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.

Figure 1

Pharmacokinetic models for denosumab (A) and ibandronate (B). For (A), drug administered subcutaneously is absorbed (k_a) into the plasma compartment (C_p, V_c) and undergoes linear (k_el) and nonlinear (V_max, K_m) elimination. Model shown in (B) is a linear 4-compartment model with a bone-specific site originally described by Pillai et al. [8].

Figure 2

Schematic diagram of the integrated bone homeostasis model, which is adapted from Lemaire et al. [15]. The model incorporates the action of denosumab and ibandronate and links the relevant biomarkers (sNTX, uNTX, uCTX) and a clinical endpoint (BMD) to physiological state variables. Details are provided under PD model in Methods.

Figure 3

Observed and model-fitted PK profiles of denosumab after six single SC doses of 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg in healthy postmenopausal women. Symbols represent mean data from the literature [9] and lines are the fitted profiles.

Figure 4

Change from baseline in NTX in serum (A) and urine (B) following six single SC doses of denosumab at 0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg in healthy postmenopausal women. Symbols represent mean data and standard errors from the literature [9] and lines are model-fitted profiles using the integrated bone homeostasis model.

Figure 5

Change from baseline in urine NTX/creatinine after multiple SC dosing of denosumab. Regimens are 6 (A), 14 (B), and 30 mg (C) of denosumab given every 3 months to postmenopausal women with low BMD. Symbols represent data from the literature [10] and lines represent model-fitted profiles using the integrated bone homeostasis model.

Figure 6

Change from baseline in lumbar spine BMD after multiple SC doses of denosumab. Regimens are 6, 14, and 30 mg of denosumab given every 3 months to postmenopausal women with low BMD. Symbols represent data from the literature [10] and lines represent model-fitted profiles using the integrated bone homeostasis model.

Figure 7

Change from baseline in urine CTX/creatinine following four IV doses of 0.25, 0.50, 1.0 and 2.0 mg of ibandronate every 3 months in postmenopausal women with osteopenia. Symbols represent mean data from the literature [8] and lines represent model-fitted profiles using the integrated bone homeostasis model.