Population Pharmacokinetics of Obinutuzumab (GA101) in Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin's Lymphoma and Exposure-Response in CLL.

Treatment regimens involving obinutuzumab (GA101) demonstrated increased efficacy to rituximab in clinical trials for non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). However, the pharmacokinetic (PK) properties and the exposure-response relationships of obinutuzumab still need to be fully described. Data from four clinical trials of obinutuzumab were analyzed to describe the PK properties in patients with NHL or CLL and the pharmacodynamic (PD) properties in patients with CLL. A population PK model with linear time-dependent clearance described the obinutuzumab concentration-time course. Diagnosis, baseline tumor size (BSIZ), body weight, and gender were the main covariates affecting obinutuzumab exposure. In patients with CLL, exposure was not associated with safety but showed positive trends of correlation with efficacy. Although efficacy correlated positively with exposure, since both efficacy and exposure correlated negatively with BSIZ, it was not possible to determine with certainty whether it would be beneficial to adjust the dose according to BSIZ.

Pharmacokinetics, pharmacodynamics, and tolerability of aleglitazar in patients with type 2 diabetes: results from a randomized, placebo-controlled clinical study.

This multicenter, randomized, double-blind, placebo-controlled, ascending-dose study investigated the pharmacokinetics, pharmacodynamic effects, safety, and tolerability of aleglitazar, a novel peroxisome proliferator-activated receptor alpha/gamma (PPARalpha/gamma) dual agonist. After a 3-week washout period, 71 patients with type 2 diabetes received either a single oral dose of aleglitazar (20, 50, 100, 300, 600, or 900 microg) or placebo, followed by once-daily dosing for 6 weeks. Few adverse events were reported, with no apparent relationship between the rate of incidence or severity of the adverse events and the dose of aleglitazar administered. Aleglitazar exposure increased in a dose-proportional manner both after a single dose and at steady state, with no accumulation. Aleglitazar produced dose-dependent improvements in levels of fasting and postprandial glucose, insulin resistance, and lipid parameters. Dose-dependent decreases from baseline in creatinine clearance exceeded 10% at doses >300 microg. The PPARalpha- and PPARgamma-related effects occurred over similar dose ranges, indicating that aleglitazar is a balanced agonist of the two receptor subtypes.

Pharmacokinetic-pharmacodynamic modeling of the electroencephalogram effect of imipenem in healthy rats.

A pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was developed to investigate the epileptogenic activity of imipenem in rats. Initially, animals received an intravenous infusion of imipenem at a rate of 2.65 mg min(-1) for 30 min. Blood samples were collected for drug assay, and an electroencephalogram (EEG) was recorded during infusion and postinfusion. A dramatic delay was observed between concentrations of imipenem in serum and the EEG effect; this effect was accompanied by tremors and partial seizures. Indirect-effect models failed to describe these data, which were successfully fitted using an effect compartment model. The relationship between effect and concentration at the effect site was best described by a spline function. The elimination rate constant from the effect compartment was severalfold lower than that from the central compartment. The robustness of the model was then confirmed after administering the imipenem dose over 60 and 90 min. In conclusion, the successful PK-PD modeling of the imipenem EEG effect in rats constitutes a major improvement for better prediction of the epileptogenic risk associated with this antibiotic.