title: Derivation of an in vivo drug exposure breakpoint for flucytosine against Candida albicans and Impact of the MIC, growth rate, and resistance genotype on the antifungal effect.
abstract: Drug exposure or pharmacodynamic breakpoints refer to a magnitude of drug exposure which separates a population into groups with high and low probabilities of attaining a desired outcome. We used a pharmacodynamic model of disseminated candidiasis to define an in vivo drug exposure breakpoint for flucytosine (5FC) against Candida albicans. The results were bridged to humans by using population pharmacokinetics and Monte Carlo simulation. An in vivo drug exposure breakpoint for 5FC was apparent when serum levels were above the MIC for 45% of the dosing interval. The Monte Carlo simulations suggested that using a human dose of 100 mg/kg of body weight/day in four divided doses, 5FC resistance was defined at an MIC of 32 mg/liter. Target attainment rates following administration of 25, 50, and 100 mg/kg/day were similar, suggesting that the use of a lower dose of 5FC is possible. Using six isolates of C. albicans with MICs ranging from 0.06 to >64 mg/liter, we also explored the influence that the MIC, the fraction of the dosing interval that the serum levels of 5FC remained above the MIC (T>MIC), the 5FC resistance genotype, and the in vivo growth rate had on the response to 5FC. The MIC and T>MIC were both critical measures affecting the generation of a drug effect but had no bearing on the magnitude of the maximal kill induced by 5FC. The in vivo growth rate was a critical additional determinant of the exposure-response relationship. There was a relationship between the 5FC resistance genotype and the exposure-response relationship.
authors.affiliation: Pediatric Oncology Branch, NCI/NIH, CRC Rm. 1-5750, 10 Center Dr., MSC 1100, Bethesda MD 20892-1100, USA. hopew@mail.nih.gov
authors.forename: William W
authors.initials: WW
authors.lastname: Hope
authors.forename: Peter A
authors.initials: PA
authors.lastname: Warn
authors.forename: Andrew
authors.initials: A
authors.lastname: Sharp
authors.forename: Susan
authors.initials: S
authors.lastname: Howard
authors.forename: Miki
authors.initials: M
authors.lastname: Kasai
authors.forename: Arnold
authors.initials: A
authors.lastname: Louie
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Walsh
authors.forename: George L
authors.initials: GL
authors.lastname: Drusano
authors.forename: David W
authors.initials: DW
authors.lastname: Denning
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D001499:Bayes Theorem; D002176:Candida albicans / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development; D002177:Candidiasis / Q000382:microbiology; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D025141:Drug Resistance, Fungal; D005437:Flucytosine / Q000494:pharmacology*; D005838:Genotype; D006801:Humans; D008826:Microbial Sensitivity Tests; D009010:Monte Carlo Method; D013534:Survival; D013997:Time Factors
chemical_list: D000935:Antifungal Agents; D005437:Flucytosine