Carboplatin Clearance Research Articles

Serum cystatin C level can be used to estimate GFR in patients with solid tumors: PRO

An accurate assessment of glomerular filtration rate (GFR) is a fundamental aspect of cancer care and research. Recent studies have demonstrated that, in patients with solid tumors, GFR estimation based on serum creatinine combined with serum cystatin C presented minimal bias compared to measured GFR, may reduce race disparity when applied to race free GFR estimating equations, and improve the prediction of carboplatin clearance.

Optimizing carboplatin dosing by an improved prediction of carboplatin clearance using a CT-enhanced estimate of renal function.

Carboplatin is generally dosed based on a modified Calvert formula, in which the Cockcroft-Gault-based creatinine clearance (CRCL) is used as proxy for the glomerular filtration rate (GFR). The Cockcroft-Gault formula (CG) overpredicts CRCL in patients with an aberrant body composition. The CT-enhanced estimate of RenAl FuncTion (CRAFT) was developed to compensate for this overprediction. We aimed to evaluate whether carboplatin clearance is better predicted by CRCL based on the CRAFT compared to the CG. Data of four previously conducted trials was used. The CRAFT was divided by serum creatinine to derive CRCL. The difference between CRAFT- and CG-based CRCL was assessed by population pharmacokinetic modelling. Furthermore, the difference in calculated carboplatin dose was assessed in a heterogeneous dataset. In total, 108 patients were included in the analysis. Addition of the CRAFT- and CG-based CRCL as covariate on carboplatin clearance led, respectively, to an improved model fit with a 26-point drop in objective function value and a worsened model fit with an increase of 8 points. In 19 subjects with serum creatinine <50 μmol/L, the calculated carboplatin dose was 233 mg higher using the CG. Carboplatin clearance is better predicted by CRAFT vs. CG-based CRCL. In subjects with low serum creatinine, the calculated carboplatin dose using CG exceeds the dose using CRAFT, which might explain the need for dose capping when using the CG. Therefore, the CRAFT might be an alternative for dose capping while still dosing accurately.

The impact of clinical equations on carboplatin dosing: A systematic review to determine appropriate dosing of carboplatin in adult cancer patients.

e15005 Background: The Calvert formula is used to estimate the carboplatin dose needed to achieve the desired Area Under the Curve (AUC) despite little consensus on which estimated Glomerular Filtration Rate (eGFR) equation best reflects renal clearance. Cockcroft-Gault (CG) is often used when calculating estimated Creatinine Clearance (CrCl) for the Calvert formula. Equations like Modification of Diet in Renal Disease or CKD-EPI (based on serum creatinine (SrCr) or cystatin C), take into account parameters such as race, gender, weight. We compared several publications to determine the most effective dosing strategy for carboplatin. Methods: Utilizing PubMed, 19 articles were found with the keywords “carboplatin, dosing, eGFR, measure GFR, creatinine clearance, muscle mass.” Our inclusion criteria consisted of being published within the last 10 years, included carboplatin dosing, and evaluated either measured GFR, measured CrCl, carboplatin clearance or toxicities caused by carboplatin. Studies not meeting these parameters were excluded. Of the 19 articles, 11 articles were identified regarding the accuracy of eGFR and its effects on carboplatin dosing and/or dose limiting toxicities. An extensive literature review of each article was used to find a consensus among the clinical equations used in carboplatin dosing. Results: There remains no consensus on the most accurate eGFR equation. Eight studies evaluated accuracy of varying equations in estimating GFR, creatinine clearance or carboplatin clearance. Two studies created new equations (one measuring GFR and the other measuring CrCl) and compared them to current equations for accuracy. Ultimately, only two studies were in agreement that CKD-EPI was the most viable option when GFR uses SrCr. Based on four studies, CG is an inadequate measurement of eGFR. CG ranked low due to a high mean percent error when compared to measured GFR, indicating a larger discrepancy between measured GFR and the estimated value of CG, as compared to other equations. Three of the studies evaluated for a correlation in skeletal muscle mass and hematological toxicities, indicating that changes in muscle mass could correlate with hematological toxicities. One small study developed a new equation based on muscle mass and SrCr and showed positive results for accuracy when compared to measure CrCl. Conclusions: Although a definitive equation to estimate renal clearance could not be established, equations like CG have limited accuracy due to race, weight, age, and gender. The single study that utilized muscle mass demonstrated the most promise and presents a better option for patients, particularly when muscle mass changes over time. Other studies illustrated that muscle mass is significantly correlated with carboplatin toxicity and should be considered for future studies to determine the safest method for dosing carboplatin.

Carboplatin Dosing in Children Using Estimated Glomerular Filtration Rate: Equation Matters.

Simple SummaryCarboplatin is a chemotherapeutic agent that is usually dosed based on body surface area or weight. However, carboplatin is cleared from the body by the kidneys. Therefore, taking the patient’s kidney function into account to calculate the adequate dose of carboplatin might result in a better exposure of carboplatin within a patient. In this study we sought to validate a carboplatin dosing method based on kidney function and compare several methods for kidney function-based carboplatin dosing in children suffering from retinoblastoma. We were able to show that carboplatin dosing based on a marker of kidney function (cystatin C) resulted in more adequate dosing than dosing on body surface area or weight.Renal function-based carboplatin dosing using measured glomerular filtration rate (GFR) results in more consistent drug exposure than anthropometric dosing. We aimed to validate the Newell dosing equation using estimated GFR (eGFR) and study which equation most accurately predicts carboplatin clearance in children with retinoblastoma. In 13 children with retinoblastoma 38 carboplatin clearance values were obtained from individual fits using MWPharm++. Carboplatin exposure (AUC) was calculated from administered dose and observed carboplatin clearance and compared to predicted AUC calculated with a carboplatin dosing equation (Newell) using different GFR estimates. Different dosing regimens were compared in terms of accuracy, bias and precision. All patients had normal eGFR. Carboplatin exposure using cystatin C-based eGFR equations tended to be more accurate compared to creatinine-based eGFR (30% accuracy 76.3–89.5% versus 76.3–78.9%, respectively), which led to significant overexposure, especially in younger (aged ≤ 2 years) children. Of all equations, the Schwartz cystatin C-based equation had the highest accuracy and lowest bias. Although anthropometric dosing performed comparably to many of the eGFR equations overall, we observed a weight-dependent change in bias leading to underdosing in the smallest patients. Using cystatin C-based eGFR equations for carboplatin dosing in children leads to more accurate carboplatin-exposure in patients with normal renal function compared to anthropometric dosing. In children with impaired kidney function, this trend might be more pronounced. Anthropometric dosing is hampered by a weight-dependent bias.

Multicentric phase II trial of TI‐CE high‐dose chemotherapy with therapeutic drug monitoring of carboplatin in patients with relapsed advanced germ cell tumors

ABSTRACTBackgroundHigh‐dose chemotherapy (HDCT) with TI‐CE regimen is a valid option for the treatment of relapsed advanced germ cell tumors (GCT). We report a phase II trial with therapeutic drug monitoring of carboplatin for optimizing area under the curve (AUC) of this drug.MethodsPatients with unfavorable relapsed GCT were treated according to TI‐CE regimen: two cycles combining paclitaxel and ifosfamide followed by three cycles of HD carboplatin plus etoposide administered on 3 days. Carboplatin dose was adapted on day 3 based on carboplatin clearance (CL) at day 1 in order to reach a target AUC of 24 mg.min/mL per cycle. The primary endpoint was the complete response (CR) rate.ResultsEighty‐nine patients who received HDCT were included in the modified intent‐to‐treat (mITT) analysis. Measured mean AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 mg.min/mL for 10th and 90th percentiles). Thirty‐five (44.3%) patients achieved a CR with or without surgery of residual masses and 20 patients achieved a partial response with negative tumor markers. With a median follow‐up of 44 months (m), median PFS was 12.3 m (95% CI: 7.5–25.9) and OS was 46.3 m (95% CI: 18.6–not reached). For high‐ and very high‐risk patients, according to the International Prognostic Score at first relapse or treated after at least one salvage treatment (n = 51), 2‐year PFS rate was 41.1%.ConclusionThe rates of complete and favorable responses were clinically relevant in this very poor risk population. Individual monitoring of carboplatin plasma concentration permitted to control more accurately the target AUC and avoided both underexposure and overexposure to the drug.

Formulae recently proposed to estimate renal glomerular filtration rate improve the prediction of carboplatin clearance.

While doses of carboplatin are mostly individualized according to the Calvert equation based on estimated Glomerular Filtration Rate (eGFR), there is still uncertainty regarding the best formula to predict GFR. Since Janowitz et al. recently proposed a new equation predicting GFR in cancer patients, we aimed to compare this equation to other carboplatin clearance (carboCL) predicting formulae. The actual carboCL of 491 patients was compared to predicted carboCL according to the Calvert formula using several equations to predict GFR (Janowitz, Cockcroft-Gault, MDRD, CKD-EPI, CKD-EPI with cystatin C (CKD-EPI-cysC)); and according to two others that directly predict carboCL (Chatelut and Thomas). The formulae were compared on Mean Percentage Error (MPE), Mean Absolute Percentage Error (MAPE) and percentage of patients with a prediction error above 20% (P20). The MPE, MAPE and P20 were, respectively, within the ranges - 5.2 to + 5.9%; 14.0-21.2% and 23-46%. The MAPE and P20 of Calvert-CKD-EPI-cysC were the lowest. The performance of Calvert-CKD-EPI was better than that of other creatinine-based formulae although not significantly different from the Calvert-Janowitz formula. Among formulae based on creatinine only, Calvert-CKD-EPI and Calvert-Janowitz are the least influenced by patient characteristics. Whereas CysC improves carboplatin CL prediction, the Calvert-CKD-EPI equation seems the most suitable creatinine-based formula to predict carboCL homogeneously in all subgroups of patients.

Estimation of Unbound Carboplatin Clearance From Total Plasma Concentrations as a Means of Facilitating Therapeutic Drug Monitoring.

Therapeutic drug monitoring of carboplatin is based on its unbound clearance (CLU) determined by Bayesian analysis on unbound (U) concentrations. However, the ultrafiltration of plasma samples presents technical and time constraints. Therefore, this study aims to estimate CLU using total plasma (P) concentrations. U and P concentration data of 407 patients were obtained from 2 clinical studies in which actual CLU had been determined for each patient. The patients were then split into development (277 patients) and prospective data sets (130 patients). Two approaches were evaluated. PK-model-only approach: a 3-compartment pharmacokinetic (PK) model based on U and P concentrations and taking into account the protein binding process was developed. The model with patient covariates was also evaluated. Linear regression approach: an equation (CLU = aCLP + b) was obtained by linear regression analysis between actual CLU and CLP, which is the total plasma clearance obtained by analyzing P concentrations according to a 2-compartment PK model. Predictive performance was then assessed within the prospective data set by estimating CLU from P concentrations using each approach and computing the relative percentage error (PE) between estimated CLU and actual CLU. The linear regression equation was CLU (L/h) = 1.15 CLP (L/h) + 0.13. The mean PE (MPE) between CLU (estimated using the equation) and the actual CLU was +1.2% (ranging from -31% to +33%) and the mean absolute PE (MAPE) was 9.7%. With the 3-compartment PK model, the MPE was +2.3% (ranging from -41% to +31%) and the MAPE was 11.1%. Inclusion of covariates in the 3-compartment model did not improve the estimation of CLU [MPE = +6.3% (from -33% to +37%); MAPE = 11.4%]. The linear equation gives a relatively good estimation of CLU based on P concentrations, making PK-based carboplatin dose adaptation possible for centers without ultrafiltration facilities.

Analysis of carboplatin dosing in patients with a glomerular filtration rate greater than 125 mL/min: To cap or not to cap? A retrospective analysis and review.

The use of the Calvert formula to calculate carboplatin doses allows clinicians to achieve the appropriate carboplatin area under the concentration (AUC) curve. Thrombocytopenia is the dose limiting toxicity of carboplatin and optimizing AUC minimizes the risk of thrombocytopenia. Carboplatin clearance directly correlates with glomerular filtration rate (GFR) and, therefore, an accurate estimation of the renal function is needed. The Calvert formula was designed using the GFR measured by 51Cr-EDTA; however, many clinicians substitute estimated creatinine clearance (CrCl) as calculated by the Cockcroft-Gault (C-G) equation. The potential for overestimating AUC occurs when clinicians substitute actual weight in obese patients or use a low serum creatinine when calculating C-G estimated CrCl. In 2010, the National Cancer Institute recommended the GFR value within the Calvert formula should not exceed 125 mL/min, thereby capping the carboplatin dose. However, there are studies demonstrating that certain patients' actual GFR values do exceed 125 mL/min. Therefore, capping the carboplatin dose in these patients may lead to underestimating the carboplatin AUC. A single-center, retrospective study was performed to evaluate the change in platelet count pre- and post-carboplatin exposure in patients with C-G estimated CrCl greater than 125 mL/min receiving capped versus uncapped carboplatin doses. A review of carboplatin dosing strategies is also presented. This study indicated there was a larger mean difference in pre- and post-platelet count in patients receiving uncapped carboplatin compared to patients receiving capped carboplatin with no differences in toxicities. Dose capping this patient population will likely lead to a lower AUC rather than the intended AUC target, which could ultimately lead to substandard outcomes.

Genome-wide association study of paclitaxel and carboplatin disposition in women with epithelial ovarian cancer

Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize cancer treatment and limit toxicity. Genome-wide approaches are unbiased, compared with candidate gene studies, but usually require large cohorts. As most chemotherapy is given cyclically multiple blood sampling is required to adequately define drug disposition, limiting patient recruitment. We found that carboplatin and paclitaxel disposition are stable phenotypes in ovarian cancer patients and tested a genome-wide association study (GWAS) design to identify SNPs associated with chemotherapy disposition. We found highly significant SNPs in ABCC2, a known carboplatin transporter, associated with carboplatin clearance (asymptotic P = 5.2 × 106, empirical P = 1.4 × 10−5), indicating biological plausibility. We also identified novel SNPs associated with paclitaxel disposition, including rs17130142 with genome-wide significance (asymptotic P = 2.0 × 10−9, empirical P = 1.3 × 10−7). Although requiring further validation, our work demonstrated that GWAS of chemotherapeutic drug disposition can be effective, even in relatively small cohorts, and can be adopted in drug development and treatment programs.

Individualization of high dose carboplatin based on therapeutic drug monitoring (TDM) for the treatment of testicular germ cell tumors (TICE protocol): Results of a multicenter phase II study.

4554 Background: We conducted a national phase II multicenter trial that aimed at evaluating the efficacy and tolerance of Paclitaxel plus Ifosfamide followed by high-dose carboplatin plus etoposide treatment (TICE) in previously treated germ cell tumors. The particularity of our study (in comparison with the standard protocol [Motzer RJ, et al. J Clin Oncol 2000 Mar; 18(6): 1173-1180.]) is that the carboplatin dose was individualized for each patient according to therapeutic drug monitoring (TDM) in order to reach the target AUC of 24 mg.min/ml over 3 days. Methods: In total, 89 patients were evaluable for pharmacokinetic study. Blood samples were taken on day 1 to determine the carboplatin clearance using a Bayesian approach (NONMEM 7.2) and to adjust the dose on day 3 to reach the target AUC of 24 mg.min/ml over 3 days. On days 2 and 3, samples were taken for retrospective assessment of the actual AUC and the intra- and inter-cycle clearance variability. Secondly, a population pharmacokinetic analysis was also performed on 59 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future patients treated with the TICE protocol. The performance of this new equation was then prospectively evaluated on the other 30 patients along with different methods of carboplatin clearance prediction. Results: TDM allowed us to control the carboplatin exposure with a mean actual AUC of 24.5 mg.min/ml (22.2 and 28.0 for 5th and 95thpercentile respectively) per cycle. We observed a modest but significant decrease of carboplatin clearance over cycles (median value of change of -11.8% from cycle 1 to cycle 3, maximum value of -36%). The new covariate equation allows unbiased and more accurate prediction of carboplatin clearance in the prospective validation cohort compared to other equations. Conclusions: Carboplatin TDM allowed the target AUC to be accurately reached and thereby avoid over- or under-exposure. We propose a new equation to predict carboplatin clearance more adapted to these particular patients (young males) that could be used as an alternative if the TDM cannot be organized. Clinical trial information: 2008-005068-14.

Estimation of glomerular filtration rate in cancer patients with abnormal body composition and relation with carboplatin toxicity.

Carboplatin clearance is correlated with glomerular filtration rate (GFR) and usually estimated with creatinine clearance using Cockcroft-Gault (CG) formula. Because plasma creatinine level is highly correlated with muscle mass, we hypothesized that an abnormal body composition with a low lean body mass (LBM) percentage [(LBM/weight)×100]may result in inadequate carboplatin dosing. Serum cystatin C is an alternative marker of GFR, not affected by muscle mass. We aimed to investigate the influence of total LBM and LBM percentage on GFR calculation, using creatinine (CrCl) or cystatin C (GFRcysC-creat) in cancer patients. Pretreatment serum creatinine and cystatin C were prospectively measured in consecutive patients. CrCl (CG formula), GFRcysC-creat (CKD-EPI creatinine-cystatin equation), and LBM (CT scan) were calculated. Severe thrombocytopenia post-carboplatin were analyzed. In 131 patients without renal insufficiency, LBM was correlated with creatinine (r=0.30, p<0.005) but not with cystatin C (r=-0.07, p=0.43). In patients with the lowest LBM percentage, the CrCl was significantly higher than GFRcysC-creat indicating an overestimation of GFR with creatinine (p=0.0004). In 24 patients treated with carboplatin AUC 5 (mg/mlmin)±paclitaxel, the risk of severe thrombocytopenia was associated with lower LBM percentage (p=0.0002) and higher CrCl/GFRcysC-creat ratio (p=0.006). By ROC analysis, the CrCl/GFRcysC-creat ratio threshold predicting severe thrombocytopenia was 1.23. A low LBM percentage increases the risk of inadequate GFR calculation by CG formula, and carboplatin overdosage with severe thrombocytopenia. High CrCl/GFRcysC-creat ratio allows the identification of these patients.

Phase II trial of TI-CE high dose chemotherapy (HDCT) with drug monitoring for individual carboplatin dosing in patients with relapsed advanced germ cell tumors: A multicentric prospective GETUG trial.

401 Background: HDCT is a valid option of treatment for relapsed advanced GCTs pts. The results of the TICE regimen as salvage therapy in poor risk pts demonstrated a 50% complete response (CR) but with very high variability of measured carboplatin area under the curve (AUC) (between 10.9-36.7 for target AUC = 24 mg.min/mL). We initiated a phase II trial of TICE with therapeutic drug monitoring (TDM) for individual carboplatin dosing in order to target the 3-day AUC to 24 mg/min/mL. Methods: Were included pts with unfavorable relapsed GCTs , secondarily classified according to the International Prognostic Factors Study Group. Pts were treated according the TICE regimen with two cycles combining paclitaxel and ifosfamide followed by three cycles HDCT: carboplatin plus etoposide with stem cell support. Carboplatin dose was adapted on day 3 based on carboplatin clearance (Cl) at day 1, in order to reach the target AUC. The primary endpoint was the CR rate (cCR sCR pCR). A Simon Minimax design was performed using the following hypothesis: p0 = 50%, p1 = 65 α = 5%, β = 10%. Results: Between 03/2009 and 11/2015 101 pts were accrued, 60 pts were treated in first relapse (34 classified as high and very high-risk) and 41 in 2ndor more relapse. 72 pts (71%) received the whole treatment, 12 pts (10%) did not receive any cycle of HDCT. 29pts (26%) stopped treatment earlier, 8 for toxicity. Three pts died on treatment. 35/79 (44.3%) evaluable pts achieved a CR. 19 pts (24%) presented a PRm-. The mean observed carboplatin AUC was 24.5 mg.min/mL (between 18.9 and 28.8) at C1.Following TDM, the modification of the total carboplatin dose during C1 was comprised between -33% and +44%, showing the benefit of TDM in comparison with individual dosing based only on carboplatin Cl predicted according to patient’s renal characteristics. Conclusions: The CR rate observed in this very poor prognosis population was 44.3% and 69.6% CR + PRm-. Carboplatin dose individualization based on TDM allowed to reach more accurately the target AUC compared to previous reports. Clinical trial information: NCT00864318.

Adaptive dosing of anticancer drugs in neonates: facilitating evidence-based dosing regimens.

PurposeSelection of the most appropriate chemotherapy dosing regimens for neonates treated within the first weeks of life represents a significant clinical dilemma. Due to a lack of information relating to the clinical pharmacology of anticancer drugs in these challenging patients, current dosing guidelines are based on limited scientific rationale. In the current study, we investigate the utilisation of therapeutic drug monitoring approaches in neonates with localised hepatoblastoma, Wilms’ tumour and stage 4S neuroblastoma, being treated with widely used anticancer drugs.MethodsPlasma concentrations of cisplatin, vincristine, etoposide and carboplatin were quantified in two neonates being treated within the first 3 weeks of life and in a 32-week preterm infant treated at a gestational age of 40 weeks. Therapeutic drug monitoring was carried out where appropriate, based on the pharmacokinetic data obtained in conjunction with clinical response and toxicity.ResultsTreatment of a child aged 2 weeks with a recommended cisplatin dose reduction for weight to 1.8 mg/kg resulted in achievement of unbound cisplatin plasma concentrations of 0.01–0.08 µg/mL, markedly lower than exposures previously reported in infants and older children. A dose increase to 2.7 mg/kg was implemented, leading to the achievement of levels more in-line with those previously reported. This increased dose level was well tolerated over six courses of treatment, resulting in a good response to cisplatin monotherapy and the patient remains in remission at 3.5 years. In contrast, a 50 % vincristine dose reduction for weight in a 3-week-old neonate resulted in plasma concentrations comparable to levels observed in older children, leading to successful treatment and continued remission at 2 years. In a third patient, etoposide and carboplatin clearance values normalised to body weight were comparable to those reported in older children, resulting in comparatively lower exposures following reduced dosing.ConclusionsThe current report provides unique data on the pharmacokinetics of several widely used anticancer drugs in neonates treated within the first few weeks of life. The provision of these data acts as a useful reference point to support future dosing decisions to be made by clinicians in the treatment of these challenging patients.

Abstract 5493: Genome-wide study of carboplatin and paclitaxel disposition in ovarian cancer patients

Abstract Germline genetic variation can affect chemotherapeutic drug disposition, toxicity and efficacy. Identifying single nucleotide polymorphisms (SNPs) that influence chemotherapy disposition may help to personalize individual treatment. Compared to the traditional candidate gene approach, a genome-wide association study (GWAS) is unbiased but usually requires a large sample size. Since most cytotoxics have a short half-life and are given cyclically, multiple blood samples are therefore required to adequately define drug disposition and systemic exposure. This limits patient sample sizes in pharmacokinetic studies. The aim of this study was to identify SNPs that are associated with carboplatin and paclitaxel pharmacokinetic parameters using a GWAS approach in two small patient cohorts. Methods: Two independent pharmacokinetic cohorts were recruited in Australia (N = 61, both carboplatin and paclitaxel) and the Netherlands (N = 35, paclitaxel only). A total of 719,665 SNPs were genotyped using Illumina Human OmniExpress arrays. Linear regression was used to test the association between each SNP and the trait of interest, both unadjusted and adjusted for corresponding covariates using PLINK. We performed separate analysis within each population and then ran meta-analysis combining results from different populations weighted by sample sizes using METAL. Results: Carboplatin and paclitaxel disposition is a relative stable phenotype. The genomic control parameters in the test statistics for the adjusted carboplatin and paclitaxel analysis were 1.03 and 1.02 respectively, suggesting that there was little concern for population substructure or other artefacts. We identified highly significant SNPs in ABCC2 associated with carboplatin clearance (asymptotic p = 5.2 × 10−6, empirical p = 1.4 × 10−5 from 107 permutations) which are highly plausible pharmacogenomic markers given the known role of ABCC2 in carboplatin efflux. We also identified a novel SNP associated with paclitaxel disposition with genome wide significance in chromosome 1 (rs17130142, asymptotic p = 2.0 × 10−9, empirical p = 1.3× 10−7), in an intergenic region, neighboring PKN2. Conclusion: Although these findings requires a validation in a larger study, our work demonstrated that GWAS of chemotherapeutic drug disposition can be effective even when performed in a relative small sample number and can be adopted in drug development and treatment programs. Citation Format: Bo Gao, Yi Lu, Annemieke J.M. Nieuweboer, Hongmei Xu, Jonathan Beesley, Ingrid Boere, Anne-Joy M. de Graan, Peter de Bruijn, Howard Gurney, Catherine Kennedy, Yoke-Eng Chiew, Sharon E. Johnatty, Philip Beale, Michelle Harrison, Craig Luccarini, Alison M. Dunning, Ron H.J. Mathijssen, Paul Harnett, Rosemary L. Balleine, Georgia Chenevix-Trench, Stuart MacGregor, Anna deFazio. Genome-wide study of carboplatin and paclitaxel disposition in ovarian cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5493. doi:10.1158/1538-7445.AM2015-5493

Abstract 1618: Carboplatin therapeutic monitoring in preterm and full-term neonates

Abstract Background: Administration of the most appropriate dose of chemotherapy to neonates with cancer is particularly challenging and in many cases is not standardized based on any scientific rationale. We report on the clinical utility of carboplatin therapeutic drug monitoring in preterm and full-term neonates within the first month of life and use the data generated to provide guidance for the treatment of future patients. Patients and methods: Carboplatin therapeutic monitoring was performed to achieve target drug exposures (AUC values) in nine preterm and full-term neonates diagnosed with retinoblastoma or neuroblastoma over an 8 year period. Carboplatin was administered over 3 days of treatment with therapeutic drug monitoring utilized to target AUC values of 5.2 - 7.8mg/ml.min. Results: AUC values achieved following therapeutic monitoring were within 15% of the target value for the individual courses of treatment in all but one patient (12/13 courses of treatment), with dose modifications of up to 215% required to achieve target AUC values, based on the initial mg/kg dosing schedule implemented. Carboplatin clearance values determined across three consecutive courses of chemotherapy in two patients increased from 3.4 to 7.1ml/min and 7.2 to 16.5 ml/min, representing increases of 210% and 230% over periods of 7 and 8 weeks respectively. Complete remission was observed in all seven patients treated for retinoblastoma and in one patient with neuroblastoma, with no renal toxicity reported and only one patient experiencing ototoxicity. Conclusion: The study highlights the benefits of utilising therapeutic drug monitoring to achieve cumulative target carboplatin AUC values in preterm and full-term neonates treated within the first few weeks of life, particularly in view of the marked increases in drug clearance observed over consecutive courses of chemotherapy. Reducing the likelihood of sensorineural hearing loss may be particularly relevant in the case of neonates with retinoblastoma, where it is likely to have an even greater impact on the quality of life of a child who may also have some degree of visual impairment. In the absence of therapeutic drug monitoring, body-weight based dosing is recommended, with dosing guidance provided for both approaches to inform the treatment of future patients. Acknowledgements: Work supported by Cancer Research UK, the North of England Children's Cancer Research Fund and the Experimental Cancer Medicine Centre Network. Citation Format: Gareth J. Veal, Julie Errington, James Hayden, David Hobin, Dermot Murphy, Rachel A. Dommett, Deborah A. Tweddle, Helen Jenkinson, Susan Picton. Carboplatin therapeutic monitoring in preterm and full-term neonates. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1618. doi:10.1158/1538-7445.AM2015-1618

Carboplatin therapeutic monitoring in preterm and full-term neonates

IntroductionAdministration of the most appropriate dose of chemotherapy to neonates is particularly challenging and frequently not standardised based on any scientific rationale. We report the clinical utility of carboplatin therapeutic drug monitoring in preterm and full-term neonates within the first month of life. MethodsCarboplatin therapeutic monitoring was performed to achieve target drug exposures area under the plasma concentration–time curve (AUC values) in nine preterm and full-term neonates diagnosed with retinoblastoma or neuroblastoma treated over an 8year period. Carboplatin was administered over 3days with therapeutic drug monitoring utilised to target cumulative AUC values of 5.2–7.8mg/mlmin. ResultsAUC values achieved were within 15% of target values for the individual courses of treatment in all but one patient (12/13 courses of treatment), with dose modifications of up to 215% required to achieve target AUC values, based on initial mg/kg dosing schedules. Carboplatin clearance determined across three consecutive chemotherapy courses in two patients increased from 3.4 to 7.1ml/min and from 7.2 to 16.5ml/min, representing increases of 210–230% over several weeks of treatment. Complete remission was observed in 8/9 patients, with no renal toxicity reported and only one patient experiencing ototoxicity. ConclusionThe study highlights the benefits of utilising therapeutic drug monitoring to achieve target carboplatin AUC values in preterm and full-term neonates treated within the first few weeks of life, particularly in view of marked increases in drug clearance observed over consecutive chemotherapy courses. In the absence of therapeutic drug monitoring, body-weight based dosing is recommended, with dosing guidance provided for both approaches to inform future treatment.

Convection-Enhanced Delivery of Carboplatin PLGA Nanoparticles for the Treatment of Glioblastoma.

We currently use Convection-Enhanced Delivery (CED) of the platinum-based drug, carboplatin as a novel treatment strategy for high grade glioblastoma in adults and children. Although initial results show promise, carboplatin is not specifically toxic to tumour cells and has been associated with neurotoxicity at high infused concentrations in pre-clinical studies. Our treatment strategy requires intermittent infusions due to rapid clearance of carboplatin from the brain. In this study, carboplatin was encapsulated in lactic acid-glycolic acid copolymer (PLGA) to develop a novel drug delivery system. Neuronal and tumour cytotoxicity were assessed in primary neuronal and glioblastoma cell cultures. Distribution, tissue clearance and toxicity of carboplatin nanoparticles following CED was assessed in rat and porcine models. Carboplatin nanoparticles conferred greater tumour cytotoxicity, reduced neuronal toxicity and prolonged tissue half-life. In conclusion, this drug delivery system has the potential to improve the prognosis for patients with glioblastomas.

Extension of the Calvert formula to patients with severe renal insufficiency

The Calvert formula was derived from the study among patients with glomerular filtration rates (GFRs) of 33-135ml/min, and it remains unclear whether the formula can be used to calculate optimal and safe dosages of carboplatin in patients with severe renal insufficiency. We evaluated the utility of this formula in patients with severe renal insufficiency. For pharmacokinetic analysis, we studied nine adult Japanese patients with advanced cancer who had an estimated GFR of lower than 30ml/min/1.73m(2), as calculated by the Japanese equation for estimating GFR, or who were receiving hemodialysis. The dose of carboplatin was calculated with the Calvert formula, in which GFR was measured by inulin clearance or was assumed to be 0 in patients requiring hemodialysis. Hemodialysis was started 23h after the end of carboplatin infusion. Although there was a significant correlation between the estimated and measured carboplatin clearance, the estimated clearance was consistently higher than the measured clearance [mean prediction error±standard deviation=41.0±26.3%] in all seven patients with renal insufficiency (GFR, median 21.4, range 7.8-31.4ml/min) and in the two hemodialysis patients. Actual areas under the concentration-time curve (AUC) (mg/mlmin) were 5.4, 5.7, 6.2, and 9.0 for the four patients with a target AUC (mg/mlmin) of 5; 5.7, 6.2, and 7.1 for the three patients with a target AUC (mg/mlmin) of 4; and 5.1 and 8.7 for the two hemodialysis patients with a target AUC (mg/mlmin) of 5. The measured clearance of carboplatin ranged from 23.0 to 51.3ml/min in the seven patients not receiving hemodialysis. The pre-hemodialysis carboplatin clearance in the hemodialysis patients was 20.5 and 11.1ml/min, respectively. For adult patients with severe renal insufficiency, the Calvert formula causes carboplatin overdosing by overestimating the carboplatin clearance.

カルボプラチン投与量算出におけるCalvert式利用に関する実態調査

The renal clearance of carboplatin, which is a second-generation platinum compound, is correlated with the glomerular filtration rate (GFR). As the area under the concentration-time curve (AUC) of free carboplatin is related with efficacy and toxicity following carboplatin administration, carboplatin dosing is defined as a target AUC and generally calculated by the Calvert formula according to the patient's GFR. We conducted a survey on the usage of the Calvert formula to clarify the current situation in Japan. As a result, the value of creatinine clearance (CLcr), which is higher than GFR due to the tubular secretion of creatinine, has been used as a substitute for GFR for the Calvert formula without appropriate correction in 71 of 109 institutions, where CLcr estimated by a Cockcroft-Gault equation and/or obtained by 24-h urinary collection are used. On the other hand, body surface area-indexed values of renal function have been directly used without conversion to individual values in 42 of 71 institutions, where GFR estimated by a Japanese equation and/or CLcr estimated by a Jelliffe equation are used. It was found that the desired dosing of carboplatin has not been administered to patients in a number of institutions. Back to the original concept of the Calvert formula, it is reasonable to use a GFR estimated by the Japanese equation and converted to an individual value. In addition, we need to assess tolerability following carboplatin administration and discuss the appropriateness of the starting dose for each patient without being overly reliant on the dose obtained by the Calvert formula.

P56 * CONVECTION-ENHANCED DELIVERY (CED) OF CARBOPLATIN NANOSPHERES FOR THE TREATMENT OF GLIOBLASTOMA

INTRODUCTION: We are currently investigating CED of the platinum-based drug, carboplatin as a novel treatment strategy for high grade glioma in adults and children. Although initial results show significant promise, our current treatment strategy requires intermittent infusions due to rapid clearance of carboplatin from the brain. Furthermore, carboplatin is not specifically toxic to tumour cells and has been associated with neurotoxicity at high infused concentrations. We sought to encapsulate carboplatin in lactic acid-glycolic acid copolymer (PLGA) to develop a novel drug delivery system with improved safety and persistence within the brain and increased cancer cytotoxicity. METHOD: We compared the neuronal and tumour cytotoxicity of free carboplatin with encapsulated carboplatin in primary neuronal and GBM cultures. We studied distribution, tissue clearance and toxicity of carboplatin nanospheres following intrastriatal CED in rats. RESULTS: Encapsulation of carboplatin in PLGA nanospheres conferred greater tumour cytotoxicity, reduced neuronal toxicity and prolonged tissue half-life compared with the free drug. CONCLUSION: Encapsulation of carboplatin in PLGA onfers increased safety, with significant increases in tumour cytotoxicity and persistence within the brain. Further investigation is required to determine the translational potential of using PLGA encapsulated-carboplatin as a novel anti-glioma treatment strategy.