title: Population pharmacokinetic-pharmacodynamic analysis of voriconazole and anidulafungin in adult patients with invasive aspergillosis.
abstract: To evaluate the exposure-response relationships for efficacy and safety of voriconazole and anidulafungin in adult patients with invasive aspergillosis (IA), a population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed with data from a phase 3, prospective, double-blind, comparative study evaluating voriconazole and anidulafungin combination therapy versus voriconazole (and placebo) monotherapy. Anidulafungin/placebo treatment duration was 2 to 4 weeks, and voriconazole treatment duration was 6 weeks. Efficacy (6-week all-causality mortality and 6-week global response [n = 176]) and safety (hepatic [n = 238], visual [n = 199], and psychiatric [n = 183] adverse events [AEs]) endpoints were analyzed separately using a binary logistic regression model. In IA patients receiving voriconazole monotherapy, no positive associations between voriconazole exposure and efficacy or safety were identified. In IA patients receiving combination therapy, no positive associations between voriconazole or anidulafungin exposures and efficacy were identified. The 6-week survival rate tended to increase as anidulafungin treatment duration increased; this finding should be considered with caution. Additionally, in IA patients receiving combination therapy, a positive association between voriconazole and anidulafungin exposures (area under the curve [AUC] and trough concentration [C(min)]) and hepatic AEs was established; a weak positive association between voriconazole exposure (AUC and C(min)) and psychiatric AEs was also established, but no association between voriconazole exposure and visual AEs was identified. Besides the drug exposures, no other covariates (i.e., CYP2C19 genotype status, age, weight, body mass index, sex, race, or neutropenia status) were identified as significant predictors of the efficacy and safety endpoints in IA patients. This study was registered on ClinicalTrials.gov (NCT00531479).
authors.affiliation: Clinical Pharmacology, Global Established Pharma Business, Pfizer Inc., Groton, Connecticut, USA ping.liu@pfizer.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Projections Research Inc., Phoenixville, Pennsylvania, USA.
authors.forename: Diane R
authors.initials: DR
authors.lastname: Mould
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077612:Anidulafungin; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D001228:Aspergillosis / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D001230:Aspergillus / Q000187:drug effects / Q000502:physiology; D001682:Biological Availability; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000503:physiopathology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D054714:Echinocandins / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006212:Hallucinations / Q000209:etiology / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D020795:Photophobia / Q000209:etiology / Q000503:physiopathology; D011446:Prospective Studies; D065819:Voriconazole / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000935:Antifungal Agents; D054714:Echinocandins; D000077612:Anidulafungin; D065819:Voriconazole