Atomoxetine Hydrochloride: Clinical Drug-Drug Interaction Prediction and Outcome

Sauer, John‐Michael; Long, Amanda; Ring, Barbara J.; Gillespie, Jennifer S.; Sanburn, Nathan P.; DeSante, Karl A.; Petullo, David; Vandenbranden, Mark; Jensen, Charles B.; Wrighton, Steven; Smith, Brian P.; Read, Holly A.; Witcher, Jennifer

doi:10.1124/jpet.103.058727

Cited by 49 publications

(33 citation statements)

References 22 publications

(27 reference statements)

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“…As shown in Table 1, the area under the plasma concentration-time curve (AUC) extrapolated to infinity (AUC inf ) and maximum plasma concentration (C max ) generally increased proportionally to dose in both Japanese and United States References: Chalon et al 2003;Cui et al 2007;Matsui et al 2012;Shang et al 2013;and Choi et al 2014. b Data are expressed as mean (% coefficient of variance), unless noted. Belle et al 2002;Sauer et al 2003;Sauer et al 2004;Cui et al 2007;and Matsui et al 2012. b Data are expressed as mean (% coefficient of variance), unless noted. EM subjects (Matsui et al 2012).…”

Section: Absorptionmentioning

confidence: 99%

Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition

Markowitz

2016

Journal of Child and Adolescent Psychopharmacology

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Atomoxetine is a selective norepinephrine (NE) reuptake inhibitor approved for the treatment of attention-deficit/ hyperactivity disorder (ADHD) in children ( ‡6 years of age), adolescents, and adults. Its metabolism and disposition are fairly complex, and primarily governed by cytochrome P450 (CYP) 2D6 (CYP2D6), whose protein expression varies substantially from person to person, and by race and ethnicity because of genetic polymorphism. These differences can be substantial, resulting in 8-10-fold differences in atomoxetine exposure between CYP2D6 poor metabolizers and extensive metabolizers. In this review, we have attempted to revisit and analyze all published clinical pharmacokinetic data on atomoxetine inclusive of public access documents from the new drug application submitted to the United States Food and Drug Administration (FDA). The present review focuses on atomoxetine metabolism, disposition, and genetic polymorphisms of CYP2D6 as they specifically relate to atomoxetine, and provides an in-depth discussion of the fundamental pharmacokinetics of the drug including its absorption, distribution, metabolism, and excretion in pediatric and adult populations. Further, a summary of relationships between genetic variants of CYP2D6 and to some degree, CYP2C19, are provided with respect to atomoxetine plasma concentrations, central nervous system (CNS) pharmacokinetics, and associated clinical implications for pharmacotherapy. Lastly, dosage adjustments based on pharmacokinetic principles are discussed.

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Section: Absorptionmentioning

confidence: 99%

Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition

Markowitz

2016

Journal of Child and Adolescent Psychopharmacology

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“…A population PK model for MDZ was developed using data from healthy adult subjects (Ernest et al, 2004). The MDZ individual concentration-time data from 112 subjects were combined from five clinical studies of similar study design and population demographics (Gorski et al, 1998(Gorski et al, , 2003Belle et al, 2002;Haehner-Daniels et al, 2004;Sauer et al, 2004;Ring et al, 2005). The data included intravenous and oral administration of MDZ in doses ranging from 1 to 15 mg.…”

Section: Methodsmentioning

confidence: 99%

Stochastic Prediction of Cyp3a-Mediated Inhibition of Midazolam Clearance by Ketoconazole

Chien¹,

Lucksiri²,

Ernest³

et al. 2006

Drug Metab Dispos

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ABSTRACT:Conventional methods to forecast CYP3A-mediated drug-drug interactions have not employed stochastic approaches that integrate pharmacokinetic (PK) variability and relevant covariates to predict inhibition in terms of probability and uncertainty. Empirical approaches to predict the extent of inhibition may not account for nonlinear or non-steady-state conditions, such as first-pass effects or accumulation of inhibitor concentration with multiple dosing. A physiologically based PK model was developed to predict the inhibition of CYP3A by ketoconazole (KTZ), using midazolam (MDZ) as the substrate. The model integrated PK models of MDZ and KTZ, in vitro inhibition kinetics of KTZ, and the variability and uncertainty associated with these parameters. This model predicted the time-and dose-dependent inhibitory effect of KTZ on MDZ oral clearance. The predictive performance of the model was validated using the results of five published KTZ-MDZ studies. The model improves the accuracy of predicting the inhibitory effect of increasing KTZ dosing on MDZ PK by incorporating a saturable KTZ efflux from the site of enzyme inhibition in the liver. The results of simulations using the model supported the KTZ dose of 400 mg once daily as the optimal regimen to achieve maximum inhibition by KTZ. Sensitivity analyses revealed that the most influential variable on the prediction of inhibition was the fractional clearance of MDZ mediated by CYP3A. The model may be used prospectively to improve the quantitative prediction of CYP3A inhibition and aid the optimization of study designs for CYP3A-mediated drug-drug interaction studies in drug development.Metabolism-based pharmacokinetic (PK) interactions are well recognized as a source of clinically significant adverse drug reactions Huang and Lesko, 2004). The early forecast of clinically significant metabolism-based pharmacokinetic drug-drug interactions is an increasingly important aspect of drug development. The assessment of drug-drug interaction potential before the conduct of a clinical trial often involves simple algebraic calculations. One such calculation is the ratio of the expected clinical exposure to the in vitro inhibition constant (K i ) of a new drug entity for a specific cytochrome P450 (Sahajwalla et al., 1999;Bjornsson et al., 2003). The primary sources of quantitative errors associated with this prediction approach are attributed to the experimental procedures used to determine the in vitro parameters, the variability in the intrinsic factors associated with PK properties of the inhibitor (e.g., absorption kinetics, plasma protein binding, and tissue partition coefficients), or the substrate (i.e., the fraction of total clearance attributed to the elimination pathway of interest), the extrinsic factors associated with the clinical study designs (e.g., dosing scheme, sampling design, and population demographics), and, most notably, the uncertainty in the effective concentration of the inhibitor at the enzyme site. In addition, complex drug disposition proper...

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“…Atomoxetine [7], a highly selective noradrenergic reuptake inhibitor with little affinity for other neurotransmitter systems, is widely used as a drug to treat attention deficit hyperactivity disorder (ADHD) [8] in children, adolescents and adults, which was proved in the United States in 2002. Studies have shown that the prevalence of ADHD was 4.31-5.83% in our country.…”

Section: Introductionmentioning

confidence: 99%

Effect of 24 Cytochrome P450 2D6 Variants Found in the Chinese Population on Atomoxetine Metabolism in vitro

Liang

Zhan²,

Wang³

et al. 2015

Pharmacology

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Objective: The aim of this article was to assess the catalytic activities of 24 cytochrome P450 2D6 (CYP2D6) variants found in the Chinese population toward atomoxetine in vitro as well as CYP2D6.1. Methods: In this study, the co-expression enzyme of human recombinant CYPOR, CYPb5, and CYP2D6.1 or other CYP2D6 variants with the baculovirus-mediated insect cells (Sf21) was used to study the catalytic activities of 24 CYP2D6 variants toward atomoxetine metabolism. The metabolite of atomoxetine (4-hydroxyatomoxetine) was detected by ultra-high performance liquid chromatography-mass spectrometry method. Results: The intrinsic clearance (Vmax/Km) values of most variants were significantly altered when compared with CYP2D6.1. CYP2D6.94, CYP2D6.D336N, CYP2D6.R440C exhibited marked increased values 172, 126, 121% respectively. CYP2D6.89 and CYP2D6.98 exhibited similar catalytic activity as the wild type, whereas 17 variants exhibited significantly decreased values (from 5 to 87%) due to increase Km and/or decrease Vmax values. However, CYP2D6.92 and CYP2D6.96 showed no or few activity because of producing nothing. Conclusions: Our results suggest that most of these newly found variants exhibit significantly changed catalytic activities compared with the wild type. And these findings provide valuable information for the growth and development of personalized medicine in China.

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Atomoxetine Hydrochloride: Clinical Drug-Drug Interaction Prediction and Outcome

Cited by 49 publications

References 22 publications

Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition

Atomoxetine: A Review of Its Pharmacokinetics and Pharmacogenomics Relative to Drug Disposition

Stochastic Prediction of Cyp3a-Mediated Inhibition of Midazolam Clearance by Ketoconazole

Effect of 24 Cytochrome P450 2D6 Variants Found in the Chinese Population on Atomoxetine Metabolism in vitro

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