Nivolumab is a fully human monoclonal antibody that inhibits programmed death-1 activation. The clinical pharmacology profile of nivolumab was analyzed by population pharmacokinetics model assessed covariate effects on concentrations in 1,895 patients who received 0.3–10.0 mg/kg 11 trials. linear with time-varying clearance. A full developed to assess pharmacokinetic parameters. clearance and volume distribution increase body weight. final included the baseline performance status (PS),...

Nivolumab 3 mg/kg every 2 weeks (Q2W) has shown benefit versus the standard of care in melanoma, non-small cell lung cancer (NSCLC), and renal carcinoma (RCC). However, flat dosing is expected to shorten preparation time improve ease administration. With knowledge nivolumab safety, efficacy, pharmacokinetics across a wide dose range body weight (BW) dosing, assessment benefit-risk profile 240-mg relative approved 3-mg/kg was approached by quantitative clinical pharmacology.A 240 mg selected...

Immuno-oncology (I-O) therapies target the host immune system, providing potential to choose a uniform dose and schedule across tumor types. However, selection for I-O agents usually occurs early in clinical development is typically based on response, which may not fully represent improved overall survival. Here, we describe an integrated approach incorporates safety efficacy data with obtained from analyses of dose-/exposure-response (D-R/E-R) relationships, used select monotherapy...

Abstract Purpose: Using standard-of-care CT images obtained from patients with a diagnosis of non–small cell lung cancer (NSCLC), we defined radiomics signatures predicting the sensitivity tumors to nivolumab, docetaxel, and gefitinib. Experimental Design: Data were collected prospectively analyzed retrospectively across multicenter clinical trials [nivolumab, n = 92, CheckMate017 (NCT01642004), CheckMate063 (NCT01721759); 50, CheckMate017; gefitinib, 46, (NCT00588445)]. Patients randomized...

Inadequate selection of the dose to bring forward in confirmatory trials has been identified as one key drivers decreasing success rates observed drug development programs across pharmaceutical industry. In recognition this problem, Pharmaceutical Research and Manufacturers America (PhRMA), formed a working group evaluate develop alternative approaches finding, including adaptive dose-ranging designs. This paper summarizes work group, results conclusions comprehensive simulation study, puts...

The Minnesota Children's Pesticide Exposure Study is a probability-based sample of 102 children 3-13 years old who were monitored for commonly used pesticides. During the summer 1997, first-morning-void urine samples (1-3 per child) obtained 88% study and analyzed metabolites insecticides herbicides: carbamates related compounds (1-NAP), atrazine (AM), malathion (MDA), chlorpyrifos (TCPy). TCPy was present in 93% samples, whereas 1-NAP, MDA, AM detected 45%, 37%, 2% respectively. Measured...

Aim Ipilimumab is a fully human, monoclonal antibody that blocks cytotoxic T ‐lymphocyte antigen‐4. The objective of the present study was to characterize clinical pharmacology profile ipilimumab using population pharmacokinetic ( PPK ) approach. Methods model developed 2095 serum concentration values from 499 patients with unresectable stage III or IV melanoma four phase II studies, doses ranging 0.3 10 mg kg −1 . structural PK determined by developing base model. effect covariates on...

Purpose: Nivolumab is a fully human IgG4 monoclonal antiprogrammed death-1 antibody with demonstrated efficacy, including durable responses and prolonged survival, in patients previously treated, advanced non-small cell lung cancer (NSCLC). Exposure-response (E-R) analyses for efficacy safety were conducted to inform the benefit-risk assessment of nivolumab this patient population.Experimental Design: The used clinical trial data from squamous (n = 293) or nonsquamous 354) NSCLC four trials...

Purpose: Dasatinib is a prototypic short half-life BCR-ABL1 tyrosine kinase inhibitor. The recommended dose of dasatinib for chronic myeloid leukemia in phase was changed from 70 mg twice daily to 100 once following Phase III dose-optimization study. To better understand the superior benefit–risk profile daily, exposure–response characterized efficacy (major cytogenetic response) and safety (pleural effusion). Patients methods: exposure patients with determined by population pharmacokinetic...

Nivolumab is a fully human IgG4 monoclonal antibody targeting the programmed death-1 (PD-1) receptor that blocks interactions between PD-1 and its ligands on tumor cells to prevent T-cell exhaustion in patients with cancer. It has demonstrated efficacy multiple types, including melanoma, non-small-cell lung cancer, renal cell carcinoma. This analysis assessed immunogenicity of nivolumab impact pharmacokinetics, safety, solid tumors enrolled 6 clinical studies. The incidence prevalence...

This analysis describes the population pharmacokinetics ( PPK ) of apixaban in nonvalvular atrial fibrillation NVAF subjects, and quantifies impact intrinsic extrinsic factors on exposure. The model was developed using data from phase I–III studies. Apixaban exposure characterized by a two‐compartment with first‐order absorption elimination. Predictive covariates apparent clearance included age, sex, Asian race, renal function, concomitant strong/moderate cytochrome P450 CYP...

Aims The development of monoclonal antibodies (mAbs) requires an understanding the interindividual variability (IIV) in pharmacokinetics (PK) at population level facilitated by PK (PopPK) modelling. However, there is no clear rationale for selecting which covariates to screen during PopPK model development. Here, we compare effect on parameters mAbs oncology and identify most commonly used affecting parameters. Methods All 25 approved therapeutic use until December 2017 Food Drug...

Estimation of uncertainties associated with model predictions is an important component the application environmental and biological models. “Traditional” methods for propagating uncertainty, such as standard Monte Carlo Latin Hypercube Sampling, however, often require performing a prohibitive number simulations, especially complex, computationally intensive Here, efficient method uncertainty propagation, Stochastic Response Surface Method (SRSM) coupled another method, Automatic...

The pharmacokinetics of alprazolam (ALP) after i.v. and p.o. administration in rats were characterized. ALP decayed biexponentially the dose (1.25 mg/kg), but concentration-time profiles doses (7 12.5 mg/kg) exhibited a double-peak phenomenon. presence two peaks was confirmed by statistical analysis serum concentration data ALP, as well observed double active metabolites (alpha-hydroxyalprazolam 4-hydroxyalprazolam). An absorption model incorporating delay site is proposed to describe data,...

Mavacamten is the first cardiac myosin inhibitor approved by US Food and Drug Administration for treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). The phase III EXPLORER-HCM (NCT03470545) study used a dose-titration scheme based on mavacamten exposure echocardiographic assessment Valsalva left ventricular outflow tract gradient (VLVOTg) ejection fraction (LVEF). Using population pharmacokinetic/exposure-response modeling simulations virtual patients, this in...

Ipilimumab is a fully human monoclonal antibody approved for the treatment of melanoma as monotherapy and melanoma, renal cell carcinoma, colorectal cancer in combination with nivolumab. time-varying clearance (CL) was assessed by population pharmacokinetics (PPK) model developed using statistically significant covariates identified previous PPK analysis plus additional covariates. Data from 3,411 patients who received ipilimumab 0.3-10 mg/kg alone or nivolumab 16 clinical trials were...

This analysis was conducted to inform dose selection of a combination nivolumab plus ipilimumab for the treatment sorafenib-experienced patients with hepatocellular carcinoma (HCC). CheckMate 040 is an open-label, multicohort, phase I/II trial in adults advanced HCC that evaluated monotherapy (0.1-10 mg/kg once every 2 weeks [q2w]) and following three combinations ipilimumab: (1) 1 3 (q3w) four doses, followed by 240 mg q2w (arm A); (2) q3w B); (3) 6 continuously C). Exposure-response...

Progression-free survival (PFS) was significantly improved with nivolumab 480 mg plus relatlimab 160 fixed-dose combination (FDC) every 4 weeks (Q4W) versus alone in patients previously untreated advanced melanoma RELATIVITY-047. In addition, RELATIVITY-020 (Part D) demonstrated a manageable safety profile and potential for durable response treated patients. Here, we evaluate the clinical pharmacology (CPP) of to support approved regimen adult adolescent its continued development solid tumors.

Objective: Characterize the population pharmacokinetics (PPK) of repotrectinib in adults and pediatrics with a model to account for time-changing clearance resulting from drug induced auto-induction.Methods: Repotrectinib is tyrosine kinase inhibitor being developed treatment harboring ROS1 positive non small cell lung cancer (NSCLC) adult or pediatric NTRK solid tumors. A dataset (with healthy volunteers patients) including 7 studies (N&#3f620) 1 study (N&#3f24) were available...

In this work, a computationally efficient Bayesian framework for the reduction and characterization of parametric uncertainty in demanding environmental 3‐D numerical models has been developed. The is based on combined application Stochastic Response Surface Method (SRSM, which generates accurate statistically equivalent reduced models) Markov chain Monte Carlo method. selected to demonstrate involves steady state groundwater flow at U.S. Department Energy Savannah River Site General...