3- Voriconazole

Stopher and Gage used size-exclusion chromatography (SEL) coupled to reversed phase HPLC for the direct injection of plasma in the analysis of an antifungal agent, voriconazole (12). Their system consisted of three columns, i.e. first a size-exclusion... 

Figure 15.5 Separation of Voriconazole and an internal standard by using SEC-HPLC. Adapted from Journal of Chromatography, B 691, D.A. Stopher and R. Gage, Determination of a new antifungal agent, voriconazole, by multidimensional high-perfomiance liquid chromatography with direct plasma injection onto a size exclusion column , pp. 441 -448, copyright 1997, with permission from Elsevier Science.

The imidazoles and triazole ( azoles) (for example, ketoconazole, itraconazole (ITRA), fluconazole (FLU), voriconazole) interfere with cytochrome P45o-dependent lanosterol C14 demethylase, leading to dqDletion of ergosterol and accumulation of lanosterol in the... 

Systemic mycoses are caused either by true pathogenic fungi (endemic in distinct areas of USA/South America) or by opportunistic fungi that induce severe infections in immunosuppressed patients. The arsenal for the treatment of deep organ mycoses is relatively small Amph B, 5FC, azoles (FLU, ITRA, voriconazole (NBA filing)) and CAS. 

Two to three weeks of fluconazole or itraconazole solution are highly effective and demonstrate similar clinical response rates.32 Doses of 100 to 200 mg are effective in immunocompetent patients but doses up to 400 mg are recommended for immunocompromised patients. Due to variable absorption, ketoconazole and itraconazole capsules should be considered second-line therapy. In severe cases, oral azoles may prove ineffective, warranting the use of amphotericin B for 10 days. Although echinocandins and voriconazole are effective in treatment of esophageal candidiasis, experience remains limited. 

If a patient is non-neutropenic and has never received prior azole therapy, fluconazole 800 mg/day is an appropriate first-line therapy for invasive candidiasis until identification of the Candida isolate. Amphotericin B deoxycholate 0.7 mg/kg per day or caspofungin 70 mg on day 1, then 50 mg/day, voriconazole, or a lipid amphotericin B formulation are recommended as empiric therapy in patients with neutropenic fever. 

Many experts now consider voriconazole as the initial drug of choice for invasive aspergillosis in patients without significant contraindications (e.g., drug interactions or preexisting liver dysfunction) to azole therapy. 

Zygomycetes are generally resistant to voriconazole and echinocandins and their presence should be suspected in any patient with progressive mold infection while receiving voriconazole and/or echinocandin therapy. 

Preclinical studies suggest mold-active azoles plus echinocandins have enhanced activity against Aspergillus A. terreus should be considered resistant to amphotericin B Activity of amphotericin B and voriconazole is decreased versus Aspergillus species higher doses or combination therapy may be indicated in more refractory cases... 

Fusariosis Lipid formulations of amphotericin B OR Voriconazole 6 mg/kg q12hour for 1 day, then 4 mg/kg q12hour OR Posaconazole 200 mg PO qid for 14 days, then 200 mg PO q12hour OR Combination therapy ... 

Although more invasive, esophageal candidiasis does not typically evolve into a life-threatening infection. However, topical therapy is ineffective. Azoles (fluconazole, itraconazole solution, or voriconazole), echinocandins, or intravenous amphotericin B (in cases of unresponsive infections) are effective treatment options. Parenteral therapy should be used in patients who are unable to take oral medications.20... 

Is voriconazole an acceptable option in this patient Are there any drug interaction concerns ... 

Voriconazole is started in the patient along with 1 mg/kg per day of methylprednisolone to control the graft-versus-host disease. Her tacrolimus dose was also decreased by 70% with the addition of voriconazole and a recent tacrolimus blood level of 1 0 ng/mL. Unfortunately, the patient remains febrile with worsening respiratory pain. A repeat CT scan of the lung demonstrates new nodules, and pleural effusion in the right lung. 

What are the possible reasons this patient appears to be progressing on voriconazole therapy ... 

What other molds may be implicated as a cause of infection that may not respond to voriconazole in this patient ... 

Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002 347 408M15. 

Kullberg BJ, Sobel JD, Ruhnke M, et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients a randomised non-inferiority trial. Lancet 2005 366 1435-1442. 

Select azole antifungals (e.g., itraconazole, voriconazole, and posaconazole) and the echinocandins are available for IA treatment. For initial therapy of IA, voriconazole had higher response and survival rates than c-AMB.102 An advantage of voriconazole is its 96% oral bioavailability, making use of this oral drug an attractive and less expensive alternative. The dose of voriconazole was 6 mg/kg IV every 12 hours for two doses, followed by 4 mg/kg IV every 12 hours for at least 7 days, at which time oral voriconazole 200 mg every 12 hours could be administered. Common toxicities reported with voriconazole include infusion-related, transient visual disturbances (i.e., blurred vision, altered color perception, photophobia, and visual hallucinations), skin reactions (i.e., rash, pruritus, and photosensitivity), elevations in hepatic transaminases and alkaline phosphatase, nausea, and headache.102 In addition, voriconazole increases the serum concentrations of medications cleared by cytochrome P-450 2C9, 2C19, and 3A4 (e.g., cyclophosphamide and calcineurin inhibitors) concomitant voriconazole-sirolimus should be avoided.103... 

Voriconazole 6 mg/kg IV loading dose every 12 hours on day 1 followed by 4 mg/kg PO/IV every 12 hours Dosage adjustment in hepatic dysfunction IV formulation contraindicated if creatinine clearance less than 50 mDminute multiple drug interactions. 

Ferretti et al. (1988) used an amino column coupled to a derivatized amylose column (Chiralpak AS) operated in the reverse-phase mode to separate the enantiomers of the antifungal agent voriconazole from several chiral impurities and one achiral impurity. Three of the chiral impurities are the other enantiomer and corresponding diastereomers of voriconazole. More chiral impurities result from a chlorinated voriconazole. Additionally, this multidimensional method could baseline separate all but two of the chiral impurities into their respective enantiomers. These separations are shown in Figure 14.5. 

FIGURE 14.5 Separations involving voriconazole (1), its mirror image (2), related diaster-eomers (3), chlorinated impurities (4), and an achiral impurity 5. (a) Achiral separation of compounds 1-5 on an amino column with hexane/ethanol mobile phase (b) Chiral separation of compounds 1-5 on Chiralpak As column with hexane/ethanol mobile phase (c) Achiral-chiral multidimensional separation with the amino and chiral column coupled in series. Reprinted from Ferretti et al. (1998) with permission from Vieweg Verlag. 

Ferretti, R., Gallinella, B., La, T.F., Zanitti, L. (1988). Direct resolution of a new antifungal agent, voriconazole(UK-109,496) and its potential impurities, by use of coupled achiral-chiral high-performance liquid chromatography. Chromatographia 47, 649-654. 

Azalides azithromycin Azoles fluconazole, itraconazole, ketoconazole, and voriconazole Macrolides erythromycin, clarithromycin Protease inhibitors amprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, and saquinavir Quinolones ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin. 

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