betadex and hydroxyitraconazole

To evaluate the effect of repeated ingestion of grapefruit juice on the systemic availability of itraconazole (ITZ) and hydroxyitraconazole (OHITZ) serum concentrations in subjects administered hydroxypropyl-beta-cyclodextrin-ITZ (HP-beta-CD ITZ) oral solution.. Randomized, two-period, crossover study.. College of pharmacy research unit.. Twenty healthy, adult volunteers (10 men, 10 women).. Subjects received 240 ml of regular-strength grapefruit juice from frozen concentrate or bottled purified water 3 times/day for 2 days. On the third day they received a single dose of HP-beta-CD ITZ oral solution 200 mg (20 ml) with 240 ml of the beverage. Two hours after dosing they received another 240 ml of the beverage.. Repeated blood samples were drawn for 72 hours after dosing. After a 14-day washout period, subjects were crossed over to the beverage they had not received previously and the above procedure was repeated. There was no difference in peak ITZ concentration (Cmax) or time to Cmax (Tmax). Coadministration of grapefruit juice reduced OHITZ Cmax nearly 10%, but this difference was not statistically significant. It produced a statistically significant increase in ITZ area under the concentration-time curves from 0-48 hours (AUC(0-48)) (17%) and from time zero extrapolated to infinity (AUC(0-infinity)) (19.5%). Apparent oral clearance of ITZ was significantly reduced (14%). Significant changes in OHITZ exposure were not observed; however, grapefruit juice coadministration produced statistically significant decreased mean OHITZ:ITZ AUC(0-48) and AUC(0-infinity) ratios. Grapefruit juice also decreased the mean OHITZ:ITZ Cmax ratio, but the difference was not statistically significant.. Repeated grapefruit juice consumption moderately affects ITZ systemic availability in subjects administered HP-beta-CD ITZ oral solution. Unlike previous findings with ITZ capsules, changes in the disposition of ITZ and OHITZ after repeated grapefruit juice consumption are consistent with grapefruit juice inhibition of intestinal cytochrome P450 3A4.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adult; Antifungal Agents; Area Under Curve; beta-Cyclodextrins; Beverages; Biological Availability; Citrus paradisi; Cross-Over Studies; Cyclodextrins; Female; Food-Drug Interactions; Humans; Itraconazole; Male; Pharmaceutical Solutions

A randomized, open-label, comparative study was conducted in 30 male patients with moderately advanced human immunodeficiency virus (HIV) infection to examine the pharmacokinetics of an investigational intravenous preparation of itraconazole compared with pharmacokinetics after administration of itraconazole capsules. The study also assessed whether adequate plasma concentrations of itraconazole could be rapidly achieved with the intravenous formulation and then maintained after cessation of intravenous therapy with itraconazole capsules. All patients received 200 mg intravenous itraconazole as a 1-hour infusion in 40% hydroxypropyl-beta-cyclodextrin (HP-beta-CD) vehicle twice daily for 2 days, and then 200 mg intravenously once daily for 5 days. Patients then received itraconazole capsules, either 200 mg twice daily or 200 mg once daily for 28 days. Steady-state plasma concentrations of itraconazole were reached by day 3 with intravenous infusion, a much shorter time than observed with administration of itraconazole capsules. Steady-state concentrations of itraconazole and hydroxyitraconazole were effectively maintained during the rest of the intravenous infusions of itraconazole. Oral follow-up with administration of 200-mg capsules once daily could not maintain the plasma concentrations of itraconazole and hydroxyitraconazole obtained at the end of the intravenous treatment, whereas twice-daily oral administration maintained or increased these concentrations. Mean plasma concentrations of itraconazole and hydroxyitraconazole on day 7 were similar to those on day 36 in the twice-daily group. Mean renal clearance was comparable to mean total body clearance, and approximately 93% to 101% of the HP-beta-CD was excreted unchanged in urine within 12 hours of administration. The HP-beta-CD was essentially eliminated through the kidney, and little accumulation in the body was observed in this patient population. Adverse events during the intravenous phase were most commonly associated with intravenous administration. Intravenous infusion of itraconazole for 7 days followed by administration of itraconazole capsules twice daily for 28 days is an effective dose regimen in patients with advanced HIV infection.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Acquired Immunodeficiency Syndrome; Administration, Oral; Adult; Aged; Antifungal Agents; beta-Cyclodextrins; Cyclodextrins; Female; Humans; Injections, Intravenous; Itraconazole; Male; Middle Aged

Pharmacokinetics and safety of a hydroxy-beta-propyl solution of itraconazole were assessed in 16 patients in an intensive care unit. On the first 2 days, four 1-h infusions of 200 mg were given at 0, 8, 24, and 32 h. From day 3 to 7, inclusive, a single 1-h infusion of 200 mg of itraconazole was given daily. The intravenous (i.v.) treatment was directly followed by repeated administrations of an oral solution of itraconazole at a dosage of either 200 mg once daily or 200 mg twice daily (b.i.d.). During i.v. treatment, steady-state concentrations of itraconazole and hydroxy-itraconazole in plasma were reached within 48 and 96 h, respectively. At the end of i.v. treatment, mean (+/- standard deviation) itraconazole and hydroxy-itraconazole trough concentrations in plasma were 0.344 +/- 0.140 and 0.605 +/- 0.205 microg/ml, respectively. After the 2-week oral follow-up of 200 mg once daily the mean trough concentration had decreased to 0.245 microg/ml, whereas after 200 mg b.i.d. it increased to 0.369 microg/ml. Diarrhea during oral treatment appeared to be dose related and may be due to the solvent hydroxypropyl-beta-cyclodextrin. More severe laboratory abnormalities were noted during the i.v. than the oral treatment phase, probably related to more severe illness in that period of intensive care, but none proved clinically important. These results suggest that plasma itraconazole levels above 0.250 microg/ml may be achieved and maintained with the 1-week i.v. schedule followed by b.i.d. oral administration, whereas the once-daily oral follow-up seems to be a suboptimal treatment.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adolescent; Adult; Antifungal Agents; beta-Cyclodextrins; Cyclodextrins; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Intensive Care Units; Itraconazole; Male; Middle Aged; Mycoses; Solutions

The aim of this study was to develop an aqueous parenteral formulation containing itraconazole (ITZ) using an o/w microemulsion system. A mixture of benzyl alcohol and medium chain triglyceride (3/1) was chosen as the oil phase. Pseudoternary phase diagrams of the microemulsion formations were constructed in order to determine the optimum ratio of oils, the concentration range of surfactant and cosurfactant and the optimum ratio between them. Consequently, the suitability of the chosen microemulsion system as a parenteral formulation was evaluated using droplet size analysis and hemolysis tests. Among the surfactants and cosurfactants screened, a mixture of polyoxyethylene (50) hydrogenated castor oil and ethanol (3/1) showed the largest o/w microemulsion region in the phase diagram. The average droplet size of the microemulsions was < 150 nm, and the hemolysis test showed this formulation to be nontoxic to red blood cells. The pharmacokinetic profiles of the ITZ-microemulsion for itraconazole and its major metabolite, hydroxyitraconazole, were compared with those of a PEG 400 solution and cyclodextrin formulations in rats. Overall, these results highlight the potential of an ITZ-microemulsion formulation for the parenteral route.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Antifungal Agents; Benzyl Alcohol; beta-Cyclodextrins; Castor Oil; Chemistry, Pharmaceutical; Emulsions; Ethanol; Excipients; Hemolysis; Injections, Intravenous; Itraconazole; Male; Particle Size; Polyethylene Glycols; Rats; Rats, Sprague-Dawley; Solubility; Solvents; Surface-Active Agents; Triglycerides; Water

This investigation was designed to evaluate the single-dose pharmacokinetics of itraconazole, hydroxyitraconazole, and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) after intravenous administration to children at risk for fungal infection. Thirty-three children aged 7 months to 17 years received a single dose of itraconazole (2.5 mg/kg in 0.1-g/kg HP-beta-CD) administered over 1 h by intravenous infusion. Plasma samples for the determination of the analytes of interest were drawn over 120 h and analyzed by high-pressure liquid chromatography, and the pharmacokinetics were determined by traditional noncompartmental analysis. Consistent with the role of CYP3A4 in the biotransformation of itraconazole, a substantial degree of variability was observed in the pharmacokinetics of this drug after IV administration. The maximum plasma concentrations (C(max)) for itraconazole, hydroxyitraconazole, and HP-beta-CD averaged 1,015 +/- 692 ng/ml, 293 +/- 133 ng/ml, and 329 +/- 200 mug/ml, respectively. The total body exposures (area under the concentration-time curve from 0 to 24 h) for itraconazole, hydroxyitraconazole, and HP-beta-CD averaged 4,922 +/- 6,784 ng.h/ml, 3,811 +/- 2,794 ng.h/ml, and 641.5 +/- 265.0 mug.h/ml, respectively, with no significant age dependence observed among the children evaluated. Similarly, there was no relationship between age and total body clearance (702.8 +/- 499.4 ml/h/kg); however, weak associations between age and the itraconazole distribution volume (r(2) = 0.18, P = 0.02), C(max) (r(2) = 0.14, P = 0.045), and terminal elimination rate (r(2) = 0.26, P < 0.01) were noted. Itraconazole infusion appeared to be well tolerated in this population with a single adverse event (stinging at the site of infusion) deemed to be related to study drug administration. Based on the findings of this investigation, it appears that intravenous itraconazole can be administered to infants beyond 6 months, children, and adolescents using a weight-normalized approach to dosing.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Adolescent; Antifungal Agents; beta-Cyclodextrins; Child; Child, Preschool; Female; Humans; Infant; Injections, Intravenous; Itraconazole; Male; Mycoses

Itraconazole (ITC) is a hydrophobic antimycotic drug with three chiral centers that is used clinically as a stereoisomeric mixture. A chiral capillary electrophoretic method for the separation of ITC stereoisomers and those of its main metabolite hydroxyitraconazole (HITC) was developed to determine the stereoselective nature of the ITC to HITC biotransformation. The method is based on the formation of inclusion complexes of the target analytes with the negatively charged sulfated beta-cyclodextrin in the presence of moderate concentrations of methanol in a low-pH phosphate buffer. The addition of polyethylene glycol 4000 was found to be critical in obtaining baseline resolution of eight peaks, two from ITC, four from HITC, and two from R051012 (internal standard), in under 20 min. Application of the developed procedure to serum samples from patients being treated with ITC showed clearly the presence of a stereoselective component in the metabolism of this antimycotic drug. This could be shown from in vitro incubations with single enzyme Supersomes to be in part due to the stereoselective formation of HITC by the human CYP3A4 enzyme. For one patient, monitoring of the ITC and HITC concentrations and peak ratios over a 103 day period of treatment with ITC showed a strong dependency of the chiral ITC ratio to the concentration of ITC, while the dominant enantiomeric ratio of HITC was largely independent of the total HITC concentration.

Topics: beta-Cyclodextrins; Cyclodextrins; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Monitoring; Electrophoresis, Capillary; Humans; Itraconazole; Methanol; Polyethylene Glycols; Stereoisomerism