Pharmacokinetics of duloxetine hydrochloride enteric-coated tablets in healthy Chinese volunteers: a randomized, open-label, single- and multiple-dose study.

BACKGROUND: Duloxetine hydrochloride is a balanced selective serotonin and norepinephrine reuptake inhibitor. Despite being widely used for the treatment of major depressive disorder in China, little information is available on the pharmacokinetic (PK) properties of duloxetine in Chinese subjects.

OBJECTIVES: This study was designed to determine the concentration of duloxetine in human plasma and to compare the PK properties of duloxetine after administration of single and multiple doses of duloxetine in healthy Chinese volunteers.

METHODS: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determining the concentration of duloxetine in human plasma was developed and applied to this single-center, open-label, single- and multiple-dose PK study. Subjects were randomized to receive a single dose of 30, 60, or 90 mg of duloxetine. Those who received the 30-mg dose continued on to the multiple-dose phase and received 30 mg twice daily for 7 days. In the single-dose phase, sequential blood samples were collected from 0 to 60 hours after drug administration. In the multiple-dose phase, samples were obtained before drug administration on days 4, 5, 6, and 7 to determine the C(ssmin) of duloxetine; on day 7, samples were collected from 0 to 60 hours after drug administration. The PK parameters that were calculated included C(max), T(max), t(1/2), AUC(0-t) AUC(0-infinity), CL, V(d), C(ssmax), C(ssmin), C(ssav), AUC(ss), AUC(ss(0-t)), and C(max):C(min) ratio. All values were expressed as mean (SD). Tolerability was assessed throughout the study.

RESULTS: The LC-MS/MS method was developed and validated. The standard calibration curve was linear in the concentration range from 0.89 to 106.8 ng/mL; the correlation coefficient was >0.995. The methodologic recovery and extraction recovery ranged from 87.22% to 113.75% and 72.81% to 89.96%, respectively. Both the intraday and interday relative SDs were <11%. Thirty Chinese subjects (3 groups of 10 subjects [5 men, 5 women] each) were enrolled in the single-dose phase of the PK study. The mean (SD) age of the subjects was 23.2 (1.8) years (range, 21-25 years); their mean (SD) weight was 61.0 (7.7) kg (range, 52-80 kg) and height was 169.0 (7.1) cm (range, 155-180 cm). The main PK parameters for duloxetine after administration of a single oral dose of 30, 60, and 90 mg were as follows: C(max) = 22.46 (15.15), 44.40 (17.18), and 60.78 (27.84) ng/mL, respectively; AUC(0-60) = 328.64 (203.64), 696.04 (337.82), and 1219.33 (598.29) ng/mL . h(-1); AUC(0-infinity)) = 359.68 (201.01), 733.82 (343.40), and 1280.51 (644.81) ng/mL . h(-1); T(max) = 6.83 (1.99), 6.10 (1.29), and 6.60 (1.58) hours; t1/2 = 12.95 (3.64), 12.81 (2.31), and 11.66 (2.06) hours; CL = 107.90 (53.05), 98.41 (41.98), and 109.58 (52.74) L/hour; and V(d) = 2518.88 (1707.71), 1879.74 (999.09), and 1858.47 (1203.69) L. The 10 subjects who received the 30-mg dose in the single-dose phase continued on to the multiple-dose phase and received 30 mg of duloxetine twice daily for 7 days. Mean (SD) values for the main PK parameters for duloxetine after administration of multiple doses were as follows: C(ssmax) = 47.33 (16.95) ng/mL; C(ssmm) = 27.92 (9.46) ng/mL; AUC(ss(0-t)) = 407.25 (125.94) ng/mL . h(-1); C(ssav) = 33.94 (13.00) ng/mL; T(max) = 6.36 (0.92) hours; t(1/2) = 11.19 (1.98) hours; CL = 83.12 (28.75) L/hour; and V(d) = 1359.01 (590.06) L.

CONCLUSIONS: In these healthy Chinese subjects, AUC and Cmax increased proportionally with the dose, whereas t(1/2) was independent of the dose. Linear PK properties were found at doses of 30 to 90 mg. No statistically significant differences were observed between the PK parameters for the subjects in the multiple-dose phase (t(1/2), CL, V(d)) and those for subjects in the single-dose phase. The AUC and C(max) were greater after administration of multiple doses than after administration of a single dose, suggesting du-loxetine accumulation with multiple-dose administration of 30 mg.