Population Pharmacokinetics of Blinatumomab in Pediatric and Adult Patients with Hematological Malignancies.

BACKGROUND AND OBJECTIVES: Blinatumomab (BLINCYTO®) is a novel bispecific T cell engager (BiTE®) approved in the USA for the treatment of relapsed or refractory B cell precursor acute lymphoblastic leukemia (ALL) in children and adults, as well as minimal residual disease ALL in adults. This analysis characterized the population pharmacokinetics of intravenous blinatumomab in pediatric and adult patients. METHODS: A total of 2417 serum concentrations of blinatumomab from 674 patients, including adult (n = 628) and pediatric patients (n = 46), from eight clinical studies were analyzed. The impact of covariates on pharmacokinetic parameters were explored, and significant covariates were further evaluated using a simulation approach. RESULTS: Blinatumomab pharmacokinetics were described by a one-compartment linear model with first-order elimination, a clearance (CL) of 2.22 L/h, and a central volume of 5.98 L. A statistically significant effect of body surface area (BSA) on CL was observed. The smallest BSA of 0.37 m2 in the pediatric population was associated with a 63% reduction in blinatumomab systemic CL, relative to an adult patient with the median BSA (1.88 m2), supporting the use of BSA-based dosing in patients of lower bodyweight. The BSA effect was minimal, with a ≤ 25% change in CL over the range of BSA in adults, supporting no need for BSA-based dosing. CONCLUSIONS: Blinatumomab pharmacokinetics were adequately described by a one-compartment linear model with first-order elimination. No covariates other than BSA on CL were identified as significant. BSA-based dosing should be considered for lightweight patients to minimize inter-subject variability in blinatumomab exposure.

Receiver Operating Characteristic Analysis and Clinical Trial Simulation to Inform Dose Titration Decisions.

Optimal dose selection in clinical trials is problematic when efficacious and toxic concentrations are close. A novel quantitative approach follows for optimizing dose titration in clinical trials. A system of pharmacokinetics (PK), pharmacodynamics, efficacy, and toxicity was simulated for scenarios characterized by varying degrees of different types of variability. Receiver operating characteristic (ROC) and clinical trial simulation (CTS) were used to optimize drug titration by maximizing efficacy/safety. The scenarios included were a low-variability base scenario, and high residual (20%), interoccasion (20%), interindividual (40%), and residual plus interindividual variability scenarios, and finally a shallow toxicity slope scenario. The percentage of subjects having toxicity was reduced by 87.4% to 93.5%, and those having efficacy was increased by 52.7% to 243%. Interindividual PK variability may have less impact on optimal cutoff values than other sources of variability. ROC/CTS methods for optimizing dose titration offer an individualized approach that leverages exposure-response relationships.

Pravastatin reverses the down-regulating effect of inflammation on beta-adrenergic receptors: a disease-drug interaction between inflammation, pravastatin, and propranolol.

Inflammatory conditions reduce the potency to prolong the PR interval of certain cardiovascular drugs including propranolol, sotalol, and verapamil in rats and humans despite elevated plasma drug concentrations. We tested whether pravastatin restores altered action and disposition of propranolol as well as inflammatory mediators concentrations in the Pre-Adjuvant Arthritis (Pre-AA) Sprague-Dawley rat model. Rats [Healthy/Placebo, Arthritis/Placebo, Healthy/Statin, and Arthritis/Statin groups (n=14-16/group)] received Mycobacterium butyricum on day 0 followed by 6 mg/kg pravastatin or placebo twice daily during days 4-8. PR-interval response to 25 mg/kg oral propranolol was measured on days 0, 4 and 8. On day 8, blood samples were collected for interferon-gamma, interleukin-10, C-reactive protein, and nitrite measurements. Propranolol enantiomer pharmacokinetics were delineated using another 4 groups (healthy n=5, Pre-AA n=9) on day 8. Pre-AA significantly reduced propranolol response despite a 10-fold increase in concentrations. Pravastatin restored the response but not the drug concentrations. Area under the % effect-time curve (% min) was 714+/-214 in Healthy/Placebo, 256+/-249 in Arthritis/Placebo, 1534+/-367 in Healthy/Statin, and 1713+/-393 in Arthritis/Statin. While pravastatin reduced elevated serum interferon-gamma concentration in the Pre-AA model, it did not influence other biomarkers. Pravastatin restores response to propranolol in inflamed rat but has no effect on the elevated propranolol concentrations. This was associated with lower serum interferon-gamma concentrations.