No Effect on Pharmacokinetic and Pharmacodynamic Parameters of Warfarin after Coadministration with Isavuconazole

Ref ID: 19294

Author:

T. Yamazaki, A. Desai, H. Pearlman, D. Kowalski, C. Lademacher, R. Townsend

Author address:

Astellas Pharma Global Dev., Inc., Northbrook, IL.

Full conference title:

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy

Date: 10 September 2014

Abstract:

Background: Isavuconazole (ISA), the active moiety of water soluble prodrug isavuconazonium sulfate, is a novel triazole antifungal agent currently in phase 3 clinical development for treatment of invasive fungal infections (caused by Aspergillus, Candida, or rare mould species). An in vitro CYP450 metabolism study suggests that ISA has the potential to inhibit CYP2C9. Warfarin, an anticoagulant is given as a racemic mixture of S- and R-stereoisomers. S-warfarin, metabolized by CYP2C9 is commonly used to probe CYP2C9 activity in clinical drug-drug interaction studiesa. Inhibition of CYP2C9 can increase S-warfarin concentration and prevent coagulation. The current study aimed to assess the effect of ISA administration on warfarin pharmacokinetics (PK) and pharmacodynamics (PD) as well as safety and tolerability. Methods: This was a phase 1, single center, open-label, drug-interaction study. 20 healthy subjects, aged 18-55 years participated in the study. On Days 1 and 20, subjects received a single 20 mg oral dose of warfarin under fasting conditions. On Days 16 and 17, subjects received 200 mg oral ISA three times daily, ~8 h apart. On Days 18 through 28, subjects received 200 mg ISA once daily. PK and PD parameters of warfarin were assessed in presence/absence (Day 20/Day 1) of ISA. PD parameters
included prothrombin time (PT) and international
normalized ratio (INR). Results: 20 subjects completed
the study. No differences in the safety profiles of ISA alone
and ISA+warfarin groups were observed. The geometric
mean ratio (GMR; %) and 90% confidence intervals (CI) of
area under the plasma concentration time curve from time
of dosing extrapolated to infinity (AUC8734;) and maximum
plasma concentration (Cmax) for S-warfarin when given in
combination with ISA vs. warfarin alone were 111 (106,
115) and 88 (83, 94), respectively. The GMR (%) and 90%
CI for INR over 24 h period and area under the curve for
PT (AUCPT) of S- warfarin when given in combination with
ISA vs. warfarin alone were 96 (93,100) and 97 (94, 100),
respectively. Conclusions: Co-administration of ISA with
warfarin did not alter the PK or PD of S-warfarin and was
well tolerated. aGuidance for Industry, Drug Interaction
Studies-Study Design, Data Analysis, Implications for
Dosing, and Labeling Recommendations.

Abstract Number: NULL

Conference Year: 2013

Link to conference website: NULL

New link: NULL

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