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

Abstract

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.

Keywords

ADHD adult ADHD atomoxetine non-linear kinetics plasma concentration

Introduction

Atomoxetine inhibits the reuptake of noradrenaline in the prefrontal cortex, and it is a non-stimulant drug most commonly used to treat symptoms of ADHD. Therefore, in many nations, it is the first or second drug of choice for the treatment of adult ADHD (Atkinson & Hollis, 2010; Saito & Watanabe, 2008; Weiss et al., 2011). Atomoxetine is known to be metabolized by cytochrome P450 (CYP) 2D6. It has already been revealed that paroxetine, a substrate of CYP2D6, has non-linear kinetics in its relationship between dose and plasma concentration (Sawamura, Suzuki, & Someya, 2004). Furthermore, some specific polymorphisms of CYP2D6 indicate people as poor metabolizers (PMs) or intermediate metabolizers (IMs) of these drugs (Ebisawa et al., 2005; Kubota, Yamaura, Ohkawa, Hara, & Chiba, 2000). As the distribution of polymorphisms may vary between races (Kubota et al., 2000), it is possible that there are some population differences in the metabolic kinetics of atomoxetine.

In clinical practice, the dose of atomoxetine administered is decided by the body weight of child patients, or for adult patients, it is started at 40 mg and increased in fixed amounts. If the efficacy is not enough, the dose of atomoxetine is increased to 80 mg and 100 mg as maintenance and extended treatments in the United States ( Strattera Package Insert [the United States], 2015 ). In Japan, it is increased to 80 mg and 120 mg ( Strattera Package Insert [Japan], 2013 ), the latter dose being higher than that used in the United States. However, to our knowledge, there is a lack of research investigating the pharmacokinetics for high dose of atomoxetine in adult Japanese patients. Therefore, we aimed to investigate the relationship between three oral doses and steady-state plasma levels of atomoxetine in adult Japanese ADHD patients.

Materials and Method

Participants and Blood Sampling

The participants of this study were aged 18 years or older with a diagnosis of ADHD according to Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5; American Psychiatric Association, 2013) criteria, who were being treated with atomoxetine at the Department of Psychiatry, Niigata University Medical and Dental Hospital, Niigata, Japan. A total of 33 patients (22 males, 11 females, M age = 29.8 ± 7.5 years, range = 19-49 years) were enrolled in the study, after receiving an explanation of the procedure and aims, and giving written consent. This study was approved by the Gene Ethics Committee of Niigata University Graduate School of Medical and Dental Sciences. Patients who had been treated with any drugs, other than benzodiazepines, or who had obvious physical illnesses were excluded from the study. It has allowed the combination of benzodiazepines because they are thought to being metabolized by enzymes other than CYP2D6 (Kronbach, Mathys, Umeno, Gonzalez, & Meyer, 1989; von Moltke, Greenblatt, Cotreau-Bibbo, Harmatz, & Shader, 1994), and to have essentially little effect.

Participants were administered 40 mg, 80 mg, and 120 mg of atomoxetine, and maintained on each daily dose for at least 2 weeks to obtain pharmacokinetic steady-state concentrations. To measure the trough value, blood was sampled 12 hr after the last dose, using Venoject® tubes (7 mL, Terumo Japan, Tokyo, Japan) including EDTA-Na. Samples were centrifuged at 3,000 rpm (150 G) for 10 min within 3 hr of collection, and plasma aliquots were stored at −80°C until assayed to determine atomoxetine steady-state plasma concentrations.

Determination of Plasma Atomoxetine Levels

Plasma concentrations of atomoxetine were measured using a high-performance liquid chromatography (HPLC) method developed in our laboratory. Five hundred microliters of 0.5 M NaOH, 100 µL of internal standard solution (trifluperidol, 10.8 µg/mL), 100 µL of methanol, and 2,500 µL pure water were added to 1,000 µL of each plasma sample. After the extraction solvent was added, the organic phase was evaporated in vacuo at 40°C to dryness. The residue was dissolved in 300 µL of the diluting and dissolving solution, and a total of 100 µL was injected into the HPLC system. The HPLC system consisted of an SPD-10A ultraviolet spectrophotometer (Shimadzu Corporation, Kyoto, Japan) and an STR-ODS II column (150 mm × 4.6 mm inner diameter, 5 µm, Shimadzu Corporation). The mobile phase consisted of phosphate buffer (0.02 M, pH = 4.6), acetonitrile, and perchloric acid (60%; 61.0:38.5:0.5, v/v/v). The lower limit of detection was 2.5 ng/mL, and the values of the intra- and inter-assay coefficients of variation were less than 10% at all calibration curve concentrations (21.9-1,400 ng/mL) for atomoxetine.

Data Analyses and Statistics

We used Pearson’s correlation coefficient analyses to determine the correlation between dose and concentration of atomoxetine. We also used ANOVA and t tests to assess any differences (non-linear relationships) in the concentration/dose between the three doses (40, 80, and 120 mg) of atomoxetine. A p value of less than .05 was regarded as statistically significant. All analyses were performed using IBM SPSS Statistics 19 (IBM Japan, Tokyo, Japan).

Results

Fifty-five plasma samples were collected from 33 participants. The mean ± SD plasma concentrations of atomoxetine at 40, 80, and 120 mg/day were 53.2 ± 67.0, 298.0 ± 390.5, and 639.3 ± 831.9 ng/mL (unless stated otherwise, all values are mean ± SD). A significant correlation was found between the dose of atomoxetine and resulting plasma concentration (r = .268, p = .004). The average plasma concentration of atomoxetine at 80 mg/day was approximately sixfold higher than that at 40 mg/day, and at 120 mg/day, it was approximately twofold higher than that at 80 mg/day. The plasma concentration/mg doses at 40, 80, and 120 mg/day were 1.33 ± 1.67, 3.73 ± 4.88, and 5.33 ± 6.93 ng/mL/mg, respectively. We observed a trending toward significance in the difference in the concentration/dose between the three dosage groups (df = 2, F = 2.904, p = .064). The plasma concentration/mg dose at 40 and 80 + 120 mg/day (pooled data for the 80 and 120 mg groups) were 1.329 ± 1.674 and 4.215 ± 5.534 ng/mL/mg. The plasma concentration/mg dose at 80 + 120 mg was significantly higher than at 40 mg (t = −2.885, p = .006), and thus a non-linear atomoxetine pharmacokinetics is suggested.

Discussion

To the best of our knowledge, the present study reveals for the first time the non-linear pharmacokinetics of different daily doses of atomoxetine and drug serum concentrations in adult Japanese patients with ADHD. Two possible causes of this non-linearity are proposed: the saturation of CYP2D6 metabolic capacity (Preskorn, 1994; Sindrup, Brosen, & Gram, 1992) and the self-inhibition of atomoxetine metabolism through the CYP2D6 enzyme pathway (Bertilsson & Dahl, 1996). Atomoxetine has shown simple competitive inhibition in an in vitro study, and did not inhibit CYP2D6 through non-competitive mechanisms (Sauer et al., 2004). Therefore, the metabolic capacity saturation hypothesis is a more likely explanation for the non-linear kinetics of atomoxetine.

Interestingly, several studies have indicated a linear correlation between the dose and concentration of atomoxetine (Matsui et al., 2012; Witcher et al., 2003). Some possible causes of this discrepancy should be considered: the difference in the measurement method, the difference in CYP2D6 polymorphisms due to the different population bases, and the differences in metabolism between adults and children. In the present study, we examined the concentration at the trough of the steady state, after administration of the same dose for at least 2 weeks. The areas under the curve to 1 mg/kg dose of the steady-state concentration (Witcher et al., 2003), or C_max, of a single dose of atomoxetine (Matsui et al., 2012) were measured in the previous researches, and this difference in measurement could be the cause of the discrepancy between those results and ours. Caucasians have 5% to 10% PM CYP2D6 polymorphisms, while the Japanese population has less than 1%. Also, the *10 allele, known as a reduced function allele, is detected in very few Caucasians, while more than 40% of Japanese people have it (Ebisawa et al., 2005). At higher doses of atomoxetine, the differences in plasma concentration between IM individuals and extensive metabolizer individuals become greater. This could cause the non-linear curve of plasma concentration seen in Japanese patients. In regard to the differences in metabolism between adults and children, Witcher et al. (2003) compared their child patients with adult participants from 12 previous studies, and concluded that there was no significant difference in the course of blood concentration between adults and children following a single dose of atomoxetine. However, there has been no study assessing the differences in the kinetics of atomoxetine between adults and children in the steady state. Although more studies are needed to elucidate these issues, the racial differences of CYP2D6 might be the most likely cause for the non-linear curve of serum concentration of atomoxetine in these three possibilities.

The non-linearity of the atomoxetine serum concentration can cause the emergence of side effects and withdrawal syndromes at high doses, similar to those seen with paroxetine. In fact, a dose setting of 105 mg was established between the standard 80 mg and 120 mg doses in the third phase of clinical trials in Japan (Takahashi et al., 2011). Furthermore, Hazell et al. (2009) reported increased discontinuation of therapy due to side effects at high doses, although there was no significant difference, and statistically significantly more nasopharyngitis due to high dose atomoxetine. Michelson et al. (2001) also reported that several side effects have significant relationships with the concentration of atomoxetine administered, and more discontinuations occur due to side effects at high doses, but these are not statistically significant. Therefore, if side effects appear, it may be necessary to increase the dose of atomoxetine more cautiously.

This study has limitations: We did not genotype for CYP2D6 and CYP2C19, so we cannot deny the possibilities of biases from rare mutant alleles due to the small sample size. Studies with larger sample sizes and genotyping are needed to resolve this problem. A study comparing 40, 80, and 120 mg doses in the same individual is also desirable, because of the possibility of varying degrees of atomoxetine non-linear pharmacokinetics due to CYP2D6 or CYP2C19 polymorphisms.

In conclusion, it is important to note that due to the non-linear kinetics of atomoxetine, clinicians should pay careful attention to the dose titration, rather than following the standard dosing protocol of starting at 40 mg and increasing to 80, and then 120 mg.

Footnotes

Declaration of Conflicting Interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Someya has received research support and honoraria from Asahi Kasei, Astellas Pharma, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, GlaxoSmithKline, Janssen Pharmaceutical, Kyowa Hakko Kirin, Meiji Seika Pharma, MSD, Novartis Pharma, Otsuka Pharmaceutical, Pfizer Japan, Shionogi, Takeda Pharmaceutical, and Yoshitomiyakuhin. Dr. Suzuki has received research support and honoraria from Janssen Pharmaceutical, Otsuka Pharmaceutical, and Mitsubishi Tanabe Pharma Corporation. The other authors have no conflicts of interest to disclose.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Author Biographies

Atsunori Sugimoto, MD, PhD, contract assistant professor, obtained a PhD from Niigata University Graduate School of Medical and Dental Sciences, Japan, in 2015. His research focus is on treatment, psychopharmacology, and biomarkers of developmental disorders especially ADHD.

Yutaro Suzuki, MD, PhD, associate professor, obtained a PhD from Niigata University Graduate School of Medical and Dental Sciences, Japan, in 2003. His research focus is on clinical psychopharmacology and pharmacogenetics.

Naoki Orime, MD, is a graduate student of Niigata University Graduate School of Medical and Dental Sciences, Japan. His research focus is on side effects of psychotropic drugs, psychopharmacology, and sex hormones in autistic spectrum disorder.

Taketsugu Hayashi, MD, is a graduate student of Niigata University Graduate School of Medical and Dental Sciences, Japan. His research focus is on gaze direction of autistic spectrum disorder and autism model primates.

Jun Egawa, MD, PhD, associate professor, obtained a PhD from Niigata University Graduate School of Medical and Dental Sciences, Japan, in 2012. His research focus is on pathogenesis and molecular genetics of developmental disorders especially autistic spectrum disorder.

Takuro Sugai, MD, PhD, assistant professor, obtained a PhD from Niigata University Graduate School of Medical and Dental Sciences, Japan, in 2009. His research focus is on clinical psychopharmacology and side effects of psychotropic drugs for depression and schizophrenia.

Yoshimasa Inoue, visiting researcher in Dokkyo Medical University, is an engineer highly skilled in liquid chromatography. His research focus is on liquid chromatography and plasma concentration of psychotropic drugs.

Toshiyuki Someya, MD, PhD, professor, obtained a PhD from Shiga University of Medical Science, Japan, in 1990. His research focus is on psychopharmacology and diagnostics in psychiatry.

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