Immunomodulation - Part IThursday, September 28, 2006, 15:30 - 17:00
Pharmacokinetic and pharmacodynamic properties of the VLA-4 inhibitor CDP323M. Baker, A. Shock, T. Parton, P. Hales, G. Parker (Slough, GB)
Introduction: CDP323 is a small molecule inhibitor of vascular cell adhesion molecule 1 (VCAM) binding to alpha-4 integrin (VLA-4) in development for the treatment of immune system disorders including multiple sclerosis (MS).
Aims and methods: Three Phase I clinical studies were conducted in 75 healthy volunteers to investigate the pharmacokinetics (PK), safety and tolerability of CDP323 administered for up to 7 consecutive days. Ex-vivo inhibition of alpha-4/VCAM binding was utilized as a pharmacodynamic (PD) biomarker. An in vitro whole blood VCAM binding assay showed that the IC50 in human blood for CT7758, the active moiety of the prodrug CDP323, was 60 nM (95%CI 33-108). Study 1 evaluated 6 single ascending-dose levels, study 2 was a 7-day, multiple dose study of 3 dose levels, while study 3 was a male/female PK/PD comparison.
Results: CDP323 was well tolerated by human volunteers at oral doses up to 1000 mg bid for 7 consecutive days with an adverse event profile comparable to that observed with placebo. A PK model was developed to describe the disposition of CT7758 and an active metabolite, CT533652, which displayed linear kinetics over the doses investigated without gender effect. The PD effect closely followed the plasma concentration time course of the two active compounds and enabled the development of a PK/PD model that described the plasma concentration disposition of both compounds and directly linked these concentrations into an effect model without hysteresis. The IC50 value for the inhibition of VCAM binding derived for CT7758 (incorporating the pharmacodynamic contribution from the metabolite CT533652) from the PK/PD model in healthy volunteers was 63 nM, (95%CI 48-78), similar to that derived in vitro.
Conclusion: Oral administration of CDP323 resulted in the inhibition of VCAM binding in human volunteers. The development of a PK/PD model has assisted in the selection of dose regimen for evaluation in therapeutic clinical trials, providing evidence that the inhibition can be maintained throughout a 12 or 24 hour dose interval at dose levels well tolerated by human subjects.