Population pharmacokinetics of ibandronate in Caucasian and Japanese healthy males and postmenopausal females.
BACKGROUND
Ibandronate is a potent, nitrogen-containing bisphosphonate that is licensed as a once-monthly oral preparation and is currently in clinical development as a novel intermittent intravenous (i.v.) injection in osteoporosis. Ibandronate pharmacokinetic (PK) data were used to develop a PK model that could ultimately be incorporated into a PK pharmacodynamic (PD) model to assist the ibandronate development program through computer-assisted trial design. This manuscript reports the use of non-linear mixed-effects modeling to characterize the PK of ibandronate, to examine the possible influence of ethnicity on the disposition of ibandronate and to develop an appropriate population PK model for ibandronate.


METHODS
A retrospective, cross-study population PK analysis was performed using PK data from five phase I studies with i.v. ibandronate (0.125 - 2.0 mg) conducted in Caucasian and Japanese healthy male volunteers, postmenopausal Caucasian women without osteopenia and postmenopausal Japanese women with osteopenia. The following covariates were investigated to establish their influence on the central volume of distribution (V1) and drug clearance (CL): age, body weight, gender, disease status (healthy versus osteopenic), creatinine clearance (CLCR), and ethnicity (Japanese versus Caucasian). Serum concentrations of ibandronate were quantified by GC-MS or ELISA, and data were modeled using non-linear mixed-effects modeling implemented by the software program NONMEM.


RESULTS
The PK of ibandronate was adequately described by a linear 3-compartment model. Disease status, body weight, gender and CLCR significantly influenced ibandronate CL (10 34%) and the latter 3 also influenced V1 (20 29%). Ethnicity was not a determinant for ibandronate PK in the final model. Although gender was the most influential covariate, differences in V1 and CL between the sexes were modest (29 and 34%, respectively) and the overall effects on ibandronate exposure (Cmax and AUC) were not clinically relevant. The final model described the observed PK of ibandronate well, and all PK parameters were estimated with an acceptable degree of precision (SE < 13%).


CONCLUSIONS
The PK of i.v. ibandronate was well described by a linear 3-compartment population PK model that included disease status, body weight, gender and CLCR as covariates, but without greatly affecting ibandronate exposure (Cmax and AUC). Ethnicity did not influence ibandronate PK and was not included in the final model.
Pillai
G
G
Modeling and Simulation Team, F Hoffmann-La Roche Ltd., Basle, Switzerland.
Gieschke
R
R
Goggin
T
T
Barrett
J
J
Worth
E
E
Steimer
J L
JL
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D044466:Asian People; D001835:Body Weight; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D001851:Bone Diseases, Metabolic / Q000188:drug therapy / Q000208:ethnology; D024042:Collagen Type I / Q000652:urine; D003404:Creatinine / Q000097:blood; D003430:Cross-Sectional Studies; D004164:Diphosphonates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077557:Ibandronic Acid; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D010455:Peptides / Q000652:urine; D017698:Postmenopause / Q000187:drug effects / Q000378:metabolism*; D012189:Retrospective Studies; D012737:Sex Factors; D014018:Tissue Distribution; D044465:White People
D050071:Bone Density Conservation Agents; D024042:Collagen Type I; D004164:Diphosphonates; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; D003404:Creatinine; D000077557:Ibandronic Acid