Evaluation of serum iohexol clearance for use in predicting carboplatin clearance in cats

Dennis B. Bailey Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

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Kenneth M. Rassnick Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

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Joshua D. Prey Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263.

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Nathan L. Dykes Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853.

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Abstract

Objective—To determine whether a glomerular filtration rate (GFR) assay based on serum iohexol clearance can be used to predict carboplatin clearance in cats.

Animals—10 cats with tumors.

Procedures—GFR was measured concurrently by use of plasma clearance of technetium Tc 99m–labeled diethylenetriaminepentaacetic acid (99mTc-DTPA) to yield GFR99mTc-DTPA and serum clearance of iohexol to yield GFRIohexol. A single dose of carboplatin was administered IV as a bolus. Dose was calculated by use of a target value for the area under the plasma platinum concentration-versus-time curve (AUCTarget) and estimation of platinum clearance (CLPT) derived from GFR99mTc-DTPA as follows: dose = AUCTarget × 2.6 × GFR99mTc-DTPA × body weight, where AUCTarget is 2.75 min·mg·mL−1. Plasma platinum concentrations were measured via atomic absorption spectrophotometry. Values for GFR99mTc-DTPA and GFRIohexol were compared by use of least-squares regression and Bland-Altman analysis. Least-squares regression was used to determine whether CLPT could be predicted from GFR99mTc-DTPA or GFRIohexol (or both).

Results—GFR99mTc-DTPA and GFRIohexol were strongly correlated (r = 0.90), but GFRIohexol values were significantly larger by a factor of approximately 1.4. Platinum clearance had a significant linear relationship to GFR99mTc-DTPA (CLPT = 2.5 × GFR99mTc-DTPA) and to GFRIohexol (CLPT = [1.3 × GFRIohexol] + 1.4).

Conclusions and Clinical Relevance—In cats, serum iohexol clearance was an accurate predictor of CLPT and can be used to calculate the carboplatin dose as follows: dose = AUCTarget × ([1.3 × GFRIohexol] + 1.4) × body weight.

Abstract

Objective—To determine whether a glomerular filtration rate (GFR) assay based on serum iohexol clearance can be used to predict carboplatin clearance in cats.

Animals—10 cats with tumors.

Procedures—GFR was measured concurrently by use of plasma clearance of technetium Tc 99m–labeled diethylenetriaminepentaacetic acid (99mTc-DTPA) to yield GFR99mTc-DTPA and serum clearance of iohexol to yield GFRIohexol. A single dose of carboplatin was administered IV as a bolus. Dose was calculated by use of a target value for the area under the plasma platinum concentration-versus-time curve (AUCTarget) and estimation of platinum clearance (CLPT) derived from GFR99mTc-DTPA as follows: dose = AUCTarget × 2.6 × GFR99mTc-DTPA × body weight, where AUCTarget is 2.75 min·mg·mL−1. Plasma platinum concentrations were measured via atomic absorption spectrophotometry. Values for GFR99mTc-DTPA and GFRIohexol were compared by use of least-squares regression and Bland-Altman analysis. Least-squares regression was used to determine whether CLPT could be predicted from GFR99mTc-DTPA or GFRIohexol (or both).

Results—GFR99mTc-DTPA and GFRIohexol were strongly correlated (r = 0.90), but GFRIohexol values were significantly larger by a factor of approximately 1.4. Platinum clearance had a significant linear relationship to GFR99mTc-DTPA (CLPT = 2.5 × GFR99mTc-DTPA) and to GFRIohexol (CLPT = [1.3 × GFRIohexol] + 1.4).

Conclusions and Clinical Relevance—In cats, serum iohexol clearance was an accurate predictor of CLPT and can be used to calculate the carboplatin dose as follows: dose = AUCTarget × ([1.3 × GFRIohexol] + 1.4) × body weight.

Carboplatin (cis-diammine-1,1-cyclobutanedicarboxylate platinum [II]) is active against a wide range of carcinomas and sarcomas in cats.1–5 The dose-limiting toxicosis for carboplatin in cats is neutropenia.1,2,6,7 Historically, dosing has been based on BSA, but this dosing strategy does not consistently predict the severity of carboplatin-associated neutropenia.1,2,6 Platinum AUC is a better predictor of carboplatin-associated neutropenia in cats.1,6 In other studies1,6 conducted by our laboratory group, a dosing strategy was derived on the basis of a targeted platinum AUC, estimated CLPT derived from patient GFR, and BWkg by use of the following equation: carboplatin dose = AUCTarget × (2.6 × GFR) × BWkg. By use of this dosing strategy, there is a steep and clearly defined relationship between AUCTarget and carboplatin-associated neutropenia; the maximum tolerated AUCTarget is 2.75 min·mg·mL−1.6

When deriving and prospectively evaluating this equation, patient GFR was calculated on the basis of plasma clearance of the radionuclide 99mTc-DTPA.1,6 This technique for GFR assessment yields results comparable to those obtained for inulin or exogenous creatinine clearance, and it is much less technically demanding because anesthesia and urinary catheter placement are not required.8,9 Unfortunately, few veterinary hospitals are able to provide nuclear medicine services. Plasma or serum clearance of iohexol is an accurate method for estimating GFR.10–12 The HPLC or x-ray fluorescence assays used to measure iohexol concentrations have not been widely available, but an HPLC-based assay recently became commercially available for use in samples obtained from dogs and cats.a This assay has been validated for use in samples obtained from dogs13 but not for those obtained from cats.b Additionally, although different GFR assays may yield similar results, those results may not be interchangeable. There is a steep dose-response curve for carboplatin-associated neutropenia when this dosing strategy is used. Thus, before replacing plasma 99m Tc-DTPA clearance with a different measurement of GFR (such as serum iohexol clearance), it is important to validate that the new assay can be used to predict CLPT.

The purpose of the study reported here was to determine whether serum iohexol clearance could be used to predict plasma CLPT in tumor-bearing cats. A secondary objective was to determine the agreement between GFR99mTc-DTPA and GFRIohexol.

Materials and Methods

Animals—Client-owned cats with histologically confirmed solid tumors were used in the study. Cats from which tumors had been surgically excised were eligible for inclusion, but cats that had received any chemotherapeutic drugs or radiation therapy were excluded. Cats were not excluded on the basis of concurrent illnesses, including any that potentially could have affected GFR (eg, renal insufficiency or hyperthyroidism). All owners provided written consent for participation of their cats, and the study design was approved by the Cornell University Institutional Animal Care and Use Committee. After completing this study, cats were allowed to continue treatment with carboplatin (when indicated) or other treatments, including surgery, radiation therapy, other chemotherapeutics, or a combination of these.

The target sample size was 10 cats. On the basis of another study1 conducted by our laboratory group, the R2 was 0.77 for the regression analysis that used plasma99m Tc-DTPA clearance to predict CLPT, and the corresponding r was 0.88. Assuming that there would be a similarly strong relationship between serum iohexol clearance and CLPT (ie, r ≥ 0.80), 10 cats would be needed to detect this relationship by use of an α of 0.05 and β of 0.10.14 When GFR measurements based on serum or plasma iohexol clearance and urine exogenous creatinine clearance were compared in cats,12,15 the resulting r was > 0.90. Similarly, when iohexol and 99mTc-DTPA clearance rates were compared in dogs,16 the r was > 0.90. Maintaining α at 0.05 and β at 0.10, as the strength of the correlation (ie, r) increases, the required sample size decreases. Therefore, 10 cats also would be sufficiently adequate to compare GFRIohexol and GFR99mTc-DTPA.

Measurement of GFR—For each cat, GFR was measured concurrently by use of plasma 99m Tc-DTPA clearance and serum iohexol clearance. A catheter was placed in a peripheral vein for injection of 99mTc-DTPA and iohexol, and a second catheter was placed in a central vein for collection of samples. Approximately 500 MCi of 99mTc-DTPA was injected IV as a bolus via the catheter in the peripheral vein. Immediately after that injection, iohexolc (300 mg of iodine/kg) was administered IV as a bolus via the same catheter. The completion of the iohexol injection was designated as time 0. After both injections were administered, blood samples were collected from the catheter in the central vein at 15, 30, 60, 180, and 240 minutes and immediately placed in EDTA-containing tubes. Blood samples also were collected at 120, 180, and 240 minutes and placed into clot tubes. All tubes were centrifuged, and plasma or serum was harvested.

Radioactivity of the plasma samples was counted by use of a sodium iodide well counterd within 2 hours after the last blood sample was collected. Values for the samples were fit to a 1-compartment monoexponential model, and AUC was calculated as C0/k, where C0 is the extrapolated radioactivity at time 0 and k is the elimination constant (slope) of the decay curve. Clearance of 99mTc-DTPA was calculated by dividing the injected dose of 99mTc-DTPA by AUC and body weight. All calculations were performed by use of a computer software program.e

Serum samples were refrigerated and stored for a minimum of 48 hours (the half-life of 99m Tc is 6.04 hours). Once the samples were confirmed to no longer be radioactive, they were shipped to a university-based laboratory.a Iohexol concentration was measured by use of HPLC, and clearance of iohexol was calculated by use of a 1-compartment monoexponential pharmacokinetic model. Use of this assay for samples obtained from dogs has been reported elsewhere.13

Carboplatin administration and pharmacokinetic analysis—Each cat received a single carboplatin treatment the day after GFR assessments were performed. Carboplatin dose was calculated by use of a previously derived equation1,6:

article image

where AUCTarget = 2.75 min·mg·mL−1. The carboplatin dose was administered IV as a bolus via a peripheral vein (but not the peripheral vein used for injection of 99mTc-DTPA and iohexol). Blood samples were collected via the central venous sampling catheter into heparinized tubes immediately before (time 0) and 15, 30, 60, 90, 120, 240, and 480 minutes after carboplatin administration. All samples were centrifuged immediately, and the plasma was separated and stored at −70°C until the platinum assay was performed.

Plasma platinum concentration was measured by use of an atomic absorption spectrophotometer with a platform graphite furnace equipped with an autosampler and accompanying computer software.f Plasma was diluted 1:10 in a diluent consisting of 0.2% nitric acid and 0.1% Triton X-100. Then, 20 μL of the diluted plasma was injected. Analytic standards were prepared in plasma diluted 1:10 with the same diluent. Concentrations used to create the standard curve ranged from 25 to 800 ng/mL. The program for the graphite furnace consisted of drying at 130° and 150°C, pyrolosis at 1,400°C, atomization at 2,200°C, and clean out at 2,400°C. Quality-control samples were analyzed at the beginning and end of each analysis to ensure assay integrity.

Noncompartmental pharmacokinetic analysis was performed by use of a computer software program.g Plasma platinum AUC was calculated for each cat by use of the trapezoidal rule, with no correction for the interval from the final time point to infinity. The CLPT was calculated by dividing the carboplatin dose by AUC and body weight.

Statistical analysis—The 99m Tc-DTPA and iohexol clearance values were compared multiple ways. First, the Wilcoxon signed rank test was used to determine whether the GFR values for these techniques were the same. When the values differed, then a Spearman correlation was used to determine whether the 2 values were significantly related, and least-squares regression was used to determine whether iohexol clearance could be predicted from 99mTc-DTPA clearance. Finally, Bland-Altman analysis was used to compare GFR values based on serum iohexol clearance and plasma 99mTc-DTPA clearance. This statistical analysis often is considered preferable to correlation analysis because it takes into account the fact that both values are approximations of the actual GFR of a patient; therefore, both are subject to sampling error and bias.17 In brief, the Bland-Altman analysis is a graphic analysis in which, for each patient, the difference between the 2 clearance values is plotted against the mean value. If all points cluster around the x-axis, and no relationship between the difference and the mean is identified, then it can be assumed that GFR values based on serum iohexol clearance and plasma 99mTc-DTPA clearance are interchangeable and the aforementioned carboplatin dosing equation can be used with either GFR measurement technique.

Least-squares regression was used to determine whether plasma 99m Tc-DTPA clearance and serum iohexol clearance could be used to predict CLPT. When a significant linear mathematic relationship was identified, the 95% CI for the slope and y-intercept were calculated. The 95% CIs for each regression line were compared to determine whether they differed. Also, they were compared with the values derived from the regression analysis performed in another study1 conducted by our laboratory group (slope = 2.6, y-intercept = 0) to determine whether results from the study reported here differed from those in our previous study. If needed, the dosing equation for each GFR measurement technique was modified accordingly.

For all calculations, a 2-sided test with P < 0.05 was considered significant. All calculations were performed by use of a computer software program.g

Results

Ten cats were enrolled in the study from July 2007 to August 2008. Breeds included were domestic short-hair (n = 6 cats), domestic longhair (2), Maine Coon (1), and Persian (1). There were 8 castrated males and 2 spayed females. Median age was 11 years (range, 7 to 13 years), and median body weight was 5.5 kg (range, 3.6 to 7.8 kg). Six cats had sarcomas; these included subcutaneous fibrosarcoma (n = 4 cats), cutaneous hemangiosarcoma (1), and intra-abdominal extraskeletal chondrosarcoma (1). Four cats had carcinomas; these included oral squamous cell carcinoma (n = 1 cat), cutaneous squamous cell carcinoma (1), mammary gland adenocarcinoma (1), and pulmonary carcinoma (1). Carboplatin-associated hematologic information for 6 of these cats has been reported elsewhere.6

Of the 10 cats, 1 was azotemic (BUN concentration, 52 mg/dL; reference range, 17 to 35 mg/dL; creatinine concentration, 3.7 mg/dL; reference range, 0.7 to 2.3 mg/dL) and isosthenuric (urine specific gravity, 1.012). Another cat with a history of renal insufficiency had a creatinine concentration within the high part of the reference range (2.0 mg/dL) and an increased BUN concentration (41 mg/dL) and poorly concentrated urine (1.014). Nonrenal causes for the increased BUN concentration were not identified in this cat.

Median GFR99mTc-DTPA for all 10 cats was 1.88 mL·min−1·kg−1 (range, 0.73 to 2.43 mL·min−1·kg−1). Median GFRIohexol was 2.48 mL·min−1·kg−1 (range, 0.68 to 4.09 mL·min−1·kg−1). Overall, GFRIohexol was significantly (P = 0.006) higher than GFR99mTc-DTPA. A scatterplot of GFRIohexol versus GFR99mTc-DTPA was generated (Figure 1). The 2 GFR values were strongly correlated (r = 0.90; P < 0.001). Least-squares regression revealed that GFRIohexol can be predicted from GFR99mTc-DTPA. The initial equation generated was GFRIohexol = (1.7 × GFR99mTc-DTPA) − 0.72 (R2 = 0.76; P = 0.001). However, the y-intercept was not significantly different from 0 (95% CI, −2.2 to 0.82). Therefore, the regression analysis was repeated by forcing the regression line through the origin. The resulting equation was GFRIohexol = 1.4 × GFR99mTc-DTPA (P < 0.001), which indicated that GFRIohexol typically was larger than GFR99mTc-DTPA by a factor of 1.4. This was further supported by the Bland-Altman analysis, which revealed that as the mean GFR increased, the difference between the GFR values for the 2 measurements increased (Figure 2).

Figure 1—
Figure 1—

Scatterplot of GFR based on serum iohexol clearance versus GFR based on plasma 99mTc-DTPA clearance in 10 tumor-bearing cats. The values are significantly correlated (r = 0.90; P = 0.006). The regression line (r = 0.90; P < 0.001) is described by the following equation: GFRIohexol = 1.4 × GFR99mTc-DTPA.

Citation: American Journal of Veterinary Research 70, 9; 10.2460/ajvr.70.9.1135

Figure 2—
Figure 2—

Bland-Altman plot comparing simultaneous GFR values based on serum iohexol clearance and plasma 99mTc-DTPA clearance in 10 tumor-bearing cats. The difference between the 2 values (GFRIohexol − GFR99mTc-DTPA) is plotted on the y-axis, and the mean of the 2 values is plotted on the x-axis.

Citation: American Journal of Veterinary Research 70, 9; 10.2460/ajvr.70.9.1135

For all 10 cats, carboplatin was prescribed at an AUCTarget of 2.75 min·mg·mL−1. The median absolute carboplatin dose was 75.9 mg (range, 22.7 to 105.11 mg). Dividing the absolute dose by the BSA of the cats yielded a resulting median dosage of 239.0 mg/m2 (range, 85.5 to 310.6 mg/m2). When total platinum concentration was measured by use of atomic absorption spectrophotometry, the median AUC was 2.95 min·mg·mL−1 (range, 1.89 to 3.88 min·mg·mL−1). Median CLPT was 4.20 min/mL/kg (range, 2.78 to 7.59 mL/min/kg).

A scatterplot of CLPT versus GFR99mTc-DTPA was generated (Figure 3). Least-squares regression revealed that CLPT can be predicted from GFR99mTc-DTPA. The initial equation generated (R2 = 0.61; P = 0.008) was CLPT = (2.2 × GFR99mTc-DTPA) + 0.57. The y-intercept was not significantly different from 0 (95% CI, −2.2 to 3.4). Therefore, the regression analysis was repeated by forcing the line through the origin. The resulting equation (P < 0.001) was CLPT = 2.5 × GFR99mTc-DTPA. The 95% CI for the slope of this equation was 2.1 to 2.8, which indicated that the results of the study reported here did not differ from those obtained in our initial study1 (slope = 2.6; 95% CI of slope = 2.2 to 3.0; and y-intercept = 0) in which 99mTc-DTPA was used to predict CLPT.

Figure 3—
Figure 3—

Scatterplot of CLPT versus GFR based on plasma 99mTc-DTPA clearance in 10 tumor-bearing cats. Carboplatin was administered on the basis of the following equation: dose = AUCTarget × 2.6 × GFR99mTc-DTPA × BWkg, where AUCTarget was set at 2.75 min·mg·mL−1 for all cats. The regression line (P < 0.001) is described by the following equation: CLPT = 2.5 × GFR99mTc-DTPA.

Citation: American Journal of Veterinary Research 70, 9; 10.2460/ajvr.70.9.1135

A scatterplot of CLPT versus GFRIohexol was generated (Figure 4). Least-squares regression revealed that CLPT ccould be predicted from GFRIohexol by use of the following equation: CLPT = (1.3 × GFRIohexol) + 1.4 (R2 = 0.83; P < 0.001). The 95% CI for the slope was 0.82 to 1.7, and the 95% CI for the y-intercept was 0.12 to 2.7, which indicated that this regression equation differed significantly from the equations relating CLPT with GFR99mTc-DTPA derived in the study reported here and our initial study.1 Therefore, carboplatin can be dosed in cats on the basis of a targeted AUC and an estimation of CLPT derived from GFRIohexol; however, the dosing equation needed to be modified when GFR was measured by use of serum iohexol clearance rather than plasma 99mTc-DTPA clearance, and that modified equation was as follows: dose = AUCTarget × ([1.3 × GFRIohexol] + 1.4) × BWkg.

Figure 4—
Figure 4—

Scatterplot of CLPT versus GFR based on serum iohexol clearance for the same 10 tumor-bearing cats described in Figure 3. The regression line (R2 = 0.83; P < 0.001) is described by the following equation: CLPT = (1.3 × GFRIohexol) + 1.4.

Citation: American Journal of Veterinary Research 70, 9; 10.2460/ajvr.70.9.1135

Discussion

Carboplatin-associated neutropenia is predicted more accurately and consistently when dosing is based on a targeted AUC and estimation of CLPT derived from patient GFR rather than conventional dosing based on patient BSA.1,6 Despite the advantage of this dosing strategy, widespread use of it has been greatly limited by the lack of techniques to measure patient GFR that are technically simple and readily available. Results of the study reported here validated the use of a GFR assay that does not require special patient preparation or handling of samples, requires collection of only 3 blood samples, is commercially available, and is relatively inexpensive.

Plasma 99mTc-DTPA and serum iohexol clearance values were strongly correlated but not interchangeable. The serum iohexol clearance values were significantly larger by a factor of 1.4. This difference could be explained by the fact that 5% to 10% of the 99mTc activity is associated with plasma proteins, whereas only 1.5% of iohexol is bound to plasma proteins.18–20 Only unbound 99mTc-DTPA or iohexol will be filtered and cleared by the kidneys; therefore, as protein binding increases, total plasma or serum clearance will decrease artifactually. Also, although the pharmacokinetic modeling methods used for the clearance calculations were the same for each assay, the collection time points differed. More specifically, the 99mTc-DTPA assay included additional earlier time points when the effects of distribution are likely to be more important.21 However, the impact of sample number and sample collection times was minimal, and the resulting margin of error was within acceptable limits for clinical practice.22,23 Nonetheless, had comparison of 99mTc-DTPA and iohexol clearance values been the primary objective of the study, the sample collection times should have been standardized. However, the primary objective of the study was to compare the use of 2 established GFR assays in predicting CLPT, and the chosen time points reflected those 2 assays.1,a

The regression analysis in which the relationship between CLPT and GFR99mTc-DTPA was evaluated yielded an equation that was similar to the equation generated in our initial study1 comparing these 2 values, which indicated that this relationship is consistent and repeatable. The consistency between CLPT and GFR99mTc-DTPA reinforces the fact that the relationship between CLPT and GFRIohexol truly differs. Additionally, although GFRIohexol and GFR99mTc-DTPA differed by a factor of 1.4, the regression equations relating CLPT to GFRIohexol and GFR99mTc-DTPA did not differ by the same factor. The slopes of the lines were 1.3 and 2.5, respectively, which yielded a factor of 1.9. The y-intercepts differed as well (1.4 and 0 mg/mL, respectively). The reasons for these differences are unknown, but they likely reflected differences in distribution, metabolism, and nonrenal elimination between carboplatin, 99mTc-DTPA, and iohexol. They also emphasized the importance of validating each new GFR assay by directly comparing GFR values to CLPT rather than by indirectly comparing the results of a new GFR assay with results of a previously validated GFR assay.

Slope of the new regression equation that compared CLPT to GFRIohexol (ie, 1.3) was not significantly different from 1 (95% CI, 0.83 to 1.8). This result is in agreement with the finding that carboplatin is eliminated primarily by passive glomerular filtration in humans and rodents.24–27 However, this has not been verified by measuring fractional urinary excretion of carboplatin in cats. The y-intercept represents nonrenal CLPT. Consistent with the convention in veterinary medicine, clearance measurements reported here were standardized on the basis of body size. Therefore, nonrenal clearance was estimated to be 1.4 mL·min−1·kg−1. In humans, no correlation was detected between BSA and nonrenal clearance24; consequently, nonrenal clearance in people is estimated as a fixed amount, irrespective of patient size. However, it is recognized that nonrenal clearance is primarily through tissue binding, which is dependent on body size.24,27 Therefore, it is plausible to expect nonrenal clearance to depend on body size. Regardless, there is only a modest difference in body weight among cats (range in the study reported here, 3.6 to 7.8 kg), and differences in body size would be expected to have only a minimal effect on CLPT.

Iohexol administration was tolerated well by all cats in this study, and no adverse effects were reported in other studies of cats10–12,15,23 or dogs10,13,15,16,23,28 in which iohexol was used to assess GFR. In human medicine, the use of IV administration of iodinated contrast media for diagnostic and interventional purposes is much more common, but serious adverse effects (including allergic reactions and nephrotoxicosis) have been reported rarely.29–33 Predisposing factors for nephrotoxicosis include underlying renal disease, diabetes mellitus, NSAID use, and hypotension.29–31 For humans at increased risk for contrast media–induced nephropathy, IV administration of fluids for several hours before and after iohexol administration is recommended.29 This also should be considered in cats with known renal insufficiency. This should have minimal impact on GFR measurement; in healthy cats, concurrent IV administration of fluids at a rate of 6 mL·kg−1·h−1 did not alter GFR values based on urine inulin clearance or plasma 99mTc-DTPA clearance.8

Measuring serum iohexol clearance is a simple and accurate method for use in predicting CLPT in cats. Although the use of the carboplatin dosing equation reported here needs to be evaluated prospectively, given that the correlation between CLPT and GFRIohexol was greater than that between CLPT and GFR99mTc-DTPA (R2 = 0.83 vs R2 = 0.61), this dosing equation is expected to be at least as effective for use in predicting carboplatin-associated neutropenia as the dosing equation derived in our initial study.1 The maximum tolerated AUC should remain constant at 2.75 min·mg·mL−1. Platinum AUC is an accurate independent predictor of carboplatin-associated neutropenia, and although it is closely related to drug clearance, it should not be affected by the choice of GFR assay used to predict drug clearance.1,25 Therefore, when serum iohexol clearance is used to estimate CLPT, carboplatin should be dosed in cats in accordance with the following equation: dose = 2.75 min·mg·mL−1 × ([1.3 × GFRIohexol] + 1.4) × BWkg.

ABBREVIATIONS

AUC

Area under the plasma concentration-versus-time curve

AUCTarget

Target value for area under the plasma platinum concentration-versus-time curve

BSA

Body surface area

BWkg

Body weight in kilograms

CI

Confidence interval

CLPT

Platinum clearance

GFR

Glomerular filtration rate

GFR99mTc-DTPA

Glomerular filtration rate based on plasma clearance of technetiumTc 99m–labeled diethylenetriamine-pentaacetic acid

GFRIohexol

Glomerular filtration rate based on serum clearance of iohexol

HPLC

High-performance liquid chromatography

99mTc-DTPA

TechnetiumTc 99m–labeled diethylene-triaminepentaacetic acid

a.

Diagnostic Center for Population and Animal Health, Michigan State University, East Lansing, Mich.

b.

Braselton WE, Michigan State University, East Lansing, Mich: Personal communication, 2007.

c.

Omnipaque 350, Amersham Health, Princeton, NJ.

d.

Ortec, Oak Ridge, Tenn.

e.

Quattro Pro, Corel Inc, Ottawa, ON, Canada.

f.

AAnalyst 600 atomic absorption spectrophotometer with Winlab 32 computer software, PerkinElmer, Waltham, Mass.

g.

Prism 4, GraphPad Software, San Diego, Calif.

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