<abstract xmlns="http://www.w3.org/1999/xhtml"><bold>Objective</bold>: The present research aimed to investigate whether a pharmacokinetic drug interaction exists between atomoxetine, a substrate of CYP2D6 and duloxetine, an enzymatic inhibitor of the same metabolic pathway.<bold>Methods</bold>: Twenty-three healthy volunteers were enrolled in an open-label, non-randomized, sequential, 2-period clinical study. During the trial, they received a single dose of atomoxetine 25 mg (Period 1:Reference) followed by a combination of atomoxetine 25 mg and duloxetine 30 mg, after a pretreatment regimen with duloxetine 30-60 mg/day for 4 days (Period 2:Test). The pharmacokinetic parameters of atomoxetine and its main metabolite (4-hydroxyatomoxetine-O-glucuronide) were estimated using a non-compartmental approach and statistical tests were used to compare these parameters between study periods.<bold>Results</bold>: A total of 22 subjects, extensive metabolizers (EMs), were considered for the final report of the study findings. Duloxetine influenced the plasma concentration-time profile of both parent drug and its glucuronidated metabolite. The pharmacokinetic and statistical analysis revealed that pretreatment with the enzymatic inhibitor increased the mean atomoxetine AUC0–t (from 1151.19±686.52 to 1495.54±812.40 [ng*h/mL]) and AUC0–∞ (from 1229.15±751.04 to 1619.37±955.01 [ng*h/mL]) while kel was decreased and the mean t1/2 was prolonged. With regard to 4-hydroxyatomoxetine-O-glucuronide, Cmax was reduced from 688.76±270.27 to 621.60±248.82 [ng/mL] after coadministration of atomoxetine and duloxetine.<bold>Conclusions</bold>: Duloxetine had an impact on the pharmacokinetics of atomoxetine as it increased the exposure to the latter by ~30%. Although the magnitude of this pharmacokinetic interaction is rather small, a potential clinical relevance cannot be ruled out with certainty without further investigation.</abstract>

Objective: The present research aimed to investigate whether a pharmacokinetic drug interaction exists between atomoxetine, a substrate of CYP2D6 and duloxetine, an enzymatic inhibitor of the same metabolic pathway.Methods: Twenty-three healthy volunteers were enrolled in an open-label, non-randomized, sequential, 2-period clinical study. During the trial, they received a single dose of atomoxetine 25 mg (Period 1:Reference) followed by a combination of atomoxetine 25 mg and duloxetine 30 mg, after a pretreatment regimen with duloxetine 30-60 mg/day for 4 days (Period 2:Test). The pharmacokinetic parameters of atomoxetine and its main metabolite (4-hydroxyatomoxetine-O-glucuronide) were estimated using a non-compartmental approach and statistical tests were used to compare these parameters between study periods.Results: A total of 22 subjects, extensive metabolizers (EMs), were considered for the final report of the study findings. Duloxetine influenced the plasma concentration-time profile of both parent drug and its glucuronidated metabolite. The pharmacokinetic and statistical analysis revealed that pretreatment with the enzymatic inhibitor increased the mean atomoxetine AUC0–t (from 1151.19±686.52 to 1495.54±812.40 [ng*h/mL]) and AUC0–∞ (from 1229.15±751.04 to 1619.37±955.01 [ng*h/mL]) while kel was decreased and the mean t1/2 was prolonged. With regard to 4-hydroxyatomoxetine-O-glucuronide, Cmax was reduced from 688.76±270.27 to 621.60±248.82 [ng/mL] after coadministration of atomoxetine and duloxetine.Conclusions: Duloxetine had an impact on the pharmacokinetics of atomoxetine as it increased the exposure to the latter by ~30%. Although the magnitude of this pharmacokinetic interaction is rather small, a potential clinical relevance cannot be ruled out with certainty without further investigation.

Atomoxetine and Duloxetine: Evaluation of a Potential Pharmacokinetic Drug-Drug Interaction

University of Medicine and Pharmacy “Iuliu Hatieganu”

Faculty of Pharmacy, Department of Pharmaceutical Technology and Biopharmaceutics

Faculty of Pharmacy, Department of Clinical Pharmacy

Faculty of Medicine, Department of Pharmacology, Toxicology and Clinical Pharmacology

Faculty of Pharmacy, Department of Pharmaceutical Botany

Faculty of Medicine, Department of Medical Informatics and Biostatistics

Acta Marisiensis - Seria Medica

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Objective: The present research aimed to investigate whether a pharmacokinetic drug interaction exists between atomoxetine, a substrate of CYP2D6 and...

Atomoxetine and Duloxetine: Evaluation of a Potential Pharmacokinetic Drug-Drug Interaction

Publicado en línea: 31 dic 2019

Páginas: 150 - 156

Recibido: 27 may 2019

Aceptado: 12 jul 2019

DOI: https://doi.org/10.2478/amma-2019-0017

Palabras clave
atomoxetine, 4-hydroxyatomoxetine-O-glucuronide, duloxetine, pharmacokinetic interaction

© 2019 Ioana Todor et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Atomoxetine and Duloxetine: Evaluation of a Potential Pharmacokinetic Drug-Drug Interaction

Publicado en línea: 31 dic 2019

Páginas: 150 - 156

Recibido: 27 may 2019

Aceptado: 12 jul 2019

DOI: https://doi.org/10.2478/amma-2019-0017

Palabras claveatomoxetine, 4-hydroxyatomoxetine-O-glucuronide, duloxetine, pharmacokinetic interaction

© 2019 Ioana Todor et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

Palabras clave
atomoxetine, 4-hydroxyatomoxetine-O-glucuronide, duloxetine, pharmacokinetic interaction