Authors: Reginster, J.-Y.; Gieschke, R.

Source: Current Drug Metabolism, Volume 7, Number 7, October 2006 , pp. 827-836(10)

Publisher: Bentham Science Publishers

Abstract:

Ibandronate, a potent, nitrogen-containing bisphosphonate for the treatment of postmenopausal osteoporosis, is the subject of an ongoing clinical development program to explore novel oral and intravenous (i.v.) dosing regimens. As part of this program, an extensive modeling and simulation project was undertaken to develop and validate a pharmacologically realistic mathematical model for ibandronate in osteoporosis, the aim being to identify practical dosing regimens for clinical evaluation. A simplified kinetics of drug action or kinetic-pharmacodynamic (K-PD) model (developed from a 4-compartment pharmacokinetic-pharmacodynamic [PK-PD] model) accurately described the urinary excretion of the C-telopeptide of the α-chain of type I collagen (uCTX). The model was extended to consider the effects of supplemental calcium therapy and allow simultaneous fitting of i.v. and oral ibandronate data, and then externally validated. This model was used successfully in the selection of appropriate once-monthly doses for further clinical evaluation and recent clinical studies have confirmed the efficacy of the doses identified. Further development of the model may include investigating the effects of ibandronate on bone mineral density and fracture risk, which would further enhance its clinical utility and predictive value. Although modeling and simulation has been used to explore the efficacy of other bisphosphonates, the extensive program with ibandronate has produced a comprehensively validated model that is the first to be prospectively tested by evaluating novel dosing regimens.

Keywords: Ibandronate; Osteoporosis; Pharmacodynamics; Pharmacokinetics; Modeling; Simulation

Document Type: Research article

DOI: http://dx.doi.org/10.2174/138920006778520624

Affiliations: 1: Unite d`Exploration du Metabolisme de l'Os et du Cartilage, CHU Centre Ville, Liege, Belgium.

Publication date: 2006-10-01

More about this publication?

• Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
  
  In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.

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