Evaluations of the calibration and validation of pharmacokinetic models of pamidronate and denosumab.

<p>Evaluations of the calibration and validation of pharmacokinetic models of pamidronate and denosumab.</p

The clinical datasets used for the calibration and validation of the integrated models with pamidronate and denosumab.

<p>The clinical datasets used for the calibration and validation of the integrated models with pamidronate and denosumab.</p

Evaluations of the calibration and validation of the integrated models with pamidronate and denosumab.

<p>Note 1: The r² is calculated before 30 days after pamidronate treatment.</p><p>Note 2: The r² is calculated to evaluate the goodness of fit paraprotein concentrations.</p

The calibration and validation of the pharmacokinetic models of pamidronate and denosumab.

<p>(a) The calibration of the pharmacokinetic model of denosumab. (b) The validation of the pharmacokinetic model of denosumab. (c) The calibration of the pharmacokinetic model of pamidronate. (d) The validation of the pharmacokinetic model of pamidronate.</p

The calibrated parameter values of the integrated models with pamidronate and denosumab.

<p>The calibrated parameter values of the integrated models with pamidronate and denosumab.</p

The structure of the integrated models with pamidronate and denosumab.

<p>Regulation mechanism 1: PTH stimulates RANKL expression on the surface of osteoblast precursors while inhibiting OPG secretion by active osteoblasts. Regulation mechanism 2: RANKL binds to RANK, which promotes differentiation of osteoclast precursors, while OPG inhibits the RANKL-RANK binding. Regulation mechanism 3: Bone resorption released TGF-β stimulates uncommitted osteoblast differentiation, inhibits osteoblast precursor differentiation and facilitates apoptosis of active osteoclasts. Regulation mechanism 4: MM cells adhere to BMSC, enabling IL-6 secretion by BMSC, RANKL expression on the surface of BMSC and MM-cell proliferation. Regulation mechanism 5: IL-6 facilitates MM-cell proliferation and stimulates RANKL expression on the surface of osteoblast precursors. Regulation mechanism 6: bone resorption released TGF-β stimulates IL-6 production by BMSC. Regulation mechanism 7: OPG is internalized and degraded by MM cells. Regulation mechanism 8: denosumab binds to RANKL to inhibit differentiation of osteoclast precursors. Regulation mechanism 9: pamidronate promotes the apoptosis of active osteoclasts. Regulation mechanism 10: pamidronate facilitates the apoptosis of MM cells. Regulation mechanism 11: NTX released from bone resorption is under the control of active osteoclasts.</p

Changes in the density of bone cells, bone volume and the density of MM cells after single anti-catabolic drug treatments.

<p>(a) Changes in osteoblast density after therapies; (b) Changes in osteoclast density after therapies; (c) Changes in bone volume after therapies; (d) Changes in MM-cell density after therapies.</p

The responses using the identified denosumab regimes.

<p>(a) The active osteoclast using the identified denosumab regimes. (b) The bone volume using the identified denosumab regimes. (c) The MM-cell density using the identified denosumab regimes.</p

The relative response and the relative index of the identified regimes of denosumab treatment.

<p>Note 1: the pamidronate regime consisting of the intravenous administration of 90 mg pamidronate every 4 weeks for a period of 2 years is used as a base.</p

The calibration and validation of the integrated computational models with pamidronate and denosumab.

<p>(a) The calibration of the integrated model with denosumab according to the NTX levels. (b) The validation of the integrated model with denosumab according to the CTX levels. (c) The calibration of the integrated model with pamidronate according to the NTX levels. (d) The validation of the integrated model with pamidronate according to the NTX levels. (e) The calibration of the integrated model with pamidronate according to the paraprotein levels.</p