Download Carboplatin Dosing Accounting for the Renal and Hematologic

CLINICAL Q&A
Tom Busse, PharmD
uestion: What is the appropriate
way to dose carboplatin (Paraplatin®, Bristol-Myers Squibb,
Princeton, NJ) when patients’ creatinine
clearance (CrCl) are decreased or a concern
exists about patients’ hematologic status
(e.g., decreasing the dose after using a standard area under the curve [AUC] dosing or
by choosing a lower AUC)?
Case study: A patient has received one
cycle of a chemotherapy regimen that includes
a carboplatin dose at an AUC of six. The patient experienced a prolonged nadir that
caused the next cycle to be delayed by one
week. The physician wishes to dose reduce
for cycle two of the chemotherapy regimen.
Should the new dose be calculated at an AUC
of four or five or should the original AUC of
six be arbitrarily reduced by 20%–25%?
Q
nswer: Neither method alone
would be appropriate as an adjustment for renal impairment; both
would result in underdosing. These methods
may be appropriate if based on toxicity from
a previously administered dose or other factors such as prior chemotherapy, radiotherapy,
or patient performance status. The manufacturer provides guidance on recommended
dosage adjustments based on hematologic responses from a previously administered dose
(Bristol-Myers Squibb, 2001) (see Table 1).
These are derived from controlled trials and
based on platelet or neutrophil count nadir.
A
For the case study in question, adjustment
of the AUC to four would be a 33% reduction; an AUC of five would be a 17% reduction. Calculating dosage to the original AUC
of six and then adjusting based on the hematologic nadir as per the guidelines would
be an appropriate strategy. The oncologist
empirically may choose to make further adjustments based on other patient factors such
as severity and duration of nadir counts or a
change in performance status. An understanding of the rationale behind AUC dosing of carboplatin is needed to properly determine patients’ dosage requirements.
Area Under the Concentration Versus
Time Curve
The pharmacokinetics of a drug can be illustrated graphically by plotting the serum
drug concentration level versus time after
drug administration. The shaded area in Figure 1 illustrates the AUC. The units in this
example are mg/ml times minutes (i.e., area
= length times width). This value is a measure of systemic drug exposure in patients.
In the case of carboplatin, AUC is predictive of hematologic toxicity and optimal efficacy (Alberts & Dorr, 1998). A smaller
relative dose would be required to achieve
an equivalent AUC in the setting of patients
with decreased drug clearance. In this case,
the peak concentration would be lower but
the time to elimination would be longer.
Formula Dosing of Carboplatin
Carboplatin is excreted principally in the
urine. The rate of clearance is correlated
closely with the glomerular filtration rate
TABLE 1. PARAPLATIN® DOSAGE ADJUSTMENT GUIDELINES
PLATELET NADIR
> 100,000
50,000–100,000
< 50,000
NEUTROPHIL NADIR
ADJUSTED DOSE FROM PRIOR COURSE
> 2,000
500–2,000
< 500
125% (i.e., increase by 25%)
No adjustment
75% (i.e., decrease by 25%)
Note. Based on information from Bristol-Myers Squibb, 2001.
104
mg/ml
Carboplatin Dosing Accounting
for the Renal and Hematologic
Status of Patients
BARBARA HOLMES GOBEL, RN, MS, AOCN®
ASSOCIATE EDITOR
0.35
0.30
0.25
0.20
0.15
0.10
0.05
00.0
0
60
120
180
Minutes
240 300
FIGURE 1. AREA UNDER THE CONCENTRATION
VERSUS TIME CURVE
(GFR) or CrCl (McEvoy, 2001). Thus, the
carboplatin AUC is related linearly to dose
when allowance is made for variations in renal function (Calvert, Harland, Newell,
Siddik, & Harrap, 1985). A formula has been
devised to calculate the total dose of
carboplatin at a predetermined AUC, with the
dose in milligrams determined by the individual patient’s GFR (Calvert et al., 1989).
In the 1990s, AUC largely has replaced body
surface area (BSA) as the basis for dosing
carboplatin in clinical trials and clinical practice. Use of AUC-based formula dosing compensates for patient variations in pretreatment
renal function that might otherwise result in
underdosing, as in patients with above average renal function, or overdosing, as in patients with impaired renal function.
The formula-dosing method used most
commonly in adults is the Calvert formula
(total dose [mg] = target AUC x [GFR +
25]). This method appears in the U.S. Food
and Drug Administration’s prescribing
information for Paraplatin (Bristol-Myers
Squibb, 2001).
Tom Busse, PharmD, is a clinical coordinator
in the department of pharmacy at Gottlieb
Memorial Hospital in Melrose Park, IL. (Mention of specific products and opinions related
to those products do not indicate or imply endorsement by the Clinical Journal of Oncology
Nursing or the Oncology Nursing Society.)
Digital Object Identifier: 10.1188/03.CJON.104-108
JANUARY/FEBRUARY 2003 • VOLUME 7, NUMBER 1 • CLINICAL JOURNAL OF ONCOLOGY NURSING
Other formulas have been devised either
as an alternative in adults (Huitema et al.,
2000; Sculier et al., 1999) or for pediatric
use (Solimando & Waddell, 2002). Discussion of these other methods is beyond the
scope of this column.
Determining the Glomerular Filtration
Rate or Creatinine Clearance
GFR, as used in the Calvert formula, is a
measure of renal function and essentially is
equivalent to CrCl. In developing the formula, Calvert et al. (1989) determined GFR
using a radiopharmaceutical method. Determining GFR this way is expensive and inconvenient. Alternative methods to calculate
GFR include a 24-hour urine collection for
CrCl or the use of a variety of formulas to
calculate an estimated CrCl. The use of estimated CrCl results in more complex dosage
calculations may not be as accurate. Despite
this, clinicians commonly estimate CrCl because it is the most convenient method
(Waddell & Solimando, 2000). Variables introduced with the use of estimated CrCl include the following.
• CrCl formula: Several methods have
been used. See Table 2 for examples. The
Paraplatin prescribing information does
not provide a specific formula. A sliderule calculator distributed by the manufacturer uses the Jelliffe method adjusted
for BSA (Jelliffe, 1973). A computer software calculator also from the manufacturer
includes two additional methods: Jelliffe
not adjusted for BSA and Cockcroft-Gault
using ideal body weight (IBW) (Bristol
Laboratories Oncology Products, 1997).
• Serum creatinine (SCr): Only relatively
stable values will provide an accurate
CrCl estimate. Abnormally low SCr may
be unreliable in some patients (Waddell
& Solimando, 2000). Variation has been
noted depending on the methods used for
determining SCr. The older laboratory
method (i.e., Jaffe) reports slightly higher
SCr than the newer enzymatic laboratory
method. Research is not clear as to which
method is more accurate for carboplatin
dosing purposes (Leger et al., 2002;
Waddell & Solimando).
• Body weight: Doses calculated using formulas that incorporate body weight or
BSA are affected by this variable. Using
actual body weight (ABW) versus IBW
or adjusted body weight will yield different results when dosing obese patients.
Actual weights tend to overestimate clearance whereas ideal weights tend to underestimate clearance in obese patients. The
best strategy may be to use actual weight
in calculations for most patients and use
adjusted weight [IBW + 40% (ABW –
IBW)] for morbid obesity (Benezet et al.,
1997; Waddell & Solimando, 2000).
These factors can lead to variations of up
to 40% between desired and achieved
carboplatin AUC when using formula dosing. The use of BSA for calculating doses
can lead to variations of 100%–300%. Thus,
any method of AUC-based carboplatin dosing is more accurate than dosing according
to BSA (Calvert et al., 1995).
Summary
Using AUC-based dosing compensates
for variations in renal function between and
within individual patients. It does not adjust
for other factors such as previous chemotherapy, previous radiotherapy, or performance status. One empiric method to adjust
for these factors would be reduction of the
ideal AUC. However, because AUC-based
dosing accounts for variations in renal function, this would not be an appropriate
method to adjust dosing based solely on renal function changes.
Author Contact: Tom Busse, PharmD, can
be reached at [email protected].
TABLE 2. FORMULAS FOR COMPUTING CREATININE CLEARANCE
METHOD
Cockcroft-Gualt
FORMULA
(140 – age) (weight in kg)
(72) (SCr in mg/dl)
Jelliffe
98 – 0.8(age in years – 20)
SCr in mg/dl
Jelliffe (adjusted for body
surface area [BSA])
x (0.85 if female)
98 – 0.8(age in years – 20)
SCr in mg/dl
x (0.9 if female)
x
(patient’s BSA)
1.73 m2
x (0.9 if female)
SCr—serum creatinine
Note. Based on information from Bristol Laboratories Oncology Products, 1997; Jelliffe, 1973.
CLINICAL JOURNAL OF ONCOLOGY NURSING • VOLUME 7, NUMBER 1 • CLINICAL Q&A
References
Alberts, D.S., Dorr, R.T. (1998). New perspectives on an old friend: Optimizing carboplatin
for the treatment of solid tumors. Oncologist,
3(1), 15–34.
Benezet, S., Guimbaud, R., Chatelut, E., Chevreau,
C., Bugat, R., & Canal, P. (1997). How to predict carboplatin clearance from standard morphological and biological characteristics in
obese patients. Annals of Oncology, 8, 607–609.
Bristol Laboratories Oncology Products. (1997).
Paraplatin dosage calculator for windows
[Computer software]. New York: Author.
Bristol-Myers Squibb. (2001). Paraplatin® prescribing information. Princeton, NJ: Author.
Calvert, A.H., Boddy, A., Baily, N.P., Siddiqui,
N., Humphreys, A., Hughes, A., et al. (1995)
Carboplatin in combination with paclitaxel in
advanced ovarian cancer: Dose determination
and pharmacokinetic and pharmacodynamic
interactions. Seminars in Oncology, 22(Suppl.
12), 91–98
Calvert, A.H., Harland, S.J., Newell, D.R., Siddik,
Z.H., & Harrap, K.R. (1985). Phase I studies
with carboplatin at the Royal Marsden Hospital. Cancer Treatment Reviews, 12(Suppl. A),
51–57.
Calvert, A.H., Newell, D.R., Gumbrell, L.A.,
O’Reilly, S., Burnell, M., Boxall, F.E., et al.
(1989). Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. Journal of Clinical Oncology, 7, 1748–
1756.
Huitema, A.D., Mathot, R.A., Tibben, M.M.,
Schellens, J.H., Rodenhuis, S., & Beijnen, J.H.
(2000). Validation of techniques for the prediction of carboplatin exposure: Application of
Bayesian methods. Clinical Pharmacology and
Therapeutics, 67, 621–630.
Jelliffe, R.W. (1973). Creatinine clearance: Bedside estimate. Annals of Internal Medicine, 79,
604 –605.
Leger, F., Seronie-Vivien, S., Makdessi, J., Lochon, I., Delord, J.P., Sarda, C., et al. (2002).
Impact of the biochemical assay for serum
creatinine measurement on the individual
carboplatin dosing: A prospective study. European Journal of Cancer, 38(1), 52–56.
McEvoy, G.K. (Ed.). (2001). Carboplatin. In
American hospital formulary service drug information (pp. 891– 899). Bethesda, MD:
American Society of Health-System Pharmacists.
Sculier, J.P., Paesmans, M., Thiriaux, J., Lecomte,
J., Bureau, G., Giner, V., et al. (1999). A comparison of methods of calculation for estimating carboplatin AUC with a retrospective pharmacokinetic and pharmacodynamic analysis in
patients with advanced NSCLC. European
Journal of Cancer, 35, 1314–1319.
Solimando, D.A, & Waddell, J.A. (2002). Pharmacokinetic dosing of carboplatin in pediatric
patients. Hospital Pharmacy, 37, 936–940.
Waddell, J.A., & Solimando, D.A. (2000). Verifying carboplatin dose calculations in adult patients with the Calvert and modified Calvert
formulas. Hospital Pharmacy, 35, 914–922.
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