Effect of renal impairment on the pharmacokinetics of exenatide.
OBJECTIVE
To evaluate the pharmacokinetics (PK), safety and tolerability of a single exenatide dose in patients with renal impairment (RI).


METHODS
Exenatide (5 or 10 microg) 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 microg 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 microg) unsuitable in severe RI or ESRD.
Linnebjerg
Helle
H
Eli Lilly and Co., Lilly Research Center, Windlesham, UK. linnebjerg_helle@lilly.com
Kothare
Prajakti A
PA
Park
Soomin
S
Mace
Kenneth
K
Reddy
Shobha
S
Mitchell
Malcolm
M
Lins
Robert
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D003404:Creatinine / Q000097:blood; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D004311:Double-Blind Method; D000077270:Exenatide; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010455:Peptides / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D016037:Single-Blind Method; D014688:Venoms / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D003404:Creatinine