R. Woestenborghs

The Clinical Pharmacokinetics of Itraconazole: An Overview

Summary: Itraconazole (R 51211) is the prototype of a class of triazole antifungals characterized by a high lipophilicity. This property determines to a large extent the pharmacokinetics of itraconazole and differentiates it from the hydrophilic triazole antifungal fluconazole.

Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects

The pharmacokinetics of a novel antipsychotic agent, risperidone, and the prolactin response were studied in 12 dextromethorphan‐phenotyped healthy men after administration of 1 mg risperidone intravenously, intramuscularly, and orally. The formation of the equipotent major metabolite, 9‐hydroxyrisperidone, exhibited CYP2D6‐related polymorphism. The plasma area under the concentration—time curve from time zero to infinity ratio of 9‐hydroxyrisperidone to risperidone averaged 3 (intravenous and intramuscular) and 6 (oral administration) in the extensive metabolizers and 0.2 in the poor metabolizers. Risperidone half‐life was about 3 hours in extensive metabolizers and 22 hours in poor metabolizers. Risperidone absolute oral bioavailability was 66%. The pharmacokinetics of the active moiety (risperidone plus 9‐hydroxyrisperidone) varied little among subjects (mean terminal half‐life, 20 ± 21/2 hours; absolute oral and intramuscular bioavailability, 100%). The prolactin response correlated best with the plasma active moiety, which showed little hysteresis. It is concluded that risperidone metabolic polymorphism on increased plasma prolactin is minimal and that the active moiety is clinically relevant.

Linearity of Pharmacokinetics and Model Estimation of Sufentanil

Background The pharmacokinetic profiles of sufentanil available in the literature are conflicting because of methodologic differences. Length of sampling and assay sensitivity are key factors involved in accurately estimating the volumes of distribution, clearances, and elimination phase. The unit disposition function of increasing doses of sufentanil were investigated and the influence of dose administered on the linearity of pharmacokinetics was assessed.

Antifungal Pulse Therapy for Onychomycosis: A Pharmacokinetic and Pharmacodynamic Investigation of Monthly Cycles of 1-Week Pulse Therapy With Itraconazole

BACKGROUND AND DESIGN In the treatment of onychomycosis, oral therapies have generally been given as a continuous-dosing regimen. For example, the suggested dose of itraconazole for the treatment of onychomycosis has thus far been 200 mg/d for 3 months. Based on the advances in our understanding of the pharmacokinetics of itraconazole, we investigated the efficacy and nail kinetics of intermittent pulse-dosing therapy with oral itraconazole in patients who were suffering from onychomycosis. Fifty patients with confirmed onychomycosis of the toenails, predominantly Trichophyton rubrum, were recruited and randomly assigned to three (n = 25) or four (n = 25) pulses of 1-week itraconazole therapy (200 mg twice daily for each month). Clinical and mycological evaluation of the infected toenails, and determination of the drug levels in the distal nail ends of the fingernails and toenails, were performed at the end of each month up to month 6 and then every 2 months up to 1 year. RESULTS In the three-pulse treatment group, the mean concentration of itraconazole in the distal ends of the toenails ranged from 67 (month 1) to 471 (month 6) ng/g, and in the distal ends of the fingernails, it ranged from 103 (month 1) to 424 (month 6) ng/g. At month 11, the drug was still present in the distal ends of the toenails at an average concentration of 186 ng/g. The highest individual concentrations of 1064 and 1166 ng/g were reached at month 6 for toenails and fingernails, respectively. At end-point follow-up, toenails in 84% of the patients were clinically cured with a negative potassium hydroxide preparation and culture in 72% and 80% of the patients, respectively. In the four-pulse treatment group, the mean concentration of itraconazole in the distal ends of the toenails ranged from 32 (month 1) to 623 (month 8) ng/g, and in the distal ends of the fingernails, it ranged from 42 (month 1) to 380 (month 6) ng/g. The highest individual concentrations of 1549 and 946 ng/g were reached at month 7 for toenails and at month 9 for fingernails, respectively. At month 12, the drug was still present in the distal ends of the toenails at an average concentration of 196 ng/g. At end-point follow-up, toenails in 76% of the patients were clinically cured with a negative potassium hydroxide preparation and culture in 72% and 80% of the patients, respectively. There were no significant intergroup differences between the three- and four-pulse treatment groups for the primary efficacy parameters. The drug was well tolerated with no significant side effects in either patient group. CONCLUSIONS Following pulse therapy with itraconazole (400 mg/d given for 1 week each month for 3 to 4 months), the drug has been detected in the distal ends of nails after the first pulse, and it has reached therapeutic concentrations with further therapy. After stopping the last pulse, the drug remains in the nail plate at levels above 300 ng/g for several months. Clinical cure rates between 76% and 84% and negative mycological examination findings between 72% and 80%, respectively, were observed in toenail onychomycosis. The data suggest that pulse therapy with itraconazole is an effective and safe treatment option for onychomycosis.

The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects

SummaryWe have studied the influence of food and dose (50, 100, 200 mg) on the oral systemic availability of the broad spectrum antifungal itraconazole and the pharmacokinetics after repeated dosing of 100 mg in six healthy volunteers.The relative systemic availability of itraconazole capsules compared with solution averaged 39.8% in the fasting state but 102% in the post-prandial state. Food did not significantly affect the tmax of the capsules. Itraconazole AUC at single doses of 50, 100, and 200 mg had a ratio of 0.3:1:2.7, and the steady-state AUC (0–24) after 15 days of 100 mg was five times the single-dose AUC.These findings suggest non-linear itraconazole pharmacokinetics in the range of therapeutically used doses. Furthermore, capsules should be given shortly after a meal to ensure optimal oral systemic availability.

Posttreatment itraconazole levels in the nail: New implications for treatment in onychomycosis

BACKGROUND A problem in the treatment of onychomycosis is the lengthy duration of therapy. The pharmacokinetics of itraconazole suggest a potential for briefer treatment. OBJECTIVE This study was designed to investigate itraconazole nail kinetics in 39 patients with onychomycosis in relation to their therapeutic outcome. METHODS All patients received itraconazole for 3 months at a dose of 100 or 200 mg daily. Itraconazole levels of distal nail clippings were determined during a 6-month posttherapy period. RESULTS Therapeutic itraconazole concentrations were found in the nail plates of fingernails and toenails for up to 6 months after treatment. Cure of the toenails was observed in 79% of the patients treated with the 200 mg dosage and in 26% of those treated with 100 mg at 6 months after therapy. CONCLUSION The data suggest that the drug reaches the nail via incorporation into the matrix and by diffusion from the nail bed and is eliminated with regrowth of the nail after discontinuation of treatment.

THE CSF AND PLASMA PHARMACOKINETICS OF SUFENTANIL AFTER INTRATHECAL ADMINISTRATION

Eight patients (7 men and 1 woman, 45-68 yr old) scheduled to undergo thoracotomy were given, preoperatively, 15 micrograms sufentanil in the lumbar intrathecal space for a study of cerebrospinal fluid (CSF) and plasma kinetics of sufentanil. Multiple samples of plasma and CSF from the lumbar region were obtained through indwelling catheters for 12 h and analyzed for sufentanil by radioimmunoassay. Pharmacokinetic parameters were derived by noncompartmental analysis. In plasma, the maximal concentration of sufentanil appeared after 0.65 +/- 0.17 h (mean +/- SEM). No equilibrium was reached between the sufentanil concentration in CSF and plasma, but the CSF/plasma concentration ratio declined from approximately 140 at 2 h to about 15 at 10 h. Extrapolation indicates that another 10 h would be required before the concentration in CSF would equal that in plasma. The mean residence time (MRT) of sufentanil in CSF was 0.92 +/- 0.08 h and in plasma was 6.8 +/- 0.6 h. The volume of distribution at steady state (Vss) in the subarachnoid compartment was 1.54 +/- 0.39 ml/kg, and the clearance from the CSF was 27 +/- 5 microliters.kg-1.min-1. The intrathecal administration of 15 micrograms sufentanil at the beginning of the operation did not produce analgesia that lasted into the postoperative period. Most patients had urinary retention, but none experienced any serious complications. This study demonstrates that the lipophilic opioid sufentanil undergoes rapid clearance from CSF and absorption to plasma after intrathecal administration. These pharmacokinetic characteristics are slower for the less lipophilic opioids meperidine and morphine. The rapid pharmacokinetics of sufentanil explain its rapid onset of action and short-lasting effects.

Effect of Food on the Pharmacokinetics of a New Hydroxypropyl‐β‐Cyclodextrin Formulation of Itraconazole

Study Objective. To compare the pharmacokinetics of a single 100‐mg oral dose of itraconazole administered as 10 ml of a 10‐mg/ml itraconazole solution in hydroxypropyl‐β‐cyclodextrin under fasting versus postprandial conditions.

Itraconazole penetrates the nail via the nail matrix and the nail bed—an investigation in onychomycosis

Nail‐matrix kinetics were studied in 21 patients (19 with onychomycosis, two with tinea corporis) as soon as taking itraconazole (Sporanox®) 100 mg daily for up to 7 months. Itraconazole was detected in the distal nail as soon as 1 month after the start of therapy (42 ng/g in fingernails and 16 ng/g in toenails). During the course of treatment, this concentration rose and reached a mean of 160 ng/g in fingernail clippings and 197 ng/g in toenail clippings. Moreover, in fingernails of 12 out of 21 patients and in toenails of six out of 20 patients, itraconazole was detected in the distal nail clippings before full outgrowth of the fastest‐growing nail. In most patients, itraconazole was detected in the distal nail clippings earlier than would be expected if the drug were incorporated only via the nail matrix, indicating that in addition to the nail matrix, a second route of penetration into the nail exists, i.e. the nail bed.

Influence of age, renal and liver impairment on the pharmacokinetics of risperidone in man

The pharmacokinetics of the antipsychotic agent risperidone were investigated in healthy young and elderly subjects, cirrhotic patients and patients with moderate and severe renal insufficiency. In a comparative trial, a single oral 1-mg dose was administered to fasting subjects. Plasma and urine concentrations of the parent compound risperidone and the active moiety (i.e. risperidone plus 9-hydroxy-risperidone) were measured by radioimmunoassays. No or only small changes in plasma protein binding were observed in hepatic and renal disease, whereas the protein binding was not influenced by aging. The inter-individual variability in plasma concentrations of the active moiety was much less than the variability in plasma concentrations of risperidone. Three out of six subjects, behaving like poor metabolizers, were on medication (thiethylperazine, amitriptyline, metoprolol) that may inhibit risperidone metabolism by CYP2D6 (debrisoquine 4-hydroxylase). The pharmacokinetics of risperidone in elderly and cirrhotic patients were comparable to those in young subjects, whereas total oral clearance was reduced in renal disease patients. The elimination rate and clearance of 9-hydroxy-risperidone was reduced in elderly and renal disease patients because of a diminished creatinine clearance. The CLoral of the active moiety, which is primarily 9-hydroxy-risperidone, was reduced by about 30% in the elderly and by about 50% in renal disease patients. In addition, the t1/2 of the active moiety was prolonged (19 h in young subjects versus about 25 h in elderly and renal disease patients). Based upon the pharmacokinetics of the active moiety, a dose reduction and a cautious dose titration is advised in the elderly and in patients with renal disease. In cirrhotic patients, the single-dose pharmacokinetics were comparable to those in healthy young subjects.