Renal Impairment Has No Impact on the Clinical Pharmacokinetics of Tirzepatide

Background and aims Tirzepatide, is being developed as potential weekly treatment for T2DM, weight management, and nonalcoholic steatohepatitis. This study evaluated pharmacokinetics (PK) and tolerability of tirzepatide in subjects with renal impairment (with or without T2DM) vs healthy subjects with normal renal function.

Materials and methods Subjects were categorised by renal impairment defined by baseline eGFR (MDRD equation): 14 normal renal function (≥ 90mL / min/1.73m2), 8 mild impairment (60-89mL/min/1.73m2), 8 moderate impairment (30-59mL/min/1.73m2), 7 severe impairment (< 30mL / min/1.73m2), and 8 end stage renal disease (ESRD) requiring dialysis. All subjects received a single subcutaneous tirzepatide dose of 5 mg. Blood samples were collected to determine tirzepatide 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. Relationship between PK parameters and eGFR (MDRD and CKD-EPI) and creatinine clearance (Cockcroft-Gault) was assessed by regression analysis.

Results 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 PK parameters for mild, moderate, and ESRD groups vs healthy subjects were observed. 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.

Conclusion There were no clinically relevant effects of renal impairment on tirzepatide PK. Thus, patients with renal impairment treated with tirzepatide may not require dose adjustments.

Publication History

Article published online:
06 May 2021