nged drug ranges from 3% to 18% of the dose.
As re-distribution of itraconazole from keratinous tissues appears to be negligible, elimination ofitraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, theconcentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and innail keratin - where itraconazole can be detected as early as 1 week after start of treatment - forat least six months after the end of a 3-month treatment period.
Specific Populations
Patients with Renal Impairment
Limited data are available on the use of oral itraconazole in patients with renal impairment. Apharmacokinetic study using a single 200-mg oral dose of itraconazole was conducted in threegroups of patients with renal impairment (uremia: n=7; hemodialysis: n=7; and continuousambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine clearance of 13mL/min. × 1.73 m2, the exposure, based on AUC, was slightly reduced compared with normalpopulation parameters. This study did not demonstrate any significant effect of hemodialysis orcontinuous ambulatory peritoneal dialysis on the pharmacokinetics of itraconazole (tmax, Cmax,
and AUC0-8h). Plasma concentration versus-time profiles showed wide intersubject variation inall three groups. After a single intravenous versus-time profiles showed wide intersubjectvariation in all three groups.
After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with mild(defined in this study as CrCl 50-79 ml/min), moderate (defined in this study as CrCl 20-49ml/min), and severe renal impairment (defined in this study as CrCl <20 ml/min) were similar tothat in healthy subjects (range of means 42-49 hours vs 48 hours in renally impaired patients andhealthy subjects, respectively). Overall exposure to itraconazole, based on AUC, was decreased
in patients with moderate and severe renal impairment by approximately 30% and 40%,respectively, as compared with subjects with normal renal function. Data are not available inrenally impaired patients during long-term use of itraconazole. Dialysis has no effect on the halflifeor clearance of itraconazole or hydroxy-itraconazole.
Patients with Hepatic ImpairmentItraconazole is predominantly metabolized in the liver. A pharmacokinetic study was conductedin 6 healthy and 12 cirrhotic subjects who were administered a single 100-mg dose ofitraconazole capsules. A statistically significant reduction in mean Cmax (47%) and a twofold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole were notedin cirrhotic subjects compared with healthy subjects. However, overall exposure to itraconazole,based on AUC, was similar in cirrhotic patients and in healthy subjects. Data are not available incirrhotic patients during long-term use of itraconazole.
Drug Interaction Studies
Omeprazole
The effect of multiple daily oral 40 mg doses (steady-state conditions) of the proton pumpinhibitor, omeprazole, on the exposure to itraconazole from a single 130 mg dose of TOLSURA(2 x 65 mg capsules) when dosed under fasted conditions was eva luated in 30 healthy adultsubjects. As illustrated in Table 8 below, the mean itraconazole AUC∞ was 22% higher and meanCmax 31% higher when TOLSURA was co-administered with omeprazole.
Table 8: Pharmacokinetics of Itraconazole Following Single Dose Administration ofTOLSUR |
