[Statutory pediatric informations available for anticancer drugs: inventory and proposals]. / Autorisation de mise sur le marché et information pédiatrique pour les médicaments de chimiothérapie des cancers: état des lieux et propositions.

UNLABELLED: Paediatric medicines are often prescribed off label because appropriate clinical and pharmacological studies have not been conducted in children. A European directive is being written to promote the development of paediatric medicines through incentives to pharmaceutical companies, as is already the case in the US. METHOD: In order to evaluate the status of anticancer drugs, we analyzed the paediatric information available in the Vidal 2000 dictionary for cytotoxic chemotherapy. RESULTS: Among the 76 products, 48 were currently used to treat children with cancer. An indication for paediatric use was described in only 29% of them. Paediatric use was mentioned in the posology chapter in 56% of cases, and in the warning or contra-indication chapter in 17% of cases. Ten products (21%) were devoid of paediatric information. DISCUSSION: The paucity of this official paediatric information contrasts with the number of clinical and pharmacological studies that have been conducted and published by paediatric oncology societies and groups. Indeed, almost 80% of children with cancer are treated using prospective therapeutic research protocols. In conclusion, anticancer medicines have been evaluated in children, but official paediatric information is poor. This situation can be significantly improved with the literature currently available. On the other hand, prospective clinical studies are needed to better define the optimal dose in children under one year of age, to evaluate long-term sequelae in cured patients and to provide appropriate galenic forms for oral chemotherapy. CONCLUSION: Incentives are urgently needed to facilitate access to therapeutic innovations in oncology and their development in children with cancer.

Heated intra-operative intraperitoneal oxaliplatin after complete resection of peritoneal carcinomatosis: pharmacokinetics and tissue distribution.

PURPOSE: This article reports the pharmacokinetics (PK) of heated intra-operative intraperitoneal oxaliplatin and its tolerance profile. Oxaliplatin has demonstrated significant activity in advanced colorectal cancer, and this is the first publication concerning its intraperitoneal administration. METHODS: Twenty consecutive patients with peritoneal carcinomatosis (PC) of either gastrointestinal or uniquely peritoneal origin underwent complete cytoreductive surgery followed by intra-operative intraperitoneal chemo-hyperthermia (IPCH) with increasing doses of oxaliplatin. We performed IPCH using an open procedure (skin pulled upwards), at an intraperitoneal temperature of 42-44 degrees C, with 2 l/m2 of 5% dextrose instillate in a closed circuit. The flow-rate was 2 l/min for 30 min. Patients received intravenous leucovorin (20 mg/m2) and 5-fluorouracil (400 mg/m2) just before the IPCH to maximize the effect of oxaliplatin. We treated at least three patients at each of the six intraperitoneal oxaliplatin dose levels (from 260 to 460 mg/m2) before progressing to the next. We analysed intraperitoneal, plasma and tissue samples with atomic absorption spectrophotometry. RESULTS: The mean duration of the entire procedure was 8.4 +/- 2.7 h. Half the oxaliplatin dose was absorbed in 30 min at all dose levels. Area under the curve (AUC) and maximal plasma concentration (Cmax) increased with dose. At the highest dose level (460 mg/m2), peritoneal oxaliplatin concentration was 25-fold that in plasma. AUCs following intraperitoneal administration were consistently inferior to historical control AUCs after intravenous oxaliplatin (130 mg/m2). Intratumoral oxaliplatin penetration was high, similar to absorption at the peritoneal surface and 17.8-fold higher than that in non-bathed tissues. Increasing instillate volume to 2.5 l/m2 instead of 2 l/m2 dramatically decreased oxaliplatin concentration and absorption. There were no deaths, nor severe haematological, renal or neurological toxicity, but we observed two fistulas and three deep abscesses. CONCLUSIONS: Heated intraperitoneal chemotherapy gives high peritoneal and tumour oxaliplatin concentrations with limited systemic absorption. We recommend an oxaliplatin dose of 460 mg/m2 in 2 l/m2 of 5% dextrose for intraperitoneal chemo-hyperthermia, at a temperature of 42-44 degrees C over 30 min. We may be able to improve these results by increasing the intraperitoneal perfusion duration or by modifying the instillate composition.

[Pharmaceutical traceability integrated with the patient file. Development of a computerized hospital application]. / Traçabilité pharmaceutique intégrée au dossier patient. Développement d'une application informatique hospitalière.

The Clinical Pharmacy Department (CPD) of the Gustave Roussy Institute, has developed a traceability software package that is integrated with the patient file. The Traceability & Medical Devices Functional Unit manages the Blood Derivative Medicinal Product traceability circuits, the circuits of over 400 Sterile Medical Devices and, generally speaking, those for all pharmaceutical goods for which traceability is imperative. The SIMBAD-TRACE software package has been developed in situ and was first open for access in March 1999. It enables pharmaceutical traceability data to be accessed from 500 networked workstations. The references tracked generated about 10,000 movements per year. In terms of performance, the system achieves three complementary objectives: 1) reporting traceability scores which reflect the ability of CPD and the establishment to pertinently respond to a complex regulatory requirement on a daily basis; 2) the contribution of the tool to cost containment with respect to allocating rare goods; the contribution of the software package to the implementation of medical device vigilance inquiries, particularly descending inquiries. Finally, SIMBAD-TRACE is one of the pillars of our Quality Assurance Program (QAP).

Application of high-performance, thin-layer chromatography to quality control of antimetabolite analogue infusion bags.

A global postproduction quality program was developed to secure chemotherapy infusion at the Gustave Roussy Institute. Despite rigorous procedures and computerized prescriptions, an analytical check was necessary to improve the quality of ready-to-use solutions of cytotoxic drugs in our Centralized Antineoplastics Reconstitution Unit. High-performance, thin-layer chromatography was selected as the analytical tool to assay 12 anticancer drugs. One of the analytical methods can separate 4 antimetabolite substances, i.e., fludarabine (FDB), cytarabine (CTB), gemcitabine (GTB), and fluorouracil (5 FU). For all infusion bags manufactured, up to 26 samples could be assayed per series using a double standard calibration (GTB and 5 FU).

[Role and functional spectrum of HPTLC in a hospital pharmaceutical quality control program]. / Place et spectre fonctionnel de l'HPTLC dans un programme d'assurance qualité pharmaceutique hospitalier.

As part of the development of a quality assurance program (QAP), a high performance thin layer chromatography (HPTLC) analysis unit was installed in the pharmacy department at Gustave-Roussy. The HPTLC-CAMAG consists of: 1) an HPTLC-Vario development chamber for optimization of the mobile phases; 2) TLC Sampler III automated sample applicators; 3) solid teflon migration chambers, i.e., horizontal tanks that enable separation to be carried out either in sandwich or in saturation mode; 4) a TLC Scanner 3 densitometer controlled by CATS 4 software; and 5) a Pentium MMX 233 MHz personal computer with an external backup unit. HPTLC quantitative and qualitative analysis has now reached a remarkably high level of development and performance. The samples (aqueous or non-aqueous solutions) that are to be processed are automatically applied by spraying (50-300 nl) in calibrated bands of a few mm (with up to 64 3-mm bands per 10 x 20 cm plate) on high-performance stationary phases and of wide technological diversity. The chromatogram is obtained in 10 min, and run over a migration pathway of 5-6 cm. The plates are read by absorption-reflection or fluorescence-reflection at an ad hoc wavelength (190-800 nm), then the peak areas which have been scanned are calculated by the trapezoid method. The calibration curves are generated by Michaelis-Menten non-linear regression, and validated by internal quality control. The analytical yield is high, i.e., up to 50 assays and 250 determinations per day. HPTLC analysis covers a wide functional range, and can be used in the following ways: 1) as a teaching tool for separative analysis and GLP; 2) it is an invaluable method for the optimization of mobile phases and for the determination of absorption spectra and absorption maxima, with a view to developing HPLC methods in complex matrices; 3) it provides major support for post-production quality control of prescribed hospital preparations of all types, e.g., those connected with parenteral nutrition, chemotherapy, synthetic narcotic analgesia; and it can also be used for dry dosage analysis; 4) it is useful in pharmaceutical assessment, e.g., in studies on the physico-chemical characteristics of various substances, such as their identity, purity, concentration, stability and compatibility, particularly with regard to generic products; 5) it can contribute to monitoring the safety of medical apparatus and equipment via the analysis of container-content interactions; 6) it provides a qualification system for personnel and procedures for within- and between-center validation of GMP. Setting up such an HPTLC quality control unit requires a basic investment of about 0.9 MF or 70,000 US dollars for a cost of no more than 10 F or 1.5 US dollars (including tax) per routine assay. After 18 months in operation and 16,500 assays, the HPTLC analysis unit has become one of the mainstays of the Gustave-Roussy QAP.

Glucuronidation of drugs by hepatic microsomes derived from healthy and cirrhotic human livers.

Pharmacokinetic studies demonstrated that the decrease in drug biotransformation in hepatic failure depends on the metabolic pathways involved. To test whether glucuronidation reactions supported by UDP-glucuronosyltransferases are differentially affected in such conditions, we investigated the in vitro glucuronidation of four selected drugs and xenobiotics (zidovudine, oxazepam, lamotrigine, and umbelliferone) by using microsomes from human healthy and unhealthy (cirrhosis, hepatitis) livers as enzyme sources. Theses substances are glucuronidated by several UDP-glucuronosyltransferase isoforms. Lidocaine N-deethylation activity measured concomitantly was used as a positive control, because the inhibition of this reaction in patients with hepatic diseases is well documented. The metabolic clearances of zidovudine and lidocaine were decreased significantly in liver cirrhosis (0.17 versus 0.37 microliter/min/mg protein and 0.40 versus 2.73 microliter/min/mg protein, respectively) as a consequence of a decrease of their corresponding Vmax of metabolism. By contrast, the metabolic clearances of oxazepam, umbelliferone, and lamotrigine glucuronidation remained unchanged. Previous studies reported that the in vivo oral clearances of zidovudine and lidocaine were decreased by 70% and 60%, respectively, in cirrhotic livers, whereas those of lamotrigine and oxazepam were not affected. Consequently, it is likely that the in vitro metabolic data, which support the in vivo results, therefore could contribute to reasonably predict the level of impairment of hepatic clearance in patients with liver cirrhosis.

[Epinephrine stability in solutions for intra-ocular irrigations]. / Stabilité de l'adrénaline dans des solutions pour irrigations intra-oculaires.

PURPOSE: Epinephrine may be used for ocular irrigation during ophthalmic surgery when diluted in balanced saline solutions. In aqueous solution, epinephrine breakdown depends on pH, light, temperature, oxidating agents and increases with time. METHODS: The stability of epinephrine in plastic bags prepared in low concentrations (1 mg/L) was studied by HPLC analysis with UV detection, completed with pH determinations, performed after storage (protected from light) in various conditions: at room temperature (+25 degrees C), at +4 degrees C (in a refrigerator), at -20 degrees C (in a freezer). Spontaneous defreezing at room temperature was compared to accelerated thawing in a microwave oven. RESULTS: Epinephrine diluted in ocular irrigation solutions (1 mg/L) was stable for 2 days at room temperature, 14 days at +4 degrees C and 35 days at -20 degrees C. Microwave thawing did not alter the stability of epinephrine. CONCLUSION: The preparation of epinephrine solutions for intra-ocular irrigation may be centralized if the bags are stored less than two weeks in a refrigerator and less than one month in a freezer.

[Determination of the ratio of serum concentrations of tobramycin between fetus and mother at birth. A model of small scale pharmacokinetics]. / Détermination des rapports de concentrations sériques foeto-maternelles de la tobramycine à la naissance. Un modèle de pharmacocinétique réduite.

Thirty women at term presenting with fever greater than or equal to 38 degrees C during labour were given a synergic combination of tobramycin-amoxicillin. Gestational ages ranged from 37 6/7 to 41 2/7 weeks. A single dose of 3 mg/kg of tobramycin was given every day intravenously. Feto-maternal tobramycin concentrations (F/M ratios) were systematically determined at birth and allowed to make a small scale pharmacokinetic study. Two curves were plotted from the pharmacokinetic analysis of maternal and fetal measurements, showing an intravenous and an intramuscular profile respectively. A high positive linear correlation (R = 0.82) was found between the F/M ratios and the time (delta T, -hours-) measured from the last administration to the mother to the time of delivery. Elimination of the aminoglycoside was slowed down in newborns (t1/2 lambda z = 5.1 hours). In newborns tobramycin levels were always less than or equal to 6 mg/l and still greater than or equal to 1 mg/l 6 hours after the last maternal injections. Measurement of F/M ratios allowed to study and compare the fetal and maternal pharmacokinetics facilitating (when necessary) the initial posologic adjustment in newborns. Such small scale pharmacokinetics could be extended, for a given gestational age, to other drugs with narrow therapeutic ranges. However, the size and the homogeneity of the population seem to be most important.

[The administration of tobramycin in the 2nd and 3rd trimester of pregnancy: contribution to a pharmacokinetic study for the adaptation of posology]. / Administration de la tobramycine au cours du deuxième et du troisième trimestre de la grossesse: apport d'une étude pharmacocinétique pour l'adaptation de la posologie.

Aminoglycosides are currently used during pregnancy for the treatment of Staphylococcus, Enterobacteriaceae, Listeria monocytogenes, and Pseudomonas aeruginosa infections. The pharmacokinetics of tobramycin, an aminoglycoside antibiotic, was investigated after a 2.5 mg/kg short intravenous infusion and a once-daily dose regime in 18 pregnant women divided into 2 groups of 9 during the second (Group I: from 20 to 28 weeks of amenorrhoea) and the third (Group II: greater than or equal to 28 weeks of amenorrhoea) trimesters of pregnancy (during these period, risks of infectious diseases are increased). Plasma concentrations of tobramycin were measured by fluorescence polarization immunoassay (FPIA). The decrease of clearance (decrement of 27.6%), at 28 weeks and more gestation leads to an increase in the half-life and the MRT observed in the second group (increment of 49% and 41% respectively), whereas the volume of distribution remained unchanged in the two groups. No accumulation of the drug was observed in pregnant women. Pharmacokinetic disorders are correlated with the duration and moreover with the weight deviation of the women i.e., the growth of the conceptus. In 10 cases, a feto-maternal concentration ratio was calculated at delivery using an umbilical cord blood sample. This findings suggest a phenomenon of accumulation in the conceptus. To limit the potential nephrotoxicity and ototoxicity of tobramycin for the mother and the fetus, a once-daily dose regime seems to be an advanced solution for treatment of nonneutropenic pregnant women.