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

R. Townsend, A. Desai, N. Azie, M. Jones, M. Engelhardt, A.-H. Schmitt-Hoffmann

Abstract: 

Objectives: Isavuconazole (ISA) is the active moiety of isavuconazonium sulfate, a water-soluble prodrug for oral and intravenous administration. ISA is a broad-spectrum triazole with in-vitro activity against clinically relevant pathogens including Aspergillus spp., Candida spp., Cryptococcus spp., and Mucorales.
This makes ISA 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 drug-drug interactions (DDIs) due to multiple co-medications.
ISA shows predictable pharmacokineticsi, high oral bioavailabilityi and no food effectii. ISA is a moderate CYP3A4 inhibitor. Unlike voriconazole (VRC), ISA 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 ISA, VRC, or posaconazole (POS).
Methods: A review of US and EU prescribing information was conducted to identify clinical pharmacology information related to multiple doses POS or VRC 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 ISA was derived from published abstracts. The effects of ISA, VRC or POS on the exposure of the respective CYP3A4 substrates - expressed as area under the curve (AUC) – were compared.
Objectives: Isavuconazole (ISA) is the active moiety of isavuconazonium sulfate, a water-soluble prodrug for oral and intravenous administration. ISA is a broad-spectrum triazole with in-vitro activity against clinically relevant pathogens including Aspergillus spp., Candida spp., Cryptococcus spp., and Mucorales.
This makes ISA 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 drug-drug interactions (DDIs) due to multiple co-medications.
ISA shows predictable pharmacokineticsi, high oral bioavailabilityi and no food effectii. ISA is a moderate CYP3A4 inhibitor. Unlike voriconazole (VRC), ISA 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 ISA, VRC, or posaconazole (POS).
Methods: A review of US and EU prescribing information was conducted to identify clinical pharmacology information related to multiple doses POS or VRC 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 ISA was derived from published abstracts. The effects of ISA, VRC or POS 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 ISA, 5-fold with POS and 10-fold with VRC. Results with immunosuppressants metabolized by CYP3A4 are tabulated below. The AUC of oral midazolam (probe substrate for CYP3A4) was increased 2-fold with ISA, 5-fold with POS and 10-fold with VRC. Results with immunosuppressants metabolized by CYP3A4 are tabulated below.

Conclusion: Considering midazolam probe substrate, ISA exhibits moderate inhibition of CYP3A4 (≥ 2 and <5 -fold), whereas POS and VRC are strong CYP3A4 inhibitors (≥ 5-fold). Clinical pharmacology studies demonstrate that the effect of ISA on CYP3A4 substrates is substantially less pronounced than POS or VRC. The clinical pharmacology profile indicates potential advantages of ISA in treating patients receiving immunosuppressants metabolized by CYP3A4.

Tables: 

abstract No: 

P0216