The effect of excipients on pharmacokinetic parameters of parenteral drugs

In the pharmaceutical industry, the main goal of early phase in vivo studies is to assess pharmacokinetic properties of a compound in laboratory animals. These data provide a basis for selecting and optimizing drug candidates. However, formulation scientists face considerable challenges in finding intravenous preparations for first animal experiments. A common problem is the solubilization of lipophilic and sparingly water-soluble compounds. The search for suitable delivery vehicles often takes place under little compound availability, incomplete physicochemical property characterization, and time constraints. In addition, many experiments have recently generated distinct evidence about the impact of formulation vehicles on the drug pharmacokinetics by affecting transporters, metabolic enzymes, and distribution processes. Consequently, drug-excipient interactions are important to consider in the development of parenteral formulations intended for the proper evaluation of animal pharmacokinetics in vivo. Gaining a better understanding of potential interactions between drug and formulation in preclinical settings may play a crucial role in clinical and commercial phases of development as well. So far, little is known about drug-excipient interactions occurring in blood, especially following iv administration of low dosed compounds (<50 ng/mL in blood) including e.g. highly active drug substances, biomarkers, PET ligands, and microdoses. The purpose of the current work was to examine the potential of excipients commonly used in formulations to modify the blood distribution and protein binding of low dosed compounds under in vitro and in vivo conditions. Drug candidates in development at Novartis were used as model compounds and chosen based on different physicochemical and pharmacokinetic properties such as aqueous solubility (poor: COM1/COM2; good: COM3), lipophilicity (low: COM4; high: COM2), membrane permeability (low: COM5; high: COM3), and blood cell/plasma distribution (mainly in cells: COM3; mainly in plasma: COM4). Selected excipients comprised one cosolvent (polyethylene glycol 200, PEG 200), one complexing agent (hydroxypropylβ-cyclodextrin, HP-β-CyD), and three non-ionic surfactants (Cremophor EL, CEL; Solutol HS 15, Solutol; D-α-tocopheryl polyethylene glycol 1000 succinate, TPGS), most of them present in commercially available intravenous formulations. TPGS, which is used orally but not as an intravenous excipient, was chosen due to its chemical structure and intrinsic properties, particularly its benzyl ring and potential modulation of transporter/enzyme activities. Preliminary tests in vitro showed that selected excipients except for TPGS were non-hemolytic at 0.5% which is consistent with data reported in the literature. TPGS at 0.5% induced marked hemolysis after longer contact time (> 1h) in various species (mouse, rat, dog, and human), whereas TPGS at 0.1% showed no hemolysis under same conditions. Nevertheless, TPGS (0.5%) was used in the non-hemolytic time range for further investigations. The concentration of all excipients was set at 0.5% in test systems which is within the relevant range following intravenous dosing in animals.