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

• Published in: Clinical drug investigation 2023-09, Vol.43 (9), p.681-690
• Main Authors: Maertens, Johan A., Rahav, Galia, Lee, Dong-Gun, Haider, Shariq, Ramirez-Sanchez, Isabel Cristina, Klimko, Nikolai, Ponce-de-León, Alfredo, Han, Seongah, Wrishko, Rebecca, Winchell, Gregory A., Grandhi, Anjana, Waskin, Hetty
• Format: Article
• Language: English
• Subjects: Aspergillosis; Double-blind studies; Drug dosages; Drug interactions; Fungal infections; Internal Medicine; Medicine; Medicine & Public Health; Mortality; NCT; NCT01782131; Neutropenia; Original; Original Research Article; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Plasma
• ISSN: 1173-2563; 1179-1918
• DOI: 10.1007/s40261-023-01282-7

Background and Objective A 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 ( C trough ) as a surrogate for exposure from the double-blind phase 3 study. Methods The 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. C trough sampling occurred throughout treatment; efficacy and safety were evaluated using quartiles determined by mean C trough 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. Results The pharmacokinetic analysis population included 506 of 575 ITT participants (437 with C trough concentrations: 228 posaconazole, 209 voriconazole). No trend was seen across quartiles of posaconazole C trough for the key efficacy endpoint of all-cause mortality through day 42. Participants in the highest quartile of voriconazole C trough had higher all-cause mortality through day 42 than participants in the lower three quartiles of voriconazole C trough . Similar findings were observed for global clinical response and C trough . No clear exposure safety trend by quartile was seen for posaconazole or voriconazole. Conclusions A 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.