Etienne Chatelut

Co-variables influencing 5-fluorouracil clearance during continuous venous infusion. A NONMEM analysis

The objective of this study was to attempt to identify patient co-variables which could influence interpatient variability in 5-fluorouracil (5-FU) clearance during a 5-day continuous venous infusion (CVI, cisplatin 100 mg/m2 day 1 then 5-FU 1 g/m2/day days 2-6). The analysis was performed using a NONMEM program according to a linear one-compartment model. A total of 186 cycles (2 samples per day, 8 a.m. and 5 p.m.) were analysed from 104 patients with various cancers (the majority of head and neck and oesophagus). The study co-variables were age, sex, body surface area, hepatic metastases, peripheral mononuclear cell dihydropyrimidine dehydrogenase activity (PMNC-DPD), liver enzymes, clock-time (8 a.m. versus 5 p.m.), elapsed time during CVI. The data showed that 5-FU clearance was significantly reduced by increased age, low PMNC-DPD, high serum alkaline phosphatase and elapsed time during infusion. These data may be useful for improving knowledge of predictive factors which can influence 5-FU exposure and thus predispose to toxic manifestations.

Comparison of the pharmacokinetics and efficacy of irinotecan after administration by the intravenous versus intraperitoneal route in mice

Abstract Irinotecan (CPT-11) is a new drug active in colorectal cancer. A comparison was made of the efficacy and pharmacokinetics of CPT-11 after i.p. versus i.v. administration to mice. We found that i.p. administration of CPT-11 to mice bearing C26 colon cancer was more efficient and less toxic than i.v. administration; a 100-mg i.p. dose induced an increase in life span equivalent to that produced by a 300-mg i.v. dose, and toxic deaths appeared after doses of 400 mg/kg given i.v. and 800 mg/kg given i.p. Pharmacokinetic parameters of CPT-11 and SN-38 were compared after i.v. or i.p. administration in mice bearing P388 leukemia ascites. Peritoneal CPT-11 and SN-38 AUC values were higher after i.p. administration than after i.v. injection. Plasmatic AUC values remained equivalent. Moreover, peritoneal CPT-11 clearance was 10-fold lower after i.p. versus i.v. administration. If the survival and pharmacologic advantage of i.p. CPT-11 in the murine model considered can be translated to a safe and practical mode of therapy in patients and if local toxicity does not prove to be a major adverse effect, then a potentially useful agent could be added to the drugs known to be active when given by the i.p. route for adjuvant therapy in colon cancer.

A limited sampling strategy for determining carboplatin AUC and monitoring drug dosage

There are several convincing reports showing relationships between the area under the curve of ultrafilterable concentration versus time (AUC) and pharmacodynamics of carboplatin. It is advisable, in treated patients, to check the AUC that is effectively delivered as compared with the prescribed AUC. To this end, limited sampling strategy seems to be an adequate approach since it limits the constraints of repeated blood sampling for both patients and nursing staff. A flexible limited sampling method for assessing ultrafilterable carboplatin AUC was developed. This method was based on a Bayesian estimation of carboplatin clearance using the NON linear Mixed Effect Model (NONMEN) program and a large pharmacokinetic and covariates database (103 patients). The optimal sampling design was a two-sample schedule (1 and 4 h after the end of infusion). During a prospective evaluation, it allowed an adequate estimation of carboplatin clearance with a non-significant bias (-4.5%) and a good precision (9%). In a second stage, this method was clinically applied to monitor carboplatin AUC in a group of 5 patients with metastatic germ cell tumours treated with intensified high dose carboplatin-based chemotherapy for 4 days. Dosage adjustments were performed according to daily controls of their AUC in order to obtain a total AUC of 20 mg/ml x min. By using this strategy all patients effectively received a total AUC very close to this targeted AUC, thus proving the clinical usefulness of this limited sampling method.

Comparison of methods for the estimation of carboplatin pharmacokinetics in paediatric cancer patients

The antitumour and toxic effects of platinum drugs, in particular carboplatin, have been related to their plasma concentration and this has led to the concept of a target area under the plasma concentration-time curve (AUC) for carboplatin dosing. A formula based on renal function has been successfully applied to carboplatin dosing in adults and modified versions have also been proposed for paediatric patients. In order to monitor carboplatin AUC with maximum efficiency and minimum patient inconvenience, limited sampling strategies are desirable. A population method with Bayesian estimation is described, based on one or two samples taken following a dose of carboplatin. Population data were obtained from 22 paediatric patients treated with 200-1000 mg/m2 carboplatin as a 60-90 min infusion. Ultrafilterable carboplatin was determined by atomic absorption spectrophotometry. A two compartment model was fitted to each data set using the Maximum Likelihood estimator of the ADAPT programme. These parameter estimates provided the prior means and covariance matrix for the Bayesian estimator using a lognormal distribution. The test data sets consisted of ultrafilterable carboplatin concentrations in 23 patients (aged 1 month-18 years) who received similar treatment. The two compartment model was fitted to data sets containing one or two points, using the Bayesian maximum a posteriori (MAP) estimator and an error model derived from the population error model parameters. Results from the Bayesian analysis and other methods for the estimation of AUC, including relating clearance to surface area or to renal function, were evaluated by comparing the AUC estimate with the AUC determined by model-independent analysis. Overall, the optimal sampling strategy performed better than estimates based on renal function, which had a median bias of 5% and precision of 22%. With one data point at 60 min postinfusion, the median bias and precision were 3 and 6%, respectively. Addition of a second data point at 30 min during the infusion improved the estimate slightly (median bias -2%, precision 3%). Bayesian estimation produced more reliable estimates of AUC compared to values based on renal function, which in turn was slightly better than using surface area. A technique, developed in adult patients, for estimating AUC from a measurement of 24 h total plasma platinum was comparable to estimates based on renal function, but was less reliable. The estimation of carboplatin AUC can be performed using only one or two plasma samples and Bayesian analysis. This approach is less biased and more precise than methods based on surface area, renal function or total platinum at 24 h postdose, but is probably best used in combination with dosing based on renal function.

Population pharmacokinetics of topotecan: intraindividual variability in total drug.

Abstract The inter- and intraindividual variabilities in topotecan clearance (CL) were explored using a population pharmacokinetic approach. Total (lactone + hydroxy acid) topotecan plasma concentrations were obtained in 31 women with metastatic epithelial ovarian cancer treated by the 30-min intravenous infusion on 5 subsequent days. The data corresponding to three occasions (days 1 and 5 of cycle 1, and day 1 of cycle 2), were analyzed using the nonlinear mixed effect model program. A large interindividual variability was observed, with CL varying from 9.1 to 42.5 l per hour (mean 21.0). Topotecan CL was related to serum creatinine level, and age. A close relationship was also observed between topotecan CL and creatinine clearance. Intraindividual variability both within cycle 1 and between the two first cycles was limited, with a mean variation of −2 ± 17%, and +5 ± 20%, respectively. A limited sampling strategy using Bayesian estimation based on two samples (5 min before the end of the 30-min infusion, and 4 h after the end of infusion) was developed. The results of this study combine relationships between topotecan pharmacokinetic parameters and patient covariates that may be useful for a priori dose adjustment, and convenient sampling procedure that can be used for further studies and drug monitoring.

Tissue distribution and pharmacokinetics of an ATWLPPR-conjugated chlorin-type photosensitizer targeting neuropilin-1 in glioma-bearing nude mice

Destruction of the neovasculature is essential for efficient tumor eradication by photodynamic therapy (PDT). The PDT anti-vascular effect can be promoted by developing addressed photosensitizers localized preferentially to the tumor vascular compartment. A new photosensitizer conjugated to an heptapeptide [H-Ala-Thr-Trp-Leu-Pro-Pro-Arg-OH (ATWLPPR)] targeting neuropilin-1, a Vascular Endothelial Growth Factor (VEGF) co-receptor, has been synthesized. It was administered intravenously for an easier access to endothelial cells lining the vasculature in human malignant glioma-bearing nude mice. Plasma pharmacokinetic parameters were derived from plasma concentration-time data using a non-compartmental analysis and validated a relatively rapid elimination from the blood compartment with an elimination rate constant of 0.062 h(-1) and a biological half-life of 11.0 h. The photosensitizer was mainly concentrated in organs such as liver, spleen and kidneys, which are rich in reticuloendothelial cells. In these organs, the elimination profiles of the photosensitizer were comparable, with half-lives as short as 12.2, 15.1 and 19.7 h, respectively. The peptidic moiety of the conjugated photosensitizer was degraded to various rates depending on the organ considered, most of the degradation process occurred in organs of the reticuloendothelial system. A metabolic product resulting from the enzymatic cleavage of the peptide bond between Ala and Thr was detected in plasma at all the examined time points from 2 h post-injection. The conjugated photosensitizer accumulated rapidly and at high levels in the tumor, with 2.3% of injected dose per gram of tumor tissue at 1 h after injection. Taking into account the aspecific uptake of the degradation product, the tumor levels of total photoactivable compounds might exhibit an interesting photodynamic activity. On the contrary, levels of total photoactivable compounds remained low in the skin. This study provides essential information for the choice of the time interval not to exceed to activate the photosensitizer.

A limited-sampling strategy for estimation of etoposide pharmacokinetics in cancer patients.

Abstract Etoposide (VP16), a widely used anticancer drug, is a topoisomerase II inhibitor. A number of studies have highlighted a correlation between hematologic toxicity and pharmacokinetic or physiological parameters. Other studies have also suggested that the anti-tumor response could be related to the plasma etoposide concentration. Therefore, it would seem of interest to individualize VP16 dose regimens on the basis of pharmacokinetic parameters. The aim of this study was to develop and validate a limited-sampling strategy allowing VP16 pharmacokinetic evaluation with minimal disturbance to the patient. A total of 34 patients (54 kinetics) received VP16 at various dose regimens, with doses ranging between 30 and 200 mg and infusion times varying between 0.5 and 2 h. The statistical characteristics of the pharmacokinetic parameters were assessed from the first courses of treatment performed in 23/34 patients; then the following three-sample protocol was designed: the end of the infusion and 5 and 24 h after the start of the infusion. For validation of the model the main pharmacokinetic parameters (clearance, half-lives, volume of distribution) were estimated in the 11 remaining patients by maximum-likelihood estimation (ML) and by Bayesian estimation (BE) using the three sampling times designed. Statistical comparison showed a good concordance between ML and BE estimates (the bias for clearance was –1.72%). The limited-sampling strategy presented herein can thus be used for accurate estimation of VP16 pharmacokinetic parameters.

A limited-sampling method for evaluation of the area under the curve of ultrafilterable carboplatin in children

Carboplatin is a widely used cytotoxic agent in numerous solid tumors of children. Since there is a large degree of interpatient variability in the area under the curve of free carboplatin for a given dose of the drug, the current tendency is to adjust the carboplatin dose so as to reach a target area under the curve rather than to determine a carboplatin dose on the basis of the body surface area. A limited-sampling method was developed for estimation of the ultrafilterable carboplatin area under the curve and for adjustment of the carboplatin dose on subsequent treatments. Population parameters were obtained from 16 children (reference group). We used the maximum a posteriori (MAP) Bayesian approach on 15 children with complete carboplatin pharmacokinetic data (test group). Two blood samples were sufficient to obtain reliable prediction of the area under the curve. The best sampling times were: (a) 30 min after the end of the infusion and (b) 5 h after the end of the infusion. On the basis of these data it is possible to prescribe prospectively a target area under the curve for free carboplatin given in a fractionated daily infusion and to adapt the carboplatin dose directly to ultrafilterable carboplatin measurements.

Optimising Carboplatin Dose using Patient Characteristics and Therapeutic Drug Monitoring

As the pharmacokinetics of carboplatin is mainly determined by renal function, AUC dosing of this drug is routinely performed. This method consists in predicting the individual carboplatin clearance and calculating the dose according to a target value of area under the plasma concentration time curve (AUC). All the equations proposed for predicting carboplatin clearance are based on body weight, age, gender, and serum creatinine level. In this way, carboplatin, which was initially contraindicated in patients with renal insufficiency, can now be administered to such patients. However, several of the assays used for serum creatinine determination are not consistent with one another. Substantial differences in carboplatin doses (even in the same patient) may be the consequence of these analytical discrepancies. A new biological parameter, cystatin C plasma level, could be an additional or even an alternative covariable for predicting carboplatin clearance. For some carboplatin regimens, such as in high-dose chemotherapy, drug monitoring of car-boplatin plasma concentrations followed by Bayesian pharmacokinetically guided dosing can be implemented. In conclusion, carboplatin AUC dosing still needs to be improved in order to standardise its use in clinical practice.