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Evaluation of Renal Function Estimation in Carboplatin Dosing

This study evaluates the modification of the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (C-G) formulas in the Calvert equation for carboplatin dosing. The aim is to determine the accuracy and clinical significance of these formulas in a population of patients with non-small cell lung cancer.

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Evaluation of Renal Function Estimation in Carboplatin Dosing

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  1. 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 Evaluation of the Modification of Diet in Renal Disease (MDRD) and Cockcroft-Gault (C-G) formulas in the Calvert equation for Carboplatin Dosing

  2. Background • Carboplatinis 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.

  3. 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. BrJ 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.

  4. 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)

  5. 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.

  6. 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

  7. 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

  8. 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)

  9. 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, m21.96 +/- 0.28 SCr, mg/dL 1 +/- 0.30 Albumin, g/dL 3.2 +/- 0.55

  10. 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

  11. Clinical Significance and Accuracy • Clinical significance • 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

  12. 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

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