Renal Changes Associated with Naproxen Sodium Administration in Cynomolgus Monkeys

Abstract

Naproxen sodium was administered to cynomolgus monkeys (Macaca fascicularis) by oral gavage at daily doses of 44, 88, or 176 mg/kg for 2 wk (2 monkeys/gender) or of 44 mg/kg for 13 wk (4 monkeys/gender). Body weight loss occurred in at least one monkey in all naproxen sodium-dosed groups in the 2-wk (up to 16% loss) and 13-wk (up to 22% loss) studies. Increases in plasma naproxen concentrations were dose proportional between 44 and 88 mg/kg but were less than dose proportional between 88 and 176 mg/kg. Up to 2-fold increases in creatinine and/or serum urea nitrogen values as well as higher renal weights occurred in monkeys receiving 176 mg/kg for 2 wk or 44 mg/kg for 13 wk. Microscopically, renal changes were observed in all naproxen sodium-dosed groups. Renal findings after 2 wk of exposure included increased interstitial ground substance, tubular dilatation, and tubulointerstitial nephritis; in the 13-wk study, cortical tubular atrophy and interstitial fibrosis were also observed. These studies identify the kidney as the target organ of naproxen sodium in cynomolgus monkeys.

Evaluation of 10 Urinary Biomarkers for Renal Safety With 5 Nephrotoxicants in Nonhuman Primates

“…27 Urine volume output did not show any consistent trends. It was concluded previously with naproxen in cynomolgus 25 that the azotemia seen in their study was likely renal in origin. The increases in biomarkers, namely, clusterin, KIM-1, and OPN, indicate intrarenal injury, but it is possible that the BUN/SCr increases indicate combination of both prerenal and intrarenal injury.…”

“…Very similar histopathological observations were reported previously in NHP, and although urinary biomarkers were not measured, SCr and BUN increases were noted. 25 Azotemia often accompanied by proteinuria is reported clinically as well. 26 Interestingly, while BUN or SCr were increased in almost all samples at SD 3, their levels did not increase with time despite continued dosing and remained relatively flat, as did generally the measured urine biomarkers as well.…”

Interspecies Differences in the Nephrotoxic Response to Cyclooxygenase Inhibition

“…The interstitial cells of the renal papilla in the dog and rat have similar expression levels of COX-1 and COX-2, and may be the earliest targets of NSAID inhibition (Brix, 2002). While monkeys developed some renal lesions after treatment, these were attributable to the precipitation of the drug into the renal tubules, and have been previously described (Leach et al, 1999) and were not likely pharmacologically mediated.…”

“…However, all animals had evidence of obstructive nephropathy, presumably due to drug accumulation in the renal tubules. Studies by Leach et al, (1999) have demonstrated that this precipitate in the kidneys of monkeys dosed with naproxen is accumulated drug. Obstructive nephropathy was characterized by the accumulation of amphophilic homogeneous to granular material (drug product) in the renal tubules, tubular dilatation and chronic tubulo-interstitial inflammation (Figure 3).…”

Kidney Pathophysiology, Toxicology, and Drug-Induced Injury in Drug Development

“…12,[26][27][28] Thus, immune complex-mediated type 3 hypersensitivity reactions and ICD are relatively common in toxicology studies, especially with biotherapeutics after repeated dose administration to monkeys. 29 The reader is strongly encouraged to refer to comprehensive reviews on ICD pathophysiology, especially as it relates collective weight-of-evidence approach, time course of complement formation, and antidrug antibody (ADA) formation and its correlation with exposure in toxicity studies. Immune complex-mediated glomerular pathology related to immunogenicity in animals is generally not considered relevant for predicting immunogenicity in humans.…”