Population pharmacokinetic analyses of pozelimab in patients with CD55-deficient protein-losing enteropathy (CHAPLE disease).

Pozelimab, a monoclonal antibody directed against C5, is the first and only treatment for adult and pediatric patients (≥ 1 year) with CD55-deficient protein-losing enteropathy (CHAPLE) disease. A target-mediated drug disposition (TMDD) population pharmacokinetic (PopPK) model was developed using pooled data from four phase 1-3 studies to characterize the pharmacokinetics (PK) of total pozelimab and total C5, and to simulate free pozelimab and free C5 to support the dose regimen in patients with CHAPLE disease. A TMDD PopPK model was developed using total pozelimab and total C5 concentration-time data from 106 participants (82 healthy volunteers; 24 patients with paroxysmal nocturnal hemoglobinuria [PNH]). This model was refined and updated to include PK data from 10 patients with CHAPLE disease from a phase 2/3 study. Stochastic simulations predicted concentration-time profiles for total pozelimab, free pozelimab, and free C5, to obtain pozelimab exposure metrics for patients with CHAPLE disease. A two-compartment TMDD model with two binding sites based on the quasi-equilibrium approximation adequately described the concentration-time profiles of total pozelimab and total C5. Body weight was identified as the most important source of pozelimab PK variability; therefore, the dose was adjusted based on body weight for the predominantly pediatric patients with CHAPLE disease. A robust TMDD PopPK model was developed to describe the PK of total pozelimab and total C5 following pozelimab administration. Reliable predictions for individual exposures of total pozelimab and free C5 were possible and supported the 10 mg/kg weight-based dose regimen in patients with CHAPLE disease.

Population Pharmacokinetics of Casirivimab and Imdevimab in Pediatric and Adult Non-Infected Individuals, Pediatric and Adult Ambulatory or Hospitalized Patients or Household Contacts of Patients Infected with SARS-COV-2.

INTRODUCTION: Casirivimab (CAS) and imdevimab (IMD) are two fully human monoclonal antibodies that bind different epitopes on the receptor binding domain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and block host receptor interactions. CAS + IMD and was developed for the treatment and prevention of SARS-CoV-2 infections. METHODS: A population pharmacokinetic (PopPK) analysis was conducted using pooled data from 7598 individuals from seven clinical studies to simultaneously fit concentration-time data of CAS and IMD and investigate selected covariates as sources of variability in PK parameters. The dataset comprised CAS + IMD-treated pediatric and adult non-infected individuals, ambulatory or hospitalized patients infected with SARS-CoV-2, or household contacts of patients infected with SARS-CoV-2. RESULTS: CAS and IMD concentration-time data were both appropriately described simultaneously by a two-compartment model with first-order absorption following subcutaneous dose administration and first-order elimination. Clearance estimates of CAS and IMD were 0.193 and 0.236 L/day, respectively. Central volume of distribution estimates were 3.92 and 3.82 L, respectively. Among the covariates identified as significant, body weight and serum albumin had the largest impact (20-34%, and ~ 7-31% change in exposures at extremes, respectively), while all other covariates resulted in small differences in exposures. Application of the PopPK model included simulations to support dose recommendations in pediatrics based on comparable exposures of CAS and IMD between different weight groups in pediatrics and adults following weight-based dosing regimens. CONCLUSIONS: This analysis provided important insights to characterize CAS and IMD PK simultaneously in a diverse patient population and informed pediatric dose selection.

Population Pharmacokinetics of Fasinumab in Healthy Volunteers and Patients With Pain Due to Osteoarthritis of the Knee or Hip.

Osteoarthritis (OA) pain management options are currently limited. Fasinumab, an anti-nerve growth factor monoclonal antibody, has been investigated in healthy volunteers and patients with OA-related pain, among other conditions. Data from 12 Phase I-III clinical trials of 92 healthy volunteers and 7430 patients with OA were used to develop a population pharmacokinetic model to characterize fasinumab concentration-time profiles and assess the covariates' effect on fasinumab pharmacokinetic parameters. Participants received single or repeated fasinumab doses intravenously (IV)/subcutaneously (SC), based on body weight (0.03-1 mg/kg IV or 0.1-0.3 mg/kg SC)/fixed dose (9-12 mg IV or 1-12 mg SC). Fasinumab concentration-time data following IV and SC administration in healthy volunteers and patients with OA-related pain were adequately described by a 2-compartment model. Bioavailability increased with higher doses; estimated at 55.1% with 1 mg SC dose, increasing in a greater-than-proportional manner above this. Body weight had the largest predicted impact on fasinumab steady-state exposures, participants at the 5th and 95th percentiles had a 43%-45% higher/22%-23% lower exposure versus reference, respectively. Other covariates had small but clinically irrelevant impacts.

Disease progression modeling of the North Star Ambulatory Assessment for Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a rare genetic disorder caused by decreased or absent dystrophin gene leading to progressive muscle degeneration and weakness in young boys. Disease progression models for the North Star Ambulatory Assessment (NSAA), a functional measurement widely used to assess outcomes in clinical trials, were developed using a longitudinal population modeling approach. The relationship between NSAA total score over time, loss of ambulation, and potential covariates that may influence disease progression were evaluated. Data included individual participant observations from an internal placebo-controlled phase II clinical trial and from the external natural history database for male patients with DMD obtained through the Cooperative International Neuromuscular Research Group (CINRG). A modified indirect response model for NSAA joined to a loss of ambulation (LOA) time-to-event model described the data well. Age was used as the independent variable because ambulatory function is known to vary with age. The NSAA and LOA models were linked using the dissipation rate constant parameter from the NSAA model by including the parameter as a covariate on the hazard equation for LOA. No covariates were identified. The model was then used as a simulation tool to explore various clinical trial design scenarios. This model contributes to the quantitative understanding of disease progression in DMD and may guide model-informed drug development decisions for ongoing and future DMD clinical trials.

Population PK and PD Analysis of Domagrozumab in Pediatric Patients with Duchenne Muscular Dystrophy.

Myostatin, a negative regulator of skeletal muscle growth, is a therapeutic target in muscle-wasting diseases. Domagrozumab, a humanized recombinant monoclonal antibody, binds myostatin and inhibits activity. Domagrozumab was investigated in a phase II trial (NCT02310763) as a potential treatment for boys with Duchenne muscular dystrophy (DMD). Pharmacokinetic/pharmacodynamic (PK/PD) modeling is vital in clinical trial design, particularly for determining dosing regimens in pediatric populations. This analysis sought to establish the PK/PD relationship between free domagrozumab and total myostatin concentrations in pediatric patients with DMD using a prior semimechanistic model developed from a phase I study in healthy adult volunteers (NCT01616277) and following inclusion of phase II data. The refined model was developed using a multiple-step approach comprising structural, random effects, and covariate model development; assessment of model adequacy (goodness-of-fit); and predictive performance. Differences in PKs/PDs between healthy adult volunteers and pediatric patients with DMD were quantitatively accounted for and evaluated by predicting myostatin coverage (the percentage of myostatin bound by domagrozumab). The final model parameter estimates and semimechanistic target-mediated drug disposition structure sufficiently described both domagrozumab and myostatin concentrations in pediatric patients with DMD, and most population parameters were comparable with the prior model (in healthy adult volunteers). Predicted myostatin coverage for phase II patients with DMD was consistently > 90%. Baseline serum myostatin was ~ 65% lower than in healthy adult volunteers. This study provides insights into the regulation of myostatin in healthy adults and pediatric patients with DMD. Clinicaltrials.gov identifiers: NCT01616277 and NCT02310763.

Population Pharmacokinetic Analysis of Rivipansel in Healthy Subjects and Subjects with Sickle Cell Disease.

BACKGROUND: Sickle cell disease is an inherited blood disorder with reduced blood-carrying capacity. It is associated with a tendency to form microclots in blood vessels, leading to painful episodes known as a vaso-occlusive crisis. Rivipansel is a pan-selectin inhibitor being studied for the treatment of a vaso-occlusive crisis in patients with sickle cell disease. METHODS: A population pharmacokinetic model of rivipansel plasma and urine concentrations was constructed using a two-compartment model and data from nine different clinical studies. Creatinine clearance was calculated using the Schwartz formula for children and the Chronic Kidney Disease Epidemiology Collaboration formula for adults. Urine volume and concentration of the study drug in urine from subjects in five clinical studies were used to estimate renal and nonrenal clearance. RESULTS: Rivipansel drug concentrations were well described by the model. The post hoc estimates of average steady-state concentrations were predicted to be similar for the adult and pediatric cohorts of the pivotal phase III study. Parameter estimates showed almost exclusively renal excretion of rivipansel, which is consistent with the known properties of the drug. CONCLUSIONS: The pharmacokinetics of rivipansel was well characterized by a two-compartment population pharmacokinetic model. Our results illustrate the important role of simulations in optimizing a potential drug dosing regimen for patients with sickle cell disease and progressive renal impairment.

Modeling of Survival and Frequency of Cardiovascular-Related Hospitalization in Patients with Transthyretin Amyloid Cardiomyopathy Treated with Tafamidis.

INTRODUCTION: ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial) demonstrated the efficacy and safety of tafamidis in transthyretin amyloid cardiomyopathy (ATTR-CM). Model-based analyses from ATTR-ACT can examine predictor effects on dose-response/exposure-response relationships. METHODS: Parametric hazard distributions were developed for all-cause mortality and frequency of cardiovascular-related hospitalization. Time-to-event models were fitted to survival data, and repeated time-to-event models were fitted to hospitalization data. Disease-specific characteristics were assessed as baseline predictors of event hazards. RESULTS: There were 441 patients in this analysis. At month 30, 70.5% (tafamidis) and 57.1% (placebo) of patients were alive, with 154/441 deaths reported; 495 cardiovascular-related hospitalizations occurred. The cumulative risk of death was 42.1% (95% confidence interval [CI] 24.2-58.0) lower with tafamidis than with placebo, regardless of New York Heart Association (NYHA) class; significant predictors of decreased risk were genotype (wild-type), greater 6-Minute Walk Test (6MWT) distance, higher left ventricular ejection fraction (LVEF), and lower blood urea nitrogen (BUN) and N-terminal pro-B-type natriuretic peptide concentrations. The average cumulative risk of cardiovascular-related hospitalization up to 30 months was 40.8% (95% CI 31.0-49.7) lower with tafamidis in NYHA class I/II patients. Significant predictors of reduced risk were greater 6MWT distance, higher LVEF, and lower BUN and troponin I concentrations. CONCLUSIONS: Tafamidis reduced cumulative mortality and hospitalization risk versus placebo in patients with ATTR-CM. Baseline predictors of outcome were consistent with the cardiovascular nature of the disease and suggested that earlier treatment may improve outcomes. CLINICAL TRIALS. GOV IDENTIFIER: NCT01994889 (date of registration: November 26, 2013).

Modeling and simulation of the modified Rankin Scale and National Institutes of Health Stroke Scale neurological endpoints in intracerebral hemorrhage.

Intracerebral hemorrhage (ICH) is a form of stroke characterized by uncontrolled bleeding into the parenchyma of the brain. There is no approved therapy for ICH and it is associated with very poor neurological outcomes with around half of subjects dying within 1 month and most subjects showing complete or partial disability. A key challenge is to identify subjects who could benefit from intervention using characteristics such as baseline hemorrhage volume and the increase in hemorrhage volume in the first few hours, which have been correlated with final outcomes in ICH. Combined longitudinal models were developed to describe stroke scales using categorical data (Modified Rankin Scale, mRS), continuous bounded data (National Institutes of Health Stroke Scale, NIHSS), and time to death. Covariate effects for baseline hematoma volume and maximum increase in hematoma volume were incorporated to assess the improvement in outcome when hematoma volume increase would be reduced by a potential treatment. The combined model provided an adequate description of stroke scales, with patients split into a Non-survival and a High-survival sub-population, and dropout due to death was well described by a constant hazard survival model. Models were compared indicating that the combined mRS/NIHSS model provided the most information, followed by the NIHSS-only model, and the mRS-only model, and finally the traditional statistical analysis on dichotomized response at 90 days. Simulations showed that substantial reductions in hematoma volume increase were required to increase the probability of a favorable outcome.

Cement augmentation of humeral head screws reduces early implant-related complications after locked plating of proximal humeral fractures.

BACKGROUND: Cement augmentation (CA) of humeral head screws in locked plating of proximal humeral fractures (PHF) was found to be biomechanically beneficial. However, clinical outcomes of this treatment have not been well evaluated to date. OBJECTIVES: To assess outcomes of locked plating of PHF with additional CA and to compare them with outcomes of conventional locked plating without CA. METHODS: 24 patients (mean age, 74.2 ± 10.1 years; 22 female) with displaced PHF were prospectively enrolled and treated with locked plating and additional CA. The Constant score (CS), the Simple Shoulder Test (SST), and the Simple Shoulder Value (SSV) were assessed 3 and 12 months postoperatively. Fracture healing and potential complications were evaluated on postoperative radiographs. The CS and complications were compared with the outcomes of a matched group of 24 patients (mean age, 73.9 ± 9.4 years; 22 female) with locked plating of displaced PHF without CA. RESULTS: At the 3­month follow-up, the mean CS was 59.9 ± 15.6 points, the mean SST was 7.5 ± 2.7 points, and the mean SSV was 63.9 ± 21.7%. All scores significantly improved by the 12-month follow-up (p < 0.05; CS, 72.9 ± 17.7; SST, 9.2 ± 3.2; SSV, 77.2 ± 17.3%). There were two cases (8%) of biological complications (n = 1 varus malunion and n = 1 humeral head necrosis). Compared with locked plating without CA, no significant differences were observed between the CS at the 3­ (57.8 ± 13.4 points; p = 0.62) and 12-month (73.0 ± 12.8 points; p = 0.99) follow-up. However, patients without CA had a significantly increased risk of early loss of reduction and articular screw perforation (p = 0.037). CONCLUSION: Locked plating of proximal humeral fractures with trauma cement augmentation of humeral head screws could be translated from the ex-vivo lab setting into the clinical situation without additional complications. Locked plating of displaced PHF with additional cement augmentation showed similar clinical outcomes but reduced the rate of early implant-related complications compared to locked plating without additional CA.

Dose Selection Based on Modeling and Simulation for Rivipansel in Pediatric Patients Aged 6 to 11 Years With Sickle Cell Disease.

This modeling and simulation exercise aimed to provide dosing recommendations for rivipansel phase III studies in children aged 6-11 years with sickle cell disease (SCD). Pharmacokinetic data from 109 patients aged 12-51 years who received rivipansel (2-40 mg/kg) in previous studies (three phase I and one phase II) were integrated to build a three-compartmental simulation model. Renal clearance simulations across the age range accounted for renal function development and postulated hyperfiltration in SCD. Simulated demographic distributions for the pediatric SCD population were used to predict concentration-time profiles from three dosing regimens, which were then compared against efficacious average steady-state concentrations observed in phase II. A dosing regimen comprising a 40-mg/kg loading dose followed by a 20-mg/kg maintenance dose every 12 hours was selected, as it will likely provide an efficacious concentration range. Its validity will be confirmed in the ongoing phase III study.