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Pharmacokinetic and Exposure Response Analysis of the Double-Blind Randomized Study of Posaconazole and Voriconazole for Treatment of Invasive Aspergillosis.
- Source :
-
Clinical drug investigation [Clin Drug Investig] 2023 Sep; Vol. 43 (9), pp. 681-690. Date of Electronic Publication: 2023 Sep 07. - Publication Year :
- 2023
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Abstract
- 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 <subscript>trough</subscript> ) as a surrogate for exposure from the double-blind phase 3 study.<br />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 <subscript>trough</subscript> sampling occurred throughout treatment; efficacy and safety were evaluated using quartiles determined by mean C <subscript>trough</subscript> 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.<br />Results: The pharmacokinetic analysis population included 506 of 575 ITT participants (437 with C <subscript>trough</subscript> concentrations: 228 posaconazole, 209 voriconazole). No trend was seen across quartiles of posaconazole C <subscript>trough</subscript> for the key efficacy endpoint of all-cause mortality through day 42. Participants in the highest quartile of voriconazole C <subscript>trough</subscript> had higher all-cause mortality through day 42 than participants in the lower three quartiles of voriconazole C <subscript>trough</subscript> . Similar findings were observed for global clinical response and C <subscript>trough</subscript> . No clear exposure safety trend by quartile was seen for posaconazole or voriconazole.<br />Conclusions: A strong exposure-response relationship was not observed across the range of exposure from the administered doses and formulations for posaconazole or voriconazole.<br />Trial Registration: NCT01782131; registered January 30, 2013.<br /> (© 2023. The Author(s).)
Details
- Language :
- English
- ISSN :
- 1179-1918
- Volume :
- 43
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Clinical drug investigation
- Publication Type :
- Academic Journal
- Accession number :
- 37676612
- Full Text :
- https://doi.org/10.1007/s40261-023-01282-7