Renal function vs chemotherapy dosing

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Ariel Phelps
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1 Renal function vs chemotherapy dosing Jenny Casanova Senior Clinical Pharmacist Repatriation General Hospital Daw Park 1

2 Methods of estimating renal function Cockcroft-Gault (1976) C-G using ideal vs actual body weight C-G using ideal body weight +30% Martin (1998) in cancer patients Wright (2001) for cancer patients over age 70 Jelliffe (2002) for unstable renal function MDRD (1999) CKI-EPI (2009) Use of Cystatin C (2012) +/- creatinine Method(s) of actually measuring glomerular filtration rate Nuclear Medicine Measurement Measures GFR based on clearance of radiolabelled chromium-51 EDTA or technetium-99 DTPA Some methods use a single sample, others use three samples Will be affected by recent administration of nephrotoxic agents including CT contrast 2

3 Creatinine clearance vs GFR Actual creatinine clearance test involves 24-hour urine collection Estimating clearance of creatinine is used as a surrogate marker for glomerular filtration rate While the Cockcroft-Gault equation is the most well-known and frequently-calculated estimates of GFR (via Creatinine Clearance), other calculators have recently gained attention as better estimates, like the MDRD & CKD-EPI. The latter have not been validated in acute renal failure, only patients with chronic kidney disease. MDRD & CKD-EPI are expressed relative to a standard body surface area of 1.73 m2 to allow for different body sizes. The units are ml/min/1.73m2. Creatinine clearance is still used as the standard for drug dosing, instead of GFR. Relevance of serum creatinine It is presumed/assumed that we make and remove creatinine at the same rate, and any changes in serum creatinine reflect changes in the kidneys ability to clear it Serum creatinine may be falsely elevated in: bodybuilders, high protein diet, creatine supplements, acute muscle injury Serum creatinine may be falsely low in: cachexia, muscle wasting disorders, paraplegia, amputees, vegetarian diet Some sites advise people not to eat any meat in the 12 hours before having a blood test for GFR estimation Trimethoprim can decrease ability to clear creatinine IDMS method results in lower serum creatinine than Jaffe 3

4 Cockcroft-Gault equation Cockcroft-Gault equation is often used as a method of estimating GFR (although it was developed as a method of predicting creatinine clearance) from knowledge of: - serum creatinine - age - weight Creatinine clearance = (((140 - age in years) x (wt in kg)) x 1.23) / (serum creatinine in micromol/l) x 0.85 if female Can be modified to reflect ideal body weight MDRD (Modification of Diet in Renal Disease) Uses 4 variables in its equation: - Age - Gender - Race (African-American; not validated in Aboriginals, Pacific Islanders or Chinese - Serum creatinine Looks at the rate of change in GFR to identify chronic kidney disease Was built solely with the purpose of staging renal disease population was mean age 52y, mean creatinine 203! In patients with near-normal kidney function, MDRD equations underestimate GFR. Results >60 ml/min/1.73m2 are likely to deviate from the true value and are not routinely reported. 4

5 CKD-EPI (Chronic Kidney Disease Epidemiology Uses the same variables as MDRD but in a different formula applies different coefficients A few studies suggest that the better estimation of GFR by the CKD-EPI equation is reflected in better clinical risk prediction than the MDRD equation; however, these studies included predominantly white people with higher levels of kidney function. CKD-EPI can also use Cystatin-C rather than Creatinine; its short half-life means that it is a more sensitive marker of changes in GFR Cystatin-C measurement not routinely done in Australia Formulae & tools exist which adjust CKD-EPI for BSA Pros & cons of various estimates Only C-G has been validated in general drug dosing Modified C-G (using IBW, but capping for low SeCr) underestimates renal function by about 8% but is consistent across all age ranges MDRD and CKD-EPI do not take account of individuals BSA but are standardised for 1.73m 2 MDRD is not useful for GFR above 60ml/min and starts overestimating GFR with increasing age CKD-EPI is more accurate than MDRD at higher GFR and BMI <20 Wright formula was based on cancer patients but overestimates low GFR and underestimates high GFR 5

6 EviQ dose recommendations for renal impairment Are these methods of estimating renal function appropriate for chemo patients? 6

7 Concordance by gender Concordance by age 7

8 Concordance by BMI Concordance in carboplatin dosing All formulae resulted in a dose of carboplatin greater than ± 20% of that targeted in over 20% of cases. All formulae significantly underdosed, with the Martin, Wright and CKD-EPI (ml/min) the least discordant. 8

Calvert formula (1995) Linear relationship between renal function and dose Carboplatin Dose = Target AUC x (GFR + 25) AUC = area under the curve for time vs concentration The Calvert formula was

9 Calvert formula (1995) Linear relationship between renal function and dose Carboplatin Dose = Target AUC x (GFR + 25) AUC = area under the curve for time vs concentration The Calvert formula was developed using 51Cr-EDTA as the GFR measurement method, but equations may be applied to calculate an estimated GFR (egfr). If using Cockcroft-Gault, cap GFR at 125ml/min, better to use actual rather than ideal body weight COSA Guidelines for carboplatin dosing 9

10 US FDA recommendations for carboplatin dosing Nov

Peter MacCallum Cancer Centre guidelines for carboplatin dosing Carboplatin doses of AUC>4 administered with curative intent should be based on nuclear GFR Calculate Cockcroft-Gault GFR

11 Peter MacCallum Cancer Centre guidelines for carboplatin dosing Carboplatin doses of AUC>4 administered with curative intent should be based on nuclear GFR Calculate Cockcroft-Gault GFR at the time of nuclear GFR measurement to assess correlation No dose capping should occur when dosing is based on nuclear GFR Doses for protocols AUC>4 can be rounded to the nearest 50mg 11

Carboplatin dose adjustments from one cycle to the next Ok to give first dose based on C-G if no NM measurement available,but adjust for future cycles once this is known Need to be aware that changes

12 Carboplatin dose adjustments from one cycle to the next Ok to give first dose based on C-G if no NM measurement available,but adjust for future cycles once this is known Need to be aware that changes in serum creatinine may result from ureteric obstruction and should trigger investigation of causes, not just dose adjustment No need to adjust with future weight changes if GFR was based on NM measurement 12

13 AUC7 can result in a dose of 1300mg if measured GFR is 160ml/min 2017 JCO paper 13

7m2 SeCr 61 Age 62 C-G GFR 87ml/min NM GFR measurement 127mL/min on 30/3

14 Calculated vs actual GFR for a real patient Chemotherapy orders checked and verified 7/4/17: ht 163cm wt 65kg BSA 1.7m2 SeCr 61 Age 62 C-G GFR 87ml/min NM GFR measurement 127mL/min on 30/3 carboplatin AUC5 gives 760mg, on day 1 of 21-day cycle gemcitabine 1000mg/m2 gives 1700mg, on day 1 & 8 14

15 Carboplatin AUC 5 calculations via various GFR methods for this patient NM measurement 127ml/min = 760mg Cockcroft-Gault 87ml/min = 560mg CKI-EPD BSA adjusted 91mL ml/min = 580mg Janowitz-Williams model 83ml/min = 540mg (see previous slide) which is nearly 30% different! What percentage error is acceptable????? 15

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Carboplatin Time to Drop the Curtain on the Dosing Debate

Carboplatin Time to Drop the Curtain on the Dosing Debate Jon Herrington, Pharm.D., BCPS, BCOP Judith Smith, Pharm.D., BCOP, CPHQ, FCCP, FISOPP Scott Soefje, Pharm.D., MBA, BCOP Heimberg J, et al. N Engl