Effect of renal impairment on the pharmacokinetics of exenatide

Abstract

What is already known about this subject • Nonclinical studies have shown that exenatide is primarily cleared by the renal system. • It was not known to what degree the clinical pharmacokinetics and tolerability would be affected by increasing renal impairment (RI). What this study adds • Patients with mild to moderate RI adequately tolerate current therapeutic doses of exenatide. • However, exenatide is not recommended in patients with severe RI or end‐stage renal disease. Aims To evaluate the pharmacokinetics (PK), safety and tolerability of a single exenatide dose in patients with renal impairment (RI). Methods Exenatide (5 or 10 µg) was injected subcutaneously in 31 subjects (one with Type 2 diabetes) stratified by renal function [Cockcroft–Gault creatinine clearance (CrCL), number of subjects]: normal (>80 ml min−1, n = 8), mild RI (51–80 ml min−1, n = 8), moderate RI (31–50 ml min−1, n = 7) or end‐stage renal disease (ESRD) requiring haemodialysis (n = 8). PK data were combined with four previous single‐dose studies in patients with Type 2 diabetes to explore the relationship of exenatide clearance (CLp/F) and CrCL. Results Mean half‐life for healthy, mild RI, moderate RI and ESRD groups were 1.5, 2.1, 3.2 and 6.0 h, respectively. After combining data from multiple studies, least squares geometric means for CLp/F in subjects with normal renal function, mild RI, moderate RI and ESRD were 8.14, 5.19, 7.11 and 1.3 l h−1, respectively. Exenatide was generally well tolerated in the mild and moderate RI groups, but not in subjects with ESRD due to nausea and vomiting. Simulations of exenatide plasma concentrations also suggest patients with ESRD should have a propensity for poor tolerability at the lowest available therapeutic dosage (5 µg q.d.). Conclusions Since tolerability and PK changes were considered clinically acceptable in patients with mild to moderate RI, it would be appropriate to administer exenatide to these patients without dosage adjustment. However, poor tolerability and significant changes in PK make the currently available therapeutic doses (5 and 10 µg) unsuitable in severe RI or ESRD.

Effect of renal impairment on the pharmacokinetics of the GLP‐1 analogue liraglutide

“…Poor tolerability and significant changes in the pharmacokinetics of a newer antidiabetic product, the incretin mimetic exenatide (exendin-4), would argue against use of the available therapeutic doses of that drug in subjects with significant renal impairment, and exenatide is not recommended for use by patients with severe renal impairment or ESRD [12,13].…”

“…As a result, metformin is contraindicated in patients with renal dysfunction [8], acarbose is not recommended for use in such patients [11], and conservative dosing of sulphonylureas is recommended [9,10]. Exenatide (exendin-4), an incretin mimetic, shows significant changes in pharmacokinetics in renal dysfunction and is not recommended for use by patients with severe renal impairment or end-stage renal disease (ESRD) [12,13].…”

Rationale and design of the EXenatide Study of Cardiovascular Event Lowering (EXSCEL) trial

“…23 During the trial, patients with 2 successive values below this eGFR threshold will be discontinued from study medication. If a usual care annual creatinine value is not available, it will be measured by the site to support patient safety.…”

“…As once-weekly exenatide is cleared by renal filtration and subsequent tubule degradation, 23 patients with an eGFR <30 mL/min/1.73 m 2 will be excluded and study medication discontinued in those whose eGFR falls below this value on 2 successive measurements.…”

Incretin Mimetics and DPP-IV Inhibitors: New Paradigms for the Treatment of Type 2 Diabetes

“…Pharmacological studies indicate that exenatide dosing is not recommended during the postprandial period, 49 and exenatide administration is not suitable for patients with severe renal impairment (creatinine clearance Ͻ30 mL/min) or end-stage renal disease. 50 However, exenatide dosage adjustments are not required when used concomitantly with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (lovastatin), digoxin, angiotensinconverting enzyme (ACE) inhibitors (lisinopril), or the anticoagulant warfarin.…”