Drug disposition in glomerular kidney diseases

Abstract

Glomerular kidney diseases comprise a group of diseases that affect the glomerulus or filtration apparatus of the nephron. The dissertation is focused on drug disposition in two glomerular kidney diseases, namely systemic lupus erythematosus nephritis (SLEN) and membranous nephropathy (MN). Both diseases are characterized by excretion of large amounts of urinary proteins or proteinuria, and categorized as nephrotic conditions. The first work contained in the thesis evaluated the feasibility of developing a nano-delivery strategy for a small molecule tyrosine kinase inhibitor (imatinib mesylate), in order to enhance delivery to the kidneys in a mouse model of systemic lupus erythematosus nephritis. The second and third work in the thesis assessed the pharmacokinetics and pharmacodynamics of a monoclonal antibody therapeutic (rituximab) in patients with membranous nephropathy. For the first work (Chapter 2), imatinib mesylate was formulated into a nanoemulsion, with further evaluation of physicochemical characterization, viability assessments, and leakage assay. The formulation containing imatinib mesylate was injected into a mouse model of lupus nephritis (MRL-MpJ/faslpr mice) and pharmacokinetics, pharmacodynamics, and kidney quantification of imatinib mesylate were analyzed. We observed a three-fold higher deposition of ImM in the kidneys of mice treated with the nanoemulsion vs. naked drug dissolved in PBS. Pharmacokinetic and Pharmacodynamic parameters between the naked drug vs nanoemulsion were not significant. For the second work, a dataset from patients with membranous nephropathy who received rituximab was evaluated. For the initial chapter (Chapter 3), a compartmental pharmacokinetic analysis was performed. We observed that rituximab half-life was shorter, clearance was faster, the exposure and volume of distribution were lower in the membranous nephropathy patients as compared to two populations of patients without kidney disease and nephrotic syndrome. For the subsequent chapter (Chapter 4), nonlinear mixed effects (NLME) pharmacokinetic modeling was assessed with the effect of covariates in addition to a pharmacodynamic evaluation. A 2- compartment model with multiplicative error best fit the patient data. None of the assessed covariates (age, gender, body surface area, height, weight) improved the fit of the base model. A 50% reduction in urinary protein excretion was selected as the success outcome for the pharmacodynamic model. For the pharmacodynamic model, there was disconnect between the PK and PD time points and hence we could not get a good PD model that could describe our PD data. However, there was a trend towards success of remission with time after treatment. The thesis contributes to the paucity of literature surrounding the disposition of small molecule drugs and large molecule therapeutic antibodies in patients with glomerular kidney diseases. In addition, the imatinib nanoemulsion research demonstrated a promising strategy for enhancing renal deposition of drugs in the treatment of various kidney diseases. The results from this thesis can be used as a launching tool to refine treatments for patients with glomerular kidney diseases. The thesis also contributes towards the understanding of rituximab pharmacokinetics in a nephrotic disease patient population with membranous nephropathy.