John-Michael Sauer

Clinical Pharmacokinetics of Atomoxetine

Atomoxetine (Strattera®), a potent and selective inhibitor of the presynaptic norepinephrine transporter, is used clinically for the treatment of attention-deficit hyperactivity disorder (ADHD) in children, adolescents and adults. Atomoxetine has high aqueous solubility and biological membrane permeability that facilitates its rapid and complete absorption after oral administration. Absolute oral bioavailability ranges from 63 to 94%, which is governed by the extent of its first-pass metabolism. Three oxidative metabolic pathways are involved in the systemic clearance of atomoxetine: aromatic ring-hydroxylation, benzylic hydroxylation and N-demethylation. Aromatic ring-hydroxylation results in the formation of the primary oxidative metabolite of atomoxetine, 4-hydroxyatomoxetine, which is subsequently glucuronidated and excreted in urine. The formation of 4-hydroxy-atomoxetine is primarily mediated by the polymorphically expressed enzyme cytochrome P450 (CYP) 2D6. This results in two distinct populations of individuals: those exhibiting active metabolic capabilities (CYP2D6 extensive metabolisers) and those exhibiting poor metabolic capabilities (CYP2D6 poor metabolisers) for atomoxetine.The oral bioavailability and clearance of atomoxetine are influenced by the activity of CYP2D6; nonetheless, plasma pharmacokinetic parameters are predictable in extensive and poor metaboliser patients. After single oral dose, atomoxetine reaches maximum plasma concentration within about 1–2 hours of administration. In extensive metabolisers, atomoxetine has a plasma half-life of 5.2 hours, while in poor metabolisers, atomoxetine has a plasma half-life of 21.6 hours. The systemic plasma clearance of atomoxetine is 0.35 and 0.03 L/h/kg in extensive and poor metabolisers, respectively. Correspondingly, the average steady-state plasma concentrations are approximately 10-fold higher in poor metabolisers compared with extensive metabolisers. Upon multiple dosing there is plasma accumulation of atomoxetine in poor metabolisers, but very little accumulation in extensive metabolisers. The volume of distribution is 0.85 L/kg, indicating that atomoxetine is distributed in total body water in both extensive and poor metabolisers. Atomoxetine is highly bound to plasma albumin (approximately 99% bound in plasma). Although steady-state concentrations of atomoxetine in poor metabolisers are higher than those in extensive metabolisers following administration of the same mg/kg/day dosage, the frequency and severity of adverse events are similar regardless of CYP2D6 phenotype.Atomoxetine administration does not inhibit or induce the clearance of other drugs metabolised by CYP enzymes. In extensive metabolisers, potent and selective CYP2D6 inhibitors reduce atomoxetine clearance; however, administration of CYP inhibitors to poor metabolisers has no effect on the steady-state plasma concentrations of atomoxetine.

Atomoxetine Pharmacokinetics in Children and Adolescents with Attention Deficit Hyperactivity Disorder

OBJECTIVE Atomoxetine is indicated for the treatment of attention deficit hyperactivity disorder in children, adolescents, and adults. This study was conducted, in part, to evaluate the single-dose and steady-state pharmacokinetics of atomoxetine in pediatric patients. METHODS This was an open-label, dose-titration study in pediatric patients with attention deficit hyperactivity disorder. Eligible patients could elect to participate in a single-dose or steady-state discontinuation pharmacokinetic evaluation including serial plasma sample collection over 24 hours. Plasma concentrations of atomoxetine, 4-hydroxyatomoxetine, and N-desmethylatomoxetine were determined using an atmospheric pressure chemical ionization liquid chromatography/mass spectrometry/mass spectrometry assay. Pharmacokinetic parameters were calculated using noncompartmental analysis. RESULTS Twenty-one cytochrome P450 2D6 extensive metabolizer patients participated in these single-dose and steady-state pharmacokinetic evaluations. Atomoxetine was rapidly absorbed, with peak plasma concentrations occurring 1 to 2 hours after dosing. Half-life averaged 3.12 and 3.28 hours after a single dose and at steady state, respectively. Minimal accumulation occurred in plasma after multiple twice-daily dosing in extensive metabolizer pediatric patients, as expected based on single-dose pharmacokinetics. As the dose (in mg/kg) increased, proportional increases in area under the curve were observed. CONCLUSIONS The pharmacokinetics of atomoxetine in extensive metabolizer patients were well characterized over a wide range of doses in this study. Atomoxetine pharmacokinetics in pediatric patients and adult subjects were similar after adjustment for body weight.

Effect of potent CYP2D6 inhibition by paroxetine on atomoxetine pharmacokinetics.

The purpose of this study was to characterize the effect of potent CYP2D6 inhibition by paroxetine on atomoxetine disposition in extensive metabolizers. This was a single‐blind, two‐period, sequential study in 22 healthy individuals. In period 1, 20 mg atomoxetine bid was administered to steady state. In period 2, 20 mg paroxetine was administered qd for 17 days. On days 12 through 17, 20 mg atomoxetine bid were coadministered. Plasma pharmacokinetics of atomoxetine, 4‐hydroxyatomoxetine, and N‐desmethylatomoxetine was determined at steady state in each treatment period. Plasma pharmacokinetics of paroxetine were determined after the 11th and 17th doses. Paroxetine increased Css,max, AUC0–12, and t1/2 of atomoxetine by approximately 3.5‐, 6.5‐, and 2.5‐fold, respectively. After coadministration with paroxetine, increases in N‐desmethylatomoxetine and decreases in 4‐hydroxyatomoxetine concentrations were observed. No changes in paroxetine pharmacokinetics were observed after coadministration with atomoxetine. It was concluded that inhibition of CYP2D6 by paroxetine markedly affected atomoxetine disposition, resulting in pharmacokinetics similar to poor metabolizers of CYP2D6 substrates.

Cytotoxicity and genotoxicity of methyleugenol and related congeners-- a mechanism of activation for methyleugenol.

Methyleugenol is a substituted alkenylbenzene found in a variety of foods, products, and essential oils. In a 2-year bioassay conducted by the National Toxicology Program, methyleugenol caused neoplastic lesions in the livers of Fischer 344 rats and B6C3F(1) mice. We were interested in the cytotoxicity and genotoxicity caused by methyleugenol and other alkenylbenzene compounds: safrole (a known hepatocarcinogen), eugenol, and isoeugenol. The endpoints were evaluated in cultured primary hepatocytes isolated from male Fischer 344 rats and female B6C3F(1) mice. Cytotoxicity was determined by measuring lactate dehydrogenase (LDH) release, while genotoxicity was determined by using the unscheduled DNA synthesis (UDS) assay. Rat and mouse hepatocytes showed similar patterns of toxicity for each chemical tested. Methyleugenol and safrole were relatively non-cytotoxic, but caused UDS at concentrations between 10 and 500 microM. In contrast, isoeugenol and eugenol produced cytotoxicity in hepatocytes with LC50s of approximately 200-300 microM, but did not cause UDS. Concurrent incubation of 2000 microM cyclohexane oxide (CHO), an epoxide hydrolase competitor, with a non-cytotoxic concentration of methyleugenol (10 microM) resulted in increased cytotoxicity but had no effect on genotoxicity. However, incubation of 15 microM pentacholorophenol, a sulfotransferase inhibitor, with 10 uM methyleugenol resulted in increased cytotoxicity but had a significant reduction of genotoxicity. These results suggest that methyleugenol is similar to safrole in its ability to cause cytotoxicity and genotoxicity in rodents. It appears that the bioactivation of methyleugenol to a DNA reactive electrophile is mediated by a sulfotransferase in rodents, but epoxide formation is not responsible for the observed genotoxicity.

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.

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.

Pharmacokinetics and tolerability of atomoxetine in adults of known CYP2D6 phenotype

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.