Kinetic-Pharmacodynamic Model of Platelet Time Course in Patients With Moderate-to-Severe Atopic Dermatitis Treated With Oral Janus Kinase 1 Inhibitor Abrocitinib.

The oral Janus kinase 1 (JAK1) inhibitor abrocitinib reduced signs and symptoms of atopic dermatitis (AD) in a placebo-controlled, randomized, double-blind, phase IIb trial (dose range 10-200 mg). A kinetic-pharmacodynamic (K-PD) model consisting of proliferation, maturation, and blood circulation compartments was developed to characterize platelet count changes during the study. The K-PD model consisted of a drug elimination constant, four system parameters describing platelet dynamics, variance terms, correlation, and residual errors.

Evaluating the Role of Janus Kinase Pathways in Platelet Homeostasis Using a Systems Modeling Approach.

Maintaining platelet homeostasis is important to avoid spontaneous bleeding and organ damage. Thrombopoietin, the primary regulator of platelet production, is affected by and acts in part via Janus kinase (JAK)-signal transducer and activator of transcription (STAT)-mediated mechanisms. Interleukin-6 is also partly responsible for inducing thrombopoietin production via the JAK-STAT pathway.

Population pharmacokinetic analysis of denosumab in patients with bone metastases from solid tumours.

Background And Objective: Denosumab (XGEVA®; AMG 162) is a fully human IgG2 monoclonal antibody, which binds to the receptor activator of nuclear factor κ-B ligand (RANKL) and prevents terminal differentiation, activation and survival of osteoclasts. We aimed to characterize the population pharmacokinetics of denosumab in patients with advanced solid tumours and bone metastases.

Methods: A total of 14 228 free serum concentrations of denosumab from 1076 subjects (495 healthy subjects and 581 advanced cancer patients with solid tumours and bone metastases) included in 14 clinical studies were pooled.

Multiscale physiology-based modeling of mineral bone disorder in patients with impaired kidney function.

A physiologically based, multiscale model of calcium homeostasis and bone remodeling was used to describe the impact of progressive loss of kidney function over a typical 10-year course of chronic kidney disease (CKD), including the evolution of secondary hyperparathyroidism (HPT) caused by diminished renal phosphate clearance and increased plasma phosphate. An important sequela of HPT is marked elevations in bone resorption and loss of bone mineral density (BMD). Clinically, this CKD-related disease state is described as mineral bone disorder, or CKD-MBD.

Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis.

Background And Objective: Inhibition of the receptor activator of nuclear factor κ-B ligand (RANKL) is a therapeutic target for treatment of bone disorders associated with increased bone resorption, such as osteoporosis. The objective of this analysis was to characterize the population pharmacokinetics of denosumab (AMG 162; Prolia®), a fully human IgG2 monoclonal antibody that binds to RANKL, in healthy subjects and postmenopausal women with osteopenia or osteoporosis.

Methods: A total of 22944 serum free denosumab concentrations from 495 healthy subjects and 1069 postmenopausal women with osteopenia or osteoporosis were pooled.

AAPS workshop report: strategies to address therapeutic protein-drug interactions during clinical development.

Therapeutic proteins (TPs) are increasingly combined with small molecules and/or with other TPs. However preclinical tools and in vitro test systems for assessing drug interaction potential of TPs such as monoclonal antibodies, cytokines and cytokine modulators are limited. Published data suggests that clinically relevant TP-drug interactions (TP-DI) are likely from overlap in mechanisms of action, alteration in target and/or drug-disease interaction.

A physiologically based mathematical model of integrated calcium homeostasis and bone remodeling.

Bone biology is physiologically complex and intimately linked to calcium homeostasis. The literature provides a wealth of qualitative and/or quantitative descriptions of cellular mechanisms, bone dynamics, associated organ dynamics, related disease sequela, and results of therapeutic interventions. We present a physiologically based mathematical model of integrated calcium homeostasis and bone biology constructed from literature data.

Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy.

Purpose: Denosumab, a fully human monoclonal antibody to RANKL, suppresses bone resorption. This study evaluated the effects of denosumab in i.v.

Population PK-PD model for Fc-osteoprotegerin in healthy postmenopausal women.

Osteoporosis is a metabolic bone disease resulting from increased bone resorption and characterized by low bone mass that leads to increased bone fragility and risk of fracture, particularly of the hip, spine and wrist. Bone resorption is dependent on receptor activator of NF-kappa B ligand (RANKL), which binds to RANK receptor on preosteoclasts to initiate osteoclastogenesis and maintains osteoclast function and survival. To neutralize the effects of RANKL, the body naturally produces the protein osteoprotegerin (OPG), which acts as a decoy receptor for RANKL and contributes to bone homeostasis.

Integrated cellular bone homeostasis model for denosumab pharmacodynamics in multiple myeloma patients.

The purpose of this study is to couple a cellular bone homeostasis model with the pharmacokinetics (PK) and mechanism of action of denosumab, an inhibitor of receptor activator of nuclear factor-kappaB ligand, to characterize the time course of serum N-telopeptide (NTX), a bone resorption biomarker, following single escalating doses in multiple myeloma (MM) patients. Mean PK and median serum NTX temporal profiles were extracted from a previously conducted randomized, double-blind, double-dummy, active-controlled, multicenter study including 25 MM patients receiving escalating denosumab doses. Nonlinear denosumab PK profiles were well described by a target-mediated disposition model that includes rapid binding of drug to its pharmacological target.

Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases.

Purpose: Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-kappaB ligand, suppresses bone resorption. In this study, we evaluated the efficacy and safety of five dosing regimens of denosumab in patients with breast cancer-related bone metastases not previously treated with intravenous bisphosphonates (IV BPs).

Patients And Methods: Eligible women (n = 255) with breast cancer-related bone metastases were stratified by type of antineoplastic therapy received and randomly assigned to one of six cohorts (five denosumab cohorts [blinded to dose and frequency]; one open-label IV BP cohort).

Denosumab in postmenopausal women with low bone mineral density.

Background: Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for osteoclast differentiation, activation, and survival. The fully human monoclonal antibody denosumab (formerly known as AMG 162) binds RANKL with high affinity and specificity and inhibits RANKL action.

Methods: The efficacy and safety of subcutaneously administered denosumab were evaluated over a period of 12 months in 412 postmenopausal women with low bone mineral density (T score of -1.

A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer.

Purpose: Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for the differentiation, function, and survival of osteoclasts, which play a key role in establishment and propagation of skeletal disease in patients with multiple myeloma or bone metastases as well as many other skeletal diseases. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, was developed to treat patients with skeletal diseases.

Experimental Design: This was a randomized, double-blind, double-dummy, active-controlled, multicenter study to determine the safety and efficacy of denosumab in patients with breast cancer (n = 29) or multiple myeloma (n = 25) with radiologically confirmed bone lesions.