Gieschke Ronald1,3, Pillai Goonaseelan (Colin)1,2, Goggin Timothy1,2, Jacqmin Philippe4, Snoeck Eric4, Girard Pascal4, Steimer Jean-Louis1,3
1Modeling and Simulation Team, 2Clinical Pharmacology and 3Biostatistics, Pharma Development, F. Hoffmann-La Roche, Basel, Switzerland, 4Pharsight Corporation, Mountain View, California 94040, USA
Ibandronate (IBN), a nitrogen-containing bisphosphonate, is under investigation in both oral and intravenous formulations for treatment and prevention of postmenopausal osteoporosis. Drug action is exerted by inhibition of osteoclast-mediated bone resorption with higher potency compared to other bisphosphonates. The objective of the current investigation was to apply the K-PD Model (Jacqmin et al PAGE 2001) to biomarker data obtained after intravenous ibandronate treatment with a view to simulating the response after oral treatment.
The basis for the current investigation was a population PD analysis of IBN effects on the biomarker urinary CTx (uCTX), a collagen breakdown product indicative of changes in osteoclast activity. In a study in 50 Japanese osteopenic women (MF9853), five intravenous dose groups (placebo, 0.25, 0.5, 1.0 and 2.0 mg) were investigated in parallel. Each patient received treatment on two occasions separated by three months and uCTx was followed closely to characterize its decrease from baseline, nadir and recovery. Applying the K-PD model gave satisfactory fits and well determined parameter estimates.
To apply this K-PD model for prediction of biomarker response after oral IBN dosing, an estimate for oral bioavailability (F) was taken from a combined analysis of two studies (Pillai et al PAGE 2001) comprising iv (MF9853) and oral (MF7159) dosing. Bioavailability after oral intake of the 2.5 mg dose was small (F=0.007) and variable (total variability = 64 CV%). After incorporation of F into the K-PD model, it was possible to retrospectively predict the effect on uCTx in a therapeutic study with oral IBN administration over a 1-year period (Ravn et al, Bone 1996; 19:527-533).
In conclusion, using iv ibandronate data a pharmacodynamic model could be built that described the time course of uCTX also after oral dosing for purposes of clinical trial simulation.
Reference: PAGE 10 (2001) Abstr 198 [www.page-meeting.org/?abstract=198]
Poster: poster