Effects of Renal Impairment on the Pharmacokinetics of the Dual GIP and GLP-1 Receptor Agonist Tirzepatide

Abstract

Background and AimsThe pharmacokinetics (PK) and single-dose tolerability of tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist being developed for once-weekly treatment of type 2 diabetes (T2D), weight management, and nonalcoholic steatohepatitis, was evaluated in subjects with renal impairment versus healthy subjects with normal renal function. Methods Forty-five subjects, categorized by baseline renal status, i.e. mild (n = 8, estimated glomerular filtration rate [eGFR] 60-89 mL/min/1.73m 2 ), moderate (n = 8, eGFR 30-59 mL/min/1.73m 2 ), severe renal impairment (n = 7, eGFR < 30 mL/min/1.73m 2 ), end-stage renal disease requiring dialysis (n = 8), and normal renal function (n = 14, eGFR ≥ 90 mL/min/1.73m 2 ), received a single subcutaneous dose of tirzepatide 5 mg. Tirzepatide plasma concentrations up to 648 h postdose were measured to compute PK parameters. The primary analysis evaluated the ratios of area under the plasma concentration-time curves (AUCs) and maximum plasma drug concentration (C max ) of renal impairment versus the normal renal function group (90% confidence interval [CI]). In addition, the relationship between PK parameters and continuous variables of renal function was assessed by linear regression. Results Tirzepatide exposure was similar across renal impairment groups and healthy subjects. The 90% CI of ratios of AUCs and C max comparing each renal impairment group versus normal renal function spanned unity, except for a 25-29% increase in AUCs in the moderate renal impairment group. There was no significant relationship between tirzepatide exposure and eGFR. Few adverse events were reported across the renal impairment and normal renal function groups. The majority were mild in severity and of a gastrointestinal nature in the renal impairment groups. Conclusion There were no clinically relevant effects of renal impairment on tirzepatide PK. Dose adjustment may not be required for patients with renal impairment. Clinical Trial Registration ClinicalTrials.gov NCT03482024.

Tirzepatide — a dual GIP/GLP-1 receptor agonist — a new antidiabetic drug with potential metabolic activity in the treatment of type 2 diabetes

“…Urva et al [62] reported the PK and tolerability of TZP in patients with or without T2DM and various degrees of renal impairment compared to healthy subjects. Forty-five subjects (30 men and 15 women) aged 40 to 84 years, with BMI ≥ 19.0 and ≤ 40.0 kg/m 2 , were included in the study.…”

A Novel Dual Incretin Agent, Tirzepatide (LY3298176), for the treatment of Type 2 Diabetes Mellitus and Cardiometabolic Health

“…Both Cmax and AUC0-inf of tirzepatide exhibit dose proportional pharmacokinetics, and neither hepatic nor renal insufficiency significantly changes Cmax, AUC, or half-life. [7][8][9] Incretin Effect Incretin hormone receptors make effective targets for drug therapy in T2DM because they account for over 50% of the insulin secreted in response to oral glucose. 10 It is now realized that GIP has the strongest insulinotropic actions of the incretin hormones and has little to no activity when diabetes develops.…”

“…Both Cmax and AUC0-inf of tirzepatide exhibit dose proportional pharmacokinetics, and neither hepatic nor renal insufficiency significantly changes Cmax, AUC, or half-life. 7–9…”

Tirzepatide: A Useful Addition for Treatment of Type 2 Diabetes and Obesity

“…Second, patients with chronic kidney disease (CKD) with estimated glomerular filtration rate (eGFR) below 45 ml/min/1.73 m 2 were excluded from these trials [5,6]. One study by Urva et al [18] has shown that renal impairment including need for hemodialysis has no clinically relevant effects on pharmacokinetics of tirzepatide. However, the latter investigation was a single-dose study that used tirzepatide in a small dose of 5 mg [18].…”

“…One study by Urva et al [18] has shown that renal impairment including need for hemodialysis has no clinically relevant effects on pharmacokinetics of tirzepatide. However, the latter investigation was a single-dose study that used tirzepatide in a small dose of 5 mg [18]. Third, patients with diabetic maculopathy and proliferative retinopathy and HbA1c levels > 10.5% were also excluded.…”