Role of isavuconazole in the treatment of invasive fungal infections

Figures & data

Table 1 In vitro activity of isavuconazole against select pathogenic fungi

Organism	Isolates (n)	Isavuconazole			References
		MIC50*	MIC90*	Range*
Candida spp.
C. albicans	621	0.015	0.03	≤0.008 to >8	^Citation14
C. glabrata	235	0.5	2	0.03–8	^Citation14
C. parapsilosis	197	0.06	0.12	≤0.008–1	^Citation14
C. tropicalis	110	0.06	0.25	0.015–4	^Citation14
C. krusei	37	0.5	1	0.12–4	^Citation14
C. lusitaniae	33	0.03	0.06	≤0.008–0.12	^Citation14
C. dubliniensis	31	0.015	0.015	≤0.008–0.015	^Citation14
Aspergillus spp.
A. fumigatus	926	0.5	1	0.06 to ≥8	^Citation14
A. flavus	454	0.5	1	0.125–4	^Citation14, ^Citation16
A. niger	218	1	2	0.06 to >8	^Citation14, ^Citation16
A. terreus	390	0.25	0.5	0.06–2	^Citation14, ^Citation16
A. nidulans	106	0.125	1	0.06–1	^Citation14, ^Citation16
Other
Cryptococcus neoformans	69	0.6	0.12	≤0.008–0.5	^Citation14
Rhizomucor	9	1	–	0.5–1	^Citation17
Lichtheimia spp.	17	1	–	0.5–2	^Citation17
Rhizopus spp.	32	1	–	0.5–4	^Citation17
Mucor spp.	13	4	–	1–8	^Citation17

Notes:

* Concentration in mcg/mL; –, data not reported.

Abbreviations: n, number; MIC₅₀, minimum inhibitory concentration for 50% of isolates; MIC₉₀, minimum inhibitory concentration for 90% of isolates.

Table 2 Comparison of pharmacokinetic parameters of selected triazoles

Parameter	Fluconazole^Citation48	Voriconazole^Citation49,Citation50	Posaconazole^Citation50,Citation51	Isavuconazole^Citation12,Citation50
Available	Oral tablets	Oral tablets	Oral suspension	Oral capsules
Formulations	Oral suspension Intravenous	Oral suspension Intravenous	Oral tablets Intravenous	Intravenous
Oral bioavailability, %	>90	>90a	Range 8–47b	98
Volume of distribution, (L/kg)	0.6	4.6	Range 5–25	Range 4.4–7.7
Protein binding, %	Range 11–12	58	>99	99
CSF penetration (relative)	Good	Good	Poor	Poor
Urine concentration - active drug	Good	Poor	Poor	Poor
Metabolism (primary route)	Minor hepatic (predominately renally eliminated)	Hepatic	Hepatic	Hepatic
Elimination (primary route)	Renal	Renal	Fecal	Fecal
Half-life, hours	31	6	Range 25–35	Range 56–104

Notes:

a Decreased when administered with food;

b oral tablets have higher bioavailability than oral suspension.

Abbreviation: CSF, cerebrospinal fluid.

Table 3 Comparative inhibition of selected CYP450 isoenzymes by triazoles

Azole	CYP2C8	CYP2C9	CYP2C19	CYP3A4
Fluconazole	++	++	+	++
Itraconazole	+	+	−	+++
Voriconazole	++	++	+++	++
Posaconazole	−	−	−	+++
Isavuconazole	−	−	−	+/++

Notes: −, no inhibition; +, mild inhibition; ++, moderate inhibition; +++, strong inhibition. Data from references.^12,52,53

Table 4 Selected drug–drug interactions with isavuconazole

Medication	Clinical significance
Ketoconazole	• Isavuconazole’s AUC increases by ~5-fold when administered with concomitant ketoconazole
	• Use with strong CYP3A4 inhibitors is contraindicated
Rifampin	• Isavuconazole’s AUC decreases by ~2-fold with concomitant rifampin
	• Use with strong CYP3A4 inducers is contraindicated
Lopinavir/ritonavir	•Isavuconazole’s AUC increases by ~2-fold with concomitant lopinavir/ritonavir
	• Use with caution
Sirolimus, tacrolimus, cyclosporine, and mycophenolate mofetil	• Isavuconazole increases the AUC of sirolimus and tacrolimus by ~2-fold, cyclosporine by ~1.25-fold, and mycophenolate mofetil by ~1.5-fold with concomitant administration
	• Use with caution, TDM of sirolimus, tacrolimus, and cyclosporine is recommended
	• 50% dose reduction of tacrolimus has been recommended
Atorvastatin, and digoxin	• Isavuconazole increases the AUC of these agents by ~1.25-fold with concomitant administration
	• Use with caution, TDM should be performed with digoxin
Midazolam	• Isavuconazole increases the AUC of midazolam by ~2-fold with concomitant administration
	• Use with caution

Note: Data from references.^12,44

Abbreviations: AUC, area under the time-concentration curve; TDM, therapeutic drug monitoring.

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