Improving the mouse model for studying the efficacy of voriconazole

The antifungal efficacy of voriconazole (VRC) differs among host species, with potent efficacy in humans but less in rodents. We investigated the possible involvement of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in the speciesspecific efficacy of VRC through pharmacokinetic analyses using genetically modified mice and primary human hepatocytes. VRC (30 mg/kg) was orally administered to wild-type, Pxr-null, Car-null, and Pxr-and Car-null (Pxr/Car-null) mice for 7 days. Hepatic VRC metabolism was significantly increased by VRC administration, and the elimination rates of plasma VRC were much higher on day 7 than on day 1 in wild-type mice. This autoinduction was also observed in Pxr-null and Car-null mice but not in Pxr/Car-null mice, suggesting coordinated roles of PXR and CAR in the autoinduction of VRC metabolism in mice. Hepatic Cyp3a11 mRNA levels were increased by VRC administration, hepatic metabolic activities for VRC were correlated with CYP3A activities, and the induced VRC metabolism was inhibited by ketoconazole (a CYP3A inhibitor). In primary human hepatocytes, VRC barely increased mRNA levels of CYP3A4 and CYP2B6 (human PXR/CAR target genes) at its therapeutic concentrations. In conclusion, these results suggest that VRC is metabolized mainly by CYP3A11 in mouse livers and that PXR-and CAR-mediated CYP3A11 induction, namely, autoinduction of VRC metabolism, is a primary reason for the ineffectiveness of VRC in mice. A limited ability of VRC to activate human PXR/CAR at its clinical concentration might explain the VRC efficacy in humans. Therefore, the ability to activate PXR/CAR might determine the VRC efficacy in different mammalian species.

Section: Discussionsupporting

confidence: 83%

Coordinated Roles of Pregnane X Receptor and Constitutive Androstane Receptor in Autoinduction of Voriconazole Metabolism in Mice

Ohbuchi

Yoshinari

Kaneko

et al. 2013

“…Due to amino acid differences in these enzymes between rodents and humans, VOR is metabolized more rapidly in rodents (45). In order to compensate for this process, other investigators used guinea pigs or mice on a grapefruit diet to increase serum levels of VOR (13,20,36,38). In the present study a different approach was elaborated to achieve a human pharmacokinetic equivalent dosage of VOR in rats.…”

Section: Discussionmentioning

confidence: 99%

Combination Therapy of Advanced Invasive Pulmonary Aspergillosis in Transiently Neutropenic Rats Using Human Pharmacokinetic Equivalent Doses of Voriconazole and Anidulafungin

Sande

Mathôt

Kate

et al. 2009

At present, voriconazole (VOR) is the drug of first choice for treating invasive pulmonary aspergillosis (IPA).However, particularly in advanced stages of disease and in the severely immunocompromised host, the mortality remains substantial. The combination of VOR with an echinocandin may improve the therapeutic outcome. We investigate here whether combining VOR and anidulafungin (ANI) in advanced IPA in transiently neutropenic rats results in a higher therapeutic efficacy. Since VOR is metabolized more rapidly in rodents than in humans, dosage adjustment for VOR is necessary to obtain an area under the plasma concentrationtime curve (AUC) in rodents that is equivalent to that of humans. In this study, the pharmacokinetics of VOR and ANI in rats were elucidated, and dosage schedules were applied that produced AUCs similar to those of humans. The developed dose schedules were well tolerated by the rats, without effects on renal and hepatic functions. VOR showed excellent efficacy in early IPA (100% rat survival). In advanced IPA, VOR was less efficacious (50% rat survival), whereas a significant decrease in galactomannan concentrations in lungs and sera was found in surviving rats. ANI administered in advanced IPA resulted in 22% rat survival, and the serum concentrations of fungal galactomannan were slightly but not significantly decreased. The addition of ANI to VOR did not result in significantly increased therapeutic efficacy in advanced IPA, resulting in 67% rat survival and a significant decrease in galactomannan concentration in serum. In conclusion, VOR monotherapy is therapeutically effective in the treatment of advanced-stage IPA and superior to the use of ANI. Combining both agents does not significantly improve the therapeutic outcome.Invasive pulmonary aspergillosis (IPA) continues to be a major problem in immunocompromised patients (18). Since voriconazole (VOR) was shown to be superior to amphotericin B (AMB) in a large randomized trial, it became the drug of choice for the treatment of IPA (22, 44). More recently, another class of antifungal agents, the echinocandins, has been used to salvage patients with refractory IPA (44). Echinocandins target 1,3-␤-D-glucan synthesis of most pathogenic fungi. Caspofungin (CAS) was the first drug of this class, and more recently anidulafungin (ANI) has become available. However, despite these new treatment options for IPA, the mortality remains substantial, with mortality rates of 25 to 35% 12 weeks after diagnosis (21, 22). Combination therapy might reduce mortality rates further. From clinical observational studies, it appeared that in 57 to 68% of the favorable results were obtained in patients when combination therapy with VOR and CAS was applied (27,37). In neither of these studies, however, was the combination therapy compared to VOR monotherapy in a randomized fashion.In this respect, preclinical research in animal models of IPA is important for investigating the potency of antifungal agents in combination. In our laboratory, we developed a model of uni...

“…BID. Additional groups of animals received grapefruit juice (Ocean Spray) in lieu of water beginning on day 3 prior to infection to improve the serum concentrations of voriconazole by inhibiting metabolism, similar to previously described studies using mice (6,18,45,46). These animals were treated with 4% polyethylene glycol (PEG) 400 (grapefruit juice controls) orally (p.o.)…”

Section: Methodsmentioning

confidence: 99%

Comparative Efficacies of Conventional Amphotericin B, Liposomal Amphotericin B (AmBisome), Caspofungin, Micafungin, and Voriconazole Alone and in Combination against Experimental Murine Central Nervous System Aspergillosis

Clemons

Espiritu

Parmar

et al. 2005

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