The next question to be answered is whether the drug has a narrow therapeutic range for the specific subpopulation (disease state) and specific indication.
Although some studies suggest a possible correlation between plasma concentration of voriconazole and efficacy, no break points in clinical response for efficacy and safety have been formally established. The suggested lower threshold for the therapeutic range varies from less than 0.25 mg/L to as high as 2 mg/L, and the upper threshold (to avoid toxic effects) varies from 4 to 6 mg/L.24,28,29,70 However, these threshold values should not be used routinely to guide dosing, since a causal relationship between plasma concentration of voriconazole and clinical response remains to be elucidated. Even if an association between concentration and efficacy or toxic effects does exist, the pharmacokinetic parameter that will best predict clinical response (Cmin, Cmax, or AUC) is unknown.
INTRINSIC VARIABILITY AND OTHER CONFOUNDERS
The possibility that the pharmacokinetic parameters are unpredictable, because of intrinsic variability or the presence of other confounding factors, must also be assessed. Viagra Online Canadian Pharmacy
In general, voriconazole exhibits a nonlinear pharmacokinet- ic profile, which is most probably attributable to its saturable hepatic clearance. In adult patients, plasma concentrations of the drug increase disproportionately, by about 3-fold with a 33% dosage increase. This phenomenon occurred when patients were given clinically recommended (usual) voriconazole doses of 100 mg, 200 mg, and 300 mg. This property of saturable metabolism may lead to variation both within and between individuals. Interestingly, saturable hepatic clearance was not observed in a pharmacokinetic study involving 35 immunocompromised children, as previously discussed.
Because voriconazole is a known substrate for CYP2C9, CYP2C19, and CYP3A4, several drug-drug interactions are possible with other agents metabolized by similar routes. The concentration of voriconazole is reduced in the presence of rifampin, rifabutin, phentoin, and ritonavir, and is increased in the presence of omeprazole, cimetidine, erythromycin, and indinavir. TDM may be warranted if toxicity or lack of response because of a drug-drug interaction is suspected. cialis 5 mg
Voriconazole is also known to inhibit the same three isoenzymes, thereby increasing the concentrations of omeprazole, phenytoin, warfarin, rifabutin, and prednisolone. Elevated concentrations of cyclosporine, tacrolimus, and sirolimus through inhibition of CYP3A4 have also been demonstrated with concomitant voriconazole administration. This may carry substantial clinical implications, as many patients being treated with voriconazole for invasive fungal infections receive concurrent therapy with immunosuppressants. Considering these possible drug interactions, drug monitoring of the affected drug or empiric dosing adjustment may be indicated.