Jennifer P. Lee, PharmD, BCPS - Paralyzed Veterans of America
Jennifer P. Lee, PharmD, BCPS - Paralyzed Veterans of America
Jennifer P. Lee, PharmD, BCPS - Paralyzed Veterans of America
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Evaluation <strong>of</strong> Methods to Estimate<br />
Renal Function vs. Actual Drug<br />
Clearance in Individuals with SCI<br />
<strong>Jennifer</strong> <strong>Lee</strong>, Pharm.D., <strong>BCPS</strong><br />
Anthony Dang, Pharm.D., <strong>BCPS</strong><br />
VA Long Beach Healthcare System<br />
jennifer.lee4332a@va.gov<br />
Aug 28 th , 2012<br />
IRB approved
Disclosures<br />
This continuing education activity is<br />
managed and accredited by Pr<strong>of</strong>essional<br />
Education Service Group. The information<br />
presented in this activity represents the<br />
opinion <strong>of</strong> the author(s) or faculty. Neither<br />
PESG, nor any accrediting organization<br />
endorses any commercial products<br />
displayed or mentioned in conjunction<br />
with this activity.<br />
Commercial Support was not received for<br />
this activity
Disclosures<br />
• <strong>Jennifer</strong> <strong>Lee</strong>, Pharm.D., <strong>BCPS</strong><br />
• Anthony Dang, Pharm.D., <strong>BCPS</strong><br />
Has no financial interest or relationships<br />
to disclose<br />
• CME Staff Disclosures<br />
Pr<strong>of</strong>essional Education Services Group<br />
staff have no financial interest or<br />
relationships to disclose.
Objectives<br />
At the conclusion <strong>of</strong> this activity, the participant will<br />
be able to:<br />
1. Evaluate different methods <strong>of</strong> estimating GFR<br />
compared to patient-specific vancomycin and<br />
AG drug clearance (CL DRUG ) in SCI patients.<br />
2. Determine if a new equation can be developed<br />
to more accurately estimate GFR in SCI<br />
patients in order to optimize dosing for<br />
vancomycin and AG.<br />
3. Assess if there is a difference in the estimation<br />
<strong>of</strong> renal function between anatomical degrees<br />
<strong>of</strong> SCI when compared to CL DRUG.
VA Long Beach Healthcare System<br />
• Tertiary Care Facility<br />
• Total SCI beds: 90
Pre-Test Assessment Questions<br />
• T / F: Higher peak and trough concentrations<br />
increase risk <strong>of</strong> aminoglycoside-induced<br />
ototoxicity and nephrotoxicity.<br />
• T / F: Creatinine production declines with age,<br />
immobility, and reduced muscle mass.<br />
• T / F: Individuals with spinal cord injury (SCI)<br />
have better drug clearance than the general<br />
population
Creatinine<br />
• A muscle breakdown product<br />
• Produced at a constant rate<br />
• Exclusively filtered by the kidneys<br />
1. Macdiarmid S. BJU International 2000;85. 1014-1018.<br />
2. Mirahmadi MK. Paraplegia. 1983 Feb;21(1):23-9.<br />
3. Cherry RJ.Trauma 2002; 53: 267-271.
Chronic SCI<br />
Limited<br />
Mobility<br />
↓<br />
Muscle<br />
Mass 1<br />
↓ SCr<br />
↑ CrCl<br />
Overdosing<br />
↑ ADR<br />
1. Macdiarmid SA. BJU International, 2000; 85: 1014-18.
Vancomycin & Aminoglycosides<br />
• Dose related toxicity:<br />
• Ototoxicity<br />
• Nephrotoxicity<br />
• Primarily renal elimination<br />
4. Rybak M. Am J Health-Syst Pharm 2009; 66: 82-98.<br />
5. Hidayat L. Arch Intern Med 2006; 166: 2138-2144.<br />
6. Kahlmeter G. J Antimicrobial Chemotherapy 1984; 13: 9-22.
Methods to estimate GFR<br />
• Cockcr<strong>of</strong>t-Gault (CG) equation 7<br />
• Modified CG equation<br />
• MDRD equation 8<br />
• CKD-EPI equation 9<br />
• 24-Hour endogenous creatinine clearance 1,10<br />
1. Macdiarmid SA. BJU International, 2000; 85: 1014-18.<br />
7. Cockcr<strong>of</strong>t DW. Nephron 1976; 16: 31–41.<br />
8. Stevens LA. J Am Soc Nephrol, 2007; 18: 2749-57.<br />
9. Levey AS. Ann Intern Med, 2009; 150(9): 604-12.<br />
10. Stabuc B. Clinical Chemistry, 2000; 46(2): 193-7.
Cockcr<strong>of</strong>t-Gault (CG) 7<br />
CL CG (mL/min) = [(140 – age) x IBW in kg] /<br />
(72 x SCr); (multiply 0.85 for females)<br />
Modified CG formula (CL M ):<br />
• SCr rounded to 1 mg/dL for patients with SCr<br />
< 1 mg/dL while using the actual SCr for patients<br />
with SCr ≥ 1 mg/dL<br />
7. Cockcr<strong>of</strong>t DW. Nephron 1976; 16: 31–41.
Overestimation by CG<br />
Study Patient Population Methodology Findings<br />
Macdiarmid et al. 1<br />
25 Paraplegic<br />
11 Tetraplegic<br />
CL CG vs. CL 24H vs.<br />
99mTc-DTPA<br />
CL 24H more<br />
accurate<br />
Mirahmadi et al. 2<br />
22 Paraplegic<br />
36 Tetraplegic<br />
22 ambulatory<br />
CL CG vs. CL 24H vs.<br />
Autoanalyser<br />
Correction factor:<br />
0.8 for paraplegic<br />
0.6 for tetraplegic<br />
Lavezo et al. 11<br />
14 SCI<br />
14 control<br />
Actual vs.<br />
Predicted CL VANCO<br />
↑half-life in SCI<br />
1. Macdiarmid SA. BJU International, 2000; 85: 1014-18<br />
2. Mirahmadi MK,. Paraplegia. 1983 Feb;21(1):23-9<br />
11. Lavezo LA. J Spinal Cord Med 1995; 16: 233-235)
MDRD equation 8<br />
4-Variable MDRD:<br />
eGFR = 175 x standardized SCr -1.154 x<br />
age -0.203 x 1.212 (if black) x 0.742 (if female)<br />
8. Stevens LA. J Am Soc Nephrol, 2007; 18: 2749-57.
CG vs. MDRD<br />
Study Patient Population Methodology Findings<br />
Chikkalingaiah<br />
KBM et al. 12<br />
116 SCI<br />
CL 24H vs. CL CG vs.<br />
MDRD<br />
Correction factor:<br />
0.7 for MDRD<br />
0.8 for CL CG<br />
Bookstaver PB<br />
et al. 13<br />
71 non-SCI<br />
Actual CL AG vs. CL CG<br />
vs. MDRD<br />
MDRD better<br />
Ryzner KL. 14<br />
55 non-SCI<br />
Actual CL AG vs. CL CG<br />
vs. MDRD<br />
CL CG better<br />
12. Bookstaver PB. Ann Pharmacother 2008, 42(12): 1758-1765.<br />
13 Ryzner KL. Ann Pharmacother 2010; 44: 1030-1037.<br />
14. Roberts GW. Age Ageing 2009; 38: 698-703.
CKD-EPI equation 9<br />
eGFR = 141 x min (SCr/ĸ, 1) α x max<br />
(SCr/ĸ, 1) -1.209 x 0.993 Age x 1.018 [if<br />
female] x 1.159 [if black]<br />
where ĸ is 0.7 for females and 0.9 for males,<br />
α is -0.329 for females and -0.411 for males,<br />
min indicates the minimum <strong>of</strong> SCr/ĸ or 1,<br />
& max indicates the maximum <strong>of</strong> SCr/ĸ or 1.<br />
9. Levey AS. Ann Intern Med, 2009; 150(9): 604-12.
CG vs. CKD-EPI<br />
Study Patient Population Methodology Findings<br />
Pai et al. 15<br />
2073 non-SCI<br />
CL AG vs. CL CG vs.<br />
MDRD vs. CKD-EPI<br />
CKD-EPI > MDRD ><br />
CL CG<br />
15. Pai MP. Antimicrob Agents Chemother. 2011 September; 55(9): 4006–4011.
24-Hour Endogenous Creatinine<br />
Clearance 10<br />
CL 24H (mL/min) = [urine creatinine x urine<br />
volume (mL)] / [SCr x time (hours) x 60]<br />
10. Stabuc B. Clinical Chemistry, 2000; 46(2): 193-7.
Methodology<br />
• IRB Approved<br />
• Study Design: Retrospective chart review<br />
• Study Period: 1/1/2008 – 12/31/08
Inclusion Criteria<br />
• Patients at VALB with an ICD-9 diagnosis<br />
<strong>of</strong> spinal cord injury for >1 year<br />
o Received amikacin, gentamicin, tobramycin,<br />
or vancomycin with at least one steady state<br />
level
Exclusion Criteria<br />
• Hemodialysis or acute kidney injury<br />
• Limb amputation<br />
• Multiple sclerosis<br />
• Inappropriate data for monitoring
Methodology<br />
• VA electronic medical record (Computerized<br />
Patient Record System)<br />
• Pharmacokinetic calculations via non-steady<br />
state short infusion model 16<br />
o C peak = (Dose/t inf ) * (1-e -kt inf)/V d * K e<br />
o C trough = C peak * e -kt<br />
o CrCl (L/hr) = Vd x Ke<br />
16. Winters M. Basic Clinical Pharmacokinetics. Fourth Ed, 2004, Lippincott Williams and Wilkins.
Methodology<br />
• Volume <strong>of</strong> distribution calculations 17 :<br />
o Vancomycin<br />
• V d = 0.17(age) + 0.22 (TBW) + 15<br />
o Aminoglycosides<br />
• Peak levels were used to calculate V d<br />
17 Rushing TA. J Pharm Technol, 2001; 17: 33-8.
Methodology<br />
• Actual drug clearance (CL DRUG )<br />
• CG CrCl (CL CG )<br />
• Modified CG CrCl (CL M )<br />
• Adjusted 24-hour endogenous CrCl (CL 24H )<br />
• MDRD equation<br />
• CKD-EPI equation
Statistical Analyses<br />
• 2-sided students t-test with alpha=0.01 for<br />
significance<br />
• 95% Power<br />
• Determined Post Hoc given results<br />
• Linear Regression<br />
• All analyses performed using Micros<strong>of</strong>t ® Excel
Results
Baseline Characteristics<br />
Mean ± S.D.<br />
Total # <strong>of</strong> patients 141<br />
Male/Female, N 140/1<br />
Tetraplegic/ Paraplegic, N 89/52<br />
Vancomycin/ Amikacin, N 109/32<br />
SCr >1 mg/dL, N 30<br />
Age (years) 65.72 ± 10.54<br />
Height (cm) 179.96 ± 7.01<br />
Weight (kg) 80.35 ± 20.69<br />
BMI (kg/m 2 ) 24.6 ± 5.78<br />
SCr (mg/dL) 0.74 ± 0.29
Evaluation <strong>of</strong> different methods to<br />
estimate GFR<br />
(N=141)<br />
Mean ± S.D.<br />
(mL/min)<br />
Difference from<br />
CL DRUG (mL/min)<br />
P-Value<br />
CL DRUG<br />
49.77 ± 19.97 0 --<br />
MDRD 119.76 ± 61.49 69.99
Number <strong>of</strong> Patients<br />
Difference between MDRD and CL DRUG<br />
50<br />
48<br />
40<br />
38<br />
30<br />
20<br />
25<br />
22<br />
10<br />
0<br />
7<br />
1<br />
90<br />
MDRD - CL DRUG (mL/min)<br />
Abbreviations: MDRD, the Modification <strong>of</strong> Diet in Renal Disease equation; CL DRUG, actual drug clearance.
Number <strong>of</strong> Patients<br />
Difference between CL M and CL DRUG<br />
80<br />
75<br />
60<br />
45<br />
40<br />
20<br />
0<br />
18<br />
2<br />
1 0<br />
90<br />
CL M - CL DRUG (mL/min)<br />
Abbreviations: CL M , modified Cockcr<strong>of</strong>t-Gault formula; CL DRUG, actual drug clearance.
Evaluation <strong>of</strong> CL M to estimate<br />
CL DRUG for vancomycin and AG<br />
Mean ± S.D.<br />
(mL/min)<br />
Difference<br />
from CL DRUG<br />
(mL/min)<br />
P-Value<br />
Combined<br />
Amikacin and<br />
Vancomycin<br />
(N=141)<br />
Amikacin<br />
(n=32)<br />
Vancomycin<br />
(n=109)<br />
CL DRUG 49.77 ± 19.97 0 --<br />
CL M 69.38 ± 13.49 19.61
Actual Drug Clearance (mL/min)<br />
120<br />
Determining SCI Study Equation<br />
100<br />
80<br />
60<br />
40<br />
y = 2.3286x 0.7<br />
R = 0.4<br />
20<br />
0<br />
0 20 40 60 80 100 120<br />
Modified Cockcr<strong>of</strong>t-Gault Predicted<br />
Drug Clearance (mL/min)
Actual Drug Clearance (mL/min)<br />
80<br />
Linear Regression Plots<br />
60<br />
40<br />
y = 0.8425x + 6.7281<br />
R = 0.4<br />
20<br />
0<br />
0 20 40 60 80<br />
Predicted Drug Clearance using CL SCI (mL/min)<br />
Abbreviation: CL SCI , spinal cord injury equation
CL DRUG vs. CL SCI<br />
• T-Test showed no difference between<br />
SCI equation and actual drug clearance.<br />
Mean S.D.<br />
(mL/min)<br />
Difference<br />
from CL DRUG<br />
(mL/min)<br />
P-Value<br />
CL DRUG 47.57 +/- 16.34 -- --<br />
CL SCI 45.22 +/- 6.16 -2.35 0.16
Different anatomical degrees <strong>of</strong> SCI<br />
(N=141)<br />
Mean Difference from<br />
CL DRUG S.D. (mL/min)<br />
P-Value<br />
Paraplegics<br />
(n = 52)<br />
Tetraplegics<br />
(n = 89)<br />
CL SCI<br />
-3.11 13.14 -5.39 21.16 0.48<br />
CL M<br />
21.04 13.81 18.76 22.26 0.5<br />
CL 24H<br />
32.60 30.78 37.02 35.29 0.45<br />
CL CG<br />
27.26 20.56 49.76 38.55
DISCUSSION
Discussion<br />
• Current methods for estimating GFR grossly<br />
overestimate drug clearance in chronic SCI<br />
patients compared to the SCI Study<br />
Equation
Discussion<br />
• CL SCI = 2.3286 * x 0.7006 , where x = CL M with<br />
SCr rounded to 1 if SCr
Limitations<br />
• Small number <strong>of</strong> patients in amikacin group<br />
• <strong>Veterans</strong> population<br />
• Variability inherent in using clinical data<br />
• Assumption: CL CR =CL V =CL AG<br />
• Accuracy <strong>of</strong> vancomycin Vd<br />
• Actual GFR values for > 60 ml/min<br />
• Abbreviated MDRD<br />
• No adjustment for BSA<br />
• Retrospective study: limited control over certain<br />
confounding variables
Conclusion<br />
• Current methods used to calculate CL CR<br />
overestimate CL DRUG in SCI patients<br />
• The proposed SCI equation:<br />
CL SCI = 2.3*x 0.7<br />
(x = CL M with SCr rounded to1 if SCr
Future Plans<br />
• Validate CL SCI in a prospective analysis<br />
• Further analysis with aminoglycosides
References<br />
1. Macdiarmid S, Mcintyre W, Anthony A, et. Al. “Monitoring <strong>of</strong> Renal Function in Patients with<br />
Spinal Cord Injury” BJU International 2000;85. 1014-1018<br />
2. Mirahmadi MK, Byrne C, Barton C, et. Al. “Prediction <strong>of</strong> creatinine clearance from serum<br />
creatinine in spinal cord injury patients.” Paraplegia. 1983 Feb;21(1):23-9<br />
3. Cherry R, Eachempati S, Hydo L et al. “Accuracy <strong>of</strong> Short-Duration Creatinine Clearance<br />
Determinations in Predicting 24-Hour Creatinine Clearance in Critically Ill and Injured Patients”<br />
J Trauma 2002; 53:267-271.<br />
4. Rybak M, Lomaestro B, Rotschafer J et al. Therapeutic monitoring <strong>of</strong> vancomycin in adult<br />
patients: a consensus review <strong>of</strong> the <strong>America</strong>n Society <strong>of</strong> Health-System Pharmacists, the<br />
Infectious Diseases Society <strong>of</strong> <strong>America</strong>, and the Society <strong>of</strong> Infectious Diseases Pharmacists.<br />
Am J Health-Syst Pharm 2009; 66: 82-98.<br />
5. Hidayat L, Hsu D, Quist R et al. High-Dose Vancomycin Therapy for Methicillin-Resist<br />
Staphylococcus aureus Infections: Efficacy and Toxicity. Arch Intern Med 2006; 166: 2138-<br />
2144.<br />
6. Kahlmeter G, Dahlager JI. Aminoglycoside Toxicity - A review <strong>of</strong> clinical studies published<br />
between 1975 and 1982. J Antimicrobial Chemotherapy 1984; 13: 9-22.<br />
7. Cockcr<strong>of</strong>t DW, Gault MH. Prediction <strong>of</strong> creatinine clearance from serum creatinine. Nephron<br />
1976; 16: 31–41.<br />
8. Stevens LA, Coresh J, Feldman HI, et al. Evaluation <strong>of</strong> the Modification <strong>of</strong> Diet in Renal<br />
Disease Study Equation in a Large Diverse Population. J Am Soc Nephrol, 2007; 18: 2749-57.<br />
9. Levey AS, Stevens LA, Schmid CH, et al. A New Equation to Estimate Glomerular Filtration<br />
Rate. Ann <strong>of</strong> Intern Med, 2009; 150(9): 604-12.
References<br />
10. Stabuc B, Vrhovec L, Stabuc-Silih M, et al. Improved Prediction <strong>of</strong> Decreased Creatinine<br />
Clearance by Serum Cystatin C: Use in Cancer Patients Before and During Chemotherapy.<br />
Clinical Chemistry, 2000; 46(2): 193-7.<br />
11. Lavezo LA, Davis RL. Vancomycin pharmacokinetics in spinal cod injured patients: a<br />
comparison with age-matched, able-bodied controls. J Spinal Cord Med 1995; 16: 233-235)<br />
12. Chikkalingaiah KBM, Grant ND, Mangold TM et al. Performance <strong>of</strong> Simplified Modification <strong>of</strong><br />
Diet in Renal Disease and Cockcr<strong>of</strong>t-Gault Equations in Patients With Chronic Spinal Cord<br />
Injury and Chronic Kidney Disease. Am J Med Sci 2010; 339(2): 108-16.<br />
13. Bookstaver PB, Johnson JW, McCoy TP et al. Modification <strong>of</strong> Diet in Renal Disease and<br />
modified Cockcr<strong>of</strong>t-Gault formulas in predicting aminoglycoside elimination. Ann Pharmacother<br />
2008, 42(12): 1758-1765.<br />
14. Ryzner KL. Evaluation <strong>of</strong> Aminoglycoside Clearance Using the Modification <strong>of</strong> Diet in Renal<br />
Disease Equation Versus the Cockcr<strong>of</strong>t-Gault Equation as a Marker <strong>of</strong> Glomerular Filtration<br />
Rate. Ann Pharmacother 2010; 44: 1030-1037.<br />
15. Pai MP, Nafziger AN, Bertino JS. Simplified Estimation <strong>of</strong> Aminoglycoside Pharmacokinetics in<br />
Underweight and Obese Adult Patients. Antimicrob Agents Chemother. 2011 September;<br />
55(9): 4006–4011.<br />
16. Winters M Basic Clinical Pharmacokinetics. Fourth Edition. 2004 Lippincott Williams and<br />
Wilkins<br />
17. Rushing TA, Ambrose PJ. Clinical application and evaluation <strong>of</strong> vancomycin dosing in adults. J<br />
Pharm Technol 2001; 17: 33–38.
Post-Test Assessment Questions<br />
• T / F: Higher peak and trough concentrations<br />
increase risk <strong>of</strong> aminoglycoside-induced<br />
ototoxicity and nephrotoxicity.<br />
• T / F: Creatinine production declines with age,<br />
immobility, and reduced muscle mass.<br />
• T / F: Individuals with spinal cord injury (SCI)<br />
have better drug clearance rates than the<br />
general population.
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