Effect of a selective CYP2C9 inhibitor on the pharmacokinetics of nateglinide in healthy subjects.
OBJECTIVE
The objective of the study was to determine the effect of a potent and selective CYP2C9 inhibitor, sulfinpyrazone (Anturane), on the pharmacokinetics of nateglinide (Starlix), a novel antidiabetic drug which is primarily (approximately 70%) metabolized via CYP2C9.


METHODS
This was a randomized, open-label, two-period, crossover study in 18 healthy volunteers. Nateglinide was administered as a single 120-mg oral dose alone (reference) on day 1 or in combination with sulfinpyrazone (test) on day 7, following twice-daily 200-mg oral doses (i.e., 400 mg/day) of sulfinpyrazone for 7 days. Pharmacokinetic parameters of nateglinide were determined following the administration of nateglinide alone, and when administered in combination with sulfinpyrazone. Plasma nateglinide concentrations were determined using a validated high-performance liquid chromatography method.


RESULTS
The administration of nateglinide in combination with sulfinpyrazone resulted in approximately 28% higher mean AUC of nateglinide (90% CI for test-reference ratio: 1.20-1.39) with no differences in mean peak plasma concentration (Cmax; 90% CI test-reference ratio: 0.86-1.12) compared with nateglinide-alone treatment. The time to reach Cmax (tmax) and the elimination half-life of nateglinide were similar between the two treatments. Both treatments were safe and well tolerated.


CONCLUSIONS
Sulfinpyrazone increased the mean exposure of nateglinide by 28% when both drugs were administered in combination. Nateglinide, given as a single dose or co-administered with multiple doses of sulfinpyrazone, was safe and well tolerated in healthy subjects.
Sabia
Helene
H
Exploratory Clinical Development, Novartis Pharmaceuticals, East Hanover, NJ 07936-1080, USA.
Sunkara
Gangadhar
G
Ligueros-Saylan
Monica
M
Wang
Yibin
Y
Smith
Harold
H
McLeod
James
J
Prasad
Pratapa
P
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D018592:Cross-Over Studies; D003510:Cyclohexanes / Q000493:pharmacokinetics*; D065729:Cytochrome P-450 CYP2C9; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D000077715:Nateglinide; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D013442:Sulfinpyrazone / Q000009:adverse effects / Q000494:pharmacology*
D003510:Cyclohexanes; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D000077715:Nateglinide; D010649:Phenylalanine; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; D013442:Sulfinpyrazone