This mechanism-based model accurately predicted VEGF concentrations and allowed for the simulation of various rhVEGF(165) dose regimens that may aid in optimization of drug delivery for future clinical trials.
Atezolizumab, a humanized immunoglobulin G1 (IgG1) monoclonal antibody targeting human programmed death-ligand 1 (PD-L1), is US Food and Drug Administration (FDA) approved in metastatic urothelial carcinoma (MUC) and is being investigated in various malignancies. This analysis based upon 906 patients from two phase I and one phase II MUC studies, is the first report of the clinical pharmacokinetics (PK) and pharmacodynamics (PD) of atezolizumab. Atezolizumab exhibited linear PK over a dose range of 1-20 mg/kg, including the labeled 1,200 mg dose. The clearance, volume of distribution, and terminal half-life estimates from population pharmacokinetic (PopPK) analysis of 0.200 L/day, 6.91 L, and 27 days, respectively, were as expected for an IgG1. Exposure-response analyses did not identify statistically significant relationships with either objective response rate or adverse events of grades 3-5 or of special interest. None of the statistically significant covariates from PopPK (body weight, gender, antitherapeutic antibody, albumin, and tumor burden) would require dose adjustment.
We have engineered two Chinese hamster ovary cell lines secreting different recombinant glycoproteins to express high levels of human beta1,4-galactosyltransferase (GT, E.C. 2.4.1.38) and/or alpha2, 3-sialyltransferase (ST, E.C. 2.4.99.6). N-linked oligosaccharide structures synthesized by cells overexpressing the glycosyltransferases showed greater homogeneity compared with control cell lines. When GT was overexpressed, oligosaccharides terminating with GlcNAc were significantly reduced compared with controls, whereas overexpression of ST resulted in sialylation of >/=90% of available branches. As expected, GT overexpression resulted in reduction of oligosaccharides terminating with GlcNAc, whereas overexpression of ST resulted in sialylation of >/=90% of available branches. The more highly sialylated glycoproteins had a significantly longer mean residence time in a rabbit model of pharmacokinetics. These experiments demonstrate the feasibility of genetically engineering cell lines to produce therapeutics with desired glycosylation patterns.
Onartuzumab is a unique, humanized, monovalent (one-armed) monoclonal antibody (mAb) against the MET receptor. The intravenous (IV) pharmacokinetics (PK) of onartuzumab were investigated in a phase I study and a phase II study in recurrent non-small cell lung cancer (NSCLC) patients. The potential for drug-drug interaction (DDI) was assessed during co-administration of IV onartuzumab with oral erlotinib, by measuring the PK of both drugs. The concentration-time profiles of onartuzumab were adequately described using a two-compartment model with linear clearance (CL) at doses between 4 and 30 mg/kg. The estimates for CL, central compartment volume (V1 ), and median terminal half-life were 0.439 L/day, 2.77 L, and 13.4 days, respectively. Statistically significant covariates included creatinine clearance (CrCL) on clearance, weight and gender on V1 , and weight on peripheral compartment volume (V2 ), but the clinical relevance of these covariates needs to be further evaluated. The current analysis did not indicate obvious DDI between onartuzumab and erlotinib. MET diagnostic status did not impact the exposure of either agent. Despite the slightly faster clearance compared with typical bivalent mAbs, the PK of onartuzumab support dosing regimens of 15 mg/kg every 3 weeks or doses equivalent to achieve the target minimum tumoristatic concentration in patients.
A population pharmacokinetic model was developed for cobimetinib in cancer patients. Covariates had minimal impact on steady-state exposure, suggesting no need for dose adjustments and supporting the recommended dose for all patients.
PurposeThis study evaluated the potential effect of trastuzumab on the electrocardiogram (ECG) QT interval and assessed the potential pharmacokinetic interaction between trastuzumab and carboplatin. Here, we report the QT and safety results.MethodsPatients with metastatic or inoperable HER2-positive solid tumors received docetaxel and carboplatin on Day 1 of each 3-week (q3w) cycle. Trastuzumab was administered intravenously, as an accelerated loading dose regimen, on Cycle 1, Day 2 and Cycle 1, Day 8, and then on Day 1 of each subsequent q3w cycle. ECG assessments were performed pre- and posttrastuzumab infusion in the first two cycles. Fridericia’s correction was applied to QT intervals (QTcF). Baseline-adjusted QTcF intervals (the change from baseline) and their 90 % confidence intervals (CIs) were calculated.ResultsThe study enrolled 59 patients. At all time points, the 90 % CI upper bound for the mean baseline-adjusted QTcF was <10 ms. At steady-state serum trastuzumab concentrations, the mean baseline-adjusted QTcF interval was −8.4 ms (90 % CI −11.1, −5.7). No patient exhibited an absolute QTcF interval of >480 ms. No relationship was observed between trastuzumab concentration and baseline-adjusted QTcF interval. At data cutoff, 84.5 % of patients had experienced grade ≥3 adverse events, the most common of which were hematologic and as expected. Left ventricular ejection fraction remained ≥45 % in all patients during the study.ConclusionsThe results suggest that trastuzumab had no clinically relevant effect on QTcF interval. The safety profile of trastuzumab in combination with carboplatin and docetaxel was consistent with the known safety profile of this combination.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-014-2603-9) contains supplementary material, which is available to authorized users.
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