John Ray
Department of Clincal Pharmacology

Pharmacokinetic/Pharmacodynamic Analysis for Voriconazole

*    Evidence suggests voriconazole exhibits time-dependent killing.

TOXICITY

Phase I studies (normal volunteers)

Increase in both ALT and AST from baseline were related to the increases in the Cmax (maximum plasma concentration approx 2 hours after the dose) and area under the curve (AUC) of voriconazole. Increases in ALT and AST appeared to be most pronounced starting at Cmax of 5.0-6.0 mg/L or an AUC of 40-50 µg.hr/L. These data would equate to a maximum trough plasma concentration of 1.5 mg/L (sample taken 12 hours after the dose).
The greatest increases in ALT (1700% increase) and AST (700% increase) from baseline occurred when the Cmax plasma concentration was 8.5 mg/L which converts to a C12 (trough) of 2.4 mg/L.

Phase II/III studies

The incidence of visual adverse events (VAE) increased with an increase in voriconazole plasma
concentration. The incidence of VAE went from <20% at a plasma concentration < 3 mg/L to 25% at a concentration of 3-4 mg/L to 40% at a voriconazole concentration of > 9.0 mg/L.
Thus, a threshold concentration of approximately 3.0 mg/L in the Phase II/III patients was apparent. The C12 (trough) plasma voriconazole concentration would have to be < 1.5 mg/L to produce plasma concentrations below 3.0 mg/L over the whole dosing interval.

EFFICACY

MIC’s for voriconazole for Aspergillus spp. is 0.2-0.58 mg/L; Candida spp. is 0.001-0.39 mg/L and C. neoformans is 0.24 mg/L. A report has suggested that voriconazole produced maximal fungistatic activity at concentrations between 1 and 4 times the MIC. Additionally, a report from Pfizer states that there was a statistically significant negative relationship between mean plasma voriconazole concentrations and the odds of success (p = 0.005). The proportion of successes in patients with mean plasma voriconazole concentrations below 0.5 mg/L was 46% compared to 56% success when the plasma concentration was > 0.5 mg/L. These data suggest the C12 plasma voriconazole concentration should remain above 0.5 mg/L over the dosing interval (this should produce a Cmax of approximately 1.6 mg/L which is below the plasma threshold for VAE).

REFERENCE INTERVAL

Summarising the above data, a preliminary reference interval for trough samples is proposed as 0.5 - 1.5 mg/L.

SAMPLE COLLECTION AND TRANSPORT

• Wait at least 5 days after commencing/changing therapy to reach steady state before collecting blood for analysis.
• Collect a 5 mL EDTA (purple top) tube 12 hours after the dose (trough collection , just before the next dose; C12).
• Outside laboratories separate plasma and send to SydPath in an Eskie with an ice brick.

CONTACT

John Ray
Phone 8382 9190
Clinical Pharmacology & Toxicology
St. Vincent’s Hospital, Sydney.