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Dealing with Time-Dependent Pharmacokinetics during the Early Clinical Development of a New Leukotriene B4 Synthesis Inhibitor

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Purpose

The aim of this study was to explore the possibility of achieving a practical dosing regimen for 2,4,6-triiodophenol (AM-24), a new leukotriene B4 (LTB4) synthesis inhibitor. First, a model capable of dealing with the nonlinearity in its pharmacokinetic profile was built, and then it was combined with a pharmacodynamic model previously established with data from earlier phase I trials.

Methods

One week after the first 240-, 350-, or 500-mg oral dose of AM-24, six additional doses were given to 24 healthy volunteers once daily. A total of 33 blood samples were obtained from each individual. Different models, including enzyme turnover models, were fitted to the data by using the software NONMEM.

Results

Drug absorption was modeled with a first-order process. Drug disposition was described with a one-compartment model, and elimination with an (auto)inhibited and a noninhibited clearance. AM-24 inhibited the enzyme production rate to a maximum of 98%. Relative bioavailability was independent of the decrease in the amount of enzyme. The estimate of the enzyme turnover half-life was 8.5 h.

Conclusions

Simulations have shown that steady-state conditions eliciting 90% of maximal LTB4 synthesis inhibition can be reached after 3 weeks during an oral treatment with AM-24 administered at the dosage of 500 mg once daily.

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Acknowledgments

We would like to thank Antoni Mollins for his help in the analytical determination of AM-24 plasma concentrations. Marta Valle was supported by a grant from the Spanish Healthy Department (CP 04/00121) in collaboration with the Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau. This work was partially supported by a grant from Industrial Farmace´utica Catabria, S.A., Spain.

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Author notes

  1. Ilonka Zsolt

    Present address: Sanofi-Aventis, S.A.U., Barcelona, Spain

Authors and Affiliations

  1. Departmento de Farmacia y Tecnología Farmacéutica, Facultad de Farmacia, Universidad de Navarra, Pamplona, Spain

    Iñaki F. Trocóniz & María J. Garrido

  2. Centre d’Investigació de Medicaments, Institut de Recerca de l‘HSCSP, Servei de Farmacologia Clínica, Hospital de la Santa Creu i Sant Pau, Departament de Farmacologia i Terapèutica de la Universitat Autònoma de Barcelona, Av Sant Antoni M Claret 167, 08025, Barcelona, Spain

    Ilonka Zsolt, Marta Valle, Rosa M. Antonijoan & Manel J. Barbanoj

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  1. Iñaki F. Trocóniz
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  2. Ilonka Zsolt
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Corresponding author

Correspondence to Manel J. Barbanoj.

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Trocóniz, I.F., Zsolt, I., Garrido, M.J. et al. Dealing with Time-Dependent Pharmacokinetics during the Early Clinical Development of a New Leukotriene B4 Synthesis Inhibitor. Pharm Res 23, 1533–1542 (2006). https://doi.org/10.1007/s11095-006-0254-1

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  • DOI: https://doi.org/10.1007/s11095-006-0254-1

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