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Fulltext Comparative bioavailability study of two ketoconazole tablet preparations

Yuen KH, Wong JW, Billa N, Choy WP, Julianto T

Med J Malaysia, 1999 Dec;54(4):482-6.
PMID: 11072466

The bioavailability of a generic preparation of ketoconazole (Zorinax from Xepa-Soul Pattinson, Malaysia) was evaluated in comparison with the innovator product (Nizoral from Janssen Pharmaceutica, Switzerland). Eighteen healthy male volunteers participated in the study conducted according to a two-way crossover design. The bioavailability was compared using the parameters, total area under the plasma concentration-time curve (AUC0-infinity), peak plasma concentration (Cmax) and time to reach peak plasma concentration (Tmax). No statistically significant difference was observed between the values of the two products in all the three parameters. Moreover, the 90% confidence interval for the ratio of the logarithmic transformed AUC0-infinity and Cmax values of Zorinax over Nizoral was found to lie between 0.82-1.04 and 0.83-1.02, respectively, being within the acceptable equivalence limit of 0.80-1.25. These findings indicate that the two preparations are comparable in the extent and rate of absorption. In addition, the elimination rate constant (ke) and apparent volume of distribution (Vd) were calculated. For both parameters, there was no statistically significant difference between the values obtained from the data of the two preparations. Moreover, the values are comparable to those reported in the literature.

Matched MeSH terms: Antifungal Agents/blood
Simple high-performance liquid chromatographic method for determination of ketoconazole in human plasma

Yuen KH, Peh KK

J Chromatogr B Biomed Sci Appl, 1998 Sep 18;715(2):436-40.
PMID: 9792531

A simple high-performance liquid chromatographic method using fluorescence detection was developed for the determination of ketoconazole in human plasma. The method entailed direct injection of the plasma sample after deproteinization using acetonitrile. The mobile phase comprised 0.05 M disodium hydrogen orthophosphate and acetonitrile (50:50, v/v) adjusted to pH 6. Analysis was run at a flow-rate of 1.5 ml/min with the detector operating at an excitation wavelength of 260 nm and an emission wavelength of 375 nm. The method is specific and sensitive with a quantification limit of approximately 60 ng/ml and a detection limit of 40 ng/ml at a signal-to-noise ratio of 3:1. Mean absolute recovery value was about 105%, while the within-day and between-day coefficient of variation and percent error values of the assay method were all less than 14%. The calibration curve was linear over a concentration range of 62.5-8000 ng/ml.

Matched MeSH terms: Antifungal Agents/blood*
Liquid chromatographic method for the determination of plasma itraconazole and its hydroxy metabolite in pharmacokinetic/bioavailability studies

Wong JW, Nisar UR, Yuen KH

J Chromatogr B Analyt Technol Biomed Life Sci, 2003 Dec 25;798(2):355-60.
PMID: 14643517

A sensitive and selective high-performance liquid chromatographic method was developed for the determination of itraconazole and its active metabolite, hydroxyitraconazole, in human plasma. Prior to analysis, both compounds together with the internal standard were extracted from alkalinized plasma samples using a 3:2 (v/v) mixture of 2,2,4-trimethylpentane and dichloromethane. The mobile phase comprised 0.02 M potassium dihydrogen phosphate-acetonitrile (1:1, v/v) adjusted to pH 3.0. Analysis was run at flow-rate of 0.9 ml/min with excitation and emission wavelengths set at 260 and 365 nm, respectively. Itraconazole was found to adsorb on glass or plastic tubes, but could be circumvented by prior treating the tubes using 10% dichlorodimethylsilane in toluene. Moreover, rinsing the injector port with acetonitrile helped to overcome any carry-over effect. This problem was not encountered with hydroxyitraconazole. The method was sensitive with limit of quantification of 3 ng/ml for itraconazole and 6 ng/ml for hydroxyitraconazole. The calibration curve was linear over a concentration range of 2.8-720 ng/ml for itraconazole and 5.6-720 ng/ml for the hydroxy metabolite. Mean recovery value of the extraction procedure for both compounds was about 85%, while the within-day and between-day coefficient of variation and percent error values of the assay method were all less than 15%. Hence, the method is suitable for use in pharmacokinetic and bioavailability studies of itraconazole.

Matched MeSH terms: Antifungal Agents/blood*
A rapid MCM-41 dispersive micro-solid phase extraction coupled with LC/MS/MS for quantification of ketoconazole and voriconazole in biological fluids

Yahaya N, Sanagi MM, Abd Aziz N, Wan Ibrahim WA, Nur H, Loh SH, et al.

Biomed Chromatogr, 2017 Feb;31(2).
PMID: 27474795 DOI: 10.1002/bmc.3803

A rapid dispersive micro-solid phase extraction (D-μ-SPE) combined with LC/MS/MS method was developed and validated for the determination of ketoconazole and voriconazole in human urine and plasma samples. Synthesized mesoporous silica MCM-41 was used as sorbent in d-μ-SPE of the azole compounds from biological fluids. Important D-μ-SPE parameters, namely type desorption solvent, extraction time, sample pH, salt addition, desorption time, amount of sorbent and sample volume were optimized. Liquid chromatographic separations were carried out on a Zorbax SB-C18 column (2.1 × 100 mm, 3.5 μm), using a mobile phase of acetonitrile-0.05% formic acid in 5 mm ammonium acetate buffer (70:30, v/v). A triple quadrupole mass spectrometer with positive ionization mode was used for the determination of target analytes. Under the optimized conditions, the calibration curves showed good linearity in the range of 0.1-10,000 μg/L with satisfactory limit of detection (≤0.06 μg/L) and limit of quantitation (≤0.3 μg/L). The proposed method also showed acceptable intra- and inter-day precisions for ketoconazole and voriconazole from urine and human plasma with RSD ≤16.5% and good relative recoveries in the range 84.3-114.8%. The MCM-41-D-μ-SPE method proved to be rapid and simple and requires a small volume of organic solvent (200 μL); thus it is advantageous for routine drug analysis.

Matched MeSH terms: Antifungal Agents/blood*
Clinical effectiveness of early posaconazole suspension pre-emptive therapy in lung transplant recipients: The Alfred's experience

Jeong W, Snell GI, Levvey BJ, Westall GP, Morrissey CO, Ivulich S, et al.

J Antimicrob Chemother, 2017 Jul 01;72(7):2089-2092.
PMID: 28369489 DOI: 10.1093/jac/dkx085

Objectives: This study describes the clinical outcomes and therapeutic drug monitoring (TDM) following posaconazole suspension pre-emptive therapy in lung transplant (LTx) recipients.
Methods: This was a single-centre, retrospective cohort study evaluating posaconazole suspension pre-emptive therapy in LTx recipients between January 2009 and December 2015.
Results: Forty-two LTx recipients were prescribed posaconazole suspension pre-emptively. Aspergillus fumigatus was the most commonly isolated fungal organism. Of the patients receiving posaconazole suspension as the initial antifungal post-LTx, 93% had eradication of colonization at 6 months after commencing therapy. In contrast, only 61% had eradication of fungal colonization when posaconazole suspension was administered following initial therapy with voriconazole. Posaconazole suspension appeared to be well tolerated, although one case was curtailed following concern about abnormal liver function and another due to nausea/vomiting. TDM was performed in 37 patients. The initial median (IQR) trough plasma concentration ( C min ) following 400 mg twice-daily posaconazole suspension was 0.78 (0.46-1.19) mg/L. Doses beyond 800 mg daily did not appear to result in a higher median C min.
Conclusions: Early initiation of posaconazole suspension pre-emptive therapy in LTx recipients appears to be well tolerated and may potentially afford favourable clinical outcomes.

Matched MeSH terms: Antifungal Agents/blood*