Dynamic tumor modeling of the dose-response relationship for everolimus in metastatic renal cell carcinoma using data from the phase 3 RECORD-1 trial.

BACKGROUND: The phase 3 RECORD-1 trial (NCT00410124) established the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who progress on sunitinib or sorafenib. In RECORD-1, patients received 10 mg everolimus daily, with dose reduction to 5 mg daily allowed for toxicity. We have developed a model of tumor growth dynamics utilizing serial measurements of the sum of the longest tumor diameters (SLD) from individual RECORD-1 patients to define the dose-response relationship of everolimus. RESULTS: The model predicts that after 1 year of continuous dosing, the change in SLD of target lesions will be +142.1% ± 98.3%, +22.4% ± 17.2%, and -15.7% ± 11.5% in the average patient treated with placebo, 5 mg everolimus, and 10 mg everolimus, respectively. This nonlinear, mixed-effects modeling approach can be used to describe the dynamics of each individual patient, as well as the overall population. This allows evaluation of how an actual dosing history and individual covariates impact on the observed drug effect, and offers the possibility of predicting clinical observations as a function of time. CONCLUSIONS: In this pharmacodynamic model of tumor response, everolimus more effectively shrinks target lesions in mRCC when dosed 10 mg daily versus 5 mg daily, although a 5-mg dose still shows an antitumor effect. These data support earlier studies that established 10 mg daily as the preferred clinical dose of everolimus, and improve our understanding of the everolimus dose-response relationship.

A phase II, double-blind, placebo-controlled, ascending-dose study of Eritoran (E5564), a lipid A antagonist, in patients undergoing cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Lipid A, the toxic moiety of endotoxin, is linked to multiple complications after cardiac surgery, including fever, vasodilation, and pulmonary and renal dysfunction. The lipid A antagonist eritoran (or E5564) prevents endotoxin-induced systemic inflammation in animals and humans. In this study we assessed the safety of eritoran administration in patients undergoing cardiac surgery and obtained preliminary efficacy data for the prophylaxis of endotoxin-mediated surgical complications. METHODS: A double-blind, randomized, ascending-dose, placebo-controlled study was conducted at nine hospitals. Patients undergoing coronary artery bypass graft and/or cardiac valvular surgery with cardiopulmonary bypass were enrolled. Patients received a 4-h infusion of placebo (n = 78) vs 2 mg (n = 24), 12 mg (n = 26), or 28 mg (n = 24) of eritoran initiated approximately 1 h before cardiopulmonary bypass. RESULTS: No significant safety concerns were identified with continuous safety monitoring, and enrollment continued to the highest prespecified dose (28 mg). No statistically significant differences were observed in most variables related to systemic inflammation or organ dysfunction/injury. CONCLUSIONS: This Phase II safety study suggests that the administration of the novel lipid A antagonist, eritoran, is not associated with overt toxicity in cardiac surgical patients. Blocking lipid A with eritoran does not appear to confer any clear benefit to elective cardiac surgical patients.

Characterization of isoprenaline- and salmeterol-stimulated interactions between beta2-adrenoceptors and beta-arrestin 2 using beta-galactosidase complementation in C2C12 cells.

beta-Arrestin is an adaptor protein that has been shown to couple G protein-coupled receptors (GPCRs) to clathrin-coated pits and target them for subsequent internalization. More recently, beta-arrestin 2 has also been shown to be involved in the activation of mitogen-activated protein kinase cascades by G protein-coupled receptors independently of G protein activation. Direct interactions between proteins can be monitored using enzyme complementation between two inactive deletion mutants of beta-galactosidase (beta-gal; Deltaalpha and Deltaomega). In the present study, we have used fusion proteins of the human beta(2)-adrenoceptor (C-terminal beta-gal Deltaalpha) and beta-arrestin 2 (beta-gal Deltaomega) to study directly the pharmacology of this interaction in C2C12 cells expressing the beta(2)-adrenoceptor-beta-gal Deltaalpha fusion protein at low physiological levels (38.2 +/- 2.7 fmol . mg protein(-1)). Isoprenaline, noradrenaline, and adrenaline (-log EC(50) = 5.9, 5.5, and 5.7, respectively) stimulated an association between the beta(2)-adrenoceptor and beta-arrestin 2 at much higher concentrations than required for activation of cAMP accumulation (-log EC(50) = 7.6, 6.3, and 7.7, respectively). This was sensitive to inhibition by the beta(2)-adrenoceptor antagonists propranolol, timolol, and ICI 118551. Both salbutamol and terbutaline behaved as partial agonists of beta-gal complementation. Furthermore, the long-acting beta(2)-agonist salmeterol (-log K(D) for inhibition of [(3)H]CGP12177 binding = 8.7) behaved as an antagonist of isoprenaline-stimulated beta(2)-adrenoceptor-arrestin 2 interactions (-log K(D) = 8.0), whereas acting as a full agonist of cAMP accumulation in the same cells (-log EC(50) = 9.2). These data suggest that salmeterol can discriminate between receptor-G(S) protein and receptor-arrestin 2 complexes (in terms of efficacy and affinity) in a way that is favorable for its long duration of action.