title: Combination therapy of advanced invasive pulmonary aspergillosis in transiently neutropenic rats using human pharmacokinetic equivalent doses of voriconazole and anidulafungin.
abstract: 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 concentration-time 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.
authors.affiliation: Erasmus MC, University Medical Center Rotterdam, Department of Medical Microbiology and Infectious Diseases, s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. w.vandesande@erasmusmc.nl
authors.forename: Wendy W J
authors.initials: WW
authors.lastname: van de Sande
authors.forename: Ron A A
authors.initials: RA
authors.lastname: Mathot
authors.forename: Marian T
authors.initials: MT
authors.lastname: ten Kate
authors.forename: Wim
authors.initials: W
authors.lastname: van Vianen
authors.forename: Mehri
authors.initials: M
authors.lastname: Tavakol
authors.forename: Bart J A
authors.initials: BJ
authors.lastname: Rijnders
authors.forename: Irma A J M
authors.initials: IA
authors.lastname: Bakker-Woudenberg
mesh_terms: D000077612:Anidulafungin; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D001232:Aspergillus fumigatus / Q000187:drug effects*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D054714:Echinocandins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000150:complications*; D011743:Pyrimidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D011743:Pyrimidines; D014230:Triazoles; D000077612:Anidulafungin; D065819:Voriconazole