The effects of lacidipine on the steady/state plasma concentrations of simvastatin in healthy subjects.
OBJECTIVE
Lacidipine, a long acting 2, 4-dihydropyridine calcium channel antagonist is frequently administered with cholesterol lowering agents, particularly in elderly populations. The effects of lacidipine on the pharmacokinetics of simvastatin were investigated, since they share the CYP3A4 pathway for metabolism.


METHODS
The study was an open, randomised, two-way crossover design, with at least 7 days washout. Eighteen healthy subjects received simvastatin, 40 mg once daily, alone and together with lacidipine, 4 mg once daily, for 8 days. The pharmacokinetics of simvastatin were studied on the eighth day. Analysis was made of total simvastatin acid concentrations (naive simvastatin acid plus that derived from alkaline hydrolysis of the lactone).


RESULTS
Lacidipine increased the maximum concentration of simvastatin (Cmax) by approximately 70% (P=0.016) and the area under the plasma concentration-time curve AUC(0,24 h) by approximately 35% (P=0.001). The mean Cmax and AUC(0,24 h) of simvastatin (95% confidence interval) when given alone were 8.76 (6.72-11.41) ng ml(-1) and 60.36 (47.15-77.28) ng ml(-1) h. During treatment with lacidipine they were, respectively, 14.89 (10.77-20.58) ng ml(-1) and 80.96 (64.62-101.44) ng ml(-1) h. No significant differences were observed in either time to peak concentration (tmax was 1.0 h for simvastatin alone and 1.5 h for the combination) or in the half-life (t1/2,z was 8.5 h in both cases). The combination was safe and well tolerated.


CONCLUSIONS
The observed increased exposure to simvastatin 40 mg following coadministration of lacidipine is unlikely to be of clinical relevance.
Glaxo Wellcome, Medicine Research Centre, Verona, Italy. lz6673@glaxowellcome.co.uk
L
L
Ziviani
L
L
Da Ros
L
L
Squassante
S
S
Milleri
M
M
Cugola
L E
LE
Iavarone
D000328:Adult; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000494:pharmacology; D018592:Cross-Over Studies; D004095:Dihydropyridines / Q000009:adverse effects / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D000960:Hypolipidemic Agents / Q000009:adverse effects / Q000097:blood*; D008297:Male; D019821:Simvastatin / Q000009:adverse effects / Q000097:blood*
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D000960:Hypolipidemic Agents; C060285:lacidipine; D019821:Simvastatin