J. Heykants

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.

Regional brain distribution of risperidone and its active metabolite 9-hydroxy-risperidone in the rat.

Risperidone is a new benzisoxazole antipsychotic. 9-Hydroxy-risperidone is the major plasma metabolite of risperidone. The pharmacological properties of 9-hydroxy-risperidone were studied and appeared to be comparable to those of risperidone itself, both in respect of the profile of interactions with various neurotransmitters and its potency, activity, and onset and duration of action. The absorption, plasma levels and regional brain distribution of risperidone, metabolically formed 9-hydroxy-risperidone and total radioactivity were studied in the male Wistar rat after single subcutaneous administration of radiolabelled risperidone at 0.02 mg/kg. Concentrations were determined by HPLC separation, and off-line determination of the radioactivity with liquid scintillation counting. Risperidone was well absorbed. Maximum plasma concentrations were reached at 0.5–1 h after subcutaneous administration. Plasma concentrations of 9-hydroxy-risperidone were higher than those of risperidone from 2 h after dosing. In plasma, the apparent elimination half-life of risperidone was 1.0 h, and mean residence times were 1.5 h for risperidone and 2.5 h for its 9-hydroxy metabolite. Plasma levels of the radioactivity increased dose proportionally between 0.02 and 1.3 mg/kg. Risperidone was rapidly distributed to brain tissues. The elimination of the radioactivity from the frontal cortex and striatum—brain regions with high concentrations of 5-HT2 or dopamine-D2 receptors—became more gradual with decreasing dose levels. After a subcutaneous dose of 0.02 mg/kg, the ED50 for central 5-HT2 antagonism in male rats, half-lives in frontal cortex and striatum were 3–4 h for risperidone, whereas mean residence times were 4–6 h for risperidone and about 12 h for 9-hydroxy-risperidone. These half-lives and mean residence times were 3–5 times longer than in plasma and in cerebellum, a region with very low concentrations of 5-HT2 and D2 receptors. Frontal cortex and striatum to plasma concentration ratios increased during the experiment. The distribution of 9-hydroxy-risperidone to the different brain regions, including frontal cortex and striatum, was more limited than that of risperidone itself. This indicated that 9-hydroxy-risperidone contributes to the in vivo activity of risperidone, but to a smaller extent than would be predicted from plasma levels. AUCs of both active compounds in frontal cortex and striatum were 10–18 times higher than those in cerebellum. No retention of metabolites other than 9-hydroxy-risperidone was observed in any of the brain regions investigated.

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.

A sensitive radioimmunoassay for fentanyl

SummaryAntiserum to fentanyl was obtained in rabbits repeatedly injected with carboxyfentanyl conjugated to bovine serum albumin. Using the antiserum, a highly sensitive radioimmunoassay has been developed, based on the dextran-coated charcoal method. It proved possible to assay the drug directly in plasma, in amounts as small as 30 picogram in 0.5 ml. The antibody was highly specific for fentanyl and no cross-reaction was observed with its major metabolites. This sensitive and specific radioimmunoassay method was employed to determine fentanyl in plasma from six volunteers after an intravenous bolus of 0.2 mg, and in plasma from dogs treated both intravenously and subcutaneously with 0.02 mg/kg. The plasma level of fentanyl could be followed for up to 6 h after a therapeutic dose in dogs and man.

Radioimmunoassay of the new opiate analgesics alfentanil and sufentanil. Preliminary pharmacokinetic profile in man

The development of two analogous radioimmunoassay (RIA) procedures based on dextran‐charcoal separation is described for the quantification of two fentanyl‐like analgesics, alfentanil and sufentanil. Immunization of rabbits with conjugates of bovine serum albumin and carboxy‐derivatives of the respective drugs resulted in the production of antisera capable of detecting less than 0.05 ng ml−1 of the parent analgesics with high specificity and almost no cross‐reactivity with major metabolites. Excellent agreement was obtained between RIA—without prior extraction—and gas chromatography for alfentanil concentrations in human plasma. Because of sufentanils low therapeutic plasma levels, no comparison could be made between its RIA and an alternative assay, however, there was strong evidence for the specificity of the assay when applied directly to plasma. With these RIA methods preliminary information was obtained on plasma concentrations and elimination of alfentanil or sufentanil in patients given an intravenous bolus injection of 50 μg kg−1 of alfentanil, or 5 μg kg−1 of sufentanil. For both analgesics, the pharmacokinetic profile in man could be described by a three‐compartment model. The terminal elimination half‐life was 88 min for alfentanil and 140 min for sufentanil. Six hours after a therapeutic dose, plasma levels were in the order of 3 and 0.3 ng ml−1 for alfentanil and sufentanil respectively.

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.

On the pharmacokinetics of domperidone in animals and man. IV. The pharmacokinetics of intravenous domperidone and its bioavailability in man following intramuscular, oral and rectal administration.

SummaryThe pharmacokinetics and bioavailability of domperidone, a novel gastrokinetic, were studied in healthy male subjects by comparing plasma concentrations and urinary excretion following intravenous, intramuscular, oral and rectal administration. Two oral dosage forms were studied: 10-mg tablets and a 10-mg/ml oral solution. The influence of a meal on the oral bioavailability and the dose-proportionality were also investigated.Plasma levels of intravenous domperidone could be described by a three-compartment model with a rapid distribution of 40% of the dose to as «shallow» peripheral compartment. The final elimination half-life was 7.5 hours. Peak plasma levels were reached within 30 minutes following intramuscular and oral administration and at 1–4 hours following rectal administration. Since domperidone showed an extensive first-pass elimination, AUC-values -a measure for the bioavailability- were consider-ably lower after oral than after parenteral administration. Equal oral and rectal doses gave a similar bioavailability. AUC-values increased proportionally with the dose over a 10–60 mg range. Cumulative urinary excretion of unchanged domperidone was proportional to corresponding AUC-values.The bioavailability was discussed in the light of the therapeutic results.

Itraconazole pharmacokinetics in patients with renal dysfunction.

The single-dose pharmacokinetics of 200 mg of oral itraconazole were studied in seven uremic patients, seven patients treated by hemodialysis, and five patients treated by continuous ambulatory peritoneal dialysis. Plasma concentration-versus-time profiles showed wide intersubject variation. This study could not demonstrate any significant effect of renal dysfunction and hemodialysis or continuous ambulatory peritoneal dialysis treatment upon the pharmacokinetics of itraconazole, and firm conclusions concerning dosing in such patients should await confirmation of our data in a larger patient population.

Alfentanil pharmacokinetics in preterm infants.

The pharmacokinetics of alfentanil were studied during the first four days after birth in 22 ventilated preterm infants who were all receiving muscle relaxants. Five minutes after a single dose of 20 micrograms/kg alfentanil median serum concentration was 66 ng/ml (range: 20-606). The median clearance was 0.87 ml/kg/min (range: 0.4-9.62) and median elimination half life 321 mins (64-1251). There were wide differences in the manner in which individual infants handled the drug and transient depression of blood pressure and heart rate was observed. These data were used to calculate an infusion dosage. In four infants 20 micrograms/kg alfentanil given by infusion over 30 minutes followed by 5 micrograms/kg/hour produced steady state median alfentanil concentrations of 54.5 ng/ml (range: 7-73 ng/ml) with no evidence of drug accumulation.