1β-Hydroxydeoxycholic Acid as an Endogenous Biomarker in Human Plasma for Assessment of CYP3A Clinical Drug-Drug Interaction Potential.

4-Hydroxycholesterol (4-HC) in plasma has been used as a biomarker to assess CYP3A drug-drug interaction (DDI) potential during drug development. However, due to the long half-life and narrow dynamic range of 4-HC, its use has been limited to the identification of CYP3A inducers, but not CYP3A inhibitors. The formation of 1-hydroxydeoxycholic acid (1-OH DCA) from deoxycholic acid (DCA) is mediated by CYP3A, thus 1-OH DCA can potentially serve as an alternative to 4-HC for assessment of CYP3A DDI potential.

Dosing Strategies and Quantitative Clinical Pharmacology for Bispecific T-Cell Engagers Development in Oncology.

Bispecific T-cell Engagers (TCEs) are promising anti-cancer treatments that bind to both the CD3 receptors on T cells and an antigen on the surface of tumor cells, creating an immune synapse, leading to killing of malignant tumor cells. These novel therapies have unique development challenges, with specific safety risks of cytokine release syndrome. These on-target adverse events fortunately can be mitigated and deconvoluted from efficacy via innovative dosing strategies, making clinical pharmacology key in the development of these therapies.

Informing the Recommended Phase III Dose of Alnuctamab, a CD3 × BCMA T-Cell Engager, Using Population Pharmacokinetics and Exposure-Response Analysis.

Alnuctamab, a B-cell maturation antigen (BCMA)-targeting T-cell engager, has demonstrated encouraging antitumor activity in the phase I study CC-93269-MM-001 treating patients with relapsed or refractory multiple myeloma. Identification of a recommended Phase III dose (RP3D) was a key objective, as such population pharmacokinetic (PopPK) and exposure-response analysis was critical. Intravenous (IV) alnuctamab was administered in fixed doses (0.

Model based assessment of food and acid reducing agent effects on oral absorption of mezigdomide (CC-92480), a novel cereblon E3 ligase modulator.

Mezigdomide is a novel cereblon E3 ligase modulator (CELMoD) agent with enhanced autonomous cell-killing activity in multiple myeloma (MM) cells, and promising immunomodulatory and antitumor activity in patients with MM. We developed a population pharmacokinetics (PKs) model for mezigdomide in healthy subjects (HSs), and quantified effects of high-fat meal and proton pump inhibitor (PPI) on human disposition parameters. Plasma concentrations from 64 HS in two phase I clinical studies (NCT03803644 and NCT04211545) were used to develop a population PK model.

Population Pharmacokinetics of Oral Azacitidine, and Exposure-Response Analysis in Acute Myeloid Leukemia.

Oral azacitidine (oral-AZA) maintenance is approved for adults with acute myeloid leukemia (AML) in remission post-intensive chemotherapy, not proceeding to hematopoietic stem cell transplantation. This study aimed to develop a population pharmacokinetic (PopPK) model to characterize oral-AZA concentration-time profiles in patients with AML, myelodysplastic syndrome, or chronic myelomonocytic leukemia. PopPK-estimated exposure parameters were used to evaluate exposure-response relationships in the phase III QUAZAR AML-001 study.

Safety, Pharmacokinetics, and Antifibrotic Activity of CC-90001 (BMS-986360), a c-Jun N-Terminal Kinase Inhibitor, in Pulmonary Fibrosis.

Approved treatments for idiopathic pulmonary fibrosis have tolerability concerns and limited efficacy. CC-90001, a c-Jun N-terminal kinase inhibitor, is under investigation as a therapy for fibrotic diseases. A Phase 1b safety, pharmacokinetics, and pharmacodynamics study of oral CC-90001 (100, 200, or 400 mg) administered once daily for 12 weeks was conducted in patients with pulmonary fibrosis (NCT02510937).

Exposure-Response Analysis to Assess the Concentration-QTc Relationship of Iberdomide.

Iberdomide is an orally available cereblon-modulating agent being developed for the treatment of hematologic malignancies and autoimmune-mediated diseases. To assess the potential concentration-QTc relationship in humans and to ascertain or exclude a potential QT effect by iberdomide, a plasma concentration and ΔQTcF (change from baseline of corrected QT interval using the Fridericia formula) model of iberdomide was developed. Iberdomide concentration and paired high-quality, intensive electrocardiogram signal from a single-ascending-dose study in healthy subjects (N = 56) were included in the analysis.

A Phase 1, Multicenter, Open-Label Study to Evaluate the Pharmacokinetics of Iberdomide in Subjects with Mild, Moderate, or Severe Hepatic Impairment Compared with Healthy Subjects.

Introduction: Iberdomide, a novel cereblon modulator (CELMoD), is currently under clinical investigation for hematology indications. To evaluate the influence of hepatic impairment on the pharmacokinetics (PK) of iberdomide and its major active metabolite M12, a phase 1, multicenter, open-label study was conducted in healthy subjects and subjects with mild, moderate, and severe hepatic impairment.

Methods: Forty subjects were enrolled in the study and divided into five groups based on hepatic function.

Safety, Pharmacokinetics, and Pharmacodynamics of CC-90001 (BMS-986360), a c-Jun N-terminal Kinase Inhibitor, in Phase 1 Studies in Healthy Participants.

CC-90001 selectively inhibits c-Jun N-terminal kinase (JNK), a stress-activated protein implicated in fibrosis. In 3 phase 1 trials evaluating CC-90001 pharmacokinetics, pharmacodynamics, and safety, healthy adults (N = 184) received oral CC-90001 in a single dose (10-720 mg) or multiple doses (30-480 mg once daily for 7-18 days) or placebo. CC-90001 was rapidly absorbed (median time to maximum concentration, 1-4 hours) and eliminated with a mean terminal elimination half-life of 12-28 hours.

Biological impact of iberdomide in patients with active systemic lupus erythematosus.

Objectives: Iberdomide is a high-affinity cereblon ligand that promotes proteasomal degradation of transcription factors Ikaros () and Aiolos (). Pharmacodynamics and pharmacokinetics of oral iberdomide were evaluated in a phase 2b study of patients with active systemic lupus erythematosus (SLE).

Methods: Adults with autoantibody-positive SLE were randomised to placebo (n=83) or once daily iberdomide 0.

Iberdomide in patients with systemic lupus erythematosus: a randomised, double-blind, placebo-controlled, ascending-dose, phase 2a study.

Objective: To evaluate safety, pharmacokinetics, pharmacodynamics and efficacy of iberdomide in patients with SLE. Iberdomide is a high-affinity cereblon ligand that targets the hematopoietic transcription factors Ikaros and Aiolos for proteasomal degradation.

Methods: A 12-week, multicentre, double-blind, placebo-controlled, dose-escalation study in active SLE was followed by a 2-year, open-label active treatment extension phase (ATEP) (NCT02185040).

Assessment of drug-drug interactions of CC-90001, a potent and selective inhibitor of c-Jun N-terminal kinase.

CC-90001 is predominantly metabolised via glucuronidation, while oxidative metabolism is a minor pathway in human hepatocytes and liver microsomes. , CC-90001 glucuronidation was catalysed by UGT1A9, UGT1A4, and UGT1A1, while oxidative metabolism was primarily mediated by CYP3A4/5 with minor contributions from CYP1A2, CYP2C9, CYP2B6, and CYP2D6.CC-90001 inhibits CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 ≤ 55% at 100 μM, and the inhibition was negligible at ≤30 μM.

Response to upfront azacitidine in juvenile myelomonocytic leukemia in the AZA-JMML-001 trial.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for most children with juvenile myelomonocytic leukemia (JMML). Novel therapies controlling the disorder prior to HSCT are needed. We conducted a phase 2, multicenter, open-label study to evaluate the safety and antileukemic activity of azacitidine monotherapy prior to HSCT in newly diagnosed JMML patients.

First-in-Human, Single- and Multiple-Ascending-Dose Studies in Healthy Subjects to Assess Pharmacokinetics, Pharmacodynamics, and Safety/Tolerability of Iberdomide, a Novel Cereblon E3 Ligase Modulator.

Pharmacokinetics, pharmacodynamics, and safety/tolerability of iberdomide (CC-220), a highly potent oral cereblon E3 ligase modulator (CELMoD), were evaluated in escalating single-dose (0.03, 0.1, 0.

Evaluation of iberdomide and cytochrome p450 drug-drug interaction potential in vitro and in a phase 1 study in healthy subjects.

Purpose: Iberdomide is a cereblon E3 ligase modulator capable of redirecting the protein degradation machinery of the cell towards the elimination of target proteins potentially driving therapeutic effects. In vitro studies demonstrated that iberdomide predominantly undergoes oxidative metabolism mediated by cytochrome P450 (CYP) 3A4/5 but had no notable inhibition or induction of CYP enzymes. Consequently, the potential of iberdomide as a victim of drug-drug interactions (DDI) was evaluated in a clinical study with healthy subjects.

Population Pharmacokinetic Model to Assess the Impact of Disease State on Thalidomide Pharmacokinetics.

A population pharmacokinetic (PPK) model to describe the pharmacokinetics of thalidomide in different patient populations was developed using data pooled from healthy subjects and patients with Hansen's disease, human immunodeficiency virus (HIV), and multiple myeloma (MM). The analysis data set had a total of 164 evaluable subjects who received various doses (50 to 400 mg) of oral thalidomide in single- and/or multiple-dose regimens. The plasma thalidomide concentrations were adequately described by a linear 1-compartment PPK model with first-order absorption and first-order elimination.

Pharmacokinetic analysis of the FAK scaffold inhibitor C4 in dogs.

Inhibition of focal adhesion kinase-vascular endothelial growth factor receptor 3 complex by C4 was previously shown to reduce tumor growth alone and synergistically with other chemotherapeutic agents in animal tumor models. Single and multiple dose IV and oral dosing studies were performed in dogs to determine C4 pharmacokinetics. C4 was administered to 4 dogs at 1.

Deletion of interleukin-6 improves pyruvate tolerance without altering hepatic insulin signaling in the leptin receptor-deficient mouse.

Obesity is associated with increased circulating interleukin-6 (IL-6), which may contribute to hepatic insulin resistance by impairing insulin receptor signaling. This study was designed to assess the impact of the systemic absence of IL-6 on the development of insulin resistance and glucose intolerance in an obese mouse model. Systemic insulin, glucose, and pyruvate tolerance tests were performed in IL-6 knockout (IL6KO) mice that had been crossed with a genetically obese (leptin receptor-deficient mouse model [Lep(db)]) mouse model.

Suppressor of cytokine signaling-3 is a glucagon-inducible inhibitor of PKA activity and gluconeogenic gene expression in hepatocytes.

SOCS3 is a cytokine-inducible negative regulator of cytokine receptor signaling. Recently, SOCS3 was shown to be induced by a cAMP-dependent pathway involving exchange protein directly activated by cAMP (Epac). We observed in livers of fasted mice that Socs3 mRNA was increased 4-fold compared with refed mice, suggesting a physiologic role for SOCS3 in the fasted state that may involve glucagon and Epac.

Loss of Kupffer cells in diet-induced obesity is associated with increased hepatic steatosis, STAT3 signaling, and further decreases in insulin signaling.

While adipose tissue-associated macrophages contribute to development of chronic inflammation and insulin resistance of obesity, little is known about the role of hepatic Kupffer cells in this environment. Here we address the impact of Kupffer cell ablation using clodronate-encapsulated liposome depletion in a diet-induced obese (DIO) and insulin resistant mouse model. Hepatic expression of macrophage markers measured by realtime RT-PCR remained unaltered in DIO mice despite characteristic expansion of adipose tissue-associated macrophages.