Pharmacokinetics Of Atomoxetine Research Articles

The Development of a PBPK Model for Atomoxetine Using Levels in Plasma, Saliva and Brain Extracellular Fluid in Patients with Normal and Deteriorated Kidney Function.

Atomoxetine is a treatment for attention-deficit hyperactivity disorder. It inhibits Norepinephrine Transporters (NET) in the brain. Renal impairment can reduce hepatic CYP2D6 activity and atomoxetine elimination which may increase its body exposure. Atomoxetine can be secreted in saliva. The objective of this work was to test the hypothesis that atomoxetine saliva levels (sATX) can be used to predict ATX brain Extracellular Fluid (bECF) levels and their pharmacological effects in healthy subjects and those with End-Stage Renal Disease (ESRD). The pharmacokinetics of atomoxetine after intravenous administration to rats with chemically induced acute and chronic renal impairments were investigated. A physiologically-based pharmacokinetic (PBPK) model was built and verified in rats using previously published measured atomoxetine levels in plasma and brain tissue. The rat PBPK model was then scaled to humans and verified using published measured atomoxetine levels in plasma, saliva, and bECF. The rat PBPK model predicted the observed reduced atomoxetine clearance due to renal impairment in rats. The PBPK model predicted atomoxetine exposure in human plasma, sATX and bECF. Additionally, it predicted that ATX bECF levels needed to inhibit NET are achieved at 80 mg dose. In ESRD patients, the developed PBPK model predicted that the previously reported 65% increase in plasma exposure in these patients can be associated with a 63% increase in bECF. The PBPK simulations showed that there is a significant correlation between sATX and bECF in human. Saliva levels can be used to predict atomoxetine pharmacological response.

Effects of paroxetine on the pharmacokinetics of atomoxetine and its metabolites in different CYP2D6 genotypes.

The aim of this study was to investigate the effects of paroxetine, a potent inhibitor of CYP2D6, on the pharmacokinetics of atomoxetine and its two metabolites, 4-hydroxyatomoxetine and N-desmethylatomoxetine, in different CYP2D6 genotypes. Twenty-six healthy subjects were recruited and divided into CYP2D6*wt/*wt (*wt=*1 or *2, n = 10), CYP2D6*wt/*10 (n = 9), and CYP2D6*10/*10 groups (n = 7). In atomoxetine phase, all subjects received a single oral dose of atomoxetine (20mg). In paroxetine phase, after administration of a single oral dose of paroxetine (20mg) for six consecutive days, all subjects received a single oral dose of atomoxetine with paroxetine. Plasma concentrations of atomoxetine and its metabolites were determined up to 24 h after dosing. During atomoxetine phase, there were significant differences in Cmax and AUC0-24 of atomoxetine and N-desmethylatomoxetine among three genotype groups, whereas significant differences were not found in relation to CYP2D6*10 allele after administration of paroxetine. AUC ratios of 4-hydroxyatomoxetine and N-desmethylatomoxetine to atomoxetine were significantly different among three genotype groups during atomoxetine phase (all, P < 0.001), but after paroxetine treatment significant differences were not found. After paroxetine treatment, AUC0-24 of atomoxetine was increased by 2.3-, 1.7-, and 1.3-fold, in CYP2D6*wt/*wt, CYP2D6*wt/*10, and CYP2D6*10/*10 groups in comparison to atomoxetine phase, respectively. AUC ratio of 4-hydroxyatomoxetine to atomoxetine in each group was significantly decreased, whereas AUC ratio of N-desmethylatomoxetine to atomoxetine significantly increased after administration of paroxetine. In conclusion, paroxetine coadministration significantly affected pharmacokinetic parameters of atomoxetine and its two metabolites, 4-hydroxyatomoxetine and N-desmethylatomoxetine. When atomoxetine was administered alone, Cmax, AUC0-24 and CL/F of atomoxetine were significantly different among the three CYP2D6 genotype groups. However, after paroxetine coadministration, no significant differences in these pharmacokinetic parameters were observed among the CYP2D6 genotype groups.

Physiologically based pharmacokinetic modelling of atomoxetine with regard to CYP2D6 genotypes

Atomoxetine is a norepinephrine reuptake inhibitor indicated in the treatment of attention‐deficit/hyperactivity disorder. It is primarily metabolised by CYP2D6 to its equipotent metabolite, 4‐hydroxyatomoxetine, which promptly undergoes further glucuronidation to an inactive 4‐HAT‐O‐glucuronide. Clinical trials have shown that decreased CYP2D6 activity leads to substantially elevated atomoxetine exposure and more adverse reactions. The aims of this study were to analyse the pharmacokinetics of atomoxetine and to develop a pharmacologically based pharmacokinetic (PBPK) model of atomoxetine in different CYP2D6 genotypes. A single 20 mg dose of atomoxetine was given to 19 healthy Korean individuals with CYP2D6*wt/*wt (*wt = *1 or *2) or CYP2D6*10/*10 genotype. Based on the results of this pharmacokinetic study, a PBPK model for CYP2D6*wt/*wt individuals was developed. This model was scaled to those with CYP2D6*10/*10 genotype, as well as CYP2D6 poor metabolisers. We validated this model by comparing the achieved pharmacokinetic parameters with diverse results from the literature. The presented PBPK model describes the pharmacokinetics after single and repeated oral atomoxetine doses with regard to CYP2D6 genotype and phenotype. This model could be utilized for identification of appropriate dosages of atomoxetine in patients with reduced CYP2D6 activity to minimize the adverse events, and to enable personalised medicine.Support or Funding InformationThis research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, &amp; Future Planning (NRF‐2016R1A2B4007381).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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

Abstract 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.

Evaluation of the Potential Pharmacokinetic Interaction between Atomoxetine and Fluvoxamine in Healthy Volunteers

Background/Aims: Attention deficit hyperactivity disorder (ADHD) is frequently associated with other psychiatric pathologies. Therefore, the present study investigated a possible pharmacokinetic interaction between atomoxetine (ATX), a treatment option for ADHD, and an antidepressant, namely, fluvoxamine (FVX). Methods: Designed as an open-label, non-randomized clinical trial, the study included 2 periods. In period 1 (reference), each subject received ATX 25 mg (single-dose), whereas in period 2 (test), all subjects were given a combination of ATX 25 mg + FVX 100 mg, following a 6-day pretreatment regimen with the enzymatic inhibitor. Non-compartmental methods were employed to determine the pharmacokinetic parameters of ATX and its main active metabolite (glucuronidated form), 4-hydroxyatomoxetine-O-glucuronide. Results: The results revealed significant differences between the study periods for C_max, AUC_0-t and AUC_0-_∞ values corresponding to ATX and its metabolite. Small, but statistically significant increases in AUC values were reported for both parent drug (1,583.05 ± 1,040.29 vs. 2,111.55 ± 1,411.59 ng*h/ml) and 4-hydroxyatomoxetine-O-glucuronide (5,754.71 ± 1,235.5 vs. 6,293.17 ± 1,219.34 ng*h/ml) after combined treatment of ATX and the enzymatic inhibitor. Conclusion: FVX had a modest effect on the pharmacokinetics of ATX and 4-hydroxyatomoxetine-O-glucuronide. The presence or absence of any clinical consequences associated with this pharmacokinetic drug-drug interaction needs to be established in future studies.

Non-Linear Pharmacokinetics of Atomoxetine in Adult Japanese Patients With ADHD

Objective: The objective was to reveal the relationship between dose and concentration of atomoxetine. Method: Fifty-five blood samples of 33 patients with ADHD were examined using high-performance liquid chromatography. Results: The plasma concentrations were 53.2 ± 67.0, 298.0 ± 390.5, and 639.3 ± 831.9 ng/mL at doses of 40 mg, 80 mg, and 120 mg, and the concentration/dose were 1.33 ± 1.67, 3.73 ± 4.88, and 5.33 ± 6.93 ng/mL/mg, respectively. Statistical analyses revealed a significant correlation between the concentration and the dose of atomoxetine (p = .004), and a trending toward significance in the difference in the concentration/dose in the three dosage groups (p = .064). The concentration/dose at 40 and 80 + 120 mg/day were 1.33 ± 1.67 and 4.22 ± 5.53 ng/mL/mg, the latter was significantly higher than the former (p = .006), which suggested non-linear pharmacokinetics. Conclusion: Clinicians should carefully titrate in high dose atomoxetine treatment.

The Effect of Myricetin on Pharmacokinetics of Atomoxetine and its Metabolite 4-Hydroxyatomoxetine In Vivo and In Vitro.

Atomoxetine is the first non-stimulant drug to be approved for the treatment of ADHD, while the effect of myricetin on the pharmacokinetic of atomoxetine in rats or human is still unknown. The present work was to study the impact of myricetin on the metabolism of atomoxetine both in vivo and in vitro. Twenty healthy male Sprague-Dawley rats were randomly divided into four groups: A (control group), B (100mg/kg myricetin), C (50mg/kg myricetin), and D (25mg/kg myricetin). A single dose of atomoxetine (10mg/kg) was administrated half an hour later. In addition, human and rat liver microsomes were performed to determine the effect of myricetin on the metabolism of atomoxetine in vitro. Group B, C, D all increased the C max and AUC of atomoxetine, but decreased the C max and AUC of 4-hydroxyatomoxetine. Moreover, myricetin showed inhibitory effect on human and rat microsomes, the IC50 of myricetin was 8.651 and 35.45µmol/L, respectively. Our study showed that myricetin could significantly inhibit the formation of atomoxetine metabolite both in vivo and in vitro. It is recommended that the effect of myricetin on the metabolism of atomoxetine should be noted and atomoxetine plasma concentration should be monitored.

Atomoxetine pharmacogenetics: associations with pharmacokinetics, treatment response and tolerability.

Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder and is predominantly metabolized by the CYP2D6 enzyme. Differences in pharmacokinetic parameters as well as clinical treatment outcomes across CYP2D6 genotype groups have resulted in dosing recommendations within the product label, but clinical studies supporting the use of genotype guided dosing are currently lacking. Furthermore, pharmacokinetic and clinical studies have primarily focused on extensive as compared with poor metabolizers, with little information known about other metabolizer categories as well as genes involved in the pharmacodynamics of atomoxetine. This review describes the pharmacogenetic associations with atomoxetine pharmacokinetics, treatment response and tolerability with considerations for the clinical utility of this information.

The influence of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite.

Background and aimsTo evaluate the effects of paroxetine on the pharmacokinetics of atomoxetine and its main metabolite, 4-hydroxyatomoxetine-O-glucuronide, after coadministration of atomoxetine and paroxetine in healthy volunteers.Methods22 healthy volunteers, extensive metabolizers, took part in this open-label, non-randomized, clinical trial. The study consisted of two periods: Reference, when a single oral dose of 25 mg atomoxetine was administrated to each subject and Test, when 25 mg atomoxetine and 20 mg paroxetine were coadministered. Between the two periods, the volunteers received an oral daily dose of 20–40 mg paroxetine, for 6 days. Atomoxetine and 4-hydroxyatomoxetine-O-glucuronide plasma concentrations were determined within the first 48 hours following drug administration. The pharmacokinetic parameters of both compounds were assessed using a non-compartmental method and the analysis of variance aimed at identifying any statistical significant differences between the pharmacokinetic parameters of atomoxetine and its main metabolite, corresponding to each study period.ResultsParoxetine modified the pharmacokinetic parameters of atomoxetine. Cmax increased from 221.26±94.93 to 372.53±128.28 ng/mL, while AUC0-t and AUC0-∞ also increased from 1151.19±686.52 to 6452.37±3388.76 ng*h/mL, and from 1229.15±751.04 to 7111.74±4195.17 ng*h/mL respectively. The main metabolite pharmacokinetics was also influenced by paroxetine intake, namely Cmax, AUC0-t and AUC0-∞ decreased from 688.76±270.27 to 131.01±100.43 ng*h/mL, and from 4810.93±845.06 to 2606.04±923.88 and from 4928.55±853.25 to 3029.82 ±941.84 respectively.ConclusionsMultiple-dose paroxetine intake significantly influenced atomoxetine and its active metabolite pharmacokinetics, causing a 5.8-fold increased exposure to atomoxetine and 1.6-fold reduced exposure to 4-hydroxyatomoxetine-O-glucuronide.

Effects of CYP2C19 Genetic Polymorphisms on Atomoxetine Pharmacokinetics

Atomoxetine is a selective norepinephrine reuptake inhibitor indicated for the treatment of attention-deficit/hyperactivity disorder. Atomoxetine metabolism is mediated by CYP2D6 and CYP2C19. This study aimed to investigate the effect of the CYP2C19 genetic polymorphism on the pharmacokinetics of atomoxetine and its metabolites, 4-hydroxyatomoxetine and N-desmethylatomoxetine. A single 40-mg oral dose of atomoxetine was administered to 40 subjects with different CYP2C19 genotypes (all participants carried the CYP2D6*1/*10 genotype). Concentrations of atomoxetine and its metabolites were analyzed using high-performance liquid chromatography with tandem mass spectrometry in plasma samples that were collected up to 24 hours after drug intake. For atomoxetine, the CYP2C19 poor metabolizer (PM) group showed significantly increased maximum plasma concentration and AUC0-∞ (area under the plasma concentration-time curve from 0 to infinity) and decreased apparent oral clearance compared with samples of the CYP2C19 extensive metabolizer (EM) and intermediate metabolizer (IM) groups (P < 0.001 for all). The half-life of atomoxetine in the CYP2C19PM group was also significantly longer than in the other genotype groups (P < 0.01 for CYP2C19EM and P < 0.05 for CYP2C19IM groups). The maximum plasma concentration and AUC 0-∞ of 4-hydroxyatomoxetine were significantly higher in the CYP2C19PM group compared with those in the CYP2C19EM and IM groups (P < 0.001 for CYP2C19EM and P < 0.05 for CYP2C19IM, respectively), whereas the corresponding values for N-desmethylatomoxetine in the CYP2C19PM group were significantly lower than those in the 2 genotype groups (P < 0.001 for both genotype groups). These results suggest that the genetic polymorphisms of CYP2C19 significantly affect the pharmacokinetics of atomoxetine.

Pharmacokinetics, Safety, and Tolerability of Atomoxetine and Effect of CYP2D6*10/*10 Genotype in Healthy Japanese Men

Atomoxetine is a cytochrome P4502D6 (CYP2D6) substrate. The reduced-activity CYP2D6*10 allele is particularly prevalent in the Japanese population and may contribute to known ethnic differences in CYP2D6 metabolic capacity. The purpose of this study was to examine atomoxetine pharmacokinetics, safety, tolerability, and the effect of the CYP2D6*10/*10 genotype after single-stepped dosing (10, 40, 90, or 120 mg) and at steady state (40 or 60 mg twice a day for 7 days) in 49 healthy Japanese adult men. Dose proportionality was shown and tolerability confirmed at all doses studied. Comparison of pharmacokinetics, safety, and tolerability between Japanese and US subjects showed no clinically meaningful ethnic differences. The CYP2D6*10/*10 subjects had 2.1- to 2.2-fold and 1.8-fold higher area under the plasma concentration-time curve values relative to the CYP2D6*1/*1 and *1/*2 subjects and the CYP2D6*1/*10 and *2/*10 subjects, respectively. The adverse events reported by CYP2D6*10/*10 subjects were indistinguishable from those of other Japanese participants. The higher mean exposure in CYP2D6*10/*10 subjects is not expected to be clinically significant.

Atomoxetine

Atomoxetine

Microdialysis Evaluation of Atomoxetine Brain Penetration and Central Nervous System Pharmacokinetics in Rats

A comprehensive in vivo evaluation of brain penetrability and central nervous system (CNS) pharmacokinetics of atomoxetine in rats was conducted using brain microdialysis. We sought to determine the nature and extent of transport at the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCB) and to characterize brain extracellular and cellular disposition. The steady-state extracellular fluid (ECF) to plasma unbound (uP) concentration ratio (C(ECF)/C(uP)=0.7) and the cerebrospinal fluid (CSF) to plasma unbound concentration ratio (C(CSF)/C(uP)=1.7) were both near unity, indicating that atomoxetine transport across the BBB and BCB is primarily passive. On the basis of the ratios of whole brain concentration to C(ECF) (C(B)/C(ECF)=170), brain cell (BC) concentration to C(ECF) (C(BC)/C(ECF)=219), and unbound brain cell concentration to C(ECF) (C(uBC)/C(ECF)=2.9), we conclude that whole brain concentration does not represent the concentration in the biophase and atomoxetine primarily partitions into brain cells. The distributional clearance at the BBB (Q(BBB)=0.00110 l/h) was estimated to be 12 times more rapid than that at the BCB (Q(BCB)=0.0000909 l/h) and similar to the clearances across brain parenchyma (CL(ECF-BC)=0.00216 l/h; CL(BC-ECF)=0.000934 l/h). In summary, the first detailed examination using a quantitative microdialysis technique to understand the brain disposition of atomoxetine was conducted. We determined that atomoxetine brain penetration is high, movements across the BBB and BCB occur predominantly by a passive mechanism, and rapid equilibration of ECF and CSF with plasma occurs.

Enhancement of atomoxetine serum levels by co-administration of paroxetine

Attention deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in childhood and adolescence. ADHD is characterized by the inability to appropriately modulate attention and/or impulse control and hyperactivity, resulting in social, academic and occupational underachievement. With a prevalence of 3–5%, ADHD is one of the most frequently seen disorders in child and adolescent psychiatry. Medication represents a major component of a multi-modal treatment plan. Treatment with stimulants is the drug therapy of first choice in ADHD of adulthood. While methylphenidate is mainly used, one third of the patients do not adequately respond to this drug. These patients may profit from a change to treatment with dual active antidepressants. Atomoxetine is a potent and selective inhibitor of the presynaptic norepinephrine transporter that influences not only norepinephrine but also dopamine concentration. It is used for the treatment of ADHD in children, adolescents and adults. The systemic clearance of atomoxetine involves three oxidative metabolic pathways, whereas the aromatic ring-hydroxylation results in the formation of the primary oxidative metabolite of atomoxetine, 4-hydroxyatomoxetine, which is then glucoronidated and excreted in urine. The formation of 4-hydroxyatomoxetine is mediated by cytochrome P450 (CYP), in particular 2D6 (Sauer et al., 2005). Variations in plasma atomoxetine exposures can occur because of genetic variation or as a consequence of co-administration with drugs that inhibit CYP2D6. Very recently Michelson et al. (2007) showed significant differences in serum plasma levels of atomoxetine between CYP2D6 extensive metabolizers (EM) and poor metabolizers (PM). Differences in the CYP2D6 genotype and phenotype as well as pharmacokinetic interventions can potentially affect the clinical profile of atomoxetine as seen in efficacy and tolerability of the drug whereas the effect of potent CYP2D6 inhibition on the pharmacokinetics of atomoxetine has rarely been investigated. Belle et al. (2002) showed …

Atomoxetine pharmacokinetics in healthy Chinese subjects and effect of the CYP2D6*10 allele

To characterize atomoxetine pharmacokinetics, explore the effect of the homozygous CYP2D6*10 genotype on atomoxetine pharmacokinetics and evaluate the tolerability of atomoxetine, in healthy Chinese subjects. Twenty-four subjects, all CYP2D6 extensive metabolizers (EM), were randomized to receive atomoxetine (40 mg qd for 3 days, then 80 mg qd for 7 days) or matching placebo (2 : 1 ratio) in a double-blind fashion. Atomoxetine serum concentrations were measured following single (40 mg) and multiple (80 mg) doses. Adverse events, clinical safety laboratory data and vital signs were assessed during the study. Atomoxetine was rapidly absorbed with median time to maximum serum concentrations of approximately 1.5 h after single and multiple doses. Atomoxetine concentrations appeared to decrease monoexponentially with a mean apparent terminal half-life (t(1/2)) of approximately 4 h. The apparent clearance, apparent volume of distribution and t(1/2) following single and multiple doses were similar, suggesting linear pharmacokinetics with respect to time. Homozygous CYP2D6*10 subjects had 50% lower clearances compared with other EM subjects, resulting in twofold higher mean exposures. No clinically significant changes or abnormalities were noted in laboratory data and vital signs. The pharmacokinetics of atomoxetine in healthy Chinese subjects appears comparable to other ethnic populations. Multiple dosing of 80 mg qd atomoxetine was well tolerated in this study.

L’atomoxétine : un nouveau traitement du trouble déficitaire de l’attention/hyperactivité de l’enfant et de l’adolescent

L’atomoxétine : un nouveau traitement du trouble déficitaire de l’attention/hyperactivité de l’enfant et de l’adolescent

Pharmacokinetics and tolerability of atomoxetine in adults of known CYP2D6 phenotype

Background/Aims This study was designed to evaluate atomoxetine pharmacokinetics, dose proportionality, and safety in CYP2D6 extensive metabolizer (EM) and poor metabolizer (PM) subjects after single dose and at steady state. Methods Part A: single-blind, placebo-controlled, single-dose escalation design from 10 to 120 mg. Part B: single-blind, placebo-controlled, multiple-dose design of 40 mg BID for 7 days. The pharmacokinetics of atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine were evaluated using noncompartmental analysis. Safety assessments included adverse events, heart rate (HR), blood pressure (BP), and orthostatic measures. Results Dose proportionality and linearity were shown in both EM and PM. PM had a 10-fold lower clearance and a longer t1/2 than EM subjects (5.23 hr vs. 24.4 hr). HR increases were similar for EM and PM in Part A, while PMs had a maximum HR about 10 bpm higher than EMs in Part B. Conclusions Atomoxetine pharmacokinetics were influenced by the CYP2D6 polymorphism. Orthostatic changes in systolic BP and HR were not clinically significant. The hemodynamic response to atomoxetine was similar across subjects, despite marked differences in exposure due to CYP2D6 polymorphism. EM and PM subjects had similar drug-related adverse event profiles, therefore no dose adjustment is necessary. Clinical Pharmacology & Therapeutics (2005) 77, P27–P27; doi: 10.1016/j.clpt.2004.11.103

Population pharmacokinetic analysis of atomoxetine in pediatric patients

Atomoxetine is a novel treatment of ADHD in children, adolescents, and adults. The purpose of this analysis was to characterize atomoxetine pharmacokinetics and the potential influence of patient factors in pediatric patients. A population pharmacokinetic model was developed using the combined sparse and serial plasma data of 420 patients with 2354 observations from 5 pediatric studies. Patient factors with clinical and demographic significance were identified a priori and evaluated on model parameters. The final model was a 1-compartment model and was validated using several methods. Covariates retained in the final model included CYP2D6 genotype, body weight, and food consumption. The results demonstrate linear pharmacokinetics across the dose range evaluated of 5 to 45 mg twice-daily. CYP2D6 poor metabolizers had a 9-fold lower clearance compared to extensive metabolizers. Clearance and volume of distribution increased nearly proportional to increased body weight, indicating dosing based on body weight is appropriate. Simulations showed that weight-based dosing provides a more narrow and predictable range of exposures in patients. Food consumption decreased the rate of atomoxetine absorption, however the decrease (9% lower Cmax) was deemed clinically insignificant. Age, gender, ethnic origin, and caffeine consumption did not influence atomoxetine disposition. This analysis provided valuable data concerning these patient factors in the target patient population. Clinical Pharmacology & Therapeutics (2004) 75, P46–P46; doi: 10.1016/j.clpt.2003.11.173

Effect of hepatic impairment on the pharmacokinetics of atomoxetine and its metabolites.

Atomoxetine is a treatment for attention-deficit/hyperactivity disorder and is primarily eliminated via cytochrome P4502D6 (CYP2D6). The pharmacokinetics of atomoxetine and its primary metabolites were investigated in 10 adults with hepatic impairment (6 moderate, 4 severe) and 10 age- and sex-matched control subjects, all being genotyped as CYP2D6 extensive metabolizers. A single oral 20-mg dose of atomoxetine was given. Multiple blood samples were collected for 48 hours in healthy subjects and for 120 hours in patients. Urine was collected up to 24 hours. Before atomoxetine administration (10-20 days), sorbitol clearance and debrisoquin (INN, debrisoquine) metabolic ratio were determined as markers of hepatic blood flow and CYP2D6 activity, respectively. The systemic clearance of atomoxetine was significantly reduced in those with hepatic impairment compared with controls, thereby resulting in increased exposure (area under the concentration-time curve from time 0 to infinity, 1.58 versus 0.85 microg. h(-1). mL(-1); P =.035) but no change in maximum concentration. Mean 4-hydroxyatomoxetine area under the concentration-time curve from time 0 to time t and maximum concentration were increased approximately 7-fold and 2-fold, respectively (P =.0001 and P =.0056, respectively). For the glucuronide conjugate of 4-hydroxyatomoxetine, the mean half-life was longer and the mean area under the concentration-time curve from time 0 to infinity and the maximum concentration were lower (P =.0028, P =.003, and P =.0001, respectively). The sorbitol clearance was lower and the debrisoquin metabolic ratio was higher, reflecting reduced hepatic blood flow and decreased CYP2D6 activity, respectively. Decreased atomoxetine clearance in patients with hepatic impairment was clearly correlated with decreased CYP2D6 activity and decreased hepatic blood flow. Mean atomoxetine plasma protein binding was lower in patients with hepatic impairment compared with controls (96.5% versus 98.7%, P =.0008). Atomoxetine was well tolerated in the 2 populations. For patients with attention-deficit/hyperactivity disorder who have hepatic impairment, dosage adjustment is recommended. Initial target doses should be reduced to 25% and 50% of the normal dose for patients with severe and moderate hepatic impairment, respectively.