A new in-vitro kinetic model to study the pharmacodynamics of antifungal agents: inhibition of the fungicidal activity of amphotericin B against Candida albicans by voriconazole.
The aim of this study was to develop and validate a new in-vitro kinetic model for the combination of two drugs with different half-lives, and to use this model for the study of the pharmacodynamic effects of amphotericin B and voriconazole, alone or in combination, against a strain of Candida albicans. Bolus doses of voriconazole and amphotericin B were administered to a starting inoculum of C. albicans. Antifungal-containing medium was eliminated and replaced by fresh medium using a peristaltic pump, with the flow-rate adjusted to obtain the desired half-life of the drug with the shorter half-life. A computer-controlled dosing pump compensated for the agent with the longer half-life. Voriconazole and amphotericin B half-lives were set to 6 and 24 h, respectively. Pharmacokinetic parameters were close to target values when both single doses and sequential doses were simulated. Voriconazole and amphotericin B administered alone demonstrated fungistatic and fungicidal activity, respectively. Simultaneous administration resulted in fungicidal activity, whereas pre-exposure of C. albicans to voriconazole, followed by amphotericin at 8 and 32 h, resulted in fungistatic activity similar to that observed with voriconazole alone. Using this model, which allowed a combination of antifungal agents with different half-lives, it was possible to demonstrate an antagonistic effect of voriconazole on the fungicidal activity of amphotericin B. The characteristics and clinical relevance of this interaction require further investigation.
Lignell
A
A
Section of Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden. anders.lignell@akademiska.se
Johansson
A
A
Löwdin
E
E
Cars
O
O
Sjölin
J
J
D000666:Amphotericin B / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D000935:Antifungal Agents / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects* / Q000254:growth & development; D015169:Colony Count, Microbial; D006207:Half-Life; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D008954:Models, Biological; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D065819:Voriconazole
D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D000666:Amphotericin B; D065819:Voriconazole