Effect of Renal Insufficiency on the Pharmacokinetics of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor
- Arthur J. Bergman, PHD1,
- Josee Cote, BS1,
- Bingming Yi, PHD1,
- Thomas Marbury, MD2,
- Suzanne K. Swan, MD3,
- William Smith, MD4,
- Keith Gottesdiener, MD1,
- John Wagner, MD, PHD1 and
- Gary A. Herman, MD, PHD1
- 1Merck Research Laboratories, West Point, Pennsylvania
- 2Orlando Clinical Research Center, Orlando, Florida
- 3DaVita Clinical Research, Hennepin County Medical Center, Minneapolis, Minnesota
- 4New Orleans Center for Clinical Research, Knoxville, Tennessee
- Address correspondence and reprint requests to Dr. Arthur Bergman, Merck Research Laboratories, P.O. Box 4, WP75B-100, West Point, PA 19486. E-mail: arthur_bergman{at}merck.com
- AUC0–∞, area under the sitagliptin plasma concentration curve from time zero to infinity
- ESRD, end-stage renal disease
- RI, renal insufficiency
Sitagliptin is an oral, once-daily, potent, and highly selective dipeptidyl peptidase–4 inhibitor for the treatment of type 2 diabetes (1). In subjects with normal renal function (creatinine clearance >80 ml/min), 75–80% of an oral dose was excreted unchanged in urine. Renal clearance was ∼350 ml/min, indicating that active secretion of sitagliptin rather than only filtration is involved in renal excretion. Thus, renal excretion is the primary mechanism of elimination for sitagliptin (2). The purpose of this study was to evaluate the pharmacokinetics of single doses of sitagliptin in patients with various degrees of renal insufficiency (RI).
RESEARCH DESIGN AND METHODS—
This was an open-label, two-part study in 30 otherwise healthy male and female subjects (18–75 years of age) with BMI ≤40 kg/m2. Subjects were assigned to one of five groups (n = 6/group), based on the following criterion for degree of RI: mild (creatinine clearance 50–80 ml/min), moderate (30–50 ml/min), severe (<30 ml/min), end-stage renal disease (ESRD) on hemodialysis, and normal (>80 ml/min). Healthy subjects (n = 145) from 11 other studies were included in a historical control group to supplement those studied here. Creatinine clearance values were based on measured 24-h urinary creatinine excretion (this study) or calculated using the Cockroft-Gault formula (historical controls). Because sitagliptin plasma concentrations were expected to increase with RI, a 50-mg dose was expected to be well …
