4-hydroxyatomoxetine-O-glucuronide | Acta Medica Marisiensis

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

Ioana Todor¹, Adina Popa², Dana Muntean¹, Maria Neag³, Ana-Maria Gheldiu⁴, Corina Briciu², Daniel Leucuta⁵, Laurian Vlase¹

1. University of Medicine and Pharmacy “Iuliu Hatieganu”, Faculty of Pharmacy, Department of Pharmaceutical Technology and Biopharmaceutics, Cluj-Napoca, Romania
2. University of Medicine and Pharmacy “Iuliu Hatieganu”, Faculty of Pharmacy, Department of Clinical Pharmacy, Cluj-Napoca, Romania
3. University of Medicine and Pharmacy “Iuliu Hatieganu”, Faculty of Medicine, Department of Pharmacology, Toxicology and Clinical Pharmacology, Cluj-Napoca, Romania
4. University of Medicine and Pharmacy “Iuliu Hatieganu”, Faculty of Pharmacy, Department of Pharmaceutical Botany, Cluj-Napoca, Romania
5. University of Medicine and Pharmacy ”Iuliu Hatieganu”, Faculty of Medicine, Department of Medical Informatics and Biostatistics, Cluj-Napoca, Romania

DOI: 10.2478/amma-2019-0017

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.

The Influence of CYP2D6 Phenotype on the Pharmacokinetic Profile of Atomoxetine in Caucasian Healthy Subjects

Ioana Todor¹, Dana Muntean¹, Maria Neag², Corina Bocsan², Anca Buzoianu², Laurian Vlase¹, Daniel Leucuta³, Ana-Maria Gheldiu¹, Adina Popa⁴, Corina Briciu⁴

1 University of Medicine and Pharmacy “Iuliu Hatieganu”, Faculty of Pharmacy, Department of Pharmaceutical Technology and Biopharmaceutics, Cluj-Napoca, Romania
2 University of Medicine and Pharmacy “Iuliu Hatieganu”, Faculty of Medicine, Department of Pharmacology, Toxicology and Clinical Pharmacology, Cluj- Napoca, Romania
3 University of Medicine and Pharmacy “Iuliu Hatieganu”, Department of Medical Informatics and Biostatistics, Cluj-Napoca, Romania
4 University of Medicine and Pharmacy “Iuliu Hatieganu”, Faculty of Pharmacy, Department of Clinical Pharmacy, Cluj-Napoca, Romania

DOI: 10.1515/amma-2017-0023

Objective: To analyze a potential phenotypic variation within the studied group based on the pharmacokinetic profile of atomoxetine and its active metabolite, and to further investigate the impact of CYP2D6 phenotype on atomoxetine pharmacokinetics.
Methods: The study was conducted as an open-label, non-randomized clinical trial which included 43 Caucasian healthy volunteers. Each subject received a single oral dose of atomoxetine 25 mg. Subsequently, atomoxetine and 4-hydroxyatomoxetine-O-glucuronide (glucuronidated active metabolite) plasma concentrations were determined and a noncompartmental method was used to calculate the pharmacokinetic parameters of both compounds. Further on, the CYP2D6 metabolic phenotype was assessed using the area under the curve (AUC) metabolic ratio (atomoxetine/ 4-hydroxyatomoxetine-O-glucuronide) and specific statistical tests (Lilliefors (Kolgomorov-Smirnov) and Anderson-Darling test). The phenotypic differences in atomoxetine disposition were identified based on the pharmacokinetic profile of the parent drug and its metabolite.
Results: The statistical analysis revealed that the AUC metabolic ratio data set did not follow a normal distribution. As a result, two different phenotypes were identified, respectively the poor metabolizer (PM) group which included 3 individuals and the extensive metabolizer (EM) group which comprised the remaining 40 subjects. Also, it was demonstrated that the metabolic phenotype significantly influenced atomoxetine pharmacokinetics, as PMs presented a 4.5-fold higher exposure to the parent drug and a 3.2-fold lower exposure to its metabolite in comparison to EMs.
Conclusions: The pharmacokinetic and statistical analysis emphasized the existence of 2 metabolic phenotypes: EMs and PMs. Furthermore, it was proved that the interphenotype variability had a marked influence on atomoxetine pharmacokinetic profile.