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. The primary hypothesis is the co-design sessions leading to the development of a testable intervention protocol. METHODS: Two co-design teams, each consisting of six children and six adults, were formed using human-centered participatory co-design facilitated by research faculty and graduate students. The process involved five co-design sessions addressing problem identification, solution generation, solution evaluation, operationalization, and prototype evaluation. Thematic analysis was employed to identify key themes and intervention components. RESULTS: Child co-designers (n = 6) ranged from 6th to 8th grade, averaging 12.6 years (SD = 1.8), while adult co-designers (n = 6) averaged 43.3 years (SD = 8.08). Thematic analysis revealed children emphasizing autonomy, the freedom to choose physical and non-physical activities, and the importance of building peer relationships during PA. Adult interviews echoed the importance of autonomy and choice in activities, with a focus on relatedness through positive role modeling. CONCLUSION: The prototype intervention and implementation strategies developed constitute a testable intervention aligned with Phase 1 of the ORBIT model. This testable prototype lays the groundwork for a collaborative campus-community partnership between the university and the local community, ensuring mutual benefits and sustainable impact.

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. The impact of CYP3A4 induction was interrogated utilizing multiple doses of 600 mg of rifampin, a strong CYP3A4 inducer. Additionally, the impact of organic anion transporting polypeptide (OATP) 1B1/3 inhibition on 960 mg of sotorasib PKs was interrogated after a single dose of 600 mg of rifampin. CYP3A4 inhibition did not significantly impact sotorasib Cmax but did lead to a 26% increase in sotorasib AUCinf . CYP3A4 induction decreased sotorasib Cmax by 35% and AUCinf by 51%. OATP1B1/3 inhibition decreased sotorasib Cmax and AUCinf by 16% and 23%, respectively. These results support that sotorasib can be given together with strong CYP3A4 and OATP1B1/3 inhibitors but the co-administration of sotorasib and strong CYP3A4 inducers should be avoided.

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. PBPK-PD models for two US Food and Drug Administration (FDA) approved siRNAs inclisiran and vutrisiran were developed as case studies leveraging available tissue-specific data and translated to humans. Key determinants of the clinical PK and PD of N-acetylgalactosamine conjugated siRNAs (GalNAc-siRNAs) with varying sequences were also identified to inform effective clinical translation strategies for emerging GalNAc-siRNA candidates. A 30-70% reduction in hepatic asialoglycoprotein receptors concentrations still allowed for sufficient amount of free cytoplasmic siRNA for RISC-loading to produce PD effects comparable in extent and duration to normal liver function. This included severe hepatic impairment for which no clinical data are available. Inclusion of other modality agnostic physiological changes relevant to organ impairment did not alter the findings. Changes in renal physiologies, including changes in GFR across various degrees of impairment, well predicted minimal changes in PD for inclisiran and vutrisiran. This work provides a quantitative mechanistic framework and insights on modality-specific factors that drive clinical translation and patient/disease-related factors that impact specific dosing considerations and clinical outcomes to help accelerate the optimal development of siRNA therapeutics.

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.) to more convenient subcutaneous (s.c.) administrations and extending beyond adults to also benefit pediatric patients. Leveraging clinical development experience across three generations of Bi-TCE molecules across both liquid and solid tumor indications from i.v./s.c. dosing in adults and pediatric subjects, we developed a mechanistic-physiologically-based pharmacokinetic (PBPK) platform model for Bi-TCEs. The model utilizes a full PBPK model framework and was successfully validated for PK predictions following i.v. and s.c. dosing across both liquid and solid tumor space in adults for eight Bi-TCEs. After refinement to incorporate physiological ontogeny, the model was successfully validated to predict pediatric PKs in 1 month - < 2 years, 2-11 years, and 12-17 years old subjects following i.v. dosing. Following s.c. dosing in pediatric subjects, the model predicted similar bioavailability, however, a shorter time to maximum concentration (Tmax ) for the three age groups compared with adults. The model was also applied to guide the dosing strategy for first generation of Bi-TCEs for organ impairment, specifically renal impairment, and was able to accurately predict the impact of renal impairment on PK for these relatively small-size Bi-TCEs. This work highlights a novel mechanistic platform model for accurately predicting the PK in adult and pediatric patients across liquid and solid tumor indications from i.v./s.c. dosing and can be used to guide optimal dose and dosing regimen selection and accelerating the clinical development for Bi-TCEs.

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). AMG 119 demonstrated robust cellular expansion with long-lasting cell persistence and a favorable exposure-response relationship. AMG 119 has been demonstrated to be clinically safe and well tolerated at the doses tested, with no dose-limiting toxicities (DLTs) reported. This is the first publication of the clinical pharmacology profile of a CAR-T cell therapy in SCLC, with encouraging cellular kinetics data supporting the potential for CAR-T cell therapy in solid tumor space.

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). Piecewise constant functions were used to describe hazards for events that occur evenly throughout the study (OS event and OS censor). The multistate TTE model was applied to describe TTE endpoints from a published phase III study. The piecewise surge functions well-described the observed surges of hazards/events for TR, PD, PFS, and OS occurring near scheduled tumor assessments and showed good agreement with all Kaplan-Meier curves. With the flexibility of piecewise hazard functions, the model was able to evaluate covariate effects in a time-variant fashion to better understand the temporal patterns of disease prognosis through different disease states. This model can be applied to advance the field of oncology trial design and optimization by: (1) enabling robust estimations of baseline hazards and covariate effects for multiple TTE endpoints, (2) providing a platform model for understanding the composition and correlations between different TTE endpoints, and (3) facilitating oncology trial design optimization through clinical trial simulations.

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. Methods: A cross-sectional survey data collection was conducted with children (n = 39) and adults (n = 63) from one middle school community in the Midwestern United States. The child sample was 33% 6th grade; 51% 7th grade and was 49% female. The adult sample was primarily between 30 and 39 years old (70%) and comprised predominantly of females (85%). Multi-level survey design was guided by the psychological needs mini-theory within self-determination theory and aimed to identify individual perceptions, barriers, and facilitators in line with the unique context of the community. Results: At the individual level, 71.8% of children and 82.2% of the overall sample (children and adults) were interested in new physical activity/sport programming for their school. Likewise, 89.7% of children and 96.8% of adults agree that PA is good for physical health. For basic psychological needs in the overall sample, relatedness was significantly greater than the autonomy and competence subscales. Children's fruit and vegetable intake were below recommended levels, yet only 43.6% of children were interested in nutritional programming. Conversely, 61.5% indicated interest at increasing leadership skills. At the policy-systems-environmental level, the respondents' feedback indicated that the condition and availability of equipment are areas in need of improvement to encourage more physical activity. Qualitative responses are presented within for physical activity-related school policy changes. Discussion: Interventions addressing children's physical activity lack sustainability, scalability, and impact due to limited stakeholder involvement and often neglect early behavioral intervention stages. The present study identified perspectives, barriers, and facilitators of physical activity, sport, psychological needs, and nutrition in a multi-level context and forms the initial campus-community partnership between scientists and community stakeholders.

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. The majority (80%) of information was found to be contained in 9 out of 14 items, extending the current knowledge on the reliability of the MSQ as a psychometric tool. Simulations across three MSQ domains show significant improvement from baseline, exceeding minimally important differences. Overall, the IRT model platform developed herein allows for systematic quantification of the effect of erenumab on the MSQ in patients with migraine.

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.)) in healthy subjects and a phase Ib multiple ascending-dose study (70-420 mg s.c. every 2 weeks (q2w)) in patients with rheumatoid arthritis. Rozibafusp alfa exhibited nonlinear PK and dose-related and reversible dual-target engagement. Maximal reduction of naïve B cells from baseline (> 40%), reflective of BAFF inhibition, was achieved with rozibafusp alfa exposure (area under the concentration-time curve from time 0 to time infinity (AUCinf ) and AUC within a dosing interval from day 0 to day 14 (AUCtau )) above 51 and 57 days•µg/mL for the single-dose (≥ 70 mg) and multiple-dose studies (≥ 70 mg q2w), respectively. ICOSL receptor occupancy on circulating B cells, a surrogate PD end point for ICOSL inhibition, was directly related to drug concentration. PK/PD analysis showed > 90% RO at rozibafusp alfa ≥ 22.2 µg/mL (≥ 420-mg single dose or ≥ 210 mg q2w multiple dose), with saturation occurring at higher drug concentrations. These results informed the design and dose selection of a phase IIb study assessing the safety and efficacy of rozibafusp alfa in patients with active systemic lupus erythematosus.

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. Simulations were performed to compare the average proteasome inhibition across five cycles of treatment for the 20/70 mg/m2 once-weekly (70 QW) and 20/56 mg/m2 twice-weekly (56 BIW) regimens. RESULTS: Results indicated that while 70 QW had a higher maximum concentration (Cmax) and lower steady-state area under the concentration-time curve (AUC) than 56 BIW, the average proteasome inhibition after five cycles of treatment between the regimens was comparable. Presumably, the higher Cmax of carfilzomib from 70 QW compensates for the lower overall AUC compared with 56 BIW, and hence 70 QW is expected to have comparable proteasome inhibition, and therefore comparable efficacy, to 56 BIW. The comparable model-predicted proteasome inhibition between 70 QW and 56 BIW also translated to comparable clinical response, in terms of overall response rate and progression-free survival. CONCLUSION: This work provides a framework for which mechanistic PK/PD modeling can be used to guide optimization of dosing intervals for therapeutics with significantly longer PD effects than PK, and help further justify patient-convenient, longer dosing intervals.

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 102 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. This analysis clarifies under which condition the immune system either assists in eliminating tumor cells or inhibits T-VEC treatment efficacy, which is critical to both efficiently design future oncolytic agents and understand cancer development.

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. This model-based method was able to robustly estimate TTP and PPS from summary level OS and PFS data, provided a quantitative approach for understanding the patterns of disease progression across different treatments through the time-variant disease progression rate function, and provided a summary of how different treatments affect TTP and PPS. The proposed method can be generalized to characterize and quantify multiple time-to-event endpoints jointly in oncology trials and improve our understanding of disease prognostics for different treatments.

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. Two main types of ACT include engineered Chimeric Antigen Receptor (CAR) T cells and T cell receptor (TCR) T cells. The application of these immuno-therapies in the last few years has been successful and has demonstrated a safe and rapid treatment regimen for solid and non-solid tumors. The current review presents an insight into the clinical pharmacology aspects of immuno-therapies, especially CAR-T cells. Here, we summarize the current knowledge of TCR and CAR-T cell immunotherapy with particular focus on the structure of CAR-T cells, the effects and toxicities associated with these therapies in clinical trials, risk mitigation strategies, dose selection approaches, and cellular kinetics. Finally, the quantitative approaches and modeling techniques used in the development of CAR-T cell therapies are described.

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

ABSTRACT: 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. Omecamtiv mecarbil has a clearance of 11.7 L/h (0.701% relative standard error) and a central volume distribution of 275 L (2.12% relative standard error). The estimated half-life of omecamtiv mecarbil was 33 hours. Body weight and estimated glomerular filtration rate were significant covariates, but their effect on exposure was modest and lacked clinical relevance. Additional covariates, including sex, race, bilirubin, albumin, concomitant medications, New York Heart Association Functional Classification, N-terminal-pro hormone B-type natriuretic peptide, troponin I, creatine kinase MB, serum hemoglobin, tablet formulation, aspartate aminotransferase, and serum urea, were tested and found to have no impact on omecamtiv mecarbil exposures. The results of this integrated evaluation of the impact of covariates on the systemic exposure of omecamtiv mecarbil suggest that dose adjustment is not required for the studied subpopulations of patients with HF.

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. Proton pump inhibitors are one of the most commonly prescribed drugs in this patient population. Given the potential for coadministration of both drugs in patients with HF, we evaluated the potential for omeprazole to affect the pharmacokinetics of OM in an open-label study in 14 healthy subjects. Subjects received a single 50-mg dose of OM on day 1, followed by 40-mg once-daily doses of omeprazole on days 4 to 8. On day 9, a single 40-mg dose of omeprazole was administered first and immediately followed by 50-mg of OM. Blood samples were collected up to 144 hours after dosing following administration of OM on days 1 and 9 to characterize plasma concentrations of OM. The ratios of the geometric least-square means (90% confidence intervals) of OM coadministered with omeprazole compared to OM alone were 94.5% (81.7%-109.3%), 94.3% (81.5%-109.1%), and 101.2% (95.4%-107.3%) for area under the plasma concentration-time curve from time 0 to infinity, area under the plasma concentration-time curve from time 0 to the last measurable concentration, and maximum observed plasma concentration, respectively. Coadministration of OM with omeprazole was not associated with any clinically significant pharmacokinetic drug interactions. Single doses of OM were safe and well tolerated when coadministered with omeprazole.

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 (0.5-mg single dose; N = 15), a P-gp substrate, and the effect of coadministration of amiodarone (600-mg single dose), a P-gp inhibitor, on the pharmacokinetics of OM (50-mg single dose; N = 14) in healthy subjects. The ratios of the geometric least squares mean (90% confidence interval [CI]) of digoxin coadministered with OM vs digoxin alone for area under the plasma concentration-time curve (AUC) from time 0 to infinity, AUC from time 0 to the time of the last quantifiable concentration, and maximum observed plasma concentration were 1.06 (90%CI, 0.99-1.14), 1.06 (90%CI, 0.98-1.14), and 1.08 (90%CI, 0.92-1.26), respectively. The ratios of the geometric least squares mean of OM coadministered with amiodarone vs OM alone for AUC from time 0 to infinity, AUC from time 0 to the time of the last quantifiable concentration, and maximum observed plasma concentration were 1.21 (90%CI, 1.08-1.36), 1.21 (90%CI, 1.07-1.36), and 1.08 (90%CI, 0.96-1.22), respectively. In conclusion, OM coadministered with digoxin or amiodarone did not result in any clinically relevant pharmacokinetic drug-drug interactions.

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. Only subjects with maximum observed plasma concentration ≤ 350 ng/mL (n = 60) were randomized into part B, where they received a single oral dose of placebo, 50 mg OM and 400 mg moxifloxacin in a 3-period, 3-treatment, 6-sequence crossover study with continuous ECG collection. RESULTS: After a 50-mg dose of OM, mean placebo-corrected change from baseline QTcF (∆∆QTcF; Fridericia correction) ranged from -6.7 ms at 1 hour postdose to -0.8 ms at 4 hours postdose. The highest upper bound of the 1-sided 95% confidence interval (CI) was 0.7 ms (4 h postdose). Moxifloxacin resulted in a clear increase in mean ∆∆QTcF, with a peak value of 13.1 ms (90% CI: 11.71-14.57) at 3 hours; lower bound of the 1-sided 95% CI was > 5 ms at all of the 3 prespecified time points. Based on a concentration-QTc analysis, an effect on ∆∆QTcF exceeding 10 ms can be excluded up to OM plasma concentrations of ~800 ng/mL. There were no serious or treatment-emergent adverse events leading to discontinuation from the study. CONCLUSION: OM does not have a clinically relevant effect on the studied ECG parameters.

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). Study 1, part B, assessed the effect of diltiazem 240 mg on the pharmacokinetics of OM 10 mg (EM; n = 8). Study 2 assessed the effect of OM 25 mg on the pharmacokinetics of midazolam 5 mg (n = 14). Coadministration with ketoconazole led to 51% and 31% increases in OM AUCinf in EM and PM subjects, respectively, whereas OM Cmax remained similar (3% higher and 14% lower for EM and PM subjects, respectively). No changes in OM pharmacokinetics were observed in EM subjects following coadministration with diltiazem. Midazolam AUCinf and Cmax decreased by 18% and 10%, respectively, when coadministered with OM. In conclusion, CYP3A4 and CYP2D6 inhibitors are unlikely to have a clinically significant effect on the pharmacokinetics of OM. In addition, OM is unlikely to have a clinically relevant effect on the pharmacokinetics of CYP3A4 substrates.

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. Study 2 (n = 50) evaluated the pharmacokinetics of OM with multiple oral doses of 25 mg MR tablets twice a day (BID) followed by up-titration to either 37.5 mg or 50 mg BID in healthy Japanese subjects. RESULTS: In Study 1, the maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) from time 0 to infinity (AUCinf) in Japanese subjects after a single oral dose of 50 mg were twice that at the 25 mg dose, consistent with that observed in Caucasian subjects. Following single oral doses of 25 mg and 50 mg, absolute bioavailability was 56.5% and 59.2% for Japanese subjects and 63.1 and 83.6% for Caucasian subjects, respectively. No ethnic differences were observed in the pharmacokinetics of OM and its metabolites following single and multiple doses of 25 mg and 50 mg. In Study 2, the mean accumulation ratios based on AUC from 0 to 12 h (AUC12) were approximately four-fold from day 1 to day 8 and from day 20 to day 27 across ethnic groups. The mean ratios of Cmax to predose concentrations (Cpredose) ranged from 1.25 to 1.38 across subgroups. CONCLUSIONS: OM showed consistent and predictable pharmacokinetics after multiple dosing in Japanese subjects.

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. The potential for a pharmacokinetic (PK) drug-drug interaction (DDI) was investigated, specifically to determine whether a single 50 mg dose of OM would impact the PKs of a single 10 mg dose of rosuvastatin in an open-label study in 14 healthy subjects. The ratios of the geometric least-square means (90% confidence intervals [CIs]) of rosuvastatin co-administered with OM compared to rosuvastatin alone were 127.1% (90% CI 113.8-141.9), 132.8% (90% CI 120.7-146.1), and 154.2% (90% CI 132.8-179.1) for area under the plasma-concentration time curve from time zero to infinity (AUCinf ), area under the plasma-concentration time curve from time zero to time of last quantifiable concentration (AUClast ), and maximum observed plasma concentration (Cmax ), respectively. Whereas the DDI study with rosuvastatin was conducted with the co-administration of a single dose of OM, in the clinical setting, patients receive OM at doses of 25, 37.5, or 50 mg twice daily (b.i.d.). Hence, to extrapolate the results of the DDI study to a clinically relevant scenario of continuous b.i.d. dosing with OM, physiologically-based pharmacokinetic (PBPK) modeling was performed to explore the potential of BCRP inhibition following continuous b.i.d. dosing of OM at the highest 50 mg dose. Modeling results indicated that following 50 mg b.i.d. dosing of OM, the predicted ratios of the geometric means (90% CIs) for rosuvastatin AUCinf and Cmax were 1.18 (90% CI 1.16-1.20) and 2.04 (90% CI 1.99-2.10), respectively. Therefore, these results suggest that OM, following multiple dose administration, is a weak inhibitor of BCRP substrates and is in accordance with that observed in the single dose OM DDI clinical study.