Effect of Renal Insufficiency on the Pharmacokinetics of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor

doi:10.2337/dc06-2545

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Brief Report

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

¹ Merck Research Laboratories, West Point, Pennsylvania
² Orlando Clinical Research Center, Orlando, Florida
³ DaVita Clinical Research, Hennepin County Medical Center, Minneapolis, Minnesota
⁴ New 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

Abbreviations: AUC_0–, area under the sitagliptin plasma concentration curve from time zero to infinity • ESRD, end-stage renal disease • RI, renal insufficiency

INTRODUCTION

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INTRODUCTION
RESEARCH DESIGN AND METHODS--
RESULTS--
CONCLUSIONS--
References

Sitagliptin is an oral, once-daily, potent, and highly selectivedipeptidyl peptidase–4 inhibitor for the treatment oftype 2 diabetes (1). In subjects with normal renal function(creatinine clearance >80 ml/min), 75–80% of an oraldose was excreted unchanged in urine. Renal clearance was $~$ 350ml/min, indicating that active secretion of sitagliptin ratherthan only filtration is involved in renal excretion. Thus, renalexcretion is the primary mechanism of elimination for sitagliptin(2). The purpose of this study was to evaluate the pharmacokineticsof single doses of sitagliptin in patients with various degreesof renal insufficiency (RI).

RESEARCH DESIGN AND METHODS—

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INTRODUCTION
RESEARCH DESIGN AND METHODS--
RESULTS--
CONCLUSIONS--
References

This was an open-label, two-part study in 30 otherwise healthymale 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 (30–50ml/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 historicalcontrol group to supplement those studied here. Creatinine clearancevalues were based on measured 24-h urinary creatinine excretion(this study) or calculated using the Cockroft-Gault formula(historical controls). Because sitagliptin plasma concentrationswere expected to increase with RI, a 50-mg dose was expectedto be well tolerated in the event of substantial increases indrug concentrations. All subjects provided written informedconsent. The protocol was approved by investigational reviewboards and carried out in accordance with the principles ofthe Declaration of Helsinki.

In Part I, 18 patients with mild to severe RI and 6 healthyconcurrent control subjects received a single 50-mg dose ofsitagliptin followed by 96 h of plasma sampling and 48 h forurine collection for sitagliptin concentrations. During period1 of Part II, patients with ESRD requiring hemodialysis receiveda single 50-mg dose of sitagliptin 48 h before their normallyscheduled hemodialysis session. Following period 1 and at leasta 1-week wash off, the same ESRD patients received a single50-mg sitagliptin dose 4 h before their hemodialysis sessionto quantify the amount of sitagliptin removed by dialysis. Plasmaand dialysate samples were collected at prespecified times upto 96 h following dosing.

Pharmacokinetic analysis
Sitagliptin was measured in plasma, urine, and dialysate samplesby mass spectrometry detection following specialized high-performanceliquid chromatography with an internal standard (3). Calculationsfor pharmacokinetic parameters were completed, according toestablished methods (4,5). The area under the sitagliptin plasmaconcentration curve from time 0 extrapolated to infinity (AUC_0–)was considered the most relevant pharmacokinetic parameter becauseit provides an estimate of the plasma drug exposure at steadystate.

Safety
Safety and tolerability were assessed from adverse experiencesand measurements of vital signs, 12-lead electrocardiograms,and laboratory safety parameters. Adverse experiences were evaluatedas to their intensity, seriousness, and relationship to studydrug.

Statistical analyses
Since sitagliptin AUC_0– had been shown to be dose proportionalfollowing single oral doses from 25 to 800 mg (2,5), AUC_0- valuesfor healthy subjects from clinical studies were adjusted basedon a 50-mg dose. Additionally, because these results were similarto the six concurrent controls, these data were pooled for theanalysis. Historical data for other pharmacokinetic parameterswere limited to those from a 50-mg dose group (Table 1). ANCOVAmodels containing creatinine clearance as a continuous or categoricalvariable and covariates of age, sex, and weight were both usedfor analysis of pharmacokinetic parameter data. Based on theapparent wide therapeutic index of sitagliptin (2,5,6), an increasein plasma sitagliptin exposure (i.e., AUC_0–) of less thantwofold was not considered clinically meaningful.

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Table 1— Summary statistics of sitagliptin pharmacokinetic parameters following administration of single oral doses of 50 mg sitagliptin in patients with varying degrees of renal function and healthy subjects with normal renal function

	RESULTS—

TOP INTRODUCTION RESEARCH DESIGN AND METHODS-- RESULTS-- CONCLUSIONS-- References

All patients completed the study. Using the continuous model,increases in sitagliptin AUC_0– were less than twofoldfor mild RI patients relative to the normal renal function controls(Table 1). From the categorical analysis, increases in sitagliptinAUC_0– were $~$ 2.3-fold higher for moderate RI patients. Increasesin sitagliptin AUC_0– were $~$ 3.8-fold higher for severe RI.Increases in sitagliptin AUC_0– were $~$ 4.5-fold higher forpatients with ESRD. C_max was moderately increased, and C₂₄ increasedas renal function decreased. T_max was significantly increasedin patients with ESRD, and the terminal t_1/2 increased withdecreasing renal function. Renal clearance of sitagliptin wasapproximately proportional to creatinine clearance.

The fraction of dose removed by dialysis was small with 13.5and 3.5% for hemodialysis initiated at 4 and 48 h postdose,respectively. Plasma protein binding was not altered in uremicplasma from the RI patients (median 36%, range 33–40%)as compared with that from concurrent control subjects (median37%, range 34–43%). Single doses of sitagliptin were welltolerated in this study.

CONCLUSIONS—

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INTRODUCTION
RESEARCH DESIGN AND METHODS--
RESULTS--
CONCLUSIONS--
References

Based on the present findings, sitagliptin dose adjustmentsare recommended for patients with moderate or severe RI or ESRDto provide plasma sitagliptin exposure comparable to patientswith normal renal function. The recommended sitagliptin dosageadjustments are as follows: no adjustment for patients withmild RI (creatinine clearance 50–80 ml/min), a twofolddecrease in the clinical dose of 100 mg q.d. (i.e., 50 mg q.d.)for patients with moderate RI (creatinine clearance 30–50ml/min) (approximate serum creatinine levels >1.7 and $≤$ 3.0mg/dl for men and >1.5 and $≤$ 2.5 mg/dl for women), and a fourfolddecrease in the clinical dose (25 mg q.d.) for patients withsevere RI (creatinine clearance <30 ml/min) or ESRD (approximateserum creatinine levels >3.0 mg/dl for men, >2.5 mg/dlfor women, or on dialysis). Moreover, since hemodialysis removedsitagliptin to a modest extent, sitagliptin can be administeredwithout respect to the timing of hemodialysis in patients withESRD.

Acknowledgments

The study was funded, in part, by Merck & Co., Inc.

The authors acknowledge the assistance of William Taggart, PhD,Merck Research Laboratories, Inc., for help in writing thismanuscript.

Footnotes

Published ahead of print at http://care.diabetesjournals.orgon 27 April 2007. DOI: 10.2337/dc06-2545. Clinical trial reg.no. NCT00418366, clinicaltrials.gov.

A.J.B., J.C., K.G., J.W., and G.A.H. are employees of and holdstock in Merk & Co., Inc. B.Y. is an employee of GlaxoSmithKlineand owns stock in GlaxoSmithKline and Merk & Co., Inc.

A table elsewhere in this issue shows conventional and SystèmeInternational (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in partby the payment of page charges. This article must thereforebe hereby marked "advertisement" in accordance with 18 U.S.CSection 1734 solely to indicate this fact.

Received for publication January 4, 2007. Accepted for publication April 2, 2007.

References

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INTRODUCTION
RESEARCH DESIGN AND METHODS--
RESULTS--
CONCLUSIONS--
References

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