Model-informed Evidence for Clinical Non-inferiority of Every-2-Weeks Versus Standard Weekly Dosing Schedule of Cetuximab in Metastatic Colorectal Cancer.

Cetuximab was initially developed and approved as a first-line treatment in patients with unresectable metastatic colorectal cancer (mCRC) for weekly administration (250 mg/m Q1W with 400 mg/m loading dose). An every-2-weeks schedule (500 mg/m Q2W) was approved recently by several health authorities. Being synchronized with chemotherapy, Q2W administration should improve patients' convenience and healthcare resource utilization.

Application of physiologically based biopharmaceutics modeling to understand the impact of dissolution differences on in vivo performance of immediate release products: The case of bisoprolol.

Merck KGaA observed slight differences in the dissolution of Concor (bisoprolol) batches over the years. The purpose of this work was to assess the impact of in vitro dissolution on the simulated pharmacokinetics of bisoprolol using in vitro-in vivo relationship established with available in vitro dissolution and corresponding plasma concentrations-time data for several bisoprolol batches. A mechanistic absorption model/physiologically based pharmacokinetics model linked with a biopharmaceutics tool such as dissolution testing, namely, physiologically based biopharmaceutics modeling (PBBM), can be valuable in determining a dissolution "safe space.

Semimechanistic Clearance Models of Oncology Biotherapeutics and Impact of Study Design: Cetuximab as a Case Study.

This study aimed to explore the currently competing and new semimechanistic clearance models for monoclonal antibodies and the impact of clearance model misspecification on exposure metrics under different study designs exemplified for cetuximab. Six clearance models were investigated under four different study designs (sampling density and single/multiple-dose levels) using a rich data set from two cetuximab clinical trials (226 patients with metastatic colorectal cancer) and using the nonlinear mixed-effects modeling approach. A two-compartment model with parallel Michaelis-Menten and time-decreasing linear clearance adequately described the data, the latter being related to post-treatment response.

Nonclinical safety, pharmacokinetics, and pharmacodynamics of atacicept.

Atacicept, a soluble recombinant fusion protein of the human immunoglobulin (Ig) G(1) Fc and the extracellular domain of the human transmembrane activator and calcium modulator and cyclophylin ligand interactor receptor, acts as an antagonist of both B lymphocyte stimulator and a proliferating-inducing ligand. Here we determined the nonclinical safety, pharmacokinetics and pharmacodynamics of atacicept in mice and cynomolgus monkeys. Subcutaneous atacicept treatment (twice weekly in cynomolgus monkeys, three times weekly in mice) was generally safe and well tolerated safe and well tolerated with dosing up to 10 mg/kg every other day for up to 39 weeks or up to 80 mg/kg when dosed for 4 weeks.

Pharmacokinetics of IL-18 binding protein in healthy volunteers and subjects with rheumatoid arthritis or plaque psoriasis.

IL-18 binding protein (BP) neutralizes the activity of IL-18, a cytokine implicated in psoriasis and rheumatoid arthritis (RA). We investigated the pharmacokinetics, pharmacodynamics and safety of recombinant human IL-18 BP (r-hIL-18 BP) in healthy volunteers and subjects with psoriasis or RA in four phase I studies. A) Healthy volunteers (n = 24) were randomised to receive a single subcutaneous (sc) injection of r-hIL-18 BP (20, 70, 210 or 350 mg) or placebo.