Pharmacokinetic and pharmacodynamic characteristics of aranidipine sustained-release, enteric-coated tablets in healthy Chinese men: a phase I, randomized, open-label, single- and multiple-dose study.
OBJECTIVE
The aim of this study was to explore the pharmacokinetic (PK) and pharmacodynamic (PD) properties and safety profiles of aranidipine and its active M-1 metabolite in healthy Chinese men.


METHODS
This Phase I, randomized, open-label, single- and multiple-dose study included healthy, nons-moking male volunteers aged 18 to 45 years. In the single-dose study, subjects were randomly assigned to receive oral sustained-release, enteric-coated aranidipine tablets 5, 10, or 20 mg. In the multiple-dose study, volunteers who had been assigned to the aranidipine 10-mg group in the single-dose study received this dose for 7 days. In the single-dose study, blood samples for the PK analyses were obtained immediately before dosing and at regular intervals up to 36 hours after dosing. In the multiple-dose study, predose blood samples were collected on days 4 through 7; on the last day of treatment, blood samples were drawn at the same times as in the single-dose study. Plasma concentrations of aranidipine and M-1 were determined using a high-performance liquid chromatography method with tandem mass-spectrometric detection. For the PD analyses, blood pressure (BP) and heart rate were measured before dosing, at regular intervals up to 24 hours after dosing, and after the final dose during repeated administration. Tolerability was assessed throughout the study, based on adverse events, physical examinations, electrocardiography, vital signs, and laboratory tests.


RESULTS
The study enrolled 30 healthy Chinese men (mean [SD] age, 23 [2] years; mean body weight, 66 [7] kg; mean height, 174 [6] cm). In the single-dose study, the mean t(1/2) for aranidipine 5, 10, and 20 mg was 3.0 (2.7), 2.7 (1.1), and 3.1 (2.2) hours, respectively; mean T(max) was 4.9 (0.4), 4.4 (1.0), and 4.3 (0.9) hours; mean C(max) was 1.1 (0.6), 2.4 (0.8), and 4.0 (2.0) microg/L; and mean AUC(last) was 4.1 (1.4), 10.3 (2.3), and 20.9 (4.2) microg . h/L. There were no significant differences in any PK parameter between dose groups. For M-1, the corresponding values were 4.6 (1.0), 4.1 (0.5), and 4.1 (0.3) hours for t(1/2); 5.6 (2.0), 5.0 (1.6), and 5.0 (0.8) hours for T(max); 18.4 (0.6), 40.5 (10.0), and 39.2 (11.3) microg/L for C(max); and 143.5 (39.1), 304.5 (108.2), and 403.9 (73.5) microg . h/L for AUC(last). Only dose-normalized Cmax and AUC(last) differed significantly between dose groups (P < 0.001 and P = 0.018, respectively). After multiple doses, the mean values for t(1/2), T(max), C(max), and AUC(0-infinity) for aranidipine 10 mg were 2.3 (0.9) hours, 5.0 (1.2) hours, 3.1 (1.1) microg/L, and 13.8 (3.6) microg . h/L, respectively. Repeated oral administration of aranidipine 10 mg was associated with a significant increase in AUC(last) (P = 0.027). The corresponding values for M-1 were 4.8 (0.9) hours, 5.7 (1.3) hours, 40.0 (11.3) microg/L, and 381.8 (161.2) microg . h/L. There were no significant differences between dose groups in any PK parameter for M-1 after single or multiple doses. In the PD analyses, the mean change from baseline in diastolic BP was statistically significant in all groups (P < 0.01) except the aranidipine 10-mg group in the single-dose study. Three volunteers (10%) reported adverse events after administration of a single dose: headache (10-mg group), palpitations (20-mg group), and dizziness (20-mg group). The headache and palpitations were considered possibly related to study drug.


CONCLUSIONS
The results of this small study in healthy Chinese men suggest that the PK properties of aranidipine were linear with respect to dose, whereas the PK properties of the active M-1 metabolite were not fully linear. There was no apparent accumulation of aranidipine or M-1 with administration of single and multiple doses. Aranidipine was generally well tolerated.
Jiang
Juanjuan
J
The Key Laboratory of Clinical Trial Research on Cardiovascular Drugs, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.
Tian
Lei
L
Huang
Yiling
Y
Li
Yishi
Y
Xu
Li
L
D000328:Adult; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003692:Delayed-Action Preparations; D004095:Dihydropyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008875:Middle Aged; D013608:Tablets, Enteric-Coated
D002121:Calcium Channel Blockers; D003692:Delayed-Action Preparations; D004095:Dihydropyridines; D013608:Tablets, Enteric-Coated; C059427:aranidipine