Pharmacokinetic interaction between ketoconazole and SPP301 in healthy volunteers.
BACKGROUND
SPP301 is a potent and highly selective ETA receptor blocker. The primary aim of the present study was to investigate the effect of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics of SPP301.


METHODS
In a randomized, open-label 2-period oral crossover study, 12 healthy male subjects received treatments A and B. Treatment A consisted of 200 mg ketoconazole once daily on Days 1 - 4 and concomitantly 5 mg SPP301 on Day 3. Treatment B consisted of 5 mg SPP301 administered alone. Plasma concentrations of SPP301 and its hydroxymethyl metabolite were measured by LC-MS/MS.


RESULTS
Ketoconazole coadministration increased the systemic availability of SPP301 and its hydroxymethyl metabolite 3-fold and prolonged their half-lives by a factor of 2. The ratios of least square means (90% CI) of pharmacokinetic parameters in the presence and absence of ketoconazole for SPP301 and its metabolite were C(max) (maximum plasma concentration) 1.22 (1.13, 1.32) and 1.2 (1.05, 1.37), AUC(0-infinity) (area under the plasma concentration-time curve from time zero to infinity) 3.16 (2.84, 3.51) and 3.14 (2.49, 3.70) and t1/2 (apparent terminal half-life) 2.21 (1.55, 2.87) and 2.00 (1.17, 2.84), i.e. an increase of systemic exposure by a factor of 3.2, with individual exposures increasing up to 5.9-fold. Single oral doses of SPP301 were well tolerated when administered alone or together with multiple doses of ketoconazole.


CONCLUSIONS
In the presence of potent CYP3A4 inhibitors exposure of SPP301 may be increased up to 6-fold.
Dieterle
W
W
Drug Disposition Consultants, Loerrach, Germany.
Mann
J
J
D000328:Adult; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004347:Drug Interactions; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000493:pharmacokinetics*
D065607:Cytochrome P-450 Enzyme Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C484919:Avosentan; D007654:Ketoconazole