971-P: Renal Impairment Has No Impact on the Clinical Pharmacokinetics of Tirzepatide

Abstract

Novel dual GIP and GLP-1 receptor agonist, tirzepatide (TZP), is being developed as a potential weekly treatment for type 2 diabetes (T2DM), weight management and nonalcoholic steatohepatitis. This study evaluated the pharmacokinetics (PK) and tolerability of TZP in subjects with renal impairment (with or without T2DM) vs. healthy subjects with normal renal function. Subjects in this single-dose study were categorized by renal impairment defined by baseline estimated glomerular filtration rate (eGFR, MDRD equation): 14 with normal renal function (≥90 mL/min/1.73m2), 8 with mild impairment (60-89 mL/min/1.73m2), 8 with moderate impairment (30-59 mL/min/1.73m2), 7 with severe impairment (<30 mL/min/1.73m2) and 8 with end stage renal disease (ESRD) requiring dialysis. All subjects received a single subcutaneous dose of 5 mg TZP. Blood samples were collected to determine TZP plasma concentrations to estimate PK parameters. Adverse events were monitored to assess safety and tolerability. Log-transformed AUC0-∞, AUC0-tlast, and Cmax were evaluated by analysis of variance and 90% CI of the ratio between groups was estimated. Additionally, relationship between TZP PK parameters and eGFR (MDRD and CKD-EPI) and creatinine clearance (Cockcroft-Gault) was assessed by regression analysis. PK parameters were similar between subjects with severe renal impairment and healthy subjects (geometric LSM ratios [90% CI] of 1.03 [0.836, 1.27], 1.04 [0.841, 1.28] and 1.23 [0.966, 1.56] for AUC∞, AUC0-tlast, and Cmax, respectively). Similar results were observed when comparing the PK parameters of mild, moderate and ESRD groups vs. healthy subjects. There was no statistically significant relationship at the two-sided 10% significance level between exposure and eGFR. No notable differences in safety profiles were observed. There were no clinically relevant effects of renal impairment on TZP PK. Thus, patients with renal impairment treated with tirzepatide may not require dose adjustments. Disclosure S. Urva: None. T. Quinlan: None. J. Landry: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. J. Martin: Employee; Self; Eli Lilly and Company. C. Loghin: Employee; Self; Eli Lilly and Company. Funding Eli Lilly and Company