title: A semimechanistic and mechanistic population PK-PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis.
abstract: OBJECTIVE
  Ibandronate, a highly potent nitrogen-containing bisphosphonate, is the subject of an ongoing clinical development programme that aims to maximize the potential of simplified, less frequent oral and intravenous (i.v.) administration in osteoporosis. A modelling and simulation project was undertaken to characterize further the clinical pharmacology of ibandronate and identify convenient intermittent oral and i.v. regimens for clinical evaluation.
  
  
  RESULTS
  Using selected data from clinical studies involving 174 women with postmenopausal osteoporosis (PMO), a classical multicompartmental pharmacokinetic-pharmacodynamic (PK-PD) model was developed that accurately described the PK of i.v. ibandronate in plasma and urine and urinary excretion of the C-telopeptide of the alpha chain of type I collagen (uCTX), a sensitive biomarker of PD response to ibandronate. To reduce processing times, the classical PK-PD model was simplified using a "kinetics of drug action" or kinetic (K)-PD model (i.e. a dose-response model as opposed to a dose-concentration-response model). The performance of the K-PD model was evaluated by fitting data simulated with the PK-PD model under various dosing regimens. The simplified model produced a virtually indistinguishable fit of the data from that of the PK-PD model. The K-PD model was extended to consider the influence of supplemental therapy (calcium with or without vitamin D) on the PD response and validated by retrospectively simulating the uCTX response in a prior Phase III and Phase II/III study of i.v. ibandronate, given once every 3 months, in 3380 women with PMO. The observed median uCTX responses at the scheduled assessment points in the completed studies were within the distribution of the simulated responses. The K-PD model for i.v. ibandronate was extended further to allow simultaneous fitting of uCTX responses after i.v. and oral administration in 676 postmenopausal women with osteoporosis, and validated by retrospectively simulating the data observed in a Phase I study of oral daily ibandronate in 180 women with PMO. The K-PD model adequately described the uCTX response after oral dosing.
  
  
  CONCLUSIONS
  This validated K-PD model is currently being used to evaluate a range of novel intermittent oral and i.v. ibandronate regimens in an ongoing clinical development programme.
authors.affiliation: Modelling and Simulation Team, F. Hoffmann-La Roche, Basel, Switzerland. goonaseelan.pillai@pharma.novartis.com
authors.forename: Goonaseelan
authors.initials: G
authors.lastname: Pillai
authors.forename: Ronald
authors.initials: R
authors.lastname: Gieschke
authors.forename: Timothy
authors.initials: T
authors.lastname: Goggin
authors.forename: Philippe
authors.initials: P
authors.lastname: Jacqmin
authors.forename: Ralph C
authors.initials: RC
authors.lastname: Schimmer
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Steimer
mesh_terms: D000284:Administration, Oral; D015415:Biomarkers / Q000032:analysis; D001862:Bone Resorption / Q000517:prevention & control; D002986:Clinical Trials as Topic; D003094:Collagen / Q000652:urine*; D024042:Collagen Type I; D004164:Diphosphonates / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D000077557:Ibandronic Acid; D007262:Infusions, Intravenous; D008954:Models, Biological; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy*; D010455:Peptides / Q000652:urine*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D024042:Collagen Type I; D004164:Diphosphonates; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; D003094:Collagen; D000077557:Ibandronic Acid