Drug interaction profiles of isavuconazole, voriconazole and posaconazole with immunosuppressants metabolized by CYP4503A4 (CYP3A4)

Author:

R. Townsend,1 A. Desai,1 N. Azie,1 M. Jones,2 M. Engelhardt2 and A. H. Schmitt-Hoffmann2

Author address:

1Astellas Pharma Global Development, Inc, Northbrook, USA and 2Basilea Pharmaceutica International Ltd, Basel, Switzerland

Date: 1 November 2015

Abstract:

Objectives Isavuconazole is the active moiety of isavuconazonium sulfate, a water-soluble prodrug for oral and intravenous administration. Isavuconazole is a broad-spectrum triazole with in vitro activity against clinically relevant pathogens including Aspergillus spp., Candida spp., Cryptococcus spp., and Mucorales. This makes isavuconazole potentially useful to treat patients with invasive mould disease (IMD) including those receiving immunosuppressants (bone marrow/solid organ transplant recipients), at risk of renal/hepatic impairment and with an increased potential for drugdrug interactions (DDIs) due to multiple co-medications. Isavuconazole shows predictable pharmacokineticsi, high oral bioavailabilityi and no food effectii. Isavuconazole is a moderate CYP3A4 inhibitor. Unlike voriconazole, isavuconazole does not inhibit CYP2C9 or CYP2C19. A review of clinical pharmacology information was therefore performed to compare the potential for DDIs between immunosuppressants metabolized by CYP3A4 and the triazoles isavuconazole, voriconazole, or posaconazole.

Methods A review of US and EU prescribing information was conducted to identify clinical pharmacology information related to multiple doses posaconazole or voriconazole on co-administration with midazolam (typical CYP3A4 probe substrate for clinical DDI studies) and immunosuppressants metabolized by CYP3A4. A literature search was also performed to obtain missing information. Clinical pharmacology information for isavuconazole was derived from published abstracts. The effects of isavuconazole, voriconazole or posaconazole on the exposure of the respective CYP3A4 substrates expressed as area under the curve (AUC) – were compared.

Results The AUC of oral midazolam (probe substrate for CYP3A4) was increased 2-fold with isavuconazole, 5-fold with posaconazole and 10-fold with voriconazole. Results with immunosuppressants metabolized by CYP3A4 are presented in the table below.

Conclusion Considering midazolam probe substrate, isavuconazole exhibits moderate inhibition of CYP3A4 (≥2 and <5 -fold), whereas posaconazole and voriconazole are strong CYP3A4 inhibitors (≥5fold).

Clinical pharmacology studies demonstrate that the effect of isavuconazole on CYP3A4 substrates is substantially less pronounced than posaconazole or voriconazole. The clinical pharmacology profile indicates potential advantages of isavuconazole in treating patients receiving immunosuppressants metabolized by CYP3A4.

References (i) Schmitt-Hoffmann, Antimicrob Agents Chemother 2006;50:279–285; (ii) Schmitt-Hoffmann, ICAAC 2008:A008; (iii) Desai, ICAAC 2012:A1936; iv Saari, Clin Pharmacol Ther 2006;79:362–70; (v) Yamazaki, ASCPT 2013:PIII-76; (vi) Yamazaki, ASCPT 2013:PIII-75; (vii) Desai, ASCPT 2013:PIII-71; (viii) Saad, Pharmacotherapy 2006;26:1730–44. ASCPT: American Society for Clinical Pharmacology & Therapeutics; ICAAC: Interscience Conference on Antimicrobial Agents & Chemotherapy.

(Encore abstract: Previously presented at the European Congress of Clinical Microbiology and Infectious Disease [ECCMID], Copenhagen, Denmark; April 25–28, 2015; P0216)

 

Abstract Number: P464

Tables: 

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