Charles Oo / ASCPT March 06 1 Repeated evaluation of the measured urinary creatinine clearance (CrCL), the predicted creatinine clearance based on Cockcroft-Gault equation (CG-CrCL) and the predicted glomerular filtration rate based on the Modification of Diet in Renal Disease Study (GRF MDRD) in elderly subjects Charles Oo, PharmD, PhD, FCP, Ya-Chi Chen, PharmD, Kahori Shimizu, Thomas Zimmerman, MD, Daiichi Asubio Pharmaceuticals, Rochelle Park, NJ. American Society of Clinical Pharmacology and Therapeutics 107 th Annual Meeting, Bartimore, Maryland Session OI-B-3; Thursday, March 9, 2-3PM

Charles Oo / ASCPT March 06 2 BACKGROUND/AIM oGlomerular filtration rate (GFR) declines with age in elderly individuals, while serum creatinine may be normal due to a simultaneous decline in muscle mass. oA variety of mathematical equations incorporating age as an important variable have been used to predict GFR, since gold standards (eg inulin or isotopic method) are cumbersome to performed. oTo evaluate the renal function of healthy elderly subjects participated in a 24- h drug infusion with a 72-hour pharmacokinetic sampling study. oFour methods of GFR estimated based on endogenous creatinine clearance are used.

Charles Oo / ASCPT March 06 3 METHOD Thirty-one male (13) and female (18) healthy elderly subjects (all Caucasians, except 1 African American, and 1 Asian), with a mean age of 62 year; range year) were admitted to a clinical research unit for 4 days for a 24-h drug infusion study with a 72-h pharmacokinetic sampling. Serum creatinine, BUN and albumin were measured on 6 occasions: screening (>-24h), 0h (prior to dosing), 24 h, 48h and 72 after dosing, and at 2 week follow-up Urinary creatinine (uCrCL) was calculated from the 24-h urinary collection at 3 time intervals: -24 to 0 h, 0 to 24h and 48 to 72h. For each interval, measured uCrCL was calculated: Where Ucr = urinary creatinine concentration (mg/dL); Uvol = urine volume (mL); Pcr = mean plasma creatinine concentration at beginning & end of the collection interval (mg/dL); Tmin =duration of urine collection (minutes)=480

Charles Oo / ASCPT March 06 4 METHOD (cont.) Cockcroft Gault-Creatinine Clearance (CG-CrCL): CG-CrCL were normalized to 1.73 per m2 body surface area. Body surface areas was calculated by the Monsteller formula: Glomerular filtration rate was predicted by the Modification of Diet in Renal Disease (MDRD) study’s 6-variable formula (MDRD1), and 4-variable formula (MDRD2). The formula automatically estimates BSA indexed GFR Where Scr = serum creationine (mg/dL); Su = serum urea level (mg/dL); Alb = serum albumin level g/dL); age in years; weight in kg; height in cm

Charles Oo / ASCPT March 06 5 Figure 1: Plot of GFR MDRD1 vs. GFR MDRD2

Charles Oo / ASCPT March 06 6 Figure 2: Plot of GFR MDRD2 vs. Cockroft Gault Creatinine Clearance

Charles Oo / ASCPT March 06 7 Figure 3: Mean Renal Clearances (+/-SD) for CG-CrCL, 24-h uCrCL and GFR MDRD2

Charles Oo / ASCPT March 06 8 Table 1: Mean CG-CrCL, measured uCrCL, and GFR-MDRD1 and MDRD2 values (±SD)

Charles Oo / ASCPT March 06 9 RESULT (cont.) GFR MDRD1 values had high correlation with GFR MDRD2 values (R 2 =0.9463; Fig 1), suggesting that the addition of 2 variables were not needed for these subjects with near normal renal function CG-CrCL values correlated well with the GFR MDRD2 (R 2 =0.4427; Fig 2), and were consistent with the literature GFR of ~80 mL/min of subjects aged years. However, MDRD2 could be a useful method: smaller SD (Table 1) and smaller range of Clearance (Fig 2) consistent with the renal function in elderly subjects. The 24-h urinary creatinine clearance (uCrCL) over-predicted the GFR (Table 1). The reason for the over-prediction is unknown, and could not be adequately explained by higher renal tubular secretion of creatinine Urine outputs were higher by 20% for the 0 to 24h and 48 to 72h intervals vs. on the first day of admission at -24 to 0h. Subsequently, CG-CrCL GFR MDRD and uCrCL were higher for those from 0 to24h and 48 to 72 h, by about mL/min. Renal clearance was elevated in the presence of higher hydration, after the subjects had settled down in the clinical research unit, and during and after the 24-h drug infusion

Charles Oo / ASCPT March CONCLUSIONS oCreatinine Clearance (CrCL) predicted by the Cockcroft-Gault equation was consistent with the GFR predicted by MDRD methods and GFR reported in the literature for the elderly subjects. Therefore, both methods could be used to predict the renal function of healthy elderly subjects. oMeasured 24-h urinary creatinine clearance (uCrCL) over-predicted the GFR reported in the literature for the elderly subjects. The result suggests limited utility for the 24-h urinary collection to predict GFR oHigher hydration status contributed to higher renal clearance

Charles Oo / ASCPT March REFERENCES Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. An Int Med 130: , 1999 Manjunath G, Sarnak M, Levey AS. Estimating the glomerular filtration rate. Dos and don’ts for assessing kidney function. Postgraduate Med. 110 (6), Oo C, Liu B and Hill G. “Change in creatinine clearance with advancing age”. J Am Geriatr Society, 50(9): , September 2002.

Charles Oo / ASCPT March BACK-UP SLIDE Reference values for GFR (mL/min/1.73 m2) by age and sex (Manjunath G, Postgraduate Med 2001)