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Dose Linearity of Lacidipine Pharmacokinetics After Single and Repeated Oral Doses in Healthy Volunteers

Clinical Pharmacokinetics volume 42, pages 99–106 (2003)Cite this article

Abstract

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.

Design

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

Participants

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

Methods

Lacidipine was administered as single doses of 2, 4, 6 and 8mg, and as multiple doses of 2, 4 and 6mg 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 (Cmax) 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 4mg reference dose. A power model was also applied as an alternative method for the evaluation of linearity.

Results

After repeated 2, 4 and 6mg 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) µg/L for Cmax and 5.29 (4.57–6.11), 11.42 (9.87–13.20) and 17.55 (15.18–20.29) µg · h/L for AUC over the administration interval at steady state (AUCτ), 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 8mg 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 (AUG∞) on day 1 and AUCτ on day 8, suggesting time-invariance of pharmacokinetics.

Conclusions

Lacidipine exhibited linear kinetics after repeated doses in the therapeutic range of 2–6mg once daily. The two different methodologies for assessing linearity gave consistent results. Only the single 8mg 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.

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Acknowledgements

We acknowledge the valuable contribution of Dott. Simone Braggio for analytical support. We thank Dr Frank Hoke for revising the manuscript and for his valuable contribution to discussions. The study was performed in the internal GSK Clinical Pharmacology Unit in Verona in compliance with current Italian laws. All related study costs were funded by GSK Italy.

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Affiliations

  1. GlaxoSmithKline Medicine Research Center, Verona, Italy

    Lucio Da Ros, Lisa Squassante &  Stefano Milleri

Authors
  1. Lucio Da Ros
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  2. Lisa Squassante
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  3. Stefano Milleri
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Correspondence to Stefano Milleri.

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Ros, L.D., Squassante, L. & Milleri, S. Dose Linearity of Lacidipine Pharmacokinetics After Single and Repeated Oral Doses in Healthy Volunteers. Clin Pharmacokinet 42, 99–106 (2003). https://doi.org/10.2165/00003088-200342010-00004

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  • DOI: https://doi.org/10.2165/00003088-200342010-00004

Keywords

  • Power Model
  • Liver Blood Flow
  • Lacidipine
  • Dose Linearity
  • Administration Interval