Population pharmacokinetics of itraconazole and its active metabolite hydroxy-itraconazole in paediatric cystic fibrosis and bone marrow transplant patients

Objective: The objective of the study was to characterise the population pharmacokinetic properties of itraconazole and its active metabolite hydroxyitraconazole in a representative paediatric population of cystic fibrosis and bone marrow transplant (BMT) patients and to identify patient characteristics influencing the pharmacokinetics of itraconazole. The ultimate goals were to determine the relative bioavailability between the two oral formulations (capsules vs oral solution) and to optimise dosing regimens in these patients. Methods: All paediatric patients with cystic fibrosis or patients undergoing BMT at The Royal Children's Hospital, Brisbane, QLD, Australia, who were prescribed oral itraconazole for the treatment of allergic bronchopulmonary aspergillosis (cystic fibrosis patients) or for prophylaxis of any fungal infection (BMT patients) were eligible for the study. Blood samples were taken from the recruited patients as per an empirical sampling design either during hospitalisation or during outpatient clinic visits. ltraconazole and hydroxy-itraconazole plasma concentrations were determined by a validated high-performance liquid chromatography assay with fluorometric detection. A nonlinear mixed-effect modelling approach using the NONMEM software to simultaneously describe the pharmacokinetics of itraconazole and its metabolite. Results: A one-compartment model with first-order absorption described the itraconazole data, and the metabolism of the parent drug to hydroxy-itraconazole was described by a first-order rate constant. The metabolite data also showed one-compartment characteristics with linear elimination. For itraconazole the apparent clearance (CLitraconazole) was 35.5 L/hour, the apparent volume of distribution (V-d(itraconazole)) was 672L, the absorption rate constant for the capsule formulation was 0.0901 h(-1) and for the oral solution formulation was 0.96 h-1. The lag time was estimated to be 19.1 minutes and the relative bioavailability between capsules and oral solution (F-rel) was 0.55. For the metabolite, volume of distribution, V-m/(F (.) f(m)), and clearance, CL/(F (.) fm), were 10.6L and 5.28 L/h, respectively. The influence of total bodyweight was significant, added as a covariate on CLitraconazoie/F and V-d(itraconazole)/F (standardised to a 70kg person) using allometric three-quarter power scaling on CLitraconazole/F, which therefore reflected adult values. The unexplained between-subject variability (coefficient of variation %) was 68.7%, 75.8%, 73.4% and 61.1% for CLitraconazoie/F, Vd(itraconazole)/F, CLm/(F (.) fm) and F-rel, respectively. The correlation between random effects of CLitraconazole and Vd((itraconazole)) was 0.69. Conclusion: The developed population pharmacokinetic model adequately described the pharmacokinetics of itraconazole and its active metabolite, hydroxy-itraconazole, in paediatric patients with either cystic fibrosis or undergoing BMT. More appropriate dosing schedules have been developed for the oral solution and the capsules to secure a minimum therapeutic trough plasma concentration of 0.5 mg/L for these patients.

Urine D-arabinitol/L-arabinitol ratio in diagnosing Candida infection in patients with haematological malignancy

Adult patients with hematologic malignancies along with HIV infected patients were prospectively studied to determine the performance of urine D-arabinitol/L-arabinitol (DA/LA) ratio in diagnosing invasive candidiasis. Ten evaluable febrile neutropenic patients had proven invasive candidiasis and elevated DA/LA ratios were found in 5. Invasive candidiasis with normal DA/LA ratios was most frequently due to Candida krusei infection. This Candida species is a non-producer of arabinitol. Only 4 of 81 febrile neutropenic patients given either antifungal prophylaxis or empiric antifungal treatment had elevated DA/LA ratios. Only 1 of 15 HIV positive patients with either oropharyngeal or esophageal candidiasis had elevated DA/LA ratios. Widespread use of fluconazole prophylaxis in bone marrow transplantation patients at the study hospital has led to an increased prevalence of C. krusei infection. This is the likely reason for the low sensitivity of the test in proven and suspected invasive Candida infections reported here. (C) 2002 Elsevier Science Inc. All rights reserved.

Plasma concentrations of tafenoquine, a new long-acting antimalarial agent, in Thai soldiers receiving monthly prophylaxis

We measured plasma tafenoquine concentrations in Thai soldiers given a monthly regimen of tafenoquine to determine whether these concentrations adequately suppressed malarial infections on the Thai- Cambodian border. After receiving a treatment course of artesunate and doxycycline, 104 male soldiers were administered a loading dose of tafenoquine ( 400 mg daily for 3 days), followed by tafenoquine monthly ( 400 mg every 4 weeks) for 5 months. Consecutive monthly mean ( +/- standard deviation) trough plasma tafenoquine concentrations were 223 +/- 41, 127 +/- 29, 157 +/- 51. 120 +/- 24, and 88 +/- ng/ mL. Only 1 soldier developed malaria during the study. At the time of malaria diagnosis, his plasma tafenoquine concentration was 40 ng/ mL, which was similar to 3- fold lower than the trough concentrations of the other soldiers. Although low tafenoquine concentrations appear to be uncommon, additional investigations are needed to determine the relationship between plasma tafenoquine concentrations and suppression of malaria.

Efficacy of monthly tafenoquine for prophylaxis of Plasmodium vivax and multidrug-resistant P-falciparum malaria

We assessed monthly doses of tafenoquine for preventing Plasmodium vivax and multidrug-resistant P. falciparum malaria. In a randomized, double-blind, placebo-controlled study, 205 Thai soldiers received either a loading dose of tafenoquine 400 mg ( base) daily for 3 days, followed by single monthly 400-mg doses (n = 104), or placebo (n = 101), for up to 5 consecutive months. In volunteers completing follow-up (96 tafenoquine and 91 placebo recipients), there were 22 P. vivax, 8 P. falciparum, and 1 mixed infection. All infections except 1 P. vivax occurred in placebo recipients, giving tafenoquine a protective efficacy of 97% for all malaria (95% confidence interval [CI], 82%-99%), 96% for P. vivax malaria (95% CI, 76%-99%), and 100% for P. falciparum malaria ( 95% CI, 60%-100%). Monthly tafenoquine was safe, well tolerated, and highly effective in preventing P. vivax and multidrug-resistant P. falciparum malaria in Thai soldiers during 6 months of prophylaxis.

Oral candidosis and the therapeutic use of antifungal agents in dentistry

This paper reviews the current concepts of mycology and candidal infections as they relate to the oral cavity. Proposed classification for the presentation of oral candidosis is outlined as are examples of these topical infections, such as erythematous, pseudomembranous and hyperplastic candidosis, as well as angular chelitis and median rhomboid glossitis. The diagnosis and principles of management of oral candidosis are discussed, the therapeutic agents available for the management of these infections are presented and a treatment protocol for the management of patients with oral candidosis is given.

Mefloquine and doxycycline malaria prophylaxis in Australian soldiers in East Timor

Objectives: To describe the tolerability of mefloquine in Australian soldiers for malaria prophylaxis, including a comparison with doxycycline. Design: Open-label, prospective study and cross-sectional questionnaire and interview. Setting and participants: Two contingents of Australian soldiers, each deployed to East Timor for peacekeeping duties over a 6-month period (April 2001-October 2001 and October 2001-May 2002). Outcome measures: Withdrawals during the study; adverse events relating to mefloquine prophylaxis; willingness to use mefloquine again on deployment. Results: Of 1157 soldiers starting on mefloquine, 75 (6.5%) withdrew because of adverse responses to the drug. There were three serious adverse events of a neuropsychiatric nature, possibly relating to mefloquine. Fifty-seven per cent of soldiers using mefloquine prophylaxis reported at least one adverse event, compared with 56% using doxycycline. The most commonly reported adverse effects of both drugs were sleep disturbance, headache, tiredness and nausea. Of the 968 soldiers still taking mefloquine at the end of their deployments, 94% indicated they would use mefloquine again. Of 388 soldiers taking doxycycline prophylaxis who were deployed with the first mefloquine study contingent, 89% indicated they would use doxycycline again. Conclusions: Mefloquine was generally well tolerated by Australian soldiers and should continue to be used for those intolerant of doxycycline.