208
Publisher:
  • Wiley, Hoboken
Projects:
  • Eksperimentalna i kliničko-farmakološka istraživanja mehanizma dejstva i interakcija lekova u nervnom i kardiovaskularnom sistemu (RS-145001)
  • Institute of Mental Health in Belgrade

DOI: 10.1111/j.1365-2125.2008.03326.x

ISSN: 0306-5251

PubMed: 19076986

WoS: 000263678100007

Scopus: 2-s2.0-61349164772
[ Google Scholar ]
8
6
URI
http://farfar.pharmacy.bg.ac.rs/handle/123456789/1249
Collections
  • Radovi istraživača / Researchers’ publications
Institution
Pharmacy
TY  - JOUR
AU  - Rakić-Ignjatović, Anita
AU  - Miljković, Branislava
AU  - Todorović, Dejan
AU  - Timotijević, Ivana
AU  - Pokrajac, Milena
PY  - 2009
UR  - http://farfar.pharmacy.bg.ac.rs/handle/123456789/1249
AB  - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT center dot Moclobemide (MCB) undergoes extensive both presystemic and systemic metabolism that can be affected by concomitant drugs. center dot 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. center dot 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 center dot VPA does not significantly affect PK or metabolism of MCB at steady state. center dot CBZ significantly decreases MCB exposure. This effect is time-dependent, being more pronounced after 3-5 weeks of co-administration. To assess the impact of valproic acid (VPA) and carbamazepine (CBZ) on moclobemide (MCB) pharmacokinetics (PK) and metabolism at steady state in depressive patients. 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. 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 C-max by 28% (from 1.911 to 1.383 mg l(-1); 95% CI -0.98197, -0.07518; P  lt  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  lt  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  lt  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. 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.
PB  - Wiley, Hoboken
T2  - British Journal of Clinical Pharmacology
T1  - Moclobemide monotherapy vs. combined therapy with valproic acid or carbamazepine in depressive patients: a pharmacokinetic interaction study
VL  - 67
IS  - 2
SP  - 199
EP  - 208
DO  - 10.1111/j.1365-2125.2008.03326.x
ER  - 
@article{
author = "Rakić-Ignjatović, Anita and Miljković, Branislava and Todorović, Dejan and Timotijević, Ivana and Pokrajac, Milena",
year = "2009",
url = "http://farfar.pharmacy.bg.ac.rs/handle/123456789/1249",
abstract = "WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT center dot Moclobemide (MCB) undergoes extensive both presystemic and systemic metabolism that can be affected by concomitant drugs. center dot 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. center dot 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 center dot VPA does not significantly affect PK or metabolism of MCB at steady state. center dot CBZ significantly decreases MCB exposure. This effect is time-dependent, being more pronounced after 3-5 weeks of co-administration. To assess the impact of valproic acid (VPA) and carbamazepine (CBZ) on moclobemide (MCB) pharmacokinetics (PK) and metabolism at steady state in depressive patients. 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. 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 C-max by 28% (from 1.911 to 1.383 mg l(-1); 95% CI -0.98197, -0.07518; P  lt  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  lt  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  lt  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. 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.",
publisher = "Wiley, Hoboken",
journal = "British Journal of Clinical Pharmacology",
title = "Moclobemide monotherapy vs. combined therapy with valproic acid or carbamazepine in depressive patients: a pharmacokinetic interaction study",
volume = "67",
number = "2",
pages = "199-208",
doi = "10.1111/j.1365-2125.2008.03326.x"
}
Rakić-Ignjatović A, Miljković B, Todorović D, Timotijević I, Pokrajac M. Moclobemide monotherapy vs. combined therapy with valproic acid or carbamazepine in depressive patients: a pharmacokinetic interaction study. British Journal of Clinical Pharmacology. 2009;67(2):199-208
Rakić-Ignjatović, A., Miljković, B., Todorović, D., Timotijević, I.,& Pokrajac, M. (2009). Moclobemide monotherapy vs. combined therapy with valproic acid or carbamazepine in depressive patients: a pharmacokinetic interaction study.
British Journal of Clinical PharmacologyWiley, Hoboken., 67(2), 199-208.
https://doi.org/10.1111/j.1365-2125.2008.03326.x
Rakić-Ignjatović Anita, Miljković Branislava, Todorović Dejan, Timotijević Ivana, Pokrajac Milena, "Moclobemide monotherapy vs. combined therapy with valproic acid or carbamazepine in depressive patients: a pharmacokinetic interaction study" 67, no. 2 (2009):199-208,
https://doi.org/10.1111/j.1365-2125.2008.03326.x .

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