Pharmacokinetic and Exposure Response Analysis of the Double-Blind Randomized Study of Posaconazole and Voriconazole for Treatment of Invasive Aspergillosis

Background and ObjectiveA double-blind phase 3 study was conducted to compare posaconazole 300 mg intravenously (IV)/300 mg orally once daily (twice daily day 1) with voriconazole 4 mg/kg IV twice daily/200 mg orally twice daily (6 mg/kg day 1) for treatment of invasive aspergillosis. This analysis was conducted to summarize the pharmacokinetics and exposure–response relationships of posaconazole and voriconazole using plasma trough concentration (Ctrough) as a surrogate for exposure from the double-blind phase 3 study.MethodsThe pharmacokinetic evaluable population included all intention-to-treat (ITT) participants with at least one plasma concentration during the treatment period. Treatment blinding was maintained without therapeutic drug monitoring. Ctrough sampling occurred throughout treatment; efficacy and safety were evaluated using quartiles determined by mean Ctrough concentrations. Exposure efficacy variables included day 42 all-cause mortality (primary study endpoint) and global clinical response. Exposure safety variables included all adverse events and treatment-related adverse events.ResultsThe pharmacokinetic analysis population included 506 of 575 ITT participants (437 with Ctrough concentrations: 228 posaconazole, 209 voriconazole). No trend was seen across quartiles of posaconazole Ctrough for the key efficacy endpoint of all-cause mortality through day 42. Participants in the highest quartile of voriconazole Ctrough had higher all-cause mortality through day 42 than participants in the lower three quartiles of voriconazole Ctrough. Similar findings were observed for global clinical response and Ctrough. No clear exposure safety trend by quartile was seen for posaconazole or voriconazole.ConclusionsA strong exposure–response relationship was not observed across the range of exposure from the administered doses and formulations for posaconazole or voriconazole.Trial registration: NCT01782131; registered January 30, 2013.