Towards understanding polyol additive effects on the pH shift-induced aggregation of a monoclonal antibody using high throughput screening and quantitative structure-activity modeling.

pH shift-induced aggregation is frequently observed in downstream processing of monoclonal antibodies and has been shown to depend on solvent composition. To quantify the stabilizing effect of polyol additives against aggregation, we determined aggregation rate constants in the presence of a set of 14 compounds. Rate constants were then correlated with molecular descriptors in a quantitative structure activity relationship (QSAR) approach.

Diversity selection, screening and quantitative structure-activity relationships of osmolyte-like additive effects on the thermal stability of a monoclonal antibody.

Solvents used for therapeutic proteins in downstream processing and in formulations often contain stabilizing additives that inhibit denaturation and aggregation. Such additives are mostly selected based on their positive effect on thermal stability of the protein, and are often derived from naturally occuring osmolytes. To better understand the structural basis underlying the effect of additives, we selected a diverse library of compounds comprising 79 compounds of the polyol, amino acid and methylamine chemical classes and determined the effect of each compound on thermal stability of a monoclonal antibody as a function of compound concentration.

Experimental Model System to Study pH Shift-Induced Aggregation of Monoclonal Antibodies Under Controlled Conditions.

Purpose: To present a convenient screening method for evaluating additive effects on the renaturation of an acid-exposed monoclonal antibody (mAb).

Methods: The assay involves brief incubation of a mAb at acidic pH and subsequent neutralization in the absence or presence of additive to induce mainly aggregation. An increase in absorbance depicted aggregation.

Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on Δ(9)-tetrahydrocannabinol challenge tests.

Aim: The severe psychiatric side effects of cannabinoid receptor type 1 (CB1 ) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of different CB1 antagonists in Δ(9) -tetrahydrocannabinol (THC) challenge tests in healthy volunteer were constructed.

Methods: The pharmacokinetic models of THC and four CB1 antagonists were built separately.

Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics.

Δ(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug.