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 (Ctrough) 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. 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.

Results: The 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.

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.

Conflict of interest statement

J.A.M. reports personal fees and non-financial support from MSD, grants, personal fees and non-financial support from Pfizer Inc., grants, personal fees and non-financial support from Gilead Sciences, personal fees and non-financial support from F2G, and personal fees and non-financial support from Cidara. G.R., S. Haider, I.C.R. and A.P. have nothing to disclose. D.-G.L. has received grants and personal fees from Pfizer, Gilead Sciences, and Yuhan. N.K. has received research grants or honoraria as a speaker or advisor from Astellas, Gilead, MSD, and Pfizer. R.W. is an employee of Merck Sharp and Dohme LLC, a subsidiary of Merck and Co., Inc., Rahway, NJ, USA, and has stock in Merck and Co., Inc., Rahway, NJ, USA. G.A.W. is working under contract with Certara USA, Inc., Princeton, NJ, USA. S. Han, A.G., and H.W. are employees of Merck Sharp and Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

© 2023. The Author(s).

Figures

Fig. 1

Mean [standard deviation (SD)] posaconazole Ctrough for participants receiving only posaconazole tablets (grey circle, grey solid line), participants receiving posaconazole IV only (black circle, dotted line), and participants starting on posaconazole IV and switching between IV and tablet (open square, solid line). Week 12 includes EOT concentration data. Ctrough trough concentration, EOT end of treatment, IV intravenously

Fig. 2

Mean (SD) voriconazole Ctrough in participants receiving only voriconazole capsules (grey circle, grey solid line), participants receiving only voriconazole IV (black circle, dotted line), and participants starting on voriconazole IV and switching between IV and capsule (open square, solid line). Week 12 includes EOT concentration data. Ctrough trough concentration, EOT end of treatment, IV intravenous

Fig. 3

Posaconazole exposure data. a All-cause mortality through day 42 by quartiles of within-participant mean posaconazole plasma Ctrough (ITT population). b Global clinical response at week 6 by quartile of within-participant mean posaconazole plasma Ctrough (FAS population). Ctrough trough concentration, FAS full analysis set, ITT intention-to-treat, Q quartile

Fig. 4

Voriconazole exposure data. a All-cause mortality through day 42 by quartiles of within-participant mean voriconazole plasma Ctrough (ITT population). b Global clinical response at week 6 by quartile of within-participant mean voriconazole plasma Ctrough (FAS population). Ctrough trough concentration, FAS full analysis set, ITT intention-to-treat, Q quartile

Fig. 5

Proportion of participants with TRAEs by quartile of within-participant mean a posaconazole Ctrough and b voriconazole Ctrough. Ctrough trough concentration, Q quartile, TRAE treatment-related adverse event