Pillai Goonaseelan (Colin)1,2, Gieschke Ronald1,3, Goggin Timothy1,2, Steimer Jean-Louis1,3
1Modeling and Simulation Team, 2Clinical Pharmacology and 3Biostatistics, Pharma Development, F. Hoffmann-La Roche, Basel, Switzerland
Introduction & Objectives Ibandronate is a high potency amino-bisphosphonate in Phase III development for osteoporosis. This class of drugs is known to have efficacy after oral administration despite low oral bioavailability and high variability. A PK model was developed using Phase I and Phase II data with an ultimate objective of developing a PK-PD model for computer assisted trial design. Specific objectives of this population PK analysis included estimation of the bioavailability of 2 oral dose strengths and examination of the PK in Japanese patients and Caucasian volunteers.
Methods
Data & Study Design
Study MF7159 – Caucasian post-menopausal healthy female volunteers (n=34, weight 68.2 ± 10.1 (53-74) kg) received 2 oral dose strengths (2.5 and 20mg) and a 0.5mg intravenous dose in a randomized crossover study. Plasma samples (n = 18) was collected frequently until 48.0 hours post-dose.
Study MF9853 – Japanese post-menopausal women with osteopenia (n=50, weight 53.5 ± 6.8 (36-63) kg) received 2 intravenous doses of ibandronate approximately 3 months apart. Plasma was collected until 48.0 hours after the first and second dose (9 and 5 samples respectively). On both occasions, urine was collected for 48 hours post-dose. Subjects received placebo, 0.5mg, 1.0mg or 2.0mg of ibandronate. Pharmacodynamic (biomarker) data was also collected in this study.
Model The plasma (Study MF7159 and Study MF9853) and urine data (Study MF9853) was fitted simultaneously to a 3 compartment PK model in NONMEM using ADVAN 12. The residual error model was additive for the urine data (cumulative amount excreted), and combined additive and proportional for the plasma data.
Results & Conclusions The bioavailability of the 2.5mg dose was estimated as 0.007 (CV 46%) and that of the 20mg dose as 0.006 (CV 61%).
Assuming no difference in the PD time-course after oral and iv treatment, the PK parameters may be used in a PK-PD model to simulate the time-course of biomarker after oral treatment.
Reference: PAGE 10 (2001) Abstr 199 [www.page-meeting.org/?abstract=199]
Poster: poster