ABSTRACT:The role of the polymorphic cytochrome P450 2D6 (CYP2D6) in the pharmacokinetics of atomoxetine hydrochloride [(؊)-N-methyl-␥-(2-methylphenoxy)benzenepropanamine hydrochloride; LY139603] has been documented following both single and multiple doses of the drug. In this study, the influence of the CYP2D6 polymorphism on the overall disposition and metabolism of a 20-mg dose of 14 C-atomoxetine was evaluated in CYP2D6 extensive metabolizer (EM; n ‫؍‬ 4) and poor metabolizer (PM; n ‫؍‬ 3) subjects under steady-state conditions. Atomoxetine was well absorbed from the gastrointestinal tract and cleared primarily by metabolism with the preponderance of radioactivity being excreted into the urine. In EM subjects, the majority of the radioactive dose was excreted within 24 h, whereas in PM subjects the majority of the dose was excreted by 72 h. The biotransformation of atomoxetine was similar in all subjects undergoing aromatic ring hydroxylation, benzylic oxidation, and N-demethylation with no CYP2D6 phenotype-specific metabolites. The primary oxidative metabolite of atomoxetine was 4-hydroxyatomoxetine, which was subsequently conjugated forming 4-hydroxyatomoxetine-O-glucuronide. Due to the absence of CYP2D6 activity, the systemic exposure to radioactivity was prolonged in PM subjects (t 1/2 ‫؍‬ 62 h) compared with EM subjects (t 1/2 ‫؍‬ 18 h). In EM subjects, atomoxetine (t 1/2 ‫؍‬ 5 h) and 4-hydroxyatomoxetine-O-glucuronide (t 1/2 ‫؍‬ 7 h) were the principle circulating species, whereas atomoxetine (t 1/2 ‫؍‬ 20 h) and Ndesmethylatomoxetine (t 1/2 ‫؍‬ 33 h) were the principle circulating species in PM subjects. Although differences were observed in the excretion and relative amounts of metabolites formed, the primary difference observed between EM and PM subjects was the rate at which atomoxetine was biotransformed to 4-hydroxyatomoxetine.Atomoxetine hydrochloride (LY139603; formerly known as tomoxetine hydrochloride) is known chemically as (Ϫ)-N-methyl-␥-(2-methylphenoxy)benzenepropanamine hydrochloride. Atomoxetine is a potent inhibitor of the presynaptic norepinephrine transporter with minimal affinity for other monoamine transporters or receptors (Wong et al., 1982;Gehlert et al., 1993). Atomoxetine is under development as a therapeutic agent for the treatment of attention deficit/hyperactivity disorder in children, adolescents, and adults.Atomoxetine is predominantly metabolized by CYP2D6 (Ring et al., 2002); therefore, its single and multiple dose pharmacokinetics are influenced by the polymorphic expression of this enzyme (Farid et al., 1985). As a result, the pharmacokinetics of atomoxetine appear to have a bimodal distribution with two distinct populations. The enzymatic activity of CYP2D6 is determined by a genetic polymorphism (Evans et al., 1980;Steiner et al., 1988), and is an important source of intersubject variability in metabolism for a number of drugs, including debrisoquine, desipramine, and dextromethorphan (Wolf and Smith, 1999). Mutations or deletion of the CYP2D6 gene results in a mino...

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.

What is already known about this subject • Atomoxetine is a cytochrome P450 2D6 (CYP2D6) substrate and its pharmacokinetics has been characterized in a predominantly White population during clinical development. • There are scant East Asian pharmacokinetic data available. • The CYP2D6*10 allele is particularly prevalent in East Asian populations and may contribute to the known ethnic differences in CYP2D6 metabolic capacity. What this study adds • The pharmacokinetics of multiple‐dose 80 mg daily atomoxetine observed in Chinese healthy subjects appears comparable to previous data in other ethnic populations. • Homozygous CYP2D6*10 subjects appear to have higher exposures, but are not a clearly distinct group compared with other CYP2D6 extensive metabolizers. Aims 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. Methods 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. Results 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 (t1/2) of approximately 4 h. The apparent clearance, apparent volume of distribution and t1/2 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. Conclusions 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.

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.

In order to study the effect of clofazimine, a powerful antimycobacterial and antiinflammatory agent, 49 patients with active Crohn's disease were randomized to either corticosteroids plus clofazimine 100 mg daily (N = 25) or to steroids and matching placebo (N = 24). A total of 28 patients (58%) went into disease remission (clofazimine 16, placebo 12; P = NS) with a fall in disease activity score from 10.5 +/- 4.4 to 3.3 +/- 3.5. Patients were treated for a further eight months with clofazimine or placebo and 18 of 28 maintained their remission and completed the study (clofazimine 12, placebo 6; P = NS). Side effects were minor and consisted of skin rash and increased pigmentation. Clofazimine as a solitary antimycobacterial agent appears ineffective in inducing remission in Crohn's disease but may have a role in either disease maintenance or combination chemotherapy.

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.

In the studies reported here, the ability of atomoxetine hydrochloride (Strattera) to inhibit or induce the metabolic capabilities of selected human isoforms of cytochrome P450 was evaluated. Initially, the potential of atomoxetine and its two metabolites, N-desmethylatomoxetine and 4-hydroxyatomoxetine, to inhibit the metabolism of probe substrates for CYP1A2, CYP2C9, CYP2D6, and CYP3A was evaluated in human hepatic microsomes. Although little inhibition of CYP1A2 and CYP2C9 activity was observed, inhibition was predicted for CYP3A (56% predicted inhibition) and CYP2D6 (60% predicted inhibition) at concentrations representative of high therapeutic doses of atomoxetine. The ability of atomoxetine to induce the catalytic activities of CYP1A2 and CYP3A in human hepatocytes was also evaluated; however, atomoxetine did not induce either isoenzyme. Based on the potential of interaction from the in vitro experiments, drug interaction studies in healthy subjects were conducted using probe substrates for CYP2D6 (desipramine) in CYP2D6 extensive metabolizer subjects and CYP3A (midazolam) in CYP2D6 poor metabolizer subjects. Single-dose pharmacokinetic parameters of desipramine (single dose of 50 mg) were not altered when coadministered with atomoxetine (40 or 60 mg b.i.d. for 13 days). Only modest changes (approximately 16%) were observed in the plasma pharmacokinetics of midazolam (single dose of 5 mg) when coadministered with atomoxetine (60 mg b.i.d. for 12 days). Although at high therapeutic doses of atomoxetine inhibition of CYP2D6 and CYP3A was predicted, definitive in vivo studies clearly indicate that atomoxetine administration with substrates of CYP2D6 and CYP3A does not result in clinically significant drug interactions.Atomoxetine hydrochloride (Strattera; formerly known as tomoxetine hydrochloride) is known chemically as (Ϫ)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine hydrochloride. Atomoxetine is a potent inhibitor of the presynaptic norepinephrine transporter with minimal affinity for other monoamine transporters or receptors (Wong et al., 1982;Gehlert et al., 1993) and is used clinically for the treatment of attention-deficit/hyperactivity disorder in children, adolescents, and adults.Atomoxetine is rapidly and completely absorbed after oral administration . The plasma pharmacokinetics of atomoxetine are linear over the recommended therapeutic dosing range (0.5-1.4 mg/kg) with proportional increases in both mean atomoxetine maximum plasma concentration (C max ) and area under the plasma concentration time curve (AUC) with increasing dose . Atomoxetine is predominantly metabolized by CYP2D6 (Ring et al., 2002); therefore, its pharmacokinetics and metabolism are influenced by the polymorphic expression of this enzyme (Farid et al., 1985;Sauer et al., 2003). As a result, the systemic clearance values of atomoxetine seem to be distributed in a bimodal manner. The enzymatic activity of CYP2D6 is regulated by a genetic polymorphism resulting in two major populations of individuals with either active met...

Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Bamlanivimab and etesevimab are potent neutralizing antibodies that target the spike protein of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). WHAT QUESTION DID THIS STUDY ADDRESS? This study characterizes the pharmacokinetics (PKs) of bamlanivimab and etesevimab and the exposure-response relationship for reduction in viral load in patients with coronavirus disease 2019 (COVID-19). The study identified the optimal doses and investigated the impact of various demographic factors that could affect therapeutic response to the neutralizing antibodies.