Carboplatin Clearance Research Articles

Carboplatin Dosing with the Calvert Formula for Adult Japanese Patients with Renal Insufficiency

ABSTRACT Aim: Carboplatin dosing is usually calculated with the Calvert formula on the basis of the patient's glomerular filtration rate (GFR) to achieve the target area under the plasma drug concentration - time curve (AUC) for each patient: Dose(mg)= target AUC(mg/ml×min)×[GFR(ml/min)+ 25]. However, the practical application of the Calvert formula in adult Japanese patients with renal insufficiency has not been studied. Methods: Between February 2011 and July 2013, 9 adult Japanese patients who had estimated GFR (eGFR) lower than 30 mL/min/1.73m2 or were on maintenance hemodialysis (HD) were studied for carboplatin pharmacokinetics after 1-hour infusion of the drug, which were combined with etoposide, gemcitabine, or paclitaxel in the treatment of their advanced cancers. The dosage of carboplatin was calculated with the Calvert formula, in which GFR was directly measured by inulin clearance or was assumed to be 0 in those requiring HD. HD was started 23 hours after the end of carboplatin infusion. Plasma concentrations of free platinum were measured with inductively coupled plasma-mass spectrometry. Results: Although there was a good correlation between estimated (GFR+25) and measured carboplatin clearances, the estimated clearances were constantly higher than the measured (MPE±SE=41 ± 10%) among all the 7 patients with renal insufficiency (eGFR, median 22.4, range 14.8 - 26.6 mL/min/1.73m2; inulin clearance, median 21.4, range 7.8 - 31.4 mL/min) and the 2 hemodialysis patients. Actual AUC were 5.4, 5.7, 6.2, and 9.0 for 4 patients with the target AUC of 5; 5.7, 6.2, and 7.1 for 3 with the target AUC of 4; and 5.1 and 8.7 for the two HD patients with the target AUC of 5 in both. The pre-dialysis carboplatin clearances of the HD patients were 20.5 and 11.1 ml/min, suggesting that the constant value of 25 of the Calvert formula, which closely corresponded to the non-renal clearance, might be too high for adult Japanese patients, particularly when they have renal insufficiency. Conclusions: For adult Japanese patients with renal insufficiency, even with the use of GFR exactly measured on the basis of inulin clearance, the Calvert formula inherently could cause carboplatin overdosing as a result of apparent overestimation of carboplatin clearance. Disclosure: Y. Yasuda: endowed chair : MSD, Dainippon Sumitomo Pharma, Chugai Pharmaceutical Co. Ltd., Kowa Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim, Nihon Medi-Physics Co. Ltd. Research support: Pfizer adviser to drug development: Astellas pharma Inc.; Y. Ando: Research support: Nippon Kayaku Co., Ltd. and Yakult Pharmaceutical industry Co., Ltd. Honoraria(lecture fee): Nippon Kayaku Co., Ltd. and Bristol-Myers Squibb Company Honoraria(manuscript fee): Janssen Pharmaceutical K.K. All other authors have declared no conflicts of interest.

Genome-wide association study for identification of candidate SNPs associated with carboplatin and paclitaxel clearance in ovarian cancer patients.

5563 Background: Epithelial ovarian cancer (EOC) is generally treated by cytoreductive surgery and carboplatin/paclitaxel chemotherapy. Five-year survival is ~20% for patients with advanced disease...

Dose adjustment of carboplatin in patients on peritoneal dialysis

The Calvert equation has been extensively used to determine the dosage of carboplatin. However, in patients on dialysis, it predicts the same dosage regardless of the frequency of dialysis. Clearance of carboplatin during hemodialysis has been studied to a lesser extent, but there have been very few studies which have investigated the clearance of carboplatin in patients on peritoneal dialysis. A mathematical formula is proposed here to predict the dose of carboplatin for a given AUC in patients on peritoneal dialysis. This formula takes into account the frequency of dialysis sessions and the time delay between carboplatin infusion and the initiation of dialysis. The formula predicts an approximately similar dosage of carboplatin as that of the Calvert formula in patients undergoing peritoneal dialysis four times per day if dialysis is initiated 12 h after infusion. The formula may help in guiding the adjustment of carboplatin dose in patients who receive a lesser number of dialysis sessions per day and in those patients whose dialysis is initiated at different times (0-24 h) after carboplatin infusion. It is suggested that usage of this formula will result in a better dosage of carboplatin to suit specific dialysis frequencies in specific patients and eventually may result in a better efficacy and toxicity profile.

Carboplatin dosing for adult Japanese patients.

Carboplatin is a platinum-based anticancer drug that has been long used to treat many types of solid cancer. Because the clearance of carboplatin strongly correlates with the glomerular filtration rate (GFR), its dosage is calculated with the Calvert formula on the basis of the patient's GFR to achieve the target area under the plasma drug concentration-time curve (AUC) for each patient. However, many lines of evidence from previous clinical studies should be interpreted with caution because different methods were used to estimate drug clearance and derive the dosage of carboplatin. There is a particularly high risk of carboplatin overdosing when the dosage is determined on the basis of standardized serum creatinine values. When deciding the dose of carboplatin for adult Japanese patients, preferred methods to assess renal function instead of directly measuring GFR include (1) 24-h urinary collection-based creatinine clearance adjusted by adding 0.2 mg/dl to the serum creatinine concentration measured by standardized methods, and (2) equation-based GFR (eGFR) with a back calculation to units of ml/min per subject. Given the limitations of serum creatinine-based GFR estimations, the GFR or creatinine clearance should be directly measured in each patient whenever possible. To ensure patient safety and facilitate a medical-team approach, the single most appropriate method available at each institute or medical team should be consistently used to calculate the dose of carboplatin with the Calvert formula.

O3-018 - Correlative Study of Low Serum Creatinine and Hematological Toxic Effects in Japanese Patients with Ovarian Cancer Treated by Dose Dense TC Therapy

ABSTRACT Background Dose dense TC (ddTC) is a novel standard therapy for patients with advanced ovarian cancer, although hematological toxic effects (hemTX), especially anemia, may increase as observed in NOVEL trial (JGOG3016). Low serum creatinine (LCr), especially Methods GFR was determined using the Cockcroft–Gault formula. Serum creatinine concentrations were measured using enzymatic assays. Minimum value of 0.7 mg/dl was not used during this period of time. The carboplatin clearance was then calculated by Calvert equation. HemTX were defined as, Grade 3 or 4 (by CTC-AE ver.4) neutropenia, anemia, and thrombocytopenia. Using electrical chart, the frequency of hemTX and correlation between serum creatinine ( Results From February 2010 to December 2011, 61 consecutive patients were treated with ddTC. LCr was observed in 73% of patients. No treatment-related death occurred. Among 61 patients, 50 (82%), 31 (51%), and 12 (19.6 %) patients experienced Grade 3/4 neutropenia, anemia and thrombocytopenia, respectively. HemTX in patients with LCr and the others were as in Table 1. Table 1 . HemTX in patients with and without LCr Patients with LCr G3/4 neutropenia 36 (80%) G3/4 anemia 24 (53.3%) G3/4 thrombocytopenia 9 (20%) Patients without LCr G3/4 neutropenia 14(87.5%) G3/4 anemia 7 (44%) G3/4 thrombocytopenia 3 (18.8%) Conclusions LCr is frequent in Japanese female patients. ddTC in practice setting seems safe, and hemTX of ddTC are similar with those observed in NOVEL trial. The rationale using a minimum value of 0.7 mg/dl should be further studied by larger population, such as patients in NOVEL trial.

Correlative study of low serum creatinine and hematological toxicities in Japanese patients with ovarian cancer treated by dose dense TC therapy.

5045 Background: Dose dense TC (ddTC) is a novel standard therapy for patients (pts) with advanced ovarian cancer, although hematological toxicities (hemTX), especially anemia, may increase as observed in NOVEL trial (JGOG3016). Low serum creatinine (LCr), especially below 0.7 mg/dl, may lead to overestimation of GFR. GOG announced that pts with LCr should use a minimum value of 0.7mg/dl to estimate GFR. The correlation between LCr and hemTX treated by ddTC is unknown. Methods: GFR was determined using the Cockcroft-Gault formula. Serum creatinine concentrations were measured using enzymatic assays. Minimum value of 0.7 mg/dl was not used during this period of time. The carboplatin clearance was then calculated by Calvert equation. HemTX were defined as, Grade 3 or 4 (by CTC-AE ver.4) neutropenia, anemia, and thrombocytopenia. Using electrical chart, frequency of hemTX and correlation between serum creatinine (less than 0.7 or not) were examined. Results: From Feb. 2010 to Dec. 2011, 61 consecutive pts were treated with ddTC. LCr was observed in 73% of pts. No treatment related death occurred. Among 61 pts, 50 (82%), 31 (51%), and 12 (19.6 %) pts experienced Grade3/4 neutropenia, anemia and thrombocytopenia, respectively. HemTX in pts with LCr and the others were as in the Table. Conclusions: LCr is frequent in Japanese female pts. ddTC in practice setting seems safe, and hemTX of ddTC are similar with those observed in NOVEL trial. The rationale using a minimum value of 0.7 mg/dl should be further studied by larger population, such as pts in NOVEL trial. [Table: see text]

The role of gender in predicting for reduced drug clearance and increased toxicity in non-small cell lung cancer (NSCLC) patients receiving carboplatin and paclitaxel.

7557 Background: There is wide variability in toxicity from chemotherapy attributed to multiple factors including pharmacogenomic (PG), ethnic and nutritional differences. Gender differences in tolerance of anticancer drugs have also been described. The aim of this ongoing study was to investigate predictors of toxicity in advanced NSCLC patients receiving palliative chemotherapy. Methods: Stage III-IV NSCLC patients, receiving paclitaxel (175 mg/m2) and carboplatin (AUC 6) 3 weekly were enrolled. Demographic, nutritional and inflammatory data were collected at baseline. Plasma samples were collected using a limited sampling strategy and drug concentrations measured using ICP-MS for carboplatin and LC-MS for paclitaxel. Empiric Bayesian estimates of clearance (CL) were obtained using population pharmacokinetic (PK) analyses and NONMEM software. Toxicities, monitored weekly in cycle 1, were graded according to CTCAEv3.0 and correlated with the PK data. Results: Forty-four male and 20 female patients were recruited. Median age was 63 years for both men and women. Women experienced more peripheral sensory neuropathy (73.7% vs. 33.3%, p = 0.003), stomatitis (26.3% vs. 7.1%, p = 0.04) and grade 2-3 vomiting (26.3% vs. 7.1%, p = 0.04) than men. There were no significant gender differences in haematological toxicities. PK analyses showed that women had lower paclitaxel CL (10.5 L/h vs. 13.0 L/h, p < 0.0001) and carboplatin CL (7.3 L/h vs. 9.3 L/h, p < 0.0001) than men. Median survival was longer for women (18.4 vs. 16.0 months), although this was not statistically significant. Asians had significant slower clearance of paclitaxel than Caucasians (11.1 L/h vs. 12.7 L/h, p = 0.044). Conclusions: Women with NSCLC had lower clearance of both carboplatin and paclitaxel than men, which was associated with an increased incidence of non-haematological toxicity. The causes for these differences should be explored with PG and metabonomic analyses.

Prospective evaluation of pharmacokinetically guided dosing of carboplatin in Japanese patients with cancer

The Calvert formula, that is, carboplatin dose (mg) = target area under the concentration versus time curve (AUC) × (glomerular filtration rate [GFR] + 25), has not been validated in Japanese subjects in whom the GFR was accurately measured. The purpose of this study is to evaluate the validity of this formula for Japanese patients with cancer and modify it for this population. The GFR was measured on the basis of inulin clearance, which is considered to reflect the accurate GFR. Inulin clearance was measured in 28 patients with cancer. The adjusted 24-h creatinine clearance (24-h Ccr) was unbiased (mean prediction error [MPE] ± SE = -2.3 ± 4.5%) and acceptably precise (root mean squared error = 23.7%) for GFR assessment. The pharmacokinetics of carboplatin were analyzed in 21 patients with a GFR of 17.2-91.4 mL/min. The original Calvert formula overestimated carboplatin clearance, resulting in an MPE of 14.3%. When we revised the Calvert formula for Japanese patients by substituting a non-renal clearance of 15 for 25, that is, dose = target AUC × (GFR + 15), the MPE decreased to -0.1% (P < 0.001). We conclude that the adjusted 24-h Ccr is acceptably precise for GFR assessment, and the non-renal clearance of carboplatin is suggested to be lower in Japanese patients with cancer than in their Western counterparts.

Pharmacokinetic analysis of carboplatin in patients with cancer who are undergoing hemodialysis

To examine the safety of carboplatin-based chemotherapy and the applicability of the Calvert formula in patients with cancer who are undergoing hemodialysis. We treated two patients who were undergoing hemodialysis and received carboplatin-based chemotherapy to treat non-small-cell lung cancer or ovarian cancer. The dose of carboplatin was calculated by the Calvert formula. Glomerular filtration rate was considered to be 0, and the target area under the plasma concentration versus time curve (AUC) was 4 (carboplatin dose, 100 mg) for patient 1 and 5 (125 mg) for patient 2. Carboplatin was administered as a 1-h intravenous infusion on day 1. Hemodialysis was performed for 3 or 4 h, starting 24 h after the infusion of carboplatin had begun. Heparinized blood samples were collected during the first cycle of chemotherapy. The AUCs in patients 1 and 2 were 4.7 and 6.1 (mg/ml min), which were about 20% higher than the target values (4 and 5 mg/ml min, respectively). In the absence of hemodialysis, the hypothetical AUCs were 6.2 and 7.6 (mg/ml min), respectively. The pre-dialysis body clearances of carboplatin were 16.1 and 16.5 ml/min, with elimination half-lives of 17.5 and 13.8 h, respectively. By performing hemodialysis 24 h after the start of chemotherapy, we obtained reproducible and robust AUC data. Use of the Calvert formula allowed carboplatin-based chemotherapy to be performed safely. Our results suggest that the non-renal clearance of carboplatin is lower in Japanese patients than in non-Asian patients.

Population Pharmacokinetics of High-Dose Carboplatin in Children and Adults

Although for conventional dosing of carboplatin, several strategies are available to individualize the dose based on renal function measurements, such approaches are still rare for high-dose regimens with autologous stem cell support. The purpose of this study was to investigate the influence of patient- and regimen-specific factors on the pharmacokinetics of carboplatin and to compare the performance of different dose individualization strategies (Calvert, Newell, Chatelut, flat dosing, dosing according to body surface area). A combined data set with 69 patients from five studies, including 13 pediatric patients, was subject to a population pharmacokinetic analysis using NONMEM. The covariate analysis revealed that carboplatin clearance after high-dose chemotherapy was highly related to creatinine clearance, body height, and infusion duration. After inclusion of these covariates, the population parameter variability of clearance decreased from 53% in the base model to 21% in the final model. We also developed an alternative model that related body weight, instead of height, to clearance by means of allometric scaling. An evaluation of the predictive performance of existing a priori dose individualization strategies revealed that flat dosing is appropriate for adult patients with normal renal function receiving a 1-hour infusion. For a long-term infusion schedule, a dose increase may be necessary. The existing dosing strategies performed poorly for the children in our data set. For this subpopulation, our allometric scaling model may be most appropriate. The two population pharmacokinetic models presented can be applied to estimate individual carboplatin clearance in high-dose chemotherapy based on body weight or height, infusion duration, and creatinine clearance. After prospective evaluation, our models may be suitable for dose adjustments.

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

To determine whether a glomerular filtration rate (GFR) assay based on serum iohexol clearance can be used to predict carboplatin clearance in cats. 10 cats with tumors. GFR was measured concurrently by use of plasma clearance of technetium Tc 99m-labeled diethylenetriaminepentaacetic acid ((99m)Tc-DTPA) to yield GFR(99mTc-DTPA) and serum clearance of iohexol to yield GFR(Iohexol). 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 (AUC(Target)) and estimation of platinum clearance (CL(PT)) derived from GFR(99mTc-DTPA) as follows: dose = AUC(Target) x 2.6 x GFR(99mTc-DTPA) x body weight, where AUC(Target) is 2.75 min.mg.mL(-1). Plasma platinum concentrations were measured via atomic absorption spectrophotometry. Values for GFR(99mTc-DTPA) and GFR(Iohexol) were compared by use of least-squares regression and Bland-Altman analysis. Least-squares regression was used to determine whether CL(PT) could be predicted from GFR(99mTc-DTPA) or GFR(Iohexol) (or both). GFR(99mTc-DTPA) and GFR(Iohexol) were strongly correlated (r = 0.90), but GFR(Iohexol) values were significantly larger by a factor of approximately 1.4. Platinum clearance had a significant linear relationship to GFR(99mTc-DTPA) (CL(PT) = 2.5 x GFR(99mTc-DTPA)) and to GFR(Iohexol) (CL(PT) = [1.3 x GFR(Iohexol)] + 1.4). In cats, serum iohexol clearance was an accurate predictor of CL(PT) and can be used to calculate the carboplatin dose as follows: dose = AUC(Target) x ([1.3 x GFR(Iohexol)] + 1.4) x body weight.

Pharmacokinetics of carboplatin and etoposide in infant neuroblastoma patients

Carboplatin and etoposide are commonly used chemotherapeutics for the treatment of many paediatric cancers. However, there are very limited published data concerning the pharmacokinetics of these agents in infants and very young children, for whom dose reductions are frequently implemented. Etoposide (5 mg/kg; 2 h i.v. infusion) was co-administered with carboplatin (6.6 mg/kg; 1 h i.v. infusion) on each of 3 days of treatment and samples were taken between 0.5 and 4 h after the start of administration, from a total of 19 neuroblastoma patients aged <1 year at diagnosis and weighing <12 kg at treatment. Pharmacokinetic analysis was carried out using a non-linear mixed effects modelling approach. Two compartment structural models were selected for both carboplatin and etoposide analysis. Body weight (BW) was strongly associated with carboplatin clearance (Cl), with a slightly weaker relationship observed with etoposide Cl. Carboplatin Cl values ranged from 12.8 to 33.6 ml/min, with total AUC values of 4.2-9.3 mg/ml.min achieved over the 3 days of treatment. Cl values normalized to BW were significantly higher in patients <12 kg than in children >12 kg, with mean +/- SD values of 2.9 +/- 0.4 and 2.5 +/- 0.4 ml/min/kg, respectively (P < 0.05). Etoposide exhibited a median half-life of 4.6 h (range 4.1-6.6), a median AUC of 7.1 mg/ml.min (range 3.4-11.0) and a median Cl of 6.6 ml/min (range 3.2-13.0). Results suggest that prediction of absolute carboplatin Cl values may be difficult in infant patients <12 kg, with a small but significant difference in Cl values normalized to BW observed in this patient group. Etoposide pharmacokinetic data support previous findings that question the utility of modified dosing in infants. The current study demonstrates the feasibility of generating informative pharmacokinetic data in infants and young children.

Evaluation of renal function and carboplatin clearance in Japanese cancer patients

2556 Background: There is a close relationship between carboplatin clearance and glomerular filtration rate (GFR). Calvert developed the following formula for the dosing of carboplatin: dose (mg) = target area under the concentration versus time curve (AUC, mg ml-1 min) × [GFR (ml min-1) + 25]. However, this formula has not been evaluated in Japanese population. In this study, we prospectively evaluated renal function and carboplatin clearance in Japanese cancer patients. Methods: GFR was measured by inulin clearance before chemotherapy. The dose of carboplatin was determined by Calvert's formula using adjusted 24-h creatinine clearance (Ccr) by adding 0.2 (mg dl-1) to serum creatinine. A pharmacokinetic study was performed during the first cycle of the chemotherapy. Blood samples were obtained at 10 points within 24 hours. The observed AUC of carboplatin and the observed carboplatin clearance were calculated. Results: Inulin clearance was estimated in 28 cancer patients. Estimation of renal function with adjusted 24-h Ccr and estimated GFR equation (eGFR) were unbiased [mean prediction error (MPE) = -2.3%, 5.2% respectively] and acceptably precise [root mean squared error (RMSE) = 23.7%, 25.7% respectively], whereas non-adjusted Ccr and the Cockcroft-Gault equation overestimated GFR (MPE = 24.2%, 12.5% and RMSE = 37.2%, 32.7% respectively). Observed carboplatin clearance was proportional to GFR in range of renal function in this study (r = 0.903) and we verified the linearity. Non-renal clearance of carboplatin in Japanese cancer patients was 5.6 (ml min-1). Conclusions: 24-h Ccr adjusted by adding 0.2 (mg dl-1) to serum creatinine and eGFR were useful in assessing renal function for carboplatin dosing. It was suggested that non-renal clearance of carboplatin in Japanese cancer patients was less than 25 (ml min-1). No significant financial relationships to disclose.

A universal formula based on cystatin C to perform individual dosing of carboplatin in normal weight, underweight, and obese patients

2527 Background: It has recently been shown that it is possible to improve the prediction of carboplatin clearance by adding plasma cystatin C level (cysC), an endogenous marker of glomerular filtration rate, to the other patient characteristics routinely used for carboplatin individual dosing, namely serum creatinine (Scr), body weight (BW), age, and sex. This multi-center pharmacokinetic study was performed to evaluate prospectively the benefit of using cysC for carboplatin individual dosing. Methods: The 357 patients included in the study were receiving carboplatin as part of established protocols. A population pharmacokinetic analysis was performed using the NONMEM program. Seven covariates were studied: Scr, cysC, age, sex, BW, ideal body weight, and lean body mass. Results: The best covariate equation was: carboplatin clearance (mL/min) = 105. (Scr/75)-0.433. (cysC/1.00)-0.290 . (BW/65)+0.547 . (age/56)-0.351 . 0.855sex, with Scr in μmol/L, cysC in mg/L, BW in kg, age in years, and sex = 0 for male. Using an alternative weight descriptor (ideal body weight or lean body mass) did not improve the prediction. This final covariate model was validated by bootstrap analysis. The bias (mean percentage error) and imprecision (mean absolute percentage error) were +2% and 15% respectively on the total population, and were of a similar magnitude in each of the three subgroups of patients defined according to their body mass index. Conclusions: For the first time, a unique formula is proposed for carboplatin individual dosing to patients which is shown to be equally valid for underweight, normal weight, and obese patients. No significant financial relationships to disclose.

A Universal Formula Based on Cystatin C to Perform Individual Dosing of Carboplatin in Normal Weight, Underweight, and Obese Patients

It has recently been shown that it is possible to improve the prediction of carboplatin clearance by adding plasma cystatin C level (cysC), an endogenous marker of glomerular filtration rate, to the other patient characteristics routinely used for carboplatin individual dosing, namely serum creatinine (Scr), actual body weight (ABW), age, and sex. This multicenter pharmacokinetic study was done to evaluate prospectively the benefit of using cysC for carboplatin individual dosing. The 357 patients included in the study were receiving carboplatin as part of established protocols. A population pharmacokinetic analysis was done using NONMEM program. Seven covariates studied were as follows: Scr, cysC, age, sex, ABW, ideal body weight, and lean body mass. The best covariate equation was as follows: carboplatin clearance (mL/min) = 117.8. (Scr/75)(-0.450). (cysC/1,00)(-0.385). (ABW/65)(+0.504). (age/56)(-0.366). 0.847(sex), with Scr in micromol/L, cysC in mg/L, ABW in kilograms, age in years, and sex = 0 for male. Using an alternative weight descriptor (ideal body weight or lean body mass) did not improve the prediction. This final covariate model was validated by bootstrap analysis. The bias (mean percentage error) and imprecision (mean absolute percentage error) were +1% and 15%, respectively, on the total population, and were of a similar magnitude in each of the three subgroups of patients defined according to their body mass index. For the first time, a unique formula is proposed for carboplatin individual dosing to patients, which is shown to be equally valid for underweight, normal weight, and obese patients.

Is the Adjustment of Serum Creatinine Level from < 0.6 mg/dL to 0.6 mg/dL Justified in Estimating Carboplatin Clearance Calculated by the Jelliffe Formula?

BackgroundIn current Gynecologic Oncology Group studies, serum creatinine level is adjusted to 0.6 mg/dL in patients with levels < 0.6 mg/dL (Adjusted-Jelliffe formula). The purpose of this study is to evaluate whether this adjustment is suitable. Patients and MethodsCarboplatin clearance was estimated in 115 patients with serum creatinine < 0.6 mg/dL who received carboplatin-based chemotherapy for gynecologic malignancies between January 1996 and August 2004. The clearance was estimated using the Cockroft-Gault, Jelliffe, and Adjusted-Jelliffe formulae. The 3 estimations were then compared with each other using the post hoc Wilcoxon signed rank test. Bias was assessed by mean percentage error (MPE), and precision was assessed by mean absolute percentage error (MAPE). The relationships between body surface area (BSA) and ratios of estimated carboplatin clearance (Jelliffe formula/Cockroft-Gault formula and Adjusted-Jelliffe formula/Cockroft-Gault formula) were evaluated by simple regression analysis. ResultsThe carboplatin clearance calculated by the Jelliffe formula was significantly larger than the other 2 formulae (P < .0001). Although MPE was reduced from +20 to +6 by adjustment of serum creatinine, MAPE was barely reduced from 21 to 14. The simple regression line represents correlation between BSA and ratios of estimated carboplatin clearance was merely translated to below by adjusting the serum creatinine level, and the bias by BSA was not corrected. ConclusionDespite adjusting the serum creatinine level, the Adjusted-Jelliffe formula overestimates the creatinine clearance when compared with the Cockcroft-Gault formula.

Carboplatin dosing in overweight and obese patients with normal renal function, does weight matter?

The purpose of this study was to determine the potential utility of alternative weight descriptors in the Cockcroft-Gault equation to more accurately predict carboplatin clearance in underweight, normal weight, overweight and obese patients. Clearance values obtained from individual fits using NONMEM were compared to predicted carboplatin clearances calculated using the modified Calvert formula in which creatinine clearance was calculated with the Cockcroft-Gault equation using diverse weight descriptors. This study indicated that lean body mass was the best weight descriptor in underweight and normal weight patients, while adjusted ideal body weight was the best weight descriptor in overweight and obese patients. However, a flat dose based on the population carboplatin clearance performed better in all weight categories than the use of the Cockcroft-Gault equation with diverse weight descriptors. These results suggest that in overweight and obese patients, with a normal renal function, a flat carboplatin dose should be administered, based on the population carboplatin clearance (8.38 l/h = 140 mL/min). Thus, in case an AUC of 5 mg min/mL is desired, the appropriate dose for carboplatin would be 5 x 140 = 700 mg.

Carboplatin (Cb) clearance (Cl) in elderly and young patients with advanced non-small cell lung cancer (ANSCLC): An exploratory analysis of the Calvert’s formula

18047 Background: It seems that elderly lung cancer patients (p) respond better to combination chemotherapy than to single-agent therapy. Application of pharmacokinetic (pk) modelling to the routine therapeutic drug monitoring in elderly p help to individualize the dosage of anticancer drugs. The aim of this study was to explore the Calvert′s formula usefulness for calculating the Cb dose in elderly p by means of the predicted AUC/actual AUC ratio. Creatinine (Cr) Cl was calculated by Cockdroft-Gault equation. Methods: Between December 2005 and September 2006, 20 chemonaive ANSCLC p were included in two groups: 10 adults p ≤ 65 years and 10 aged p ≥ 75 years. Treatment consisted in Cb day 1 and gemcitabine 1250 mg/m2 days 1 and 8 every 21 days. Cb dose was calculated for a foreseen AUC = 5 in young adults and AUC = 4 in aged p. Three blood samples were collected at 1–2 hours(h), 3–5 h, 12–24 h postinfusion. Total and ultrafiltrated Cb was determined using a flameless atomic absortion spectrometer. For pk analysis non lineal effects models implemented in NONMEM program were used. Individual pk parameters were calculated and predictors in the structural model were analized. Results: Table 1 shows mean and variation coefficient of some biometric characteristics. Pk parameters analysis: ClAUC5 p = 137 mL/min; Clfactor (parameter for measuring Cl changes according to age) = 0.44; Cl AUC4 p = 59.7 mL/min. Cb Cl in elderly p was 43.55% with respect to younger p. In younger p estimated Cb Cl was 5.69% higher than Cb Cl calculated using the Calvert equation. In elderly p, the opposite effect was achieved, estimated Cb Cl was 26.85% lower than Cb Cl calculated Conclusions: The Cb Cl calculation by means of Calvert formula showed underestimation of the dose in younger p and upperestimation of the dose in elderly p. It is necessary to investigate the covariates which contribute to take away the strength of the Calvert equation, which could to affect the efficacy and toxicity of Cb. [Table: see text] No significant financial relationships to disclose.

Difference of carboplatin clearance estimated by the Cockroft–Gault, Jelliffe, Modified-Jelliffe, Wright or Chatelut formula

Difference of carboplatin clearance estimated by the Cockroft–Gault, Jelliffe, Modified-Jelliffe, Wright or Chatelut formula

Flat Dosing of Carboplatin Is Justified in Adult Patients with Normal Renal Function

The Calvert formula is a widely applied algorithm for the a priori dosing of carboplatin based on patients glomerular filtration rate (GFR) as accurately measured using the 51Cr-EDTA clearance. Substitution of the GFR in this formula by an estimate of creatinine clearance or GFR as calculated by formulae using serum creatinine (SCR; Cockcroft-Gault, Jelliffe, and Wright) is, however, routine clinical practice in many hospitals. The goal of this study was to validate this practice retrospectively in a large heterogeneous adult patient population. Concentration-time data of ultrafilterable platinum of 178 patients (280 courses, 3,119 samples) with different types of cancer receiving carboplatin-based chemotherapy in conventional and high doses were available. Data were described with a linear two-compartment population pharmacokinetic model. Relations between SCR-based formulae for estimating renal function and carboplatin clearance were investigated. None of the tested SCR-based estimates of renal function were relevantly related to the pharmacokinetic variables of carboplatin. Neither SCR (median, 51; range, 18-124 micromol/L) nor the estimated GFR using the three different formulae was related to carboplatin clearance. Our data do not support the application of modifications of the Calvert formula by estimating GFR from SCR in the a priori dosing of carboplatin in patients with relatively normal renal function (creatinine clearance, >50 mL/min). For targeted carboplatin exposures, the original Calvert formula, measuring GFR using the 51Cr-EDTA clearance, remains the method of choice. Alternatively, in patients with normal renal function, a flat dose based on the mean population carboplatin clearance should be administered.