Clinical Pharmacokinetics and Kinetic-Dynamic Relationships of Dilevalol and Labetalol

Summary

Dilevalol and labetalol are examples of a growing number of new β-blockers which combine nonselective β-adrenoceptor antagonism with vasodilator activity. Dilevalol is one of the 4 stereoisomers of labetalol, and is estimated to form approximately 25% of the racemic drug. Labetalol itself is an α-antagonist but dilevalol, which has negligible affinity for α-receptors, exerts its vasodilator effect via β 2-agonism.

Both drugs are rapidly and completely absorbed in 60 to 90 min and subject to extensive first-pass hepatic metabolism; the average bioavailability after oral administration is around 20 to 35%, and there is wide interindividual variability in plasma drug concentrations and dosage requirements. The volume of distribution of dilevalol (17 to 25 L/kg) is higher than that reported for labetalol (3 to 16 L/kg), although both drugs are concentrated in the extravascular compartment. Correspondingly, the elimination half-life of dilevalol at steady-state is around 15h compared with 8h for labetalol. There is evidence that the pharmacokinetics of dilevalol change (a reduction in clearance) in translation from single-dose to long term therapy. There is no clinically significant effect of age on the steady-state disposition of either drug and the pharmacokinetics of labetalol appear to be unchanged during pregnancy. Although there is a linear relationship between dose and area under the concentration-time curve, early studies found no evidence of a simple relationship between dose or plasma drug concentration and the fall in blood pressure. However, an integrated pharmacokinetic-pharmacodynamic model has been used to correlate concentrations of both drugs with reductions in systolic and diastolic blood pressure in individuals. This approach derives a mathematical description of antihypertensive response which integrates pharmacokinetic and pharmacodynamic information and also takes account of placebo effects and changes in drug concentration and blood pressure during the dosage interval.

The pharmacokinetic-pharmacodynamic relationships of labetalol are characterised by a linear model. For example, in a group of healthy volunteers, the ‘responsiveness’ to labetalol was −0.19mm Hg/µg/L. In contrast, the relationships of dilevalol are best described by a Langmuir maximum effect model, and so individual responses to short and long term treatment have been quantified by the concentration-effect parameters of maximum effect and drug concentration required to produce 50% of this. This integrated method of analysis with dilevalol and labetalol has revealed that (a) drug concentrations are related to the fall in blood pressure in individual subjects; (b) there is no relationship between age and antihypertensive response; and (c) there is a direct correlation for an individual patient between response to the first dose and the response during long term therapy.

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Donnelly, R., Macphee, G.J.A. Clinical Pharmacokinetics and Kinetic-Dynamic Relationships of Dilevalol and Labetalol. Clin. Pharmacokinet. 21, 95–109 (1991). https://doi.org/10.2165/00003088-199121020-00002

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Keywords

  • Clinical Pharmacology
  • Labetalol
  • Hepatic Blood Flow
  • Plasma Drug Concentration
  • Effect Compartment