title: Integrated model for denosumab and ibandronate pharmacodynamics in postmenopausal women.
abstract: This study aims to characterize the pharmacodynamic properties of denosumab, a RANK ligand inhibitor, and ibandronate, a bisphosphonate, using an integrated bone homeostasis model in postmenopausal women. Mean temporal profiles of denosumab, serum and urine N-telopeptide (sNTX, uNTX), lumbar spine bone mineral density (BMD) following denosumab administration, and urine C-telopeptide (uCTX) and lumbar spine BMD upon ibandronate administration were extracted from the literature. A mechanistic model was developed that integrates denosumab pharmacokinetics with binding to RANK ligand and ibandronate inhibition of osteoclast precursor differentiation to active osteoclasts (AOC). Biomarker concentrations were linked to the AOC pool. The BMD was characterized by a turnover model with stimulation of bone formation and degradation by AOB (active osteoblasts) and AOC pools. The estimated basal sNTX, uNTX and uCTX concentrations were 7.24 nm, 14.4 nmol/mmolCr and 31µg/mmolCr. The BMD degradation rate was 0.00161 day(-1) with stimulation constants associated with AOB and AOC of 1214 and 790 pm(-1) . The plasma ibandronate concentration producing 50% of maximum inhibition of osteoclast differentiation was 522 ng/l. The integrated model, which incorporates multiple pathways of therapeutic intervention, quantitatively describes changes in clinical biomarkers of bone turnover and BMD after denosumab and ibandronate exposures in postmenopausal women.
authors.affiliation: Chemical and Biological Engineering, University at Buffalo, State University of New York, Buffalo, New York, 14260, USA.
authors.forename: Dhananjay D
authors.initials: DD
authors.lastname: Marathe
authors.forename: Anshu
authors.initials: A
authors.lastname: Marathe
authors.forename: Donald E
authors.initials: DE
authors.lastname: Mager
mesh_terms: D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D054316:Biomarkers, Pharmacological / Q000097:blood / Q000652:urine; D015519:Bone Density / Q000187:drug effects*; D050071:Bone Density Conservation Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D024042:Collagen Type I / Q000097:blood / Q000652:urine; D000069448:Denosumab; D004164:Diphosphonates / Q000493:pharmacokinetics / Q000494:pharmacology*; D004311:Double-Blind Method; D005260:Female; D006706:Homeostasis; D006801:Humans; D000077557:Ibandronic Acid; D008954:Models, Biological; D010455:Peptides / Q000097:blood / Q000652:urine; D017698:Postmenopause; D053245:RANK Ligand / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D054316:Biomarkers, Pharmacological; D050071:Bone Density Conservation Agents; D024042:Collagen Type I; D004164:Diphosphonates; D010455:Peptides; D053245:RANK Ligand; C052929:collagen type I trimeric cross-linked peptide; D000069448:Denosumab; D000077557:Ibandronic Acid