Sean Oosterholt (1), Amit Taneja (1), Oscar Della Pasqua (1, 2)
(1) Division of Pharmacology, Leiden University, Leiden, The Netherlands; (2) GlaxoSmithKline, London, United Kingdom
Objectives: The assessment of the analgesic effect of NCEs is primarily based on qualitative behavioral measures of pain [1]. This however, does not reflect the mechanisms underlying the anti-inflammatory response in chronic inflammatory pain conditions. In contrast, prostaglandins are known to be important mediators of inflammation, resulting from the activation of cyclo-oxygenase (COX) after tissue damage. Our investigation shows how inflammatory mediators, such as PGE2, can be used as biomarker of the analgesic effect and contribute to the rationale for the dose selection in humans. We illustrate the concept using a model-based approach to GW406381, an investigational COX-2 inhibitor with anti-hyperalgesic activity preclinical models of inflammatory pain.
Methods: Data from a multiple dose phase I study in 24 healthy subjects were used for the PK and PD analysis. Concentration vs. time data were simulated as basis for the assessment of the exposure-response relationship using a threshold for sustained PGE2 inhibition levels as the primary criterion for dose selection, with concentrations around IC80 considered as the optimal exposure level [2] and concentrations > IC95 assumed to exceed the therapeutic window. The impact of different clinical scenarios was then evaluated using simulations. Among other factors, metabolic induction, hepatic impairment and severity of inflammatory response were evaluated.
Results: The PK was best described by a two-compartment model with first order absorption and a lag time. The PD, as determined by prostaglandin inhibition was described by an Imax model. Model predictions show that the therapeutic dose range of GW406381 in patients with normal organ function should be between 150-250mg. Dose adjustments were anticipated for patients showing hepatic impairment and induced metabolism. In addition, we also demonstrate that drug concentrations remain within the therapeutic range longer when the drug is administered according to a twice daily dosing regimen.
Conclusions: The use of pharmacodynamic markers to guide dose selection offers a more robust basis for the dose rationale for analgesic drugs. Moreover, the use of simulation scenarios enables one to identify opportunities for personalisation of the dose and titration requirements for different patient sub-populations.
References:
[1] EMA, Note for guidance on clinical investigation of medicinal products for treatment of nociceptive pain. CPMP/EWP/612/00.
[2] Huntjens, D.R., M. Danhof, and O.E. Della Pasqua, Pharmacokinetic-pharmacodynamic correlations and biomarkers in the development of COX-2 inhibitors. Rheumatology (Oxford), 2005. 44(7): p. 846-59.
Reference: PAGE 22 (2013) Abstr 2714 [www.page-meeting.org/?abstract=2714]
Poster: Other Drug/Disease Modelling