Effects of Renal Impairment on the Pharmacokinetics of the Dual GIP and GLP-1 Receptor Agonist Tirzepatide.
The 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.
Forty-five subjects, categorized by baseline renal status, i.e. mild (n = 8, estimated glomerular filtration rate [eGFR] 60-89 mL/min/1.73m2), moderate (n = 8, eGFR 30-59 mL/min/1.73m2), severe renal impairment (n = 7, eGFR < 30 mL/min/1.73m2), end-stage renal disease requiring dialysis (n = 8), and normal renal function (n = 14, eGFR ≥ 90 mL/min/1.73m2), 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 (Cmax) 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.
Tirzepatide exposure was similar across renal impairment groups and healthy subjects. The 90% CI of ratios of AUCs and Cmax 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.
There were no clinically relevant effects of renal impairment on tirzepatide PK. Dose adjustment may not be required for patients with renal impairment.
ClinicalTrials.gov NCT03482024.
Urva S
，Quinlan T
，Landry J
，Martin J
，Loghin C
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Effects of Hepatic Impairment on the Pharmacokinetics of the Dual GIP and GLP-1 Receptor Agonist Tirzepatide.
Tirzepatide, a novel, once-weekly, dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, is approved in the US as a treatment for type 2 diabetes and is under development for long-term weight management, heart failure with preserved ejection fraction, and nonalcoholic steatohepatitis. This study evaluated the pharmacokinetics and tolerability of tirzepatide in participants with hepatic impairment (with or without type 2 diabetes) versus healthy participants with normal hepatic function.
Participants in this parallel, single-dose, open-label study were categorized by hepatic impairment defined by the baseline Child-Pugh (CP) score A (mild impairment; n = 6), B (moderate impairment; n = 6), or C (severe impairment; n = 7) or normal hepatic function (n = 13). All participants received a single subcutaneous 5-mg dose of tirzepatide. Blood samples were collected to determine tirzepatide plasma concentrations to estimate pharmacokinetic parameters. The primary pharmacokinetic parameters of area under the drug concentration-time curve from zero to infinity (AUC0-∞) and maximum observed drug concentration (Cmax) were evaluated using an analysis of covariance. The geometric least-squares means (LSM) and mean ratios for each group, between control and hepatic impairment levels, and the corresponding 90% confidence intervals (CIs) were estimated. The analysis of the time to maximum observed drug concentration was based on a nonparametric method. The relationships between the pharmacokinetic parameters and CP classification parameters (serum albumin level, total bilirubin level, and international normalized ratio) were also assessed. Adverse events were monitored to assess safety and tolerability.
Tirzepatide exposure, based on AUC0-∞ and Cmax, was similar across the control and hepatic impairment groups. Statistical analysis showed no difference in the geometric LSM AUC0-∞ or Cmax between participants in the control group and the hepatic impairment groups, with the 90% CI for the ratios of geometric LSM spanning unity (AUC0-∞ ratio of geometric LSM vs control [90% CI 1.08 [0.879, 1.32], 0.960 [0.790, 1.17], and 0.852 [0.699, 1.04] and Cmax ratio of geometric LSM vs control [90% CI]: 0.916 [0.726, 1.16], 1.00 [0.802, 1.25], and 0.972 [0.784, 1.21] for mild, moderate and severe hepatic impairment groups, respectively). There was no change in median time to Cmax of tirzepatide across all groups (time to Cmax median difference vs control [90% CI]: 0 [- 4.00, 12.00], 0 [- 12.00, 12.00], and 0 [- 11.83, 4.17], respectively). There was no significant relationship between the exposure of tirzepatide and the CP score (p > 0.1 for AUC0-∞, Cmax, and apparent total body clearance). Similarly, there was no clinically relevant relationship between the exposure of tirzepatide and serum albumin level, total bilirubin level, or international normalized ratio. The geometric LSM half-life values were also similar across the control and hepatic impairment groups. No notable differences in safety profiles were observed between participants with hepatic impairment and healthy control participants.
Tirzepatide pharmacokinetics was similar in participants with varying degrees of hepatic impairment compared with healthy participants. Thus, people with hepatic impairment treated with tirzepatide may not require dose adjustments.
ClinicalTrials.gov identifier number NCT03940742.
Urva S
，Quinlan T
，Landry J
，Ma X
，Martin JA
，Benson CT
... -
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Pharmacokinetics and Safety of Cotadutide, a GLP-1 and Glucagon Receptor Dual Agonist, in Individuals with Renal Impairment: A Single-Dose, Phase I, Bridging Study.
Cotadutide is a balanced glucagon-like peptide-1 and glucagon receptor dual agonist under development for the treatment of non-alcoholic steatohepatitis and type 2 diabetes with chronic kidney disease. We evaluated the pharmacokinetics (PK), safety and immunogenicity of a single dose of cotadutide in individuals with varying degrees of renal impairment.
In this phase I bridging study, individuals 18-85 years of age, with a body mass index of 17-40 kg/m2 and varying degrees of renal function {end-stage renal disease (ESRD; creatinine clearance [CrCl] < 20 mL/min); severe renal impairment (CrCl ≥ 20 to < 30 mL/min); lower moderate renal impairment (CrCl ≥ 30 to < 44 mL/min); upper moderate renal impairment (CrCl ≥ 45 to < 60 mL/min); normal renal function (CrCl ≥ 90 mL/min)} were treated with a single dose of subcutaneous cotadutide 100 µg under fasted conditions in the lower abdomen. The co-primary endpoints were area under the plasma concentration-time curve from time zero to 48 h (AUC48) and the maximum observed plasma concentration (Cmax) for cotadutide. Safety and immunogenicity were secondary endpoints. This trial is registered with ClinicalTrials.gov (NCT03235375).
A total of 37 individuals were enrolled in the study (only three enrolled in the ESRD group, therefore this group was excluded from the primary PK analysis). AUC48 and Cmax values for cotadutide were similar across all renal function groups {severe renal impairment vs. normal renal function: AUC48 geometric mean ratio (GMR) 0.99 (90% confidence interval [CI] 0.76-1.29); lower moderate renal impairment versus normal renal function: AUC48 GMR 1.01 (90% CI 0.79-1.30); upper moderate renal impairment versus normal renal function: AUC48 GMR 1.09 (90% CI 0.82-1.43)}. A sensitivity analysis that combined the ESRD and severe renal impairment groups did not show notable changes in the AUC48 and Cmax GMRs. The incidences of treatment-emergent adverse events (TEAE) ranged from 42.9 to 72.7% across all groups and were mostly mild to moderate in severity. Only one patient had a grade III or worse TEAE during the study period. No positive antidrug antibody results were observed.
These results suggest that the PK and tolerability of cotadutide are unaffected by renal function and that dose adjustments may not be required in individuals with renal impairment.
Klein G
，Petrone M
，Yang Y
，Hoang T
，Hazlett S
，Hansen L
，Flor A
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