Evaluation of a pharmacokinetic interaction between valsartan and simvastatin in healthy subjects.
OBJECTIVE
The potential for a pharmacokinetic drug interaction between valsartan, an antihypertensive drug, and simvastatin, a lipid-lowering agent, was investigated in this study. This was an open-label, multiple-dose, randomized, three-period, cross over study in 18 healthy subjects. Each subject received one 160 mg valsartan tablet or one 40 mg simvastatin tablet or co-administration of valsartan (160 mg) and simvastatin (40 mg) tablets for 7 days, with a 7-day inter-dose washout period. The steady-state pharmacokinetics of valsartan, simvastatin beta-hydroxy acid (active metabolite of simvastatin) and simvastatin (pro-drug) were determined on day 7 of each dosing period.


RESULTS
The results were interpreted based on the point estimates and the 90% confidence intervals. These results indicated that the area under the curve of plasma concentration from 0 to 24 hours (AUC(0-24)) of valsartan, simvastatin beta-hydroxy acid and simvastatin was increased by 14%, 19%, and 23%, respectively, with the combination treatment. In addition, the maximum concentration (C(max)) of valsartan and simvastatin beta-hydroxy acid was increased by 10% and 22%, respectively, and the C(max) of simvastatin was decreased by 26% with the combination treatment. All treatments were safe and well tolerated.


CONCLUSIONS
Based on the wide therapeutic dosage ranges of valsartan and simvastatin, and the highly variable pharmacokinetics of three analytes, the observed differences in the exposure and C(max) of valsartan, simvastatin beta-hydroxy acid and simvastatin in the combination treatment are unlikely to be of clinical relevance.
Sunkara
Gangadhar
G
Novartis Pharmaceuticals, East Hanover, NJ 07936-1080, USA. gangadhar.sunkara@novartis.com
Reynolds
Christine V
CV
Pommier
Francoise
F
Humbert
Henri
H
Yeh
ChingMing
C
Prasad
Pratapa
P
D000328:Adult; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D016001:Confidence Intervals; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005069:Evaluation Studies as Topic; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D011336:Probability; D012016:Reference Values; D012307:Risk Factors; D012680:Sensitivity and Specificity; D019821:Simvastatin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016037:Single-Blind Method; D013777:Tetrazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D013997:Time Factors; D014633:Valine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000068756:Valsartan
D000959:Antihypertensive Agents; D000960:Hypolipidemic Agents; D013777:Tetrazoles; D000068756:Valsartan; D019821:Simvastatin; D014633:Valine