Prospective validation of an equation based on plasma cystatin C for monitoring the glomerular filtration rate in children treated with cisplatin or ifosfamide for cancer.

We recently proposed an equation to estimate the glomerular filtration rate (GFR) in children with cancer based on plasma cystatin C and serum creatinine levels together with body weight (the "CysPed equation"). The current clinical study reports a prospective evaluation of this equation in 18 children treated by nephrotoxic chemotherapy. The CysPed equation resulted in less bias and greater precision compared to two equations previously proposed equations by Schwartz, with or without plasma cystatin C. Moreover, the decrease in GFR due to chemotherapy was clearly identified by the CysPed equation. This equation may be used to monitor the renal function in childhood cancer units.

Plasma cystatin C is a marker of renal glomerular injury in children treated with cisplatin or ifosfamide.

BACKGROUND: Plasma cystatin C is a potential marker of the glomerular filtration rate (GFR), and urinary cystatin C has been proposed as a marker of tubular dysfunction. PROCEDURE: A prospective study (NCT02822404) was conducted to assess the benefit of considering cystatin C plasma and urinary levels to better evaluate cisplatin and/or ifosfamide renal toxicity in children with cancer. Plasma 51 Cr-EDTA clearance as a marker of GFR and urinary markers of tubular toxicity were monitored in 40 children treated by cisplatin and/or ifosfamide. Several equations previously proposed to estimate GFR, with or without inclusion of plasma cystatin C level, were compared. A population pharmacokinetic approach was also used to analyze plasma 51 Cr-EDTA data, and evaluate the relationship between patient covariates (including plasma cystatin C level) and GFR during the course of chemotherapy treatment. RESULTS: Equations including plasma cystatin C described GFR changes during chemotherapy better than those without this variable. An equation based on plasma cystatin C, serum creatinine, and body weight enabled us to accurately describe the evolution of GFR during chemotherapy. The urinary cystatin C/creatinine ratio was compared between children with or without tubular toxicity, according to a standard assessment of tubular dysfunction. However, although the urinary cystatin C/creatinine ratio was increased in children with tubular toxicity, this marker does not provide additional information to the well-known markers of tubulopathy. CONCLUSIONS: Monitoring of plasma cystatin C may be substituted to radionucleide glomerular exploration in children treated by cisplatin and/or ifosfamide.

Therapeutic Drug Monitoring of Carboplatin in High-Dose Protocol (TI-CE) for Advanced Germ Cell Tumors: Pharmacokinetic Results of a Phase II Multicenter Study.

Purpose: We aimed to evaluate the performance of therapeutic drug monitoring (TDM) approach in controlling interpatient variability of carboplatin exposure (AUC) in patients treated with TI-CE high-dose chemotherapy for advanced germ cell tumors and to assess the possibility of using a formula-based dosing method as a possible alternative.Experimental Design: Eighty-nine patients receiving carboplatin for 3 consecutive days during 3 cycles 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. A population pharmacokinetic analysis was also performed on 58 patients using NONMEM to develop a covariate equation for carboplatin clearance prediction adapted for future TI-CE patients, and its performance was prospectively evaluated on the other 29 patients along with different methods of carboplatin clearance prediction.Results: The mean actual AUC was 24.4 mg.min/mL per cycle (22.4 and 26.8 for 10th and 90th percentiles, respectively). The new covariate equation [CL (mL/min) = 130.7 × (Scr/83)-0.826 × (BW/76)+0.907 × (Age/36)-0.223 with Scr in µmol/L, BW in kilograms, age in years] allows unbiased and more accurate prediction of carboplatin clearance compared with other equations.Conclusions: TDM allows controlling and reaching the target AUC. Alternatively, the new equation of carboplatin clearance prediction, better adapted to these young male patients, could be used if TDM cannot be implemented. Clin Cancer Res; 23(23); 7171-9. ©2017 AACR.

Should therapeutic drug monitoring of the unbound fraction of imatinib and its main active metabolite N-desmethyl-imatinib be developed?

PURPOSE: The European Society for Medical Oncology recommends therapeutic drug monitoring (TDM) for imatinib, based on total plasma concentrations in cases of sub-optimal response, failure, or adverse events. Imatinib is highly bound to alpha-1 acid glycoprotein (AGP) in the plasma. We determined the unbound plasma fraction of both imatinib and its main active metabolite (N-desmethyl-imatinib) in plasma from 44 patients. The objective was to quantify the inter-individual variability of the protein binding of imatinib in order to discuss the potential benefits and limits of TDM of free plasma concentrations. PATIENTS AND METHODS: The quantification of unbound fraction of imatinib and N-desmethyl-imatinib was performed using plasma ultrafiltration coupled with LC-MS/MS measurement. 60 pre-dose plasma samples were obtained at steady state within TDM in 44 chronic myeloid leukemia patients. RESULTS: The mean unbound fractions of imatinib and N-desmethyl-imatinib were 2.94 and 5.10 %, respectively, with inter-individual variability (CV in %) of 57 % for imatinib and 71 % for the metabolite. For 11 patients, repeated blood sampling gave a mean intra-individual variability of 28 % for imatinib and 34 % for N-desmethyl-imatinib. No correlation was observed between these measured individual imatinib unbound fraction values and those obtained using an equation based on AGP levels previously proposed by Widmer et al. The mean N-desmethyl-imatinib/imatinib ratio was determined for both total (0.69) and unbound (1.10) concentrations, with inter-individual variabilities of 71 and 86 %, respectively. CONCLUSION: The large inter-individual variability for the unbound fraction of both imatinib and N-desmethyl-imatinib warrants further evaluation of the pharmacokinetic-pharmacodynamic relationship as a potential relevant marker of imatinib therapeutic outcomes.

Population pharmacokinetics of erlotinib and its pharmacokinetic/pharmacodynamic relationships in head and neck squamous cell carcinoma.

UNLABELLED: A clinical study was conducted to determine the safety and efficacy of neoadjuvant erlotinib treatment in patients with head and neck squamous cell carcinoma [Thomas F, Rochaix P, Benlyazid A, et al. Pilot study of neoadjuvant treatment with erlotinib in non-metastatic head and neck squamous cell carcinoma. Clin Cancer Res 2007;13:7086-92]. The aim of the present analysis was to explore the impact of several covariates on the pharmacokinetics of erlotinib and its main metabolite (OSI-420) and to determine PK/PD relationships. PATIENTS AND METHODS: Plasma concentrations of erlotinib and OSI-420 of 42 patients were analysed using the NONMEM program to evaluate the impact of patients' covariates on erlotinib pharmacokinetics. The presence of single nucleotide polymorphisms (SNP) in ABCB1 (2677G>T/A and 3435C>T), ABCG2 (421C>A) and CYP3A5 (6986G>A) was investigated. Pharmacokinetic/pharmacodynamic relationships between plasma drug exposure (AUC) and early drug response or toxicity were also studied. RESULTS: The covariates retained to predict erlotinib clearance were ALAT (alanine amino transferase), age and ABCG2 polymorphism. A significant link between drug exposure and the grade of skin rash was observed but early response to treatment was not correlated to the erlotinib AUC. CONCLUSIONS: Erlotinib treatment may present criteria justifying dose individualisation but further studies, including more patients, are necessary to define the modalities of this adaptation.

Urinary cystatin C can improve the renal safety follow-up of tenofovir-treated patients.

A receiver operating curve analysis was performed to assess the predictive value of the urinary cystatin C to urinary creatinine ratio for the renal monitoring of tenofovir. Urinary cystatin C to urinary creatinine ratio was measured in 37 samples from patients referred for suspected tenofovir-induced Fanconi syndrome. The best threshold (14 microg/mmol) was associated with sensitivity, 90.9%; specificity, 88.5%; positive predictive value, 76.9%; and negative predictive value, 95.8%. Urinary cystatin C to urinary creatinine ratio allows to rule out a Fanconi syndrome in most cases; thus, it should be used for the safety follow-up of nucleotide reverse transcriptase inhibitor-treated patients.

[Interest of cystatin C for individual dosing of anticancer drugs cleared by the kidneys]. / Intérêt de la cystatine C pour l'adaptation de posologie des médicaments anticancéreux à élimination rénale.

Cystatin C is a protein freely filtered in the renal glomerulus, then reabsorbed and completely metabolised within the tubular cells. The possibility to predict the clearance of compounds eliminated by the kidneys (and then to control their interindividual variability) was evaluated for two cytotoxic drugs (carboplatin and topotecan) in adults and EDTA (ethylene diamine tetraacetic acid), a compound used to determine the glomerular filtration rate in children. The population pharmacokinetic approach based on NONMEM program was used. For each of the three compounds, the cystatin C serum level was better predictive of clearance than that of creatinine. Moreover, for carboplatin and EDTA, the best equation between clearance and patients' characteristics included both cystatin C and creatinine level. A generalisation of cystatin C assay would contribute to standardise the clinical practices in Oncology.

Contribution of the MDRD equation and of cystatin C for renal function estimates in cancer patients.

BACKGROUND: Serum creatinine (SCr) and Cockcroft-Gault creatinine clearance (CG CrCL) are used to estimate glomerular filtration rate (GFR). Other markers have been proposed including serum cystatin C (cysC) and the Modification of Diet in Renal Disease (MDRD) study equation. PATIENTS AND METHODS: We have compared the diagnostic performances of SCr, cysC, CG CrCL, and the MDRD equation in 144 cancer patients. For reference we used either the measured or the predicted carboplatin clearance, which is around the GFR + 25 mL/min. RESULTS: CysC was more sensitive than SCr (70.1% vs 13.4%) but was not very specific (61% for a cut-off = 0.95 mL). CysC values were higher in 40 cancer patients vs 40 healthy controls with a similar and normal mean CG CrCL (1.08 vs 0.71 mg/L; p < 0.001). CG and the MDRD equations gave similar values for Pearson's coefficient, ROC-plot AUC, and precision, except for patients with poor general status, where the MDRD equation was better (MAPE: 12.4% vs 19.6%, p < 0.001; R: 0.908 vs 0.813). CONCLUSIONS: In cancer patients, cysC is a more sensitive indicator of the glomerular filtration rate than SCr, but its diagnostic performance is lower than for CG CrCL. There may be no advantage in replacing the CG equation by the MDRD equation except for patients with severe malnutrition and/or inflammation.

Cystatin C as a new covariate to predict renal elimination of drugs: application to carboplatin.

BACKGROUND AND OBJECTIVE: The individual dosing of drugs that are mainly eliminated unchanged in the urine is made possible by assessing renal function. Most of the methods used are based on serum creatinine (SCr) levels. Cystatin C (CysC) has been proposed as an alternative endogenous marker of the glomerular filtration rate (GFR). Carboplatin is one of the drugs for which elimination is most dependent on the GFR. A prospective clinical trial including 45 patients was conducted to assess the value of serum CysC as a predictor of carboplatin clearance (CL). METHODS: The patients were receiving carboplatin as part of established protocols. Carboplatin was administered as a daily 60-minute infusion at doses ranging from 290 to 1700mg. A population pharmacokinetic analysis was performed using the nonlinear mixed effect modelling NONMEM program according to a two-compartment pharmacokinetic model. RESULTS: Data from 30 patients were used to test the relationships between carboplatin CL and morphological, biological and demographic covariates previously proposed for prediction of the GFR. The interindividual variability of carboplatin CL decreased from 31% (no covariate) to 14% by taking into account five covariates (SCr, CysC, bodyweight [BW], age and sex). Prospective evaluation of these relationships using the data from the other 15 patients confirmed that the best equation to predict carboplatin CL was based on these five covariates, with a mean absolute percentage error of 13% as an assessment of precision. NONMEM analysis of the whole dataset (n = 45 patients) was performed. The best covariate equation corresponding to the overall analysis was: CL (mL/min) = 110 x (SCr/75)-0.512 x (CysC/1.0)-0.327 x (BW/65)0.474 x (age/56)-0.387 x 0.854sex, with SCr in micromol/L, CysC in mg/L, BW in kilograms, age in years and sex = 0 if male and 1 if female. To put the value of CysC as an endogenous marker of the GFR into perspective, covariate equations without SCr were also evaluated; a better prediction was obtained by considering CysC together with age and BW (interindividual variability of 16.6% vs 23.3% for CysC alone). CONCLUSION: CysC is a marker of drug elimination that is at least as good as SCr for predicting carboplatin CL. The model based on five covariates was superior to those based on only four covariates (with BW, age and sex combined with either SCr or CysC), indicating that CysC and SCr are not completely redundant to each other. Further pharmacokinetic evaluation is needed to determine whether SCr or CysC is the better marker of renal elimination of other drugs.

Serum cystatin C is a better marker of topotecan clearance than serum creatinine.

PURPOSE: To evaluate plasma cystatin level as a covariate to predict topotecan pharmacokinetics. Cystatin C, a member of the cystatin superfamily of cysteine proteinase inhibitors, has been recently proposed as an alternative endogenous marker of glomerular filtration. Renal function is known as a key factor of topotecan clearance. EXPERIMENTAL DESIGN: Data were obtained from 59 patients who underwent drug monitoring for individual dosing of topotecan. Topotecan plasma concentrations versus time were analyzed using a nonlinear mixed effect model according to a two-compartment pharmacokinetic model and a first-order conditional estimation method. A proportional error model was used for residual and interpatient variabilities. Data-splitting was done randomly to create a model-building data set (44 patients) and a model validation data set (15 patients). RESULTS: Using the building data set, four covariates significantly decreased the objective function value and interindividual variability on topotecan clearance (CL) when tested individually: ideal body weight (IBW), serum creatinine, age, and cystatin C level. The best model was: CL (L/hour) = 20.2 [cystatin C (mg/L) / 1.06](-0.60) [IBW (kg) / 57](0.95). Prospective evaluation using the validation data set confirmed that the model based on cystatin C had a better predictive value than the models based on serum creatinine or body surface area. CONCLUSION: Cystatin C is a marker of drug elimination which is superior to serum creatinine for topotecan. It deserves to be further explored as a promising covariate for drug dosing as well as selection criteria for clinical studies of drugs eliminated mainly or partially by the kidney.