Role of Therapeutic Drug Monitoring: USE IN SPECIAL POPULATIONS

At this point, it is important to reassess whether the relationship between concentration and pharmacologic response still applies to the patient’s specific subpopulation (disease state) and specific indication.

CYP2C19 Genotype

Genetic polymorphism of CYP2C19, the primary metab­olizing isoenzyme of voriconazole, was found to contribute to the wide variation in plasma concentrations of voriconazole between individuals. Patients who were homozygous for poor metabolism had 4-fold greater exposure to the drug. The incidence of homozygosity for poor metabolism is approximately 2%, and is reported to be as high as 19% among non-Indian Asians. However, wide variability was observed within each genotype in those studies. The clinical implications, if any, of CYP2C19 genetic polymorphism in the clinical setting are unknown, as these were not considered in the clinical trials. viagra soft

Renal Dysfunction

The pharmacokinetics of both single-dose and multiple- dose courses of voriconazole therapy have been studied in patients with mild to severe renal impairment. Clearance of voriconazole administered orally and intravenously did not appear to be affected by renal function, as shown in studies of single-dose (200 mg) oral therapy and multiple-dose IV therapy (6 mg/kg loading dose for 2 doses, then 3 mg/kg IV for 5.5 days). As such, no dose adjustments have been suggested for patients with renal dysfunction. However, the excipient cyclodextrin, which is used in the IV formulation of voriconazole, is known to accumulate in patients with creatinine clearance values less than 50 mL/min. Although the clinical significance of accumulation of this compound in patients with renal dysfunction is unclear, the drug manufacturer advises using the oral formulation of voriconazole if possible in this circumstance.

A small study examined the pharmacokinetics of a single oral dose of voriconazole (200 mg) given to 5 patients who were undergoing peritoneal dialysis. Less than 1% of the administered dose was recovered in the dialysate 24 h after dosing. The authors concluded, on the basis of minimal peritoneal clearance of voriconazole, that no dosing adjustment is needed for this patient population. However, this conclusion is limited by the small sample size and the use of a single dose. Given the saturable metabolism of voriconazole, caution should be used in applying the results of this study to patients who are receiving peritoneal dialysis therapy.
Fuhrmann and others characterized voriconazole pharmacokinetics in patients receiving continuous venovenous hemodiafiltration (CVVHDF). A total of 9 patients, 1 of whom had underlying liver cirrhosis, received a standard IV loading dose of voriconazole, followed by a maintenance dose. Prefilter, postfilter, and ultradiafiltrate samples were drawn for determination of voriconazole concentration at the time of Cmax and at the end of the dosing interval (Cmin) following the first dose. The clearance of voriconazole via CVVHDF was low, and total clearance was in agreement with that reported in pre­viously published studies, except for prolonged elimination half-life (52 h) and reduced total clearance (4 L/h) in the patient with cirrhosis. On the basis of these data, the investigators recommended no dose adjustments for patients undergoing CVVHDF. Follow-up voriconazole concentrations (up to the third dose) were determined for only 3 patients; as such, drug accumulation cannot be ruled out. Further study is needed to guide dosing in this population. levitra 20 mg

Hepatic Dysfunction

In a pharmacokinetic study of single-dose voriconazole therapy (200 mg) the area under the concentration-time curve (AUC) was 2.3 times higher for patients with chronic but stable hepatic impairment (Child-Pugh classes A and B) than for those with normal hepatic function. A downward dose adjustment study was carried out to compare the effect of mul­tiple dosing of voriconazole between patients with cirrhosis (Child-Pugh class B), who were receiving 100 mg PO twice daily, and patients with normal hepatic function, who were receiving 200 mg PO twice daily. On the basis of the results of these 2 studies, the drug manufacturer now recommends that the maintenance dose for patients with hepatic dysfunction should be half of that indicated for individuals with normal hepatic function. No data are yet available for patients with severe hepatic impairment. canadian antibiotics

Pediatric Patients

Two pharmacokinetic studies were conducted in 35 immunocompromised children between 2 and 12 years of age.13,32 A population pharmacokinetic analysis performed in both studies indicated that the pharmacokinetic characteristics of voriconazole in children are best described with a linear model, unlike the nonlinear profile seen in adults. Pharmacokinetic simulations showed that a maintenance dosing regimen of 4 mg/kg IV q12h is needed to achieve AUC values similar to those seen in adults receiving 3 mg/kg q12h.


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