Volume 37, Number 9, pp 936–940
2002 Facts and Comparisons
Cancer Chemotherapy Update
Pharmacokinetic Dosing of Carboplatin in
Dominic A. Solimando, Jr., M.A., FAPhA, FASHP, BCOP and J. Aubrey Waddell, PharmD, BCOP
targeted AUC has largely replaced body surface area (BSA)
The increasing complexity of cancer chemotherapy
as the basis for dosing this medication in adult patients. For
makes it mandatory that pharmacists be familiar with
adults, the most frequently used carboplatin AUC dose cal-
these highly toxic agents. This column focuses on the
culation methods are the Calvert formula and the modified
commercially available and investigational agents used to
Calvert formula,8,9 but these methods are not applicable to
treat malignant diseases, reviewing issues related to the
preparation, dispensing, and administration of cancer
chemotherapy. Questions or suggestions for topics
PEDIATRIC RENAL-BASED DOSING NOMO-
should be addressed to Dominic A. Solimando, Jr., Oncol-
ogy Pharmacy Services, Inc., 4201 Wilson Boulevard
Although they have been studied less extensively than
#110-545, Arlington, VA 22203; or J. Aubrey Waddell,
the Calvert dosing formula, three methods for determining
Assistant Chief, Department of Pharmacy, Walter Reed
the carboplatin dose based on renal function in pediatric
Army Medical Center, 6900 Georgia Avenue, NW, Wash-
patients have been reported:
ington, DC 20307-5001. E-mail: OncRxSvc@aol.com.
The opinions or assertions contained herein are the private views
of the author and are not to be construed as official or reflecting Carboplatin dose (mg) =
the views of the U.S. Department of the Army or the Department ([uncorrected 51Cr-EDTA clearance x 1.2] + 20) x AUC
of Defense. where:
1. AUC is selected by the oncologist or specified in the clin-
ical trial protocol,
ABBREVIATIONS 2. Uncorrected 51Cr-EDTA clearance represents the
AUC = area under the plasma concentration vs time curve patient’s glomerular filtration rate, and
BSA = body surface area 3. 1.2 and 20 are constants whose derivations are not
BW = body weight specifically identified.
GFR = glomerular filtration rate
CGF = Cockcroft and Gault formula For example, the carboplatin dose required to reach a
JF = Jelliffe formula desired AUC of 6 for a patient with a 51Cr-EDTA clearance of
100 mL/minute is 840 mg.
INTRODUCTION In a pilot study of a carboplatin, etoposide, and
Carboplatin is a widely used antineoplastic agent, active bleomycin (JEB) regimen for germ cell tumors, Pinkerton et
against a broad spectrum of neoplasms. A number of stud- al10 used this renal dosing formula to calculate carboplatin
ies have correlated carboplatin’s antitumor activity and toxic- doses in 13 of 21 patients. The carboplatin doses for the
ity with its pharmacokinetics. These studies have demon- remaining eight patients were based on body surface area
strated a direct relationship between the AUC and carbo- (BSA) (mg/m2). Since evaluation of the pharmacokinetic-
platin’s activity and toxicity.1–6 Since carboplatin clearance is based dosing of carboplatin was not the primary objective of
almost exclusively (60% to 80%) renal,7 most methods for this trial, the report does not provide data concerning the
pharmacokinetic dosing of carboplatin incorporate the accuracy or precision of the formula in calculating doses that
glomerular filtration rate (GFR) as a key variable. achieve the desired AUC.
In the past decade, pharmacokinetic dosing based on a
936 Volume 37, September 2002
Cancer Chemotherapy Update
Equation 211 Equation 315
Carboplatin dose (mg/m ) = Carboplatin dose (mg) =
(Target AUC) x [(0.93 x GFR) + 15] Target AUC x (GFR + [0.36 x BWkg])
where: 1. Target AUC is selected by the oncologist or specified in
1. Target AUC is selected by the oncologist or specified in the clinical trial protocol,
the clinical trial protocol, 2. GFR is the patient’s glomerular filtration rate,
2. GFR is the patient’s glomerular filtration rate, 3. 0.36 is a constant representing nonrenal clearance, and
3. 0.93 is a factor used to relate carboplatin renal clearance 4. BWkg is the patient’s weight in kilograms.
to GFR, and
5. 15 is a constant representing nonrenal clearance. For example, the carboplatin dose required to reach a
desired AUC of 6 for a patient weighing 19 kg with a GFR of
For example, the carboplatin dose required to reach a 95 mL/minute is 611 mg.
desired AUC of 5 for a patient with a BSA of 0.7 m2 and a In a study of carboplatin pharmacokinetics and pharma-
GFR of 90 mL/minute is 345 mg (493.5 mg/m2). Note: The codynamics in pediatric patients, Newell et al reported devel-
formula gives the dose in mg/m2. This value must be oping the formula in Equation 3 as a modification of the
multiplied by the BSA to determine the dose to be Calvert method used in adults.15,16 They also noted a signifi-
administered. cant variation on GFR, depending on the method used to
In a series of trials, Marina et al11,12 and Tonda et al13 val- determine 51Cr-EDTA clearance. Plasma clearances deter-
idated the use of this formula in pediatric patients with a vari- mined as the product of volume of distribution (Vd) and the
ety of solid tumors. Murry et al also validated this method of clearance constant were considered less reliable due to the
calculating carboplatin doses for continuous infusions.14 In extremely large Vd in some patients. Normalization of the
heavily pretreated patients receiving a combination of ifos- clearance to BSA (mL/min/1.73 m2) was also found to be
famide, carboplatin, and etoposide, (ICE), Marina’s group unreliable.
reported a maximum tolerated AUC of 6 in patients with pre- Newell’s group found that determining GFR as a func-
vious CNS radiation or high cumulative doses of cisplatin tion of the 51Cr-EDTA half-life and an estimate of the Vd pro-
and etoposide, and a maximum AUC of 7 in the remainder of vided more reliable predictions of the carboplatin AUC.
their study group. Using the formula in equation 2, they were Newell used two methods to estimate the 51Cr-EDTA half-life.
able to achieve measured AUCs within 30% of the target The first, based on a published 51Cr-EDTA Vd, results in the
AUC in 68% of their patients.11 following formula for determining the carboplatin dose:
In a small study (n = 15) of previously untreated patients
receiving the ICE regimen, Marina’s group was able to Equation 415
achieve measured AUCs within 15% of the target AUC in Carboplatin dose (mg) =
50% of the patients. They also noted a great variability in the Target AUC x ([0.693/51Cr-EDTA t1/2] x
dose of carboplatin required, reporting a range of 362 mg/m2 ([1.75 x 583 x BW0.678)]) + [0.36 x BWkg])
to 1029 mg/m2 required to reach a target AUC of 8.12 where:
In a trial of newly diagnosed patients with CNS tumors 1. Target AUC is selected by the oncologist or specified in
receiving cyclophosphamide, etoposide, and carboplatin, the clinical trial protocol,
Tonda et al reported measured AUCs within 20% of the tar- 2. 0.693/51Cr-EDTA t1/2 represents the 51Cr-EDTA clearance
get AUC in 71% of their patients.13 In this study, a maximum constant,
GFR of 100 mL/min/m2 was used. The carboplatin doses for 3. 583 x BW0.678 represents the 51Cr-EDTA extra cellular fluid
patients whose measured GFR exceeded 100 mL/min/m2 volume,
were calculated using this lower figure. 4. 1.75 x 583 x BW0.678 represents the calculated 51Cr-EDTA
Marina’s and Tonda’s studies utilized a short (1-hour) volume of distribution
infusion. Murry et al reported using the same formula for cal- 5. BWkg is the patient’s weight in kilograms, and
culating carboplatin doses for 24-hour infusions. In this 6. 0.36 is a constant representing nonrenal clearance.
study, the measured AUC in 13 of 19 courses (68.4%) were
within 35% of the target AUC. Murry’s group also reported An alternate approach reported by Newell et al was
that the median dose to achieve a target AUC of 8 was 817 based on reports that the 51Cr-EDTA volume of distribution in
mg/m2 (range: 611 mg/m2 to 988 mg/m2).14 adults is 52% of the estimated total body water (TBW). Using
that information, they came up with the alternate formula in
Hospital Pharmacy 937
Cancer Chemotherapy Update
Equation 515 dose was not based on the pharmacokinetic formula
Carboplatin dose(mg) = received a dose of 600 mg/m2. Since the trial was an evalu-
Target AUC x ([0.693/51Cr-EDTA t1/2] x ation of the efficacy of the treatment regimen rather than the
([0.52 x 843 x BW0.891)]) + [0.36 x BWkg]) pharmacokinetics of carboplatin, actual AUCs were not
reported. The report does not mention how close the admin-
where: istered carboplatin dose was to the target AUC; nor does it
1. Target AUC is selected by the oncologist or specified in provide a comparison between the patients whose dose was
the clinical trial protocol, based on BSA vs the ones based on the pharmacokinetic
2. 0.693/51Cr-EDTA t1/2 represents the 51Cr-EDTA clearance formula.18
3. 843 x BW0.678 represents the 51Cr-EDTA estimated total DETERMINING GFR
body water, All of the methods discussed are based on a measured
4. 0.52 x 843 x BW0.891 represents the calculated 51Cr-EDTA GFR, using a radiotagged marker to measure renal clear-
volume of distribution, ance. Pinkerton et al10, Newell et al15, Thomas et al17 and
5. BWkg is the patient’s weight in kilograms, and Mann et al18 used the clearance of chromium 51 edathamil
6. 0.36 is a constant representing nonrenal clearance. (51Cr-EDTA) as a measure of the GFR. 51Cr-EDTA is not uni-
versally available. In the US, 51Cr-EDTA is only available
Thomas et al validated equation 5 in a randomized under investigational protocol. 99mTcDTPA is commercially
prospective trial. Patients were randomly assigned to receive available in the US; 99mTcDTPA clearance has been used
carboplatin dosed according to the pharmacokinetic formula successfully in place of 51Cr-EDTA clearance.
or on the basis of BSA. Patients were enrolled in several dif- Accordingly, Marina et al11 used technetium 99-diethyl-
ferent protocols for a variety of solid tumors. The target car- enetriamine pentaacetic acid (99Tc-DTPA) as their marker for
boplatin AUC was set at 1.325 mg/mL/min/100 mg/m2 of the renal clearance. Other methods of measuring GFR, such as
carboplatin dose specified in the protocol in which the patient I-iothalamate, unlabelled iothalamate, iohexol, or inulin
was enrolled (eg, a patient on a protocol requiring 400 mg/m2 clearance, have been used to determine GFR19, but trials val-
of carboplatin would have a target AUC of 5.3). Seventy-four idating these methods for use with equations 1 through 6
percent of the patients whose carboplatin dose was deter- have not been published.
mined pharmacokinetically had a measured AUC within 20%
of the target AUC, compared with 49% of patients whose car- ESTIMATING RATHER THAN MEASURING
boplatin dose was calculated according to their BSA.17 GFR
A variation of Newell’s formula—equation 6—was used Since direct measurement of GFR can be inconvenient
to determine the carboplatin dose for some patients in a trial and costly,20 a number of alternative methods for determining
of carboplatin, etoposide and bleomycin for nongonadal renal function have been reported. The two most common
germ cell tumors.18 methods of estimating renal function are the Cockcroft and
Gault21 (CGF) and the Jelliffe22 (JF) methods.
Equation 618 In their review, Wright et al advised against use of the
Carboplatin dose (mg) = CGF method as a means of estimating the GFR for carbo-
6 x [uncorrected GFR + [15 x BSA)] platin dosing because “[it is] derived in an inappropriate
patient population, takes no account of non-GFR elimination
where: of creatinine and is highly dependent on the method used to
1. 6 = Target AUC, measure creatinine in serum.”20 In a commentary on Newell’s
2. GFR is the patient’s glomerular filtration rate, paper,15 Hande stated, “carboplatin AUC can be accurately
3. 15 is a constant representing nonrenal clearance, and predicted based on simple laboratory tests available to all
4. BSA is the patient’s body surface area in m2. oncologists: a serum creatinine or creatinine clearance.”23
However, neither of these methods were used by Newell
For example, the carboplatin dose required to reach the to derive the formula, or in Thomas’ trial.17 Nor did any of the
desired AUC of 6 for a patient with a GFR of 90 mL/minute groups who developed pharmacokinetic-based formulas val-
and a BSA of 0.75 m2 is 607.5 mg. idate their methodology using estimates of GFR based on
In this trial, the GFR for some patients was estimated serum creatinine or creatinine clearance measurements or
from the serum creatinine; other patients in the study had estimates.10–14 Accordingly, use of such estimates in any of
their GFR measured by 51Cr-EDTA clearance. The methods the methods reported for pharmacokinetic-based dosing of
used to calculate the BSA or the GFR from the serum crea- carboplatin in pediatric patients cannot be recommended.
tinine were not specified. The patients whose carboplatin
938 Volume 37, September 2002
Cancer Chemotherapy Update
REFERENCES cer Chemother Pharmacol. 1996;38(5):395–400.
1. Egorin MJ, Van Echo DA, Tipping SJ, et al. Pharmacoki- 14.Murry DJ, Sandlund JT, Stricklin LM, et al. Pharmacoki-
netics and dosage reduction in cis-diammine(1,1-cyclobu- netics and acute renal effects of continuously infused carbo-
tanedicarboxylato)platinum in patients with impaired renal platin. Clin Pharmacol Ther. 1993;54(4):374–80.
function. Cancer Res. 1984;44:5432–8.
15.Newell DR, Pearson AD, Balmanno K, et al. Carboplatin
2. Newell DR, Siddik ZH, Gumbrell LA, et al. Plasma free pharmacokinetics in children: The development of a pediatric
platinum concentrations in patients treated with high dose dosing formula. The United Kingdom Children’s Cancer
carboplatin. Eur J Cancer Clin Oncol. 1987;23:1399–1405. Study Group. J Clin Oncol. 1993;11(12):2314–23.
3. Harland SJ, Gumbrell LA, Horwich A. Carboplatin dose in 16.Calvert AH, Newell DR, Balmanno K, et al. Pharmacoki-
combination chemotherapy for testicular cancer. Eur J Can- netics of carboplatin in children and the development of a
cer. 1991;27:691–5. paediatric dose equation. In: Howell SB (ed.). Platinum and
Other Coordination Compounds in Cancer Chemotherapy.
4. Horwich A, Dearnaley DF, Nichols J, et al. Effectiveness New York, NY: Plenum; 1991, 335-343.
of carboplatin, etoposide and bleomycin combination
chemotherapy in good prognosis metastatic testicular non- 17.Thomas H, Boddy AV, English MW, et al. Prospective val-
seminomatous germ cell tumors. J Clin Oncol. 1991;9:62–9. idation of renal function-based carboplatin dosing in children
with cancer: A United Kingdom Children’s Cancer Study
5. Jodrell DI, Egorin MJ, Canetta RM, et al. Relationship Group Trial. J Clin Oncol. 2000;18(21):3614–21.
between carboplatin exposure and tumor response and tox-
icity in patients with ovarian cancer. J Clin Oncol. 18.Mann JR, Raafat F, Robinson K, et al. UKCCSG’s germ
1998;10:520–8. cell tumour (GCT) studies: Improving outcome for children
with malignant extracranial nongonadal tumours—carbo-
6. Jones A, Wiltshaw E, Harper P, et al. A randomized study platin, etoposide, and bleomycin are effective and less toxic
of high vs conventional dose carboplatin for previously than previous regimens. United Kingdom Children’s Cancer
untreated ovarian cancer. Br J Cancer. 1992;65(suppl Study Group. Med Pediatr Oncol. 1998;30(4):217–27.
19.Rahn KH, Heidenreich S, Bruckner D. How to assess
7. van der Vijgh WJF. Clinical pharmacokinetics of carbo- glomerular function and damage in humans. J Hypertens.
platin. Clinical Pharmacokinet. 1991; 21:242–61. 1999;17:309–17.
8. Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin 20.Wright JG, Boddy AV, Highley M, et al. Estimation of
dosage: Prospective evaluation of a simple formula based on glomerular filtration rate in cancer patients. Br J Cancer.
renal function. J Clin Oncol. 1989;7:1748–56. 2001;84(4):452–9.
9. Waddell JA, Solimando DA. Verifying carboplatin dose 21.Cockcroft DW, Gault MH. Prediction of creatinine clear-
calculations with the Calvert formula and the modified ance from serum creatinine. Nephron. 1976;16(1):31–41.
Calvert formula in adult patients. Hosp Pharm. 35(9):914–22.
22.Jeliffe R. Creatinine clearance: Bedside estimate. Ann
10.Pinkerton CR, Broadbent V, Horwich A, et al. “JEB”: A Intern Med. 1973;79(4):604–5.
carboplatin based regimen for malignant germ cell tumours
in children. Br J Cancer. 1990;62(2):257–62. 23.Hande KR. Pharmacologic-based dosing of carboplatin:
A better method. J Clin Oncol. 1993;11(12):2295–6. n
11. Marina NM, Rodman J, Shema SJ, et al. Phase I study of
escalating targeted doses of carboplatin combined with ifos-
famide and etoposide in children with relapsed solid tumors.
J Clin Oncol. 1993;11(3):554–60.
12.Marina NM, Rodman JH, Murry DJ, et al. Phase I study of
escalating targeted doses of carboplatin combined with ifos-
famide and etoposide in treatment of newly diagnosed pedi-
atric solid tumors. J Natl Cancer Inst. 1994;86(7):544–8.
13.Tonda ME, Heideman RL, Petros WP, et al. Carboplatin
pharmacokinetics in young children with brain tumors. Can-
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