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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.

SUBMITTER: Marathe DD

PROVIDER: S-EPMC3202061 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Integrated model for denosumab and ibandronate pharmacodynamics in postmenopausal women.

Marathe Dhananjay D DD Marathe Anshu A Mager Donald E DE

Biopharmaceutics & drug disposition 20110922 8

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 mode ...[more]

PMID: 21953540

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Project description:UNLABELLED: Serious adverse events of infections that occurred in subjects receiving denosumab or placebo in the Fracture Reduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were examined in detail. Serious adverse events of infections in denosumab subjects had heterogeneous etiology, with no clear clinical pattern to suggest a relationship to time or duration of exposure to denosumab. INTRODUCTION: Denosumab reduces the risk for new vertebral, hip, and nonvertebral fractures compared with placebo. In the pivotal phase 3 fracture trial (FREEDOM), the overall safety profile and incidence of adverse events including adverse events of infections were similar between groups. Serious adverse events of erysipelas and cellulitis were more frequent in denosumab-treated subjects. In this report, we further evaluate the details of infectious events in FREEDOM to better understand if RANKL inhibition with denosumab influences infection risk. METHODS: FREEDOM was an international multicenter, randomized, double-blind, placebo-controlled study in postmenopausal women with osteoporosis randomly assigned to receive placebo (n = 3,906) or denosumab 60 mg every 6 months (n = 3,902). The incidence of adverse events and serious adverse events categorized within the Medical Dictionary for Regulatory Activities system organ class, "Infections and Infestations," was compared between the placebo and denosumab groups by body systems and preferred terms. The temporal relationship between occurrence of serious adverse events of infections of interest and administration of denosumab was explored. RESULTS: Serious adverse events of infections involving the gastrointestinal system, renal and urinary system, ear, and endocarditis were numerically higher in the denosumab group compared with placebo, but the number of events was small. No relationship was observed between serious adverse events of infections and timing of administration or duration of exposure to denosumab. CONCLUSIONS: Serious adverse events of infections that occurred with denosumab treatment had heterogeneous etiology, with no clear clinical pattern to suggest a relationship to time or duration of exposure to denosumab.

Dataset Information

Integrated model for denosumab and ibandronate pharmacodynamics in postmenopausal women.

Publications

Integrated model for denosumab and ibandronate pharmacodynamics in postmenopausal women.

Similar Datasets

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