Dataset Information

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

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_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.

SUBMITTER: Maertens JA

PROVIDER: S-EPMC10514181 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Maertens Johan A JA Rahav Galia G Lee Dong-Gun DG Haider Shariq S Ramirez-Sanchez Isabel Cristina IC Klimko Nikolai N Ponce-de-León Alfredo A Han Seongah S Wrishko Rebecca R Winchell Gregory A GA Grandhi Anjana A Waskin Hetty H

Clinical drug investigation 20230907 9

<h4>Background and objective</h4>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<sub>trough</sub>) as a surrogate for ...[more]

PMID: 37676612

Similar Datasets

Project description:Abstract Background Invasive aspergillosis (IA) is a life-threatening disease with limited treatment options and is associated with delays in effective treatment and significant early mortality. Posaconazole (POS) is a broad-spectrum triazole antifungal, that exhibits potent activity against yeasts and molds. We evaluated the antifungal susceptibility profiles of isolates collected during a randomized, prospective, phase 3, double-blind, double-dummy study comparing posaconazole with voriconazole (1:1 randomization) given for ≤12 weeks in the primary treatment of IA (ClinicalTrials.gov, NCT01782131; EudraCT, 2011-003938-14) using CLSI and EUCAST reference testing methodologies. Methods More than 90 study sites located in 23 countries enrolled subjects in the clinical trial. A total of 127 isolates were recovered from documented infections during 2013 through 2019. Fungal isolates were identified using molecular methods and antifungal susceptibility testing was performed by reference broth microdilution methods. The following antifungal agents tested were: posaconazole, itraconazole, voriconazole, caspofungin, and amphotericin B Results Of the 127 samples tested, 119 were identified as Aspergillus species. Aspergillus fumigatus (N=76) was the most prevalent species, followed by A. flavus species complex (N=19), A. section Nigri (N=10), A. section Terrei (N=7). Overall, posaconazole (MIC50/MIC 90, 0.5/1 mg/L) displayed similar activity to voriconazole (MIC50/MIC90, 0.5/1 mg/L) and itraconazole (MIC50/MIC90, 1/2 mg/L) against 119 Aspergillus species Isolates, by both, CLSI and EUCAST method. Posaconazole (MIC50/MIC90, 0.5/0.5 mg/L) and voriconazole (MIC50/MIC90, 0.25/0.5 mg/L) inhibited all 76 A. fumigatus isolates at MIC of 1 mg/L. Among 19 A. flavus species complex isolates recovered from this study, posaconazole (MIC50/MIC90, 0.5/1 mg/L), voriconazole (MIC50/MIC90, 1/1 mg/L) and itraconazole (MIC50/MIC90, 0.5/1 mg/L) displayed equivalent activity. Conclusion Posaconazole displayed good activity against all Aspergillus species isolates included in this study. In addition, posaconazole in vitro activity against Aspergillus species was similar to that observed by voriconazole and itraconazole. Disclosures Mariana Castanheira, PhD, 1928 Diagnostics (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Leah Woosley, n/a, Merck & Co, Inc. (Research Grant or Support) Mary Motyl, PhD, Merck & Co, Inc (Employee, Shareholder) Seongah Han, PhD, Merck & Co, Inc. (Employee) Havilland Campbell, BS, Merck & Co, Inc. (Employee)

Dataset Information

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

Background and objective

Methods

Results

Conclusions

Trial registration

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets