Dose linearity of lacidipine pharmacokinetics after single and repeated oral doses in healthy volunteers.
OBJECTIVE
To assess the dose proportionality of lacidipine after single and repeated oral doses, and to obtain new information on the pharmacokinetics of the compound since improvement of the plasma assay method.


METHODS
Open, randomised, four-way cross-over trial.


METHODS
24 healthy male and female volunteers, aged 18-46 years.


METHODS
Lacidipine was administered as single doses of 2, 4, 6 and 8 mg, and as multiple doses of 2, 4 and 6 mg for 8 days. Pharmacokinetic evaluations were performed on study days 1 and 8. Plasma concentrations of lacidipine were determined by a validated high-performance liquid chromatography-radioimmunoassay method. The ratios of dose-normalised peak plasma concentration (C(max)) and area under the concentration-time curve (AUC) were calculated and then compared across dose groups by analysis of variance to assess dose linearity against a 4 mg reference dose. A power model was also applied as an alternative method for the evaluation of linearity.


RESULTS
After repeated 2, 4 and 6 mg doses of lacidipine, geometric least square mean values (95% CI) were 1.76 (1.46-2.12), 3.56 (2.96-4.29) and 5.23 (4.34--6.30) microg/L for C(max) and 5.29 (4.57-6.11), 11.42 (9.87-13.20) and 17.55 (15.18-20.29) microg x h/L for AUC over the administration interval at steady state (AUC(tau)), respectively. Mean half-life ranged between 13.2 hours and 18.7 hours. Precision of these estimates was limited by the small number of sampling timepoints collected in the final part of the curve. After administration of single doses, no statistically significant deviation from linearity was found except for the 8 mg dose, but a trend of greater than proportional exposure was evident with increasing dose. Following repeated administration, dose linearity over the therapeutic range was observed. No statistically significant difference was observed between AUC to infinity (AUC( infinity)) on day 1 and AUC(tau) on day 8, suggesting time-invariance of pharmacokinetics.


CONCLUSIONS
Lacidipine exhibited linear kinetics after repeated doses in the therapeutic range of 2-6 mg once daily. The two different methodologies for assessing linearity gave consistent results. Only the single 8 mg dose, which is outside the recommended therapeutic range, resulted in greater than predicted exposure. After low doses, the analytical method still does not allow complete characterisation of kinetics. Time-invariance of lacidipine kinetics is suggested.
Da Ros
Lucio
L
GlaxoSmithKline Medicine Research Center, Verona, Italy.
Squassante
Lisa
L
Milleri
Stefano
S
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D019540:Area Under Curve; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D004095:Dihydropyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged
D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C060285:lacidipine