2005 - Pamplona - Spain

PAGE 2005: poster
Tamara  van Steeg

The influence of an increase in plasma protein binding on the pharmacokinetics and pharmacodynamics of S(-)-Propranolol

Tamara van Steeg(1), Elke Krekels(1), Jan Freijer(3), Fiona Macintyre(2) Meindert Danhof(1) and Elizabeth C.M. de Lange(1)

(1) Division of Pharmacology, LACDR, Leiden University, Leiden, The Netherlands (2) Pfizer, Research & Development., United Kingdom (3) LAP&P Consultants BV, Leiden, The Netherlands

PDF of poster

Objectives: Protein binding can have a major impact on a drug’s pharmacokinetics (PK) and pharmacodynamics (PD). At present the theoretical basis of the influence of plasma protein binding on PK is well-established1. The role of plasma-protein binding on pharmacodynamics however has so far not been established in a systematic manner. The objective of this research is to determine the influence of alterations in plasma protein binding on the PD in silico and corroborate the findings in vivo.

Methods: In order to determine the influence of the affinity of the drug for both protein and receptor on in vivo drug effects a sensitivity analysis in berkeley madonna was performed, on the basis of a mechanism-based pharmacodynamic receptor interaction model.

The PK-PD of S(-)-Propranolol was investigated under varying plasma protein levels in rats. Heart rate under isoprenaline-induced tachycardia was used as a biomarker for receptor occupancy.

Results: Simulations show that in case of high receptor affinity protein binding has minimal effect on the target occupancy. For S(-)-propranolol the model showed that changes in plasma protein levels result in a slight rightward shift of the concentration-effect curve. This indicates that the pharmacodynamics are largely non-restrictive. All pharmacokinetic profiles were described with a 3-compartment model using alpha-1-acid glycoprotein levels as a covariate on V2. The population analysis of the pharmacodynamic dat is still in progressof the pharmacodynamic data is still in progress.

Conclusion: Simulations show that the role of plasma protein binding in in vivo pharmacodynamics can be identified using a mechanism-based PD model. For drugs with a high receptor affinity protein binding can be non-restrictive for the pharmacodynamics.

References:
1Rowland & Tozer, Clinical pharmacokinetics – concepts and applications, 3rd edition, Williams & Wilkins,1995




Reference: PAGE 14 (2005) Abstr 788 [www.page-meeting.org/?abstract=788]
poster
Top