A mechanism-based model for the population pharmacokinetics of free and bound aflibercept in healthy subjects.

AIM: Aflibercept (VEGF-Trap), a novel anti-angiogenic agent that binds to VEGF, has been investigated for the treatment of cancer. The aim of this study was to develop a mechanism-based pharmacokinetic (PK) model for aflibercept to characterize its binding to VEGF and its PK properties in healthy subjects. METHODS: Data from two phase I clinical studies with aflibercept administered as a single intravenous infusion were included in the analysis. Free and bound aflibercept concentration-time data were analysed using a nonlinear mixed-effects modelling approach with MONOLIX 3.1. RESULTS: The best structural model involved two compartments for free aflibercept and one for bound aflibercept, with a Michaelis-Menten type binding of free aflibercept to VEGF from the peripheral compartment. The typical estimated clearances for free and bound aflibercept were 0.88 l day(-1) and 0.14 l day(-1), respectively. The central volume of distribution of free aflibercept was 4.94 l. The maximum binding capacity was 0.99 mg day(-1) and the concentration of aflibercept corresponding to half of maximum binding capacity was 2.91 µg ml(-1). Interindividual variability of model parameters was moderate, ranging from 13.6% (V(max) ) to 49.8% (Q). CONCLUSION: The present PK model for aflibercept adequately characterizes the underlying mechanism of disposition of aflibercept and its nonlinear binding to VEGF.

Population pharmacokinetics and pharmacodynamics of enoxaparin in unstable angina and non-ST-segment elevation myocardial infarction.

AIMS: A major concern with any antithrombotic therapy is an increase in the risk of haemorrhage. The aim of this study was to analyse population pharmacokinetics and pharmacokinetic/pharmacodynamic (PK/PD) relationships for enoxaparin in patients with unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI), which may help predict risk of haemorrhage. METHODS: Anti-factor Xa (anti-Xa) activity was measured as marker of enoxaparin concentration in 448 patients receiving the drug as a single 30-mg intravenous bolus followed by 1.0 or 1.25 mg kg(-1) subcutaneously twice a day. A population pharmacokinetic analysis was conducted and individual estimates of enoxaparin clearance and area under the curve were tested as prognostic factors for the occurrence of haemorrhagic episodes. RESULTS: Basic population PK parameters were an enoxaparin clearance of 0.733 l h(-1)[95% confidence interval (CI) 0.698, 0.738], a distribution volume of 5.24 l (95% CI 4.20, 6.28) and an elimination half-life of 5.0 h. Enoxaparin clearance was significantly related to patient weight and creatinine clearance, and was the only independent predictor of experiencing both all (10.7%, P = 0.0013) and major (2.2%, P = 0.0004) haemorrhagic events. A creatinine clearance of 30 ml min(-1) was associated with a decrease in enoxaparin clearance of 27% compared with that in a patient with a median creatinine clearance of 88 ml min-1, and was related to a 1.5- and 3.8-fold increase in the risk of 'all' and 'major' haemorrhagic episodes, respectively. CONCLUSIONS: Enoxaparin clearance depends on body weight, and, therefore, weight-adjusted dosing is recommended to minimize interpatient variability in drug exposure and the risk of haemorrhage. The importance of an increased risk of haemorrhage with decreasing renal function must be weighed against the benefit of treatment with enoxaparin in patients with UA and NSTEMI.

Alpha-1-acid glycoprotein as an independent predictor for treatment effects and a prognostic factor of survival in patients with non-small cell lung cancer treated with docetaxel.

PURPOSE: To identify predictors of treatment outcome and survival in patients with non-small cell lung cancer (NSCLC) treated with docetaxel. EXPERIMENTAL DESIGN: The data were collected from 180 NSCLC patients enrolled in six docetaxel Phase II studies at a dose of 100 mg/m(2). Clinical end points for this study were safety reported as the first course adverse events requiring dose reduction, and efficacy was measured by response rate and survival. The independent variables included docetaxel dose, individual estimates of clearance, area under the plasma concentration time curve, extent of previous treatment, and covariables related to the patient's demographics, extent of disease, and performance status. The data were analyzed using a logistic regression model for response and severe adverse events and a Cox multivariate regression model for survival. RESULTS: Docetaxel exposure as measured by the area under the plasma concentration time curve was the only significant predictor (P < 0.0001) of severe toxicity during the first course of therapy. Baseline alpha1-acid glycoprotein (AAG) was the only significant predictor of response with an odds ratio of 0.44 for changes in AAG from 1.11 to 1.85 grams/liter (P = 0.0039). Cumulative dose, AAG, and extent of disease were independent predictors of survival (P < 0.005). The median survival varied from 15.6 months for patients with a low AAG (AAG < or = 1.11 grams/liter) to 5.5 months for patients with a high AAG (AAG >/= 1.85 grams/liter). CONCLUSION: AAG appears to be an independent predictor of response and a major objective prognostic factor of survival in patients with NSCLC treated with docetaxel chemotherapy.