Intrapleural administration of lipoplatin in an animal model.

BACKGROUND: Lipoplatin is a new liposomal cisplatin already tested in solid tumors with encouraging results. Little is known about the activity of lipoplatin administered intrapleurally (IP). AIM: The aim of this study was to assess in an animal model the pharmacokinetics, and potentially induced histopathological lesions of lung and kidney after IP vs. IV injection of lipoplatin. METHODS: 15 male Wistar rats were assigned to an IV group at dose 10mg/kg of lipoplatin (group 1) and to IP groups at 10 (group 2) or 20mg/kg (group 3) equal to 60 and 120 mg/m(2) in humans respectively. After lipoplatin administration, serial plasma samples were analyzed by atomic absorption spectrometry for the maximum plasma concentration (C(max)), the area under the plasma concentration-time curve (AUC), and the total body clearance (CL). Pleura, lungs and kidneys of the rats were histologically examined for possible lesions. RESULTS: The C(max) was significantly higher in groups 1 vs. 2 (p = 0.02) and vs. 3 (p = 0.01). The AUC of groups 3 vs. 1 was significantly higher (p = 0.028) but the AUC of groups 2 vs. 1 was significantly lower (p = 0.02). CL in IP rats did not differ considerably compared to the IV. Inflammatory changes were noted in the pleura of IP rats and mild kidneys lesions in IV group. CONCLUSION: Compared to the IV route, IP20 administration of lipoplatin yielded higher AUC, equal CL, but a significantly lower C(max). As C(max) is a determinant of lipoplatin toxicity, IP administration might offer a more effective therapeutic index while improving tolerability. We noted fibrotic changes in the pleura of IP rats, and mild kidneys changes in IV rats, as expected.

Intrapleural administration of pemetrexed: a pharmacokinetic study in an animal model.

BACKGROUND: Pemetrexed is a key drug for the treatment of malignant pleural mesothelioma. The intrapleural administration of pemetrexed might increase its efficacy and decrease its toxicity in comparison with intravenous administration. The aim of this study was to assess in an animal model the pharmacokinetics of pemetrexed administered intrapleurally compared with intravenously. METHODS: Thirty Wistar rats were randomly assigned to four groups defined by route (intravenous or intrapleural) and dose (10 or 100 mg/kg) of pemetrexed. After pemetrexed administration, serial plasma pemetrexed concentrations were analyzed by high performance liquid chromatography to determine the maximum plasma concentration (C(max)), the area under the plasma concentration-time curve (AUC), and the total body clearance (CL). RESULTS: The C(max) was significantly lower after intrapleural versus intravenous administration of 10 mg/kg pemetrexed (14.36 microg/ml versus 29.83 microg/ml; p = 0.008) or 100 mg/kg pemetrexed (70.64 microg/ml versus 218.64 microg/ml; p = 0.001). At either dose, the AUC and the CL did not significantly differ according to the route of administration. CONCLUSIONS: While intravenous and intrapleural administration of pemetrexed yielded similar AUC and CL, the intrapleural route yielded a significantly lower C(max). As Cmax is a determinant of pemetrexed toxicity, intrapleural administration might offer a means of widening the effective therapeutic index of the drug by improving tolerability. Future studies are needed to confirm this hypothesis in malignant pleural mesothelioma patients.

High-dose methotrexate in adults with osteosarcoma: a population pharmacokinetics study and validation of a new limited sampling strategy.

Preoperative high-dose methotrexate (HD-MTX) with folinic acid (leucovorin) rescue is still a mainstay in the treatment of osteosarcoma. This anticancer agent is characterized by a narrow therapeutic index and wide interpatients variability. To ensure effective and safe administration of HD-MTX, we had earlier developed an adaptive-dosing schedule with a feedback strategy. In our institute, the MTX dosage was tailored according to individual pharmacokinetics parameters, determined in real time both from two blood samples (3.5 and 4.5 h) and from Bayesian population parameters. Up to 20 g of MTX was safely administered as 8-h infusions. Low MTX elimination rate has, however, been reported in 15-20% of the patients, and forecasting the MTX elimination phase and the management of leucovorin rescue is still a challenging issue in clinical oncology. This study aims at identifying the clinical or biological covariates related to impaired MTX clearance, and at validating a new limited sampling strategy (LSS), allowing for the accurate prediction of the MTX terminal elimination phase. This retrospective study was carried out on 49 patients (30 men, 19 women; mean age, 26.7 years) treated for osteosarcoma with HD-MTX. The population and individual pharmacokinetics parameters were computed, before the identification of the relevant covariates. Different LSSs were then tested, to predict accurately when the MTX plasma concentrations would drop below 0.2 micromol/l, the threshold associated with the end of the rescue of leucovorin with alkaline hydration. Two main covariates (creatinemia clearance and alanine aminotransferase) were correlated with MTX clearance. Conversely, the impact of body surface area on MTX pharmacokinetics was weak, suggesting that dosing schedules based on body surface area were inadequate and potentially hazardous. A new LSS predicting accurately when the MTX concentration would reach 0.2 micromol/l has been validated; blood samples are stopped as soon as the MTX concentration drops to 1 micromol/l. With this LSS, our retrospective study suggests that 60% of the patients would have left the hospital earlier than they actually did owing to a better forecasting of the MTX decrease, thus improving their quality of life while improving the cost-effectiveness for the institute. HD-MTX can be administered safely using an adaptive-dosing strategy with drug monitoring. Moreover, pharmacokinetic modeling permits the accurate forecasting of the MTX elimination profile, thus allowing for a better management of the postinfusion care of cancer patients treated with particularly high doses of this drug.

Therapeutic drug monitoring for dose individualization of Cisplatin in testicular cancer patients based upon total platinum measurement in plasma.

Cisplatin (CDDP) is an anticancer agent widely used in testicular cancer, for which pharmacokinetic (PK)/pharmacodynamic relationships have usually been based upon measurement of its unbound fraction in plasma. Because it has been shown that free CDDP clearance can be related to patient's body surface area (BSA), dosage is mostly adjusted a priori using only this single parameter, with mixed results for accurately predicting CDDP exposure and reducing toxicities. In contrast, the authors present here an original, 5-day continuous infusion schedule, coupled to a daily Bayesian adaptive dosing with feedback strategy, based upon the rapid assay of total, rather than free, CDDP in plasma. Nineteen patients (66 therapeutic courses) were treated with platinum-based combinational therapy. Plasma samples were analyzed to allow real-time Bayesian estimation of individual PK parameters with subsequent prospective dose adjustment in order to reach a target Cmax (Cend) of 1.95 mg/L of total platinum. Performance of the Bayesian dosing method was evaluated by comparing target Cmax with achieved Cmax. The mean+/-SD Cmax achieved was 1.93+/-0.16 mg/L. No statistically significant difference was observed between experimental and target values (P>0.05, t test), and Cend achievement was done with an overall 6.6% precision, a performance to be compared with the initial 54% interpatient variability observed in CDDP clearance. A nonlinear mixed effect model population PK analysis was subsequently performed to identify retrospectively the covariates associated with PK parameters of total CDDP. It showed a good correlation (r=0.84, P=0.004) between total platinum clearance and therapeutic course number. A weaker correlation (r=0.59) was found between BSA and total CDDP clearance and, importantly, no additional relationship was established with BSA when successive therapeutic courses, and not only the first one, were considered. This highlights the critical importance of total drug accumulation on CDDP pharmacokinetics when several infusions are to be administered in a row and, therefore, the need for real-time dose individualization that takes into account the course number, rather than BSA. Finally, doses of CDDP administered during each course were significantly higher (+20%, P<0.01) than the ones classically normalized with BSA, thus leading to an overall greater drug exposure in the patients. It is noteworthy that despite these markedly higher doses, little severe toxicity was reported, and all of the patients presented in this study were still alive and disease free after a follow-up of up to 15 years.

Dose individualization of carboplatin after a 120-hour infusion schedule: higher dose intensity but fewer toxicities.

Carboplatin (CBDCA) is a widely used anticancer agent for which dose-effect and dose-toxicity relationships have been demonstrated, thus stressing the need for a controlled exposure to this drug. So far, carboplatin administration could only be individualized a priori following 2 classic methods, which are based on the evaluation of renal clearance: Calvert's and Chatelut's formulas. This study was designed to develop and evaluate the performance of an alternative CBDCA 120-hour schedule coupled to a Bayesian adaptive dosing with feedback strategy. Precision of the dosing method was assessed in 84 patients (256 courses performed during a 10-year period), by comparing CBDCA plasma concentrations observed at the end of the infusion with initial target values. A comprehensive monitoring of treatment-related toxicities also was performed. Finally, the authors compared doses actually delivered following the dose-tailoring method with the theoretical, standard, ones calculated retrospectively with Calvert's and Chatelut's formulas. No significant differences were found between experimental and theoretical concentrations. According to the target exposure chosen (3 levels), the mean doses administered to our patients were 517, 719, and 902 mg of CBDCA compared with 550, 509, and 538 or 657, 604, and 644 mg, which would have been given following Calvert or Chatelut formulas, respectively. These results showed that our Bayesian method led to the administration of up to 60% higher doses of carboplatin compared with those based only on the evaluation of renal clearance. Despite the markedly higher doses administered, no severe toxicities were reported in the patients treated following this new schedule. It is noteworthy that neither hematologic growth factors nor stem cells, usually associated with high-dose regimen, were used as support in this study. These data strongly suggest that it is possible to deliver higher dose- intensities of carboplatin, even in elderly, unselected patients, without increasing toxicities and with no growth factor support, provided that a therapeutic drug monitoring strategy with real-time tailored dosing is performed.

Population pharmacokinetics of etoposide: application to therapeutic drug monitoring.

Antineoplastic agent etoposide (VP16) displays narrow therapeutic index and erratic pharmacokinetics, and dose individualization is a convenient way for overcoming the interpatient variability, so as to maintain the drug exposure within a therapeutic range. The authors proposed a population-based Bayesian methodology to adjust routinely VP16 dosage when given as a 5-day infusion. The mean VP16 pharmacokinetic parameters of the reference population calculated from 14 patients following the two-stage method were CL = 1.92 +/- 0.512 L/h and t(1/2) = 6.7 +/- 2 hours. The reference population was next used prospectively for Bayesian dose individualization for 25 patients (47 courses) undergoing 5-day infusions of VP16. Resulting steady-state concentrations proved to be successfully adjusted to the target values in 77% of the courses. Therefore, the method presented here meets the requirements for routine therapeutic drug monitoring of VP16, a major anticancer drug extensively used in clinical oncology.

Distribution of calibrated talc after intrapleural administration: an experimental study in rats.

STUDY OBJECTIVE: Many reports have shown that talc is the most effective and least expensive agent for the creation of a pleural symphysis. However, its use still remains controversial due to severe acute respiratory side effects possibly related to the systemic dissemination of talc particles. The purpose of this study was to assess the distribution of calibrated talc after intrapleural administration in rats. MATERIAL AMD METHODS: Thirty-seven Wistar male rats were randomly assigned to undergo pleurodesis by talc slurry (33 rats) or by simple chest tube drainage (control group; 4 rats). Forty milligrams of calibrated talc suspended in 1 mL sterile saline solution was injected into rats in the treated group. The animals were randomly assigned for autopsy at 24 or 72 h after pleural injection. Lungs, parietal pleura, diaphragm, liver, kidneys, spleen, pericardium, brain, and blood were assessed by polarized light for birefringent talc particle detection and counting. RESULTS: No deaths were observed. The autopsies showed no pleurodesis at 24 and 72 h. Despite high doses of talc (extrapolated from the dose of 10 g in a 70-kg adult man), few talc particles were found in the liver of two rats, in the spleen of one rat, and only one particle of talc was observed at the brain surface of the rat studied by scanning electron microscopy. No particles were found in the other organs, in particular in the contralateral lung and blood, contrasting with previously published results using noncalibrated talc particles. CONCLUSIONS: The lack of systemic dispersion of talc particles, with the packaging talc we currently use in our clinical practice, is probably due to the size of the talc particles, which are larger than the other talc preparations. Calibrated talc is required in case of intrapleural administration for pleurodesis to avoid systemic dissemination and potential secondary acute respiratory failures.