Development of a physiologically based pharmacokinetic model for intravenous lenalidomide in mice.

ABSTRACT

PURPOSE: Lenalidomide is used widely in B-cell malignancies for its immunomodulatory activity. It is primarily eliminated via the kidneys, with a significant proportion of renal elimination attributed to active processes. Lenalidomide is a weak substrate of P-glycoprotein (P-gp), though it is unclear whether P-gp is solely responsible for lenalidomide transport. This study aimed to determine whether the current knowledge of lenalidomide was sufficient to describe the pharmacokinetics of lenalidomide in multiple tissues. METHODS: A physiologically based pharmacokinetic model was developed using the Open Systems Pharmacology Suite to explore the pharmacokinetics of lenalidomide in a variety of tissues. Data were available for mice dosed intravenously at 0.5, 1.5, 5, and 10 mg/kg, with concentrations measured in plasma, brain, heart, kidney, liver, lung, muscle, and spleen. P-gp expression and activity were sourced from the literature. RESULTS: The model predictions in plasma, liver, and lung were representative of the observed data (median prediction error 13%, - 10%, and 30%, respectively, with 90% confidence intervals including zero), while other tissue predictions showed sufficient similarity to the observed data. Contrary to the data, model predictions for the brain showed no drug reaching brain tissue when P-gp was expressed at the blood-brain barrier. The data were better described by basolateral transporters at the intracellular wall. Local sensitivity analysis showed that transporter activity was the most sensitive parameter in these models for exposure. CONCLUSION: As P-gp transport at the blood-brain barrier did not explain the observed brain concentrations alone, there may be other transporters involved in lenalidomide disposition.