Pharmacokinetics and Renal Tissue Distribution of Erlotinib in a Rat Model of Autosomal Dominant Polycystic Kidney Disease(Pages 16-24)

Cinthia V. Pastuskovas1, Hope Goldman2, Noel Dybdal3 and Bert L. Lum4

1Department of Preclinical and Translational Pharmacokinetics; 2Department of Angiogenesis and Tumor Biology; 3Department of Safety Assessment and Pathology; 4Department of Clinical Pharmacology, Genentech Inc., South San Francisco, CA, 94080, USA


Abstract: Background: Polycystic kidney disease (PKD) is a common hereditary disorder with an incidence of 1:700 to 1:1000 for the autosomal dominant polycystic kidney disease (ADPKD) and 1:10,000 for the autosomal recessive (ARPKD) forms. The epithelial growth factor (EGFR) axis may play a role in both forms by promoting epithelial cell proliferation and cyst formation.

Objectives: To characterize the plasma and tissue pharmacokinetics (PK), and cellular distribution of the oral EGFR inhibitor, erlotinib, in the Hanover-Sprague Dawley (Han:SPRD) heterozygote rat model of ADPKD to support preclinical development strategies.

Methods: Twenty-one Han:SPRD heterozygous male rats were administered a single erlotinib dose of 15 mg/kg with concentrations erlotinib and its’ major metabolite, OSI-420 determined in plasma and tissues using LC-MS/MS. To assess cellular distribution, microautoradiography was performed following a single oral dose of [14C] erlotinib (15 mg/kg, ~200 µCi/kg).

Results: Following dosing, erlotinib readily appeared in plasma and distributed into the renal tissue and PKD cysts at concentrations that were approximately 1.5-fold higher than the plasma compartment. Cellular distribution studies demonstrated that radioactivity associated with erlotinib was localized into the cyst lumen of the Han:SPRD rat model. The observed plasma concentrations are consistent with those observed in cancer patients.

Conclusion: Oral erlotinib in the Han:SPRD rat model demonstrated measurable concentrations in plasma and preferential distribution into renal tissue and cysts, suggesting a potential role in the treatment of PKD and further supports additional nonclinical studies including PK, target modulation, and PK/PD modeling to define the dose and schedules for clinical development in PKD.

Keywords: Erlotinib, pharmacokinetics, distribution, polycystic kidney disease, EGFR inhibition, Han:SPRD Rat, tissue pharmacokinetics, microradiography.