Comparison of the pharmacokinetics, pharmacodynamics and tolerability of tezosentan between caucasian and Japanese subjects.
OBJECTIVE
To investigate the pharmacokinetics, pharmacodynamics and tolerability of the dual endothelin receptor antagonist tezosentan in caucasian and Japanese subjects.


METHODS
Twelve subjects of each ethnic origin were treated in a double-blind, randomized design with sequential 3-h infusions of 2.5, 5.0, 12.5 and 25 mg h(-1), or placebo. Vital signs, ECG and adverse events were recorded and blood samples collected for determination of plasma concentrations of tezosentan and endothelin-1 (ET-1).


RESULTS
Tezosentan was well tolerated in both ethnic groups with no clinically significant differences in laboratory measurements, ECG parameters and vital signs. The plasma concentration-time profiles of tezosentan were described by a three-compartment model with half-lives of approximately 5 min, 41 min and 3.6 h. Mean clearance and volume of distribution were approximately 35 l h(-1) and 20 l, respectively. Differences in the means (95% confidence intervals) between ethnic groups in these two parameters were 6.0 l h(-1) (-1.3, 13.3) and 4.3 l (-1.3, 9.9), respectively. Baseline ET-1 concentrations were similar but increases in response to tezosentan were greater in caucasian than in Japanese subjects. An indirect response model described the relationship between tezosentan and ET-1 plasma concentrations. The mean concentrations inhibiting 50% of ET-1 clearance (IC(50)) in caucasian and Japanese subjects were 243 and 227 ng ml(-1), respectively, with a difference in the means of 28.6 ng ml(-1) (-52.7, 110).


CONCLUSIONS
The data in healthy subjects suggest that caucasian and Japanese patients can be treated with a similar dosing regimen of tezosentan.
Actelion Pharmaceuticals Ltd, Department of Clinical Pharmacology, Allschwil, Switzerland. jasper.dingemanse@actelion.com
Jasper
J
Dingemanse
Kulasiri A
KA
Gunawardena
Paul L M
PL
van Giersbergen
D000328:Adult; D019540:Area Under Curve; D044466:Asian People; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004361:Drug Tolerance; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D005260:Female; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D013777:Tetrazoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D013997:Time Factors; D044465:White People
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011725:Pyridines; D013777:Tetrazoles; C120582:tezosentan