Population Pharmacokinetics of Sotorasib in Healthy Subjects and Advanced Solid Tumor Patients Harboring a KRAS Mutation from Phase 1 and Phase 2 Studies.

Sotorasib is a novel KRAS inhibitor that has shown robust efficacy, safety, and tolerability in patients with KRAS mutation. The objectives of the population pharmacokinetic (PK) analysis were to characterize sotorasib population PK in healthy subjects and patients with advanced solid tumors with KRAS mutation from 6 clinical studies, evaluate the effects of intrinsic and extrinsic factors on PK parameters, and perform simulations to further assess the impact of identified covariates on sotorasib exposures. A two-compartment disposition model with three transit compartments for absorption and time-dependent clearance and bioavailability well described sotorasib PK.

Impact of a High-Fat Meal on the Pharmacokinetics of Sotorasib, a KRAS G12C Inhibitor.

Sotorasib is a small molecule drug that specifically and irreversibly inhibits the KRAS p.G12C mutant protein. This analysis investigated the impact of a high-calorie high-fat meal on the pharmacokinetics, safety, and tolerability of sotorasib in both healthy volunteers and patients with KRAS G12C advanced solid tumors.

Contribution of youth sport participation to physical activity levels and cardiovascular disease risk factors in 5-year-old to 14-year-old children: a study protocol for systematic review and meta-analysis.

Introduction: Cardiovascular disease (CVD) accounts for 18 million deaths per year, disproportionately burdens under-represented racial and ethnic groups, and has economic costs greater than any other health condition. Participation in youth sport may be an effective strategy to improve CVD-related risk factors but studies of youth sport participation have shown mixed results for improving health outcomes. Therefore, the objective of this systematic review is to examine how participation in youth sport contributes to physical activity levels and CVD risk factors in children aged 5-14 years old.

Human-centered participatory co-design with children and adults for a prototype lifestyle intervention and implementation strategy in a rural middle school.

Purpose: The significance of regular physical activity (PA) in reducing cardiovascular disease (CVD) risk is widely acknowledged. However, children in rural areas encounter specific barriers to PA compared to their urban counterparts. This study employs human-centered participatory co-design, involving community stakeholders in developing a multi-level PA intervention named Hoosier Sport.

Effect of Strong CYP3A4 Inhibition, CYP3A4 Induction, and OATP1B1/3 Inhibition on the Pharmacokinetics of a Single Oral Dose of Sotorasib.

Sotorasib is a small molecule that irreversibly inhibits the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein with a G12C amino acid substitution mutant protein. The impact of cytochrome P450 (CYP) 3A4 inhibition and induction on sotorasib pharmacokinetics (PKs) was evaluated in 2 separate studies in healthy volunteers (N = 14/study). The impact of CYP3A4 inhibition was interrogated utilizing repeat doses of 200 mg of itraconazole, a strong CYP3A4 inhibitor, on 360 mg of sotorasib PKs.

Predicting Clinical Pharmacokinetics/Pharmacodynamics and Impact of Organ Impairment on siRNA-Based Therapeutics Using a Mechanistic Physiologically-Based Pharmacokinetic-Pharmacodynamic Model.

Approved and emerging siRNA therapeutics are primarily designed for targeted delivery to liver where the therapeutic gene silencing effects occurs. Impairment of hepatic/renal function and its impact on siRNA pharmacokinetics/pharmacodynamics (PKs/PDs) are yet to be mechanistically evaluated to describe the unanticipated clinical observations for this novel modality. We developed pathophysiologically relevant models for organ impairment within a physiologically-based PK-PD (PBPK-PD) modeling framework focusing on modality-specific mechanistic factors to evaluate impact on siRNA PKs and PDs.

Multilevel needs assessment of physical activity, sport, psychological needs, and nutrition in rural children and adults.

Introduction: Physical activity yields significant benefits, yet fewer than 1 in 4 youth meet federal guidelines. Children in rural areas from low socioeconomic (SES) backgrounds face unique physical activity contextual challenges. In line with Stage 0 with the NIH Stage Model for Behavioral Intervention Development, the objective of the present study was to conduct a community-engaged needs assessment survey with middle school children and adults to identify perceptions, barriers, and facilitators of physical activity, sport, psychological needs, and nutrition from a multi-level lens.

A multistate platform model for time-to-event endpoints in oncology clinical trials.

A multistate platform model was developed to describe time-to-event (TTE) endpoints in an oncology trial through the following states: initial, tumor response (TR), progressive disease (PD), overall survival (OS) event (death), censor to the last evaluable tumor assessment (progression-free survival [PFS] censor), and censor to study end (OS censor), using an ordinary differential equation framework. Two types of piecewise functions were used to describe the hazards for different events. Piecewise surge functions were used for events that require tumor assessments at the scheduled study visit times (TR, PD, and PFS censor).

A Mechanistic Physiologically-Based Pharmacokinetic Platform Model to Guide Adult and Pediatric Intravenous and Subcutaneous Dosing for Bispecific T Cell Engagers.

Bispecific T cell engagers (Bi-TCEs) have revolutionized the treatment of oncology indications across both liquid and solid tumors. Bi-TCEs are rapidly evolving from conventional intravenous (i.v.

Evaluation of the effect of erenumab on migraine-specific questionnaire in patients with chronic and episodic migraine.

Erenumab is a fully human anti-canonical calcitonin gene-related peptide receptor monoclonal antibody approved for migraine prevention. The Migraine-Specific Quality-of-Life Questionnaire (MSQ) is a 14-item patient-reported outcome instrument that measures the impact of migraine on health-related quality of life. Erenumab data from four phase II/III clinical trials were used to develop an item response theory (IRT) model within a nonlinear mixed effects framework, (i) evaluate the MSQ item information with respect to patient disability, (ii) characterize the longitudinal progression of the MSQ, and (iii) quantify the effect of erenumab on the MSQ in patients with migraine.

Clinical Pharmacology Profile of AMG 119, the First Chimeric Antigen Receptor T (CAR-T) Cell Therapy Targeting Delta-Like Ligand 3 (DLL3), in Patients with Relapsed/Refractory Small Cell Lung Cancer (SCLC).

With the promise of a potentially single-dose curative regimen, CAR-T cell therapies have brought a paradigm shift in the treatment and management of hematological malignancies with 6 approved products in the USA. However, there are no approved CAR-T cell therapies for solid tumors. Herein, we report the clinical pharmacology profile of AMG 119, the first CAR-T cell therapy targeting delta-like ligand 3 (DLL3), in patients with relapsed/refractory (R/R) small cell lung cancer (SCLC).

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Properties of Rozibafusp Alfa, a Bispecific Inhibitor of BAFF and ICOSL: Analyses of Phase I Clinical Trials.

Rozibafusp alfa (AMG 570) is a first-in-class bispecific IgG2-peptide fusion designed to inhibit inducible T-cell costimulator ligand (ICOSL) and B-cell activating factor (BAFF). The pharmacokinetics (PK) and pharmacodynamics (PD) of rozibafusp alfa were investigated in two randomized, placebo-controlled clinical studies: a phase Ia single ascending-dose study (7-700 mg subcutaneously (s.c.

Mechanistic Pharmacokinetic/Pharmacodynamic Modeling in Support of a Patient-Convenient, Longer Dosing Interval for Carfilzomib, a Covalent Inhibitor of the Proteasome.

Background: Carfilzomib is an irreversible second-generation proteasome inhibitor that has a short elimination half-life but much longer pharmacodynamic (PD) effect based on its irreversible mechanism of action, making it amenable to longer dosing intervals. A mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was built using a bottom-up approach, based on the mechanism of action of carfilzomib and the biology of the proteasome, to provide further evidence of the comparability of once-weekly and twice-weekly dosing.

Methods: The model was qualified using clinical data from the phase III ENDEAVOR study, where the safety and efficacy of bortezomib (a reversible proteasome inhibitor) and carfilzomib were compared.

Oncolytic viral kinetics mechanistic modeling of Talimogene Laherparepvec (T-VEC) a first-in-class oncolytic viral therapy in patients with advanced melanoma.

Talimogene Laherparepvec (T-VEC) is a first-in-class oncolytic virotherapy approved for the treatment of unresectable melanoma recurrent after initial surgery. Biodistribution data from a phase II study was used to develop a viral kinetic mechanistic model describing the interaction between cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), the immune system, and T-VEC treatment. Our analysis found that (1) the viral infection rate has a great influence on T-VEC treatment efficacy; (2) an increase in T-VEC dose of 10 plaque-forming units/ml 21 days and beyond after the initial dose of T-VEC resulted in an ~12% increase in response; and (3) at the systemic level, the ratio of resting innate immune cells to the death rate of innate immune impact T-VEC treatment efficacy.

Estimation of time to progression and post progression survival using joint modeling of summary level OS and PFS data with an ordinary differential equation model.

measures such as progression-free survival (PFS) and overall survival (OS) are commonly reported in literature for oncology trials, while time to progression (TTP) and post progression survival (PPS) are not usually reported. A time-variant transition hazard model was developed using an ordinary differential equation (ODE) model to estimate TTP and PPS from summary level PFS and OS. The model was applied to published data from immune checkpoint inhibitor trials for non-small cell lung cancer (NSCLC) in a meta-analysis framework.

Recent advances and clinical pharmacology aspects of Chimeric Antigen Receptor (CAR) T-cellular therapy development.

Advances in immuno-oncology have provided a variety of novel therapeutics that harness the innate immune system to identify and destroy neoplastic cells. It is noteworthy that acceptable safety profiles accompany the development of these targeted therapies, which result in efficacious cancer treatment with higher survival rates and lower toxicities. Adoptive cellular therapy (ACT) has shown promising results in inducing sustainable remissions in patients suffering from refractory diseases.

Population Pharmacokinetic Properties of Omecamtiv Mecarbil in Healthy Subjects and Patients With Heart Failure With Reduced Ejection Fraction.

Omecamtiv mecarbil is a small molecule that has been shown to improve cardiac function in patients with heart failure (HF) with reduced ejection fraction and is currently being developed as an oral modified release tablet for subjects with chronic HF. The objectives of this study were to analyze the pharmacokinetic (PK) properties of omecamtiv mecarbil and to investigate the effects of potential covariates on pertinent PK parameters using population PK modeling of data from 3 clinical trials in healthy subjects (n = 85) and 3 clinical trials in patients with HF (n = 4261). The population PK analysis was performed using a nonlinear mixed effects modeling approach.

Pharmacokinetic Drug-Drug Interaction Study of Omecamtiv Mecarbil With Amiodarone and Digoxin in Healthy Subjects.

Omecamtiv mecarbil (OM), a novel cardiac myosin activator, is being evaluated for the treatment of heart failure with reduced ejection fraction. In vitro studies demonstrate OM as a substrate and inhibitor of P-glycoprotein (P-gp), which can result in drug-drug interactions. Two phase 1, open-label studies assessed the effect of coadministration of OM (50-mg single dose) on the pharmacokinetics of digoxin (0.

Evaluation of drug-drug interaction potential between omecamtiv mecarbil and rosuvastatin, a BCRP substrate, with a clinical study in healthy subjects and using a physiologically-based pharmacokinetic model.

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure. In vitro, OM is an inhibitor of BCRP. Rosuvastatin, a BCRP substrate, is one of the most commonly prescribed medications in patients with heart failure.

Pharmacokinetics, Tolerability, and Safety of Single and Multiple Omecamtiv Mecarbil Doses in Healthy Japanese and Caucasian Subjects.

Background And Objectives: Omecamtiv mecarbil (OM) is a cardiac myosin activator under development for the treatment of heart failure. The pharmacokinetics of single and multiple doses of OM were investigated in healthy Japanese subjects in two clinical studies.

Methods: Study 1 (n = 36) evaluated the bioavailability and pharmacokinetics after intravenous infusion (15 mg/h for 4 h) and an oral modified release (MR) tablet in healthy Japanese and Caucasian subjects using 25 mg single and multiple doses and 50 mg single dose.

Pharmacokinetic Drug-Drug Interaction Study of Omecamtiv Mecarbil With Omeprazole, a Proton Pump Inhibitor, in Healthy Subjects.

Omecamtiv mecarbil (OM) is a novel cardiac myosin activator in development for the treatment of heart failure (HF) with reduced ejection fraction. OM is administered as a 25-, 37.5-, or 50-mg modified-release formulation in patients with HF.

Panitumumab: A Review of Clinical Pharmacokinetic and Pharmacology Properties After Over a Decade of Experience in Patients with Solid Tumors.

Panitumumab is a fully human monoclonal antibody that binds to the epidermal growth factor receptor (EGFR), thereby inhibiting the growth and survival of tumors expressing EGFR. Panitumumab received approval in the USA in 2006 for the treatment of wild-type RAS (defined as wild-type in both KRAS and NRAS) metastatic colorectal cancer. Over the last 10 years, the pharmacokinetic and pharmacodynamic profile of panitumumab has been studied to further evaluate its safety, efficacy, and optimal dosing regimen.

Pharmacokinetic Evaluation of the CYP3A4 and CYP2D6 Drug-Drug Interaction and CYP3A4 Induction Potential of Omecamtiv Mecarbil: Two Open-Label Studies in Healthy Subjects.

Omecamtiv mecarbil (OM) is a cardiac myosin activator under development for the treatment of heart failure. The effect of CYP3A4 and CYP2D6 inhibition on OM pharmacokinetics and the potential for OM to induce CYP3A4 was assessed in 2 studies. Study 1, part A, assessed the effect of ketoconazole 200 mg on the pharmacokinetics of OM 10 mg in CYP2D6 extensive metabolizers (EMs; n = 8) or poor metabolizers (PMs; n = 8).

Omecamtiv mecarbil does not prolong QTc intervals at therapeutic concentrations.

Aims: Omecamtiv mecarbil (OM) is a novel selective cardiac myosin activator under investigation for the treatment of heart failure. This study aimed to evaluate the effect of therapeutic concentrations of OM on electrocardiogram (ECG) parameters and exclude a clinically concerning effect on the rate-corrected QT (QTc) interval.

Methods: In part A, 70 healthy subjects received a 25 mg oral dose of OM, and pharmacokinetics were assessed.