Pharmacokinetics and tolerability of duloxetine following oral administration to healthy Chinese subjects.

OBJECTIVES: The objectives of the study were to characterise the pharmacokinetics and assess the tolerability of duloxetine in healthy Chinese subjects after single and multiple oral 60 mg dosing. METHODS: This was a single-centre, double-blind, randomised, placebo-controlled, single-period study in healthy native Chinese subjects. A total of 32 subjects, 19 men (14 on duloxetine, 5 on placebo) and 13 women (10 on duloxetine, 3 on placebo) between the ages of 20 and 39 years, participated in the study. Duloxetine 60 mg (enteric-coated pellets in a capsule) was given orally once on day 1 and once daily on days 4 to 9. Sequential blood samples were collected over 72 hours after the dose on days 1 and 9, and a predose sample was obtained on days 7 and 8. Duloxetine concentrations in plasma were determined by a validated liquid chromatography-tandem mass spectrometry method. The tolerability evaluation included a physical examination, vital signs, adverse event monitoring and clinical laboratory evaluations. RESULTS: Duloxetine disposition on oral administration is characterised by a one-compartment pharmacokinetic model. Duloxetine is well absorbed, with a median time of maximum plasma concentration at 6 and 4 hours following single and multiple dosing, respectively. At steady state, the mean apparent oral clearance (CL(ss)/F), mean apparent volume of distribution (V(ss)/F) and mean terminal elimination half-life (t((1/2))) were 86.8 L/h, 1570L and 11 hours, respectively. CL/F and V(ss)/F on single dosing were not statistically significantly different (p > 0.05) compared with multiple dosing. The linearity index, calculated as the ratio of the area under the plasma concentration-time curve (AUC) during the dosing interval tau at steady state (AUC(tau)(,ss)) to the AUC from time zero to infinity after single dosing (AUC(infinity,single dose)) was 1.15 (coefficient of variation 35.7%). The accumulation in duloxetine exposure was estimated to be 50% on multiple dosing compared with single dosing, consistent with the t((1/2)) and dosing interval (24 hours). The pharmacokinetic parameters of duloxetine in Chinese subjects were not statistically significantly different from those reported previously in Caucasian and Japanese subjects. There were no clinically significant adverse events, abnormal safety laboratory data or vital sign changes reported. CONCLUSION: Duloxetine pharmacokinetics in healthy Chinese subjects given a 60 mg once-daily dosing regimen were well characterised and consistent with known duloxetine pharmacokinetics in healthy Caucasian and Japanese subjects. Both single dosing and multiple once-daily dosing of duloxetine 60 mg were well tolerated by healthy Chinese subjects in this study.

L-5-Hydroxytryptophan augments the neuroendocrine response to a SSRI.

The objective of the study was to assess l-5-hydroxytryptophan's (l-5HTP) augmentation effect on the neuroendocrine response to a SSRI (citalopram). A neuroendocrine challenge study was conducted in healthy Asian male subjects. The neuroendocrine response to oral citalopram and l-5HTP was measured primarily as the prolactin and cortisol area under the response curve (or AUC). The study comprised 2 studies: Study 1. A double blind, randomised dose ranging study was conducted with l-5HTP (50-200 mg) to explore the prolactin and/or cortisol dose response and select a dose that provided a threshold neuroendocrine response. Study 2. A randomized comparison of citalopram 20 vs 40 mg was used to assess the effect of these doses on prolactin and cortisol. Based on the results of the dose response assessments with l-5HTP and cortisol, 200 mg l-5HTP was subsequently used in Study 2 to explore the augmentation of the neuroendocrine response to 20 mg citalopram. Citalopram, but not l-5HTP, increased prolactin AUC(0-3h) while 5HTP and citalopram increased cortisol AUC(0-3h). A 200 mg dose of l-5HTP significantly augmented the prolactin and cortisol response AUC(0-3h) to 20mg oral citalopram. The results of the study suggest that an augmented neuroendocrine challenge may be a suitable marker to demonstrate increased 5-HT-mediated responses when exploring novel agents as improved SSRIs.

The response of Asian patients with functional dyspepsia to eradication of Helicobacter pylori infection.

OBJECTIVES/BACKGROUND: The role of Helicobacter pylori infection in functional dyspepsia (FD) remains controversial. Several randomized controlled trials involving populations in the West, observed no statistically significant advantage over placebo. However, none of these studies involved Asian populations which have high infection rates. METHODS: A double blind, randomized, placebo-controlled trial of H. pylori eradication for FD was conducted in our Singapore-based Asian population. Forty-one patients received active treatment consisting of a 1-week course of omeprazole 20 mg once daily, clarithromycin 250 mg twice daily and tinidazole 500 mg twice daily whereas another 41 patients received matching placebo tablets. A dyspepsia score was derived by grading 5 dyspeptic symptoms on a Likert scale. Symptom assessment and urea breath test were repeated at 6 weeks, 6 and 12 months from the start of treatment. The primary end point was symptom resolution, defined as a dyspepsia score of 0 or 1 at the end of 12 months follow-up. RESULTS: On intention-to-treat analyses, symptom resolution was observed in 24% of patients on active treatment and 7% on placebo; the difference in proportion of patients with symptom resolution was statistically significant (P=0.02, 95% confidence interval: 1.1-17.7). H. pylori eradication rates perprotocol and intention-to-treat were 80.0 and 68.3%, on active treatment and 5.6 and 4.9% on placebo (both P values<0.0001). Among patients with H. pylori eradicated on active treatment the symptom resolution rate was 39% (10 of 26), whereas it was 3% (one of 35) among patients in the placebo group who had persistent H. pylori infection. In multivariate analysis, posttreatment H. pylori status was the only predictor of symptom resolution. The majority of patients, 91.5%, had ulcer-like dyspepsia; heartburn and acid regurgitation were uncommon, and no increase was observed after treatment. CONCLUSION: In contrast to Western populations, our results suggest that patients with FD in Asia would benefit from treatment for H. pylori infection with as much as a 13-fold increased chance of symptom resolution following its eradication.

Olanzapine pharmacokinetics are similar in Chinese and Caucasian subjects.

AIM: To compare the pharmacokinetic profiles and dose proportionality of olanzapine in Chinese and Caucasian subjects. METHODS: Randomized, three-period study with 12 Chinese and 12 Caucasian, healthy, male subjects administered 2.5, 5 and 10 mg olanzapine. Noncompartmental pharmacokinetic parameters were derived. RESULTS: No statistically significant racial differences in the weight-normalized pharmacokinetic parameters were observed except for Vz/Fnorm, which was 17% lower at the 5- and 10-mg dose in the Chinese group (95% confidence interval 8.49, 10.1 and 8.05, 9.73, respectively), compared with the Caucasian group (9.53, 12.8 and 9.39, 12.0, respectively). Olanzapine's pharmacokinetics were linear and dose proportional in both racial groups. CONCLUSION: The pharmacokinetics of olanzapine are similar in both Chinese and Caucasian racial groups.