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A group of 36 patients in the hematology department of Saint-Antoine Hospital, Paris, France, was on chemotherapy. The patients were also given antiacid drugs to prevent gastrointestinal toxicity and itraconazole as prophylaxis against aspergillosis. The antifungal drug was given as 100-mg capsules three times a day shortly after meals. The plasma itraconazole and hydroxyitraconazole concentrations were measured by high-performance liquid chromatography at steady state. Of 36 patients, 29 (81%) had adequate plasma itraconazole concentrations (> or = 250 ng/ml) after 8 +/- 2 days. The 7 patients with low plasma itraconazole concentrations were given 200 mg three times a day. Of the 36 patients, 34 (94%) had effective plasma concentrations within 2 weeks of the beginning of treatment. The two remaining patients were lost to follow-up. The proposed itraconazole regimen provides effective prophylaxis against aspergillosis and represents a substantial economic advantage over a single daily dose of 400 to 600 mg. The marked intrapatient and interpatient variations in plasma itraconazole indicate the need for regular therapeutic drug monitoring to ensure effective plasma itraconazole concentrations in all neutropenic patients.

Itraconazole is a new triazole antifungal agent. Active orally, this drug is effective against a wide range of fungal pathogens that includes Aspergillus species, and its use in leukemic and AIDS patients is currently on the increase. Oral itraconazole absorption presents up to threefold interindividual variation in man and is reduced in AIDS patients. Consequently an individual itraconazole adjusting dosage is necessary to ensure adequate clinical antifungal activity. Itraconazole undergoes extensive metabolism and the main isolated metabolite, hydroxyitraconazole, is found in plasma at concentrations 2-3-fold higher than parent drug and presents in vitro the same antifungal activity. At present, despite the contribution of this metabolite to the overall activity of the drug, no well-documented assay was reported in the literature for the codetermination of itraconazole and hydroxyitraconazole in plasma. Due to the wide variety of coadministered drugs to patients receiving itraconazole, the purpose of the developed method was to obtain a specific assay sensitive enough for itraconazole therapeutic monitoring. Therefore, a three-step liquid-liquid extraction procedure following by reversed-phase chromatography and spectrofluorimetric detection was performed. This assay allowed determination of 20 ng/ml of both itraconazole and its active metabolite with an acceptable precision using a 0.5-ml plasma sample; no analytic interference was encountered from 45 coadministered drugs tested.

Monitoring of cyclosporine (CsA) in whole blood is complicated by the important intra- and interindividual variabilities in its pharmacokinetics and by its narrow therapeutic range. Consequently, an individual CsA adjusting dosage is necessary to ensure adequate immunosuppression without major toxic effects. This can be achieved by several methods of drug determination, including immunoassays and high-performance liquid chromatography (HPLC). Despite the use of specific monoclonal antibodies, immunoassays tend to overestimate (at least slightly) CsA blood levels due to a certain percentage of cross-reactivity with drug metabolites; so, at the present time, HPLC remains the reference method. The main problems of CsA analysis by liquid chromatographic (LC) methods depends on its physicochemical properties: a low detection wavelength and the need to use the LC column at a high temperature. A sensitive assay for the determination of CsA in whole blood has been developed using C8 solid-phase column extraction followed by normal-phase LC of the sample. This assay allowed determination of 25 ng/ml CsA in whole blood with an acceptable precision (intra- and interassay variabilities ranged from 7.7 to 10.4%, respectively n = 5). Standard curves constructed daily over the concentration range 25 to 400 ng/ml showed good reproducibility [coefficient of variation (CV) = 5.3%; n = 5] and the assay was linear up to 1,000 ng/ml. A chromatographic run was achieved in 5 min and no late eluting peak was observed. This method has proven to be reliable from the French interlaboratory cyclosporine quality assessment scheme and has been used routinely over 2 years to determine residual blood concentrations of liver transplant recipients.

Mefenamic acid (MA) is a nonsteroidal antiinflammatory analgesic agent widely used clinically. A simple and sensitive liquid-chromatographic assay has been developed for the quantitative determination of MA in human plasma. A reverse phase, 10-microns cyano column (25 x 0.4 cm), a mobile phase of water-acetonitrile-methanol-17 M acetic acid (69:15:15:1 by volume), and an ultraviolet detection (290 nm) are used for the separation of MA and internal standard (methyl-clonazepam). MA and internal standard are extracted from acidified plasma into diethyl ether and after evaporation of the organic phase, the residue is redissolved in methanol. Calibration curves are linear in the range 0.05-3.20 micrograms/ml, and at the plasma level corresponding to the quantification limit (0.05 microgram/ml) coefficients of variation are 7.5% and 10.2% for repeatability and reproducibility studies, respectively. This assay was successfully used in the study of pharmacokinetics of MA in human plasma after a single oral administration of a low MA dose.