Pharmacokinetics
Letrozole was rapidly absorbed from the gastrointestinal tract (maximum concentration (Cmax) reached within 2 h). With repeated daily administration, Cmax and the area under the concentration–time curve (AUC) increased by 5.5- and 2.4-fold, respectively, consistent with accumulation [PK analyses of everolimus were consistent with significantly lower maximum and trough concentrations (Ctrough) from those previously reported (Cmax: 5 mg, 2.63 ng/mL; 10 mg, 5.38 ng/mL vs. 32 and 61 ng/mL, respectively [Serum concentrations of carotuximab known to saturate CD105 receptors (200 ng/mL) were rapidly achieved and consistently maintained (supplementary Fig. 1B). With dose escalation from 3 to 15 mg/kg, AUC and half-life increased supraproportionally while clearance decreased by a similar magnitude probably due to target saturation (supplementary table 2). PK simulations using a two-compartment model suggest accumulation of carotuximab in the extravascular volume of distribution (Fig. 