Pharmacodynamics of norepinephrine reuptake inhibition: Modeling the peripheral and central effects of atomoxetine, duloxetine, and edivoxetine on the biomarker 3,4‐dihydroxyphenylglycol in humans

Abstract

Norepinephrine, a neurotransmitter in the autonomic sympathetic nervous system, is deaminated by monoamine oxidase to 3,4-dihydroxyphenylglycol (DHPG). Inhibition of the NE transporter (NET) using DHPG as a biomarker was evaluated using atomoxetine, duloxetine, and edivoxetine as probe NET inhibitors. Pharmacokinetic and pharmacodynamic data were obtained from healthy subjects (n = 160) from 5 clinical trials. An indirect response model was used to describe the relationship between drug plasma concentration and DHPG concentration in plasma and cerebrospinal fluid (CSF). The baseline plasma DHPG concentration (1130-1240 ng/mL) and Imax (33%-37%) were similar for the 3 drugs. The unbound plasma drug IC50 (IC50U ) based on plasma DHPG was 0.973 nM for duloxetine, 0.136 nM for atomoxetine, and 0.041 nM for edivoxetine. The baseline CSF DHPG concentration (1850-2260 ng/mL) was similar for the 3 drugs, but unlike plasma DHPG, the Imax for DHPG was 38% for duloxetine, 53% for atomoxetine, and75% for edivoxetine. The IC50U based on CSF DHPG was 2.72 nM for atomoxetine, 1.22 nM for duloxetine, and 0.794 nM for edivoxetine. These modeling results provide insights into the pharmacology of NET inhibitors and the use of DHPG as a biomarker.

Developmental Changes in Pharmacokinetics and Pharmacodynamics

“…As mentioned previously, challenges in optimizing the dose of the norepinephrine reuptake inhibitor atomoxetine require consideration of the impact of normal growth and development (ontogeny) and pharmacogenomics on the disposition of the drug. Kielbasa and Lobo used atomoxetine as a probe to examine inhibition of the norepinephrine transporter. Specifically, plasma and cerebrospinal fluid concentration of 3,4‐dihydroxyphenylglycol, the metabolic product of norepinephrine deamination by monoamine oxidase, were examined as a potential biomarker of drug effect in both the central (ie, blood) and peripheral (ie, brain) compartments.…”

Selective Monomethylation of Amines with Methanol as the C1 Source

“…Oenethyl (34 bb) [25] was synthesized from the precursor in ag ood yield (76 %) using the developed method. Finally,t he methylation procedure was applied for the last step of amulti-step synthesis of atomoxetine (35 bb), which is among the top 100 best-selling ADHD drugs [26] and was obtained in good yield (65 %).…”

Exploratory Biomarker Study of the Triple Reuptake Inhibitor SEP‐432 Compared to the Dual Reuptake Inhibitor Duloxetine in Healthy Normal Subjects

“…In CSF, both SEP-432 and [18,19]. Both compounds also increased 5-HT in CSF, but only the results with duloxetine were significant.…”