Optimize administration protocol of capecitabine plus docetaxel combination in metastatic breast cancer patients.

Combining several cytotoxics is the current mainstay for treating breast cancer patients. The combination between capecitabine and docetaxel was found to be more efficient than capecitabine or docetaxel when both were used as single agents. However, the administration protocol for this combination has been empirically chosen from single-agent trials. Based on already available population analysis, we propose here to optimize the administration protocol of this association so as to enhance efficacy while limiting treatment-related toxicity. Efficacy parameters evaluated from population analysis using a disturbed tumor growth model and safety characteristics from the available databases evidenced that: 1) Docetaxel is more efficient than capecitabine at the start of the treatment, but becomes less efficient next because of acquisition of resistance; 2) Over a long period of time, capecitabine is better tolerated than docetaxel. These characteristics allowed the following recommendations for an optimized modality of combination: 1) The treatment has to be started at the maximum tolerated dose for docetaxel; this dose should be individualized right from the start of the second cycle of treatment; 2) In parallel, capecitabine has to be started at a dose lower than its maximum tolerated dose. 3) When docetaxel becomes less efficient than capecitabine because of resistance, docetaxel dose has to be reduced but not discontinued. 4) If adverse events show during the treatment, it is recommended to reduce docetaxel, rather than capecitabine dosage. Combining modeling and statistical analysis of clinical data permit to optimize combination treatments. This procedure could be extended to others treatments involving combination of several cytotoxics.

Progress in strategies for dosage regimen individualization.

Several findings suggest that patient outcome would be improved with individualized doses. The aim of this paper is to describe major approaches, methods and underlying basic foundations implemented, in clinical practice, for dosage individualization. Also we propose a new method codified by kinetic nomograms as reliable alternative to traditional Bayesian methods. Clinical and simulation data were reported to evaluate performances of the proposed methods. Real examples of therapeutic drug monitoring were selected. Bayesian methods were used to individualize high-dose methotrexate rate infusion and amikacin dosage regimen, and kinetic nomograms to adjust sirolimus doses. 1) Using only few measurements, Bayesian method resulted in accurate estimates of individual pharmacokinetic parameters of high dose methotrexate infusion. Targeting a pre-defined end-of-infusion level, infusion rate was individualized according to the previously obtained pharmacokinetic parameters. 2) With the same reasoning, individual pharmacokinetic parameters of amikacin were obtained by Bayesian estimation using three individual samples. Subsequent dosage adjustment allowed achievement of therapeutic goals at steady state. 3) Without computing individual pharmacokinetic parameters, nor using pharmacokinetic software, kinetic nomograms steered individual sirolimus blood levels within its therapeutic window with only two samples and in the first week after starting treatment. This contribution relates traditional Bayesian methods developed in 80's but not yet fully integrated in clinical context because of their complexity. The contribution focuses on recent developments based on population approaches, rendering the dosage adjustment methodology a simple and quick bedside application.

Population pharmacokinetic analysis of 5-FU and 5-FDHU in colorectal cancer patients: search for biomarkers associated with gastro-intestinal toxicity.

PURPOSE: The anticancer drug 5-fluorouracile (5-FU) which is indicated for the treatment of a variety of solid malignancies such as colorectal, breast, head and neck neoplasms is extensively biotransformed to 5 fluoro-5,6- dihydrouracil (5-FDHU) by the dihydropyrimidine deshydrogenase enzyme (DPD). DPD deficiency is recognized as an important risk factor, predisposing patient to undergo severe/lethal toxicities. To date, relationships between 5-FU, 5- FDHU and toxicity following i.v. bolus administration has not been studied using the population pharmacokinetics approach. METHODS: Retrospective pharmacokinetic data of 5-FU and 5-FDHU from 127 colorectal cancer patients were used for the population pharmacokinetic analysis. Treatment schedule consisted of an adjuvant therapy with 5-FU plus leucovorin. 5- FU and 5-FDHU complete plasma profiles recorded on day-1 of the first chemotherapy cycle were modeled simultaneously using NONMEM software. Gastro-intestinal adverse events graded according to the WHO criteria were recorded after the first cycle. A population logistic regression model was developed to identify predictive factors of these adverse events. RESULTS: A three-compartment pharmacokinetic mixture model best described 5-FU and 5-FDHU kinetics profiles. Linear and saturated elimination from the central compartment of 5-FU and a linear elimination from the 5-FDHU compartment were used. A bimodal distribution of the inter-compartmental clearance was observed allowing two subpopulation with high (17 L/h) and low values (3.35 L/h). DPD-phenotype is suspected to explain this mixture. No covariates were introduced in the final model. Also, no relationship was found between maximal metabolism rate and DPD-phenotype. Predictive factors associated with occurrence of high grade gastro-intestinal adverse events were gender, dose and lean body mass suggesting serious cautions with the BSA-weighted dose for women. For the low-grade toxicities, 5-FU area under curve was predictive for woman and 5-FDHU area under curve for men. CONCLUSION: A population pharmacokinetic mixture model was developed to describe kinetic profiles of 5-FU and its major metabolite. This model has significant implications, to identify patients with potentially low DPD phenotype requiring earlier adjustment of the 5-FU dose. Also this analysis highlights the need for developing alternative dosing-scheme for women.

Kinetic nomograms assist individualization of drug regimens.

BACKGROUND AND OBJECTIVES: Therapeutic drug monitoring is applied to a range of drugs. To predict an appropriate dosing regimen, models based on Bayesian techniques have been used. However, this approach requires a well trained professional and sophisticated software. The objectives of this study were first to develop kinetic nomograms as a useful tool to achieve individual drug blood concentrations within the therapeutic window, using few samples and in a short period of time; and second to evaluate the performance of these nomograms in dosage adjustment and compare them with the Bayesian procedure by use of simulation. METHODS: Kinetic nomograms involve collection of concentration-time profiles following repeated administrations of a fixed identification protocol and targeting of a steady-state concentration. The profiles divide the concentration-time space into several areas, each of them corresponding to a given adjusted drug dose. Kinetic nomograms are grounded on the statistical description of the interindividual variability provided by population pharmacokinetic approaches. To use them, the assayed drug concentration in a blood sample is first located in the kinetic nomogram and then the dose corresponding to the area containing this location is read. Evaluation of performance and comparison with the traditional Bayesian procedure were done by a simulation study using the immunosuppressant drug sirolimus (rapamycin). All calculations were performed by use of Matlab software. RESULTS: The simulation study confirmed the need for individual dosage adjustment; 71.6% of individuals underwent modification of the identification protocol of 1 mg twice daily in order to reach steady-state trough concentrations of 8 ng/mL. When the regimens were adjusted by kinetic nomograms and the Bayesian procedure, the steady-state trough concentrations of sirolimus showed low variability (coefficients of variation [CVs] of 23.4% and 24.0%, respectively) as compared with those obtained by standard recommended protocols of 4 mg once daily (CV 68.6%). The doses adjusted by kinetic nomograms and the Bayesian procedure were linearly linked and highly correlated (r = 0.96), and both provided simultaneous control of minimum and maximum drug concentrations (63.9% and 68.7% of cases between 6 and 20 ng/mL, respectively). CONCLUSION: Kinetic nomograms allow rapid and reliable dosage adjustment after the start of drug therapy. They are interesting alternatives to the cumbersome Bayesian procedure, and they provide dosage adjustment even for drugs that exhibit large intraindividual variability. In the clinical context, kinetic nomograms render individual dosage adjustment a simplified bedside application, and they could assist population studies aiming at dose individualization.

DPD-based adaptive dosing of 5-FU in patients with head and neck cancer: impact on treatment efficacy and toxicity.

BACKGROUND: Fluoropyrimidine drugs are widely used in head and neck cancer (HNC). DPD deficiency is a pharmacogenetics syndrome associated with severe/lethal toxicities upon 5-FU or capecitabine intake. We have developed a simple, rapid, and inexpensive functional testing for DPD activity, as a means to identify deficient patients and to anticipate subsequent 5-FU-related toxicities. We present here the impact of fluoropyrimidine dose tailoring based on DPD functional screening in a prospective, open, non-controlled study, both in term of reduction in severe toxicities and of treatment efficacy. METHODS: About 65 patients with HNC (59 ± 9 years, 52M/13F, Prospective Group) were entered into the study. Screening for DPD deficiency was performed prior to the beginning of the chemotherapy or radiochemotherapy. DPD status was evaluated by monitoring U/UH2 ratio levels in plasma as a surrogate marker for enzymatic functionality. 5-FU doses were reduced according to the extent of the detected DPD impairment, and adjusted on the basis of age, general condition, and other clinical/paraclinical covariates, if required. Treatment-related toxicities and subsequent impact on treatment delay were carefully monitored next for comparison with a retrospective, Reference subset of 74 other patients with HNC (mean age: 59 ± 10, 58M/16F, Reference Group), previously treated in the same institute with similar schedule but using standard 5-FU dosage. RESULTS: Thirty-one out of 65 patients (48%) were identified as mildly (28%) to markedly (20%) DPD deficient. Subsequently, dose reductions ranging from 10 to 100% with 5-FU were applied in those patients. In this group, six patients (9%) experienced severe toxicities, none of them being life threatening, and no toxic death was encountered. In comparison, 16 out of 74 patients (22%) of the Reference Group displayed severe side effects after standard 5-FU administration, 13% being life-threatening toxicities (e.g., G4 neutropenia + sepsis). Moreover, one toxic death was observed in this Reference Group. No postponement or cancelation of forthcoming chemoradiotherapy courses occurred in the Prospective Group, whereas treatment had to be disrupted in six patients (8%) from the Reference Group. No difference in first-line therapy efficacy was evidenced between the two subsets (78 vs. 79% response, P = 0.790). CONCLUSIONS: Although non-randomized, this study strongly suggests that prospective determination of DPD status has an immediate clinical benefit by reducing the drug-induced toxicities incidence in patients treated with 5-FU, allowing an optimal administration of several courses in a row, while maintaining efficacy. Our preliminary results thus advocate for systematic DPD screening in patients eligible for treatment with fluoropyrimidine drugs in HNC.

Effects of hyperthermia on pharmacokinetics of ertapenem in rats.

The aim of this study was to document the influence of hyperthermia on the pharmacokinetics of ertapenem. Two groups of Wistar rats, normothermic (n = 6) and hyperthermic (n = 8), were injected a single intravenous bolus of ertapenem (15 mg/kg of body weight). Hyperthermia-induced animals were placed in a water-bath at 47 degrees C and control group animals were kept in a water-bath at 25 degrees C to obtain a stable mean core temperature of 39.8 and 36.9 degrees C respectively. Hyperthermia induced significant higher plasma concentrations and exposure, whereas total apparent clearance and volume of distribution were significantly decreased. If confirmed in humans, these results will be of interest to take into account such modifications in hyperthermic clinical situations.