Evaluation of the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (C-G) formulas in the Calvert equation for Carboplatin Dosing Whitney Jones, PharmD Candidate1; LeAnn B. Norris, PharmD, BCPS2; P. Brandon Bookstaver, PharmD, BCPS2; Richard Schulz, PhD2 1University of South Carolina College of Pharmacy, Columbia, SC; 2South Carolina College of Pharmacy, USC Campus, Columbia, SC

Background Carboplatin is a second generation platinum agent Used in the treatment of NSCLC 70% is excreted in the urine The Calvert equation Carboplatin dose = AUC (GFR+25) Standard method for carboplatin dose calculation1,2 Correlation between renal clearance and glomerular filtration rate (GFR)3,4 1Calvert AH, et al. Clin Oncol 1989;7:1748-56. 2Duffull SB, et al. Clin Pharmacokinet 1997; 33(3): 161-83. 3Calvert AH, et al. Cancer Chemother Pharmacol 1982; 9: 140-7. 4Herrington JD, et al. Cancer Chemother Pharmacol 2006;57:241-7.

Background C-G equation (original) Commonly used in the Calvert formula Inaccuracies in carboplatin dosing5 MDRD equation More accurate than the C-G equation (GFR < 60 ml/min) Sparse data is available in cancer patients and drug dosing6 Modified C-G (mC-G) equation Greater accuracy with CrCl < 50 mL/min and BMI < 257 Improves upon bias and precision of C-G equation8 5Ando Y, et al. Br J Cancer 1997;76:1067. 6Wright JG, et al. Br J Cancer 2001;84(4):452-9. 7Shoker A, et al. Clin Nephrol 2006;66(2):89-97. 8Rostoker G, et al. J Nephrol 2007;20:576-85.

Renal Clearance Equations Original C-G (C-G), ml/min CrCl = (140-age) x IBW / SCr x 72 (0.85 female) 6-variable MDRD formula, ml/min GFR/1.73m2 = 170 x (SCr -0.999) x (Age -0.176) x (0.762 female) x (1.180 A.A.) x (BUN -0.170) x (Alb.318) Modified C-G (mC-G), ml/min CrCl/1.73m2 = (140-age) x TBW / SCr x 72 (0.85 female)

Study Objective To determine whether a significant difference exists in comparison of renal function and carboplatin dosing using the original C-G, mC-G, and 6-variable MDRD formulas in a population of patients treated for non-small cell lung cancer.

Methods Retrospective, non-interventional study Conducted at a Veterans Administration Hospital (Columbia, SC) Inclusion Criteria: Age > 18 years Completion of at least one dose of carboplatin Exclusion Criteria: Any diagnosis other than NSCLC Albumin measurement > 1 month from first carboplatin dose Patients were not duplicated in this study

Endpoints Primary endpoints: Difference in estimate renal function (CrCl or GFR) between 3 study formulas Difference in calculated carboplatin doses using renal function estimates of 3 study formulas

Analysis Paired Student t tests were performed Intra-patient variability measured as clinical significance, defined as ≥ 20% difference Accuracy defined as +/- 30% difference in renal estimation (compared to C-G)

Results Table 1 Demographics n = 128 Gender Male 125 Female 3 Race Non-African American 79 African American 49 Characteristic Mean (+/-SD) Age, years 62.99 +/- 9.12 TBW, kg 78.88 +/- 20.93 BSA, m2 1.96 +/- 0.28 SCr, mg/dL 1 +/- 0.30 Albumin, g/dL 3.2 +/- 0.55

Results Evaluation of Carboplatin Clearance Calculations Mean Diff SD 95% CI P-value C-G v. mC-G 5.83 12.58 3.63 – 8.03 <0.001 C-G v. MDRD 4.73 24.13 0.511 – 8.95 0.028 mC-G v. MDRD -1.09 25.91 -5.63 – 3.44 0.634 Evaluation of Carboplatin Dose Calculations Mean Diff. SD 95% CI P-value C-G v. mC-G 6.05 109.6 -13.12 – 25.22 0.533 C-G v. MDRD 7.64 183.46 -24.45 – 39.73 0.648 mC-G v. MDRD 1.59 131.79 -21.47 – 24.64 0.892

Clinical Significance and Accuracy Discordance in 14.84% of doses when comparing C-G to mC-G Discordance in 46.09% of doses when comparing C-G to MDRD Accuracy (30%) of Renal Estimations Number % Achievement C-G vs. mC-G 3 3.13 C-G vs. MDRD 32 25

Discussion/Conclusions Differences exist between the C-G, mC-G, and 6-variable MDRD formulas Application of individual formulas could result in clinically significant carboplatin dosing modifications A prospective, controlled study would aid in determining the optimal formula for renal function estimations in carboplatin dosing Investigation of patient populations Correlation of carboplatin levels and renal function prediction

Evaluation of the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (C-G) formulas in the Calvert equation for Carboplatin Dosing Whitney Jones, PharmD Candidate1; LeAnn B. Norris, PharmD, BCPS2; P. Brandon Bookstaver, PharmD, BCPS2; Richard Schulz, PhD2 1University of South Carolina College of Pharmacy, Columbia, SC; 2South Carolina College of Pharmacy, USC Campus, Columbia, SC