Duloxetine pharmacokinetics are similar in Japanese and Caucasian subjects

Abstract

What is already known about this subject• The pharmacokinetics of duloxetine have been assessed in a number of clinical studies.• Duloxetine is eliminated through oxidative metabolism via CYP1A2 and, to a lesser degree, CYP2D6.• There is strong evidence that the prevalence of CYP2D6 phenotypes and the activity of CYP1A2 enzyme activity differ between Japanese and Caucasians.• Given the characteristics of duloxetine metabolism, there is good reason to assess pharmacokinetic differences between Japanese and Caucasians. What this study adds• Duloxetine pharmacokinetics in Japanese or Caucasian subjects is not meaningfully different after single or multiple doses of duloxetine.• The magnitude of pharmacokinetic differences between groups is small relative to the pharmacokinetic variability in either group, and these small differences can be accounted for by differences in body weight.• The result of this study suggests that different dose recommendations for Caucasian or Japanese patients are not likely to be necessary. AimsTo compare single-and multiple-dose duloxetine pharmacokinetics between healthy Japanese and Caucasians. MethodsTwenty-four subjects of each race were given single oral doses of duloxetine (20, 40 and 60 mg) in a randomized, double-blind study. Another 20 subjects of each race received 20, 40 mg or placebo (2 : 2 : 1) twice-daily for 5 days. ResultsFollowing single doses, the mean duloxetine C max and AUC were approximately 20% greater in Japanese. This difference could be explained by the 15% lower average body weight in Japanese. Similar results were observed following multiple dosing. ConclusionDuloxetine pharmacokinetics are not meaningfully different between Japanese and Caucasians. Racial comparison of duloxetine pharmacokineticsBr J Clin Pharmacol 63 :3 311

Adverse events, toxicity and post-mortem data on duloxetine: Case reports and literature survey

“…For example, in three studies, the combined average maximal plasma concentration (C max ) following single dose administration of 20 mg, 40 mg, or 60 mg of duloxetine was 22.9 ng/mL (n = 16), 46 ng/mL (n = 24), and 69.6 ng/mL (n = 12), respectively 20,21,29 ; whereas average C max values from two other studies for single dosage 20, 40, and 60 mg duloxetine yielded 13.7 ng/mL (n = 22), 27.8 ng/mL (n = 16), and 42.2 ng/mL (n = 16), respectively. 19,22 The levels obtained in the latter two studies were consistently found to be 0.6 times those of the former three studies across all single dosage regimens, although the basis for this difference is uncertain. According to the manufacturer, duloxetine has an elimination half-life (t 1/2 ) of about 12 h (range 8-17 h).…”

“…80 kg 27 ). Compilation of data from other studies generates an average V d of 1563 l (%19.5 L/kg) for 118 subjects, [19][20][21][22]28 with a reported average ranging from 962 l (%12 L/kg) for the 12 non-elderly subjects in the study by Skinner et al, 20 up to 2909 l (%36.4 L/kg) for the 6 healthy subjects examined by Suri and colleagues. 19 Although blood levels increase in approximate proportionality to dosage 29 (up to 60 mg/day, see below), the pharmacologic investigations show an apparent dichotomy in the peak levels obtained.…”

“…17 There is a median 2 h lag until absorption begins. 18 Once ingested, the mean time until maximum blood concentration is achieved (T max ) has been variously reported to be between 3.5 and 6 h. [19][20][21][22] The drug is extensively bound to plasma proteins, with the reported degree of protein binding being on the order of 90-95%, predominantly due to binding with albumin and a1 acid glycoprotein. [23][24][25] In preclinical studies supported by the manufacturer, duloxetine's volume of distribution (V d ) has been reported to be 1640 l, 26 or approximately 20.5 L/kg for the average adult in the United States (i.e.…”

“…According to the manufacturer, duloxetine has an elimination half-life (t 1/2 ) of about 12 h (range 8-17 h). 18 Analysis of pooled study data (n = 114) [19][20][21][22]28,29 yields an aggregate mean t 1/2 of 11.79 h. Metabolism occurs predominantly in the liver with biotransformation involving the cytochrome P450 system (CYP), primarily (80-90% 30 ) through CYP 2D6 and 1A2 isoforms. 21 The predominant biotransformation pathways (see Fig.…”

Effectiveness and Tolerability of Duloxetine in 2 Different Ethnic Samples

“…These results appear to hold in studies comparing different ethnic samples (8,9). As duloxetine has a dual effect on both the serotonin and norepinephrine systems (10), it appears to be a viable therapeutic option for treating depressive disorders, effective in the management of somatic symptoms, especially pain, more frequently present depressed non-Westernized populations (11).…”