Pharmacological interactions of isavuconazole

Abstract

The interactions between the various drugs a patient receives at any given time are crucial for justifying treatments, especially considering the often severe adverse effects associated with them. These interactions are particularly significant for azole antifungals, such as voriconazole, fluconazole, posaconazole, and itraconazole. The most recently marketed azole, isavuconazole, stands out due to its lower inhibitory effect on various CYP450 enzymes and transport proteins. While it can induce some isoenzymes of the CYP450 superfamily, its impact is minimal. As a result, we can conclude that its interactions with other drugs are less pronounced, which reduces the need for treatment adjustments or dose modifications. Additionally, isavuconazole boasts high oral bioavailability, an extensive volume of distribution, and a notably long elimination half-life. A significant side effect common to all azoles, but not associated with isavuconazole, is the prolongation of the QTc interval, which can sometimes lead to the risk of Torsades de Pointes. These advantages make isavuconazole the preferred antifungal choice for patients on multiple medications.

Resumen

Las interacciones entre los distintos fármacos que recibe un paciente en un momento dado son cruciales para justificar los tratamientos, sobre todo teniendo en cuenta los efectos adversos, a menudo graves, que se asocian a ellos. Estas interacciones son especialmente significativas en el caso de los antifúngicos azólicos, como el voriconazol, el fluconazol, el posaconazol y el itraconazol. El azol comercializado más recientemente, el isavuconazol, destaca por su menor efecto inhibidor sobre diversas enzimas CYP450 y proteínas transportadoras. Aunque puede inducir algunas isoenzimas de la superfamilia CYP450, su impacto es mínimo. Como resultado, podemos concluir que sus interacciones con otros fármacos son menos pronunciadas, lo que reduce la necesidad de ajustar el tratamiento o modificar la dosis. Además, el isavuconazol presenta una elevada biodisponibilidad oral, un amplio volumen de distribución y una semivida de eliminación notablemente larga. Un efecto secundario importante común a todos los azoles, pero no asociado al isavuconazol, es la prolongación del intervalo QTc, que a veces puede provocar riesgo de torsades de pointes. Estas ventajas hacen del isavuconazol el antifúngico preferido para los pacientes que toman varios medicamentos.

The antifungal drugs belonging to the large group of azoles have several important features to consider in healthcare practice. One of the most significant is their ability to inhibit the activity of certain CYP450 isoenzymes and transport proteins, a characteristic shared by many azole compounds. Additionally, there is a potential risk of prolonging the QTc interval, which can lead to significant drug interactions. This is particularly concerning because it often results in increased concentrations of the drug whose metabolism or transport is being inhibited. Nevertheless, the degree of interaction among the azole compounds varies, with voriconazole and fluconazole demonstrating a stronger interaction as they inhibit CYP2C9, CYP2C19, and CYP3A4.^3,22 In contrast, posaconazole¹⁴ and itraconazole⁸ exhibit a significant inhibitory effect, particularly against CYP3A4 and P-glycoprotein (P-gp). Finally, isavuconazole, which is the antifungal of interest in this review, is notable for its lower inhibitory potential, resulting in fewer interactions with other drugs.¹

Isavuconazole drug interactions

Isavuconazole is a moderate inhibitor of the CYP3A4/5 isoenzyme, with a slight induction of CYP2B6 activity. It also has a mild inhibitory effect on P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic cation transporter (OCT2), and uridine glucuronosyltransferase (UGT¹). Additionally, it is a substrate for CYP3A4, CYP2B6, and P-gp.¹ The moderate inhibition of CYP3A4, combined with the mild effects on other enzymes, suggests that isavuconazole is associated with a lower incidence and severity of drug interactions compared to other azoles with stronger inhibitory effects.

1

Anxiolytics

Midazolam is a substrate of CYP3A4/5, and when used in conjunction with isavuconazole, it results in an increase in the area under the curve (AUC) and maximum concentration (Cmax) by 103% and 72%, respectively. It is essential to closely monitor clinical signs and symptoms, and a dose reduction is recommended if necessary.^1,17

2

Anticoagulants

2.1

Dabigatran

The concentrations of dabigatran etexilate may rise due to the inhibition of P-gp. Therefore, monitoring is recommended, and if necessary, the dose of the anticoagulant should be adjusted. However, this adjustment is unlikely to be needed, considering the limited extent of P-gp inhibition caused by isavuconazole.¹

2.2

Warfarin

The coadministration of warfarin, a substrate of CYP2C9, with isavuconazole results in an increase in the AUC of S-warfarin by 11% and R-warfarin by 20%. This indicates that there is no significant interaction between warfarin and isavuconazole, and therefore, no dose adjustment is necessary.^1,2

3

Oral contraceptives

Ethinyl estradiol and norethisterone are substrates of CYP3A4/5. When coadministered with isavuconazole, the AUC and Cmax of ethinyl estradiol increase by 8% and 14%, respectively, while norethisterone experiences increases of 16% and 6%. No dose adjustment is necessary.^1,17

4

Antidepressants

Bupropion is a substrate of CYP2B6. When administered along with isavuconazole, a reduction in the AUC and Cmax of 42% and 31%, respectively, were reported. Therefore, it may be necessary to increase the dose of bupropion.^1,23

5

Antidiabetics

5.1

Metformin

The AUC and Cmax of metformin increase by 52% and 23%, respectively, when coadministered with isavuconazole, due to the inhibition of the organic anion transport protein (OAT2). If needed, the dose of metformin may be reduced.^1,24

5.2

Pioglitazone

Pioglitazone is a mild inducer of CYP3A4/5, which may lead to decreased concentrations of isavuconazole. Coadministration should be avoided unless the potential benefits outweigh the risks.¹

5.3

Repaglinide

Repaglinide is a substrate of both CYP2C8 and the organic anion transporter protein OATP1B1. It has been reported that the AUC and Cmax of this diabetes medication can decrease by 8% and 14%, respectively. However, no dose adjustment is necessary.^1,23

6

Antiemetics

Aprepitant is a mild inducer of CYP3A4/5. When taken alongside isavuconazole, the concentration of isavuconazole may be reduced. Therefore, coadministration should be avoided unless the potential benefits outweigh the risks.¹

7

Antiepileptics

Carbamazepine, phenobarbital, and phenytoin are potent inducers of CYP3A4/5, which may lead to reduced concentrations of isavuconazole. Therefore, the concurrent use of isavuconazole with these antiepileptic medications is contraindicated.¹

8

Antihyperuricemics

Colchicine is a substrate of P-gp, which means that its concentration may increase when used in conjunction with isavuconazole. Given that colchicine has a narrow therapeutic index, it is important to monitor its levels and, if necessary, adjust the dosage accordingly.¹

9

Anti-infectives

9.1

Antiretrovirals

Efavirenz is a potent inducer of CYP3A4, and its combination with isavuconazole is contraindicated, as it may reduce the concentration of the antifungal.¹

Etravirine is a moderate inducer of CYP3A4/5 and also acts as a substrate for CYP2B6, which may lead to decreased levels of etravirine.¹

Indinavir, on the other hand, is a strong inhibitor and substrate of CYP3A4/5. Reports indicate a reduction of 36% in Cmax and 52% in AUC for indinavir, although no dose adjustment is necessary.¹ The concentrations of protease inhibitors may either decrease (as observed with lopinavir/ritonavir) or increase, so careful monitoring is essential to prevent drug toxicity.¹

Nevirapine acts as both an inducer and substrate of CYP3A4/5 and CYP2B6, which can lead to fluctuations in the concentrations of non-analog TI inhibitors. Therefore, careful monitoring is essential to prevent drug toxicity.¹

When administered together, the combination of lopinavir 400 mg and ritonavir 100 mg – both strong inhibitors and substrates of CYP3A4/5 – does not require dose adjustment with isavuconazole. However, reductions in Cmax and AUC have been observed, with decreases of 23% and 27% for lopinavir, and 33% and 31% for ritonavir, respectively. While no dose adjustment is necessary, it is advisable to conduct therapeutic drug monitoring to identify any potential lack of antiviral efficacy.¹

Administering ritonavir at doses exceeding 200 mg per day can significantly lower isavuconazole concentrations, making doses of 200 mg or higher contraindicated.¹ However, coadministering letermovir with isavuconazole does not result in any change to the concentrations of either medication.¹⁶ Therefore, their combined use can be safely considered without special precautions.

9.2

Clarithromycin

This antibiotic is a strong inhibitor of CYP3A4/5, which can lead to increased levels of isavuconazole. While dose adjustment of isavuconazole is not required, it is important to proceed with caution, as the risk of adverse reactions to the drug may be increased.¹

9.3

Flucloxacillin

In a patient receiving both flucloxacillin and isavuconazole simultaneously, the concentration of isavuconazole was found to be below 1 mg/L. Therefore, it is advisable to consider increasing the dose of isavuconazole and to monitor its plasma concentration.^20,21

9.4

Ketoconazole

Ketoconazole is a strong inhibitor of CYP3A4/5 activity. It has been reported to increase the Cmax and AUC of isavuconazole by 9% and 422%, respectively. Therefore, the concurrent use of isavuconazole and ketoconazole is contraindicated.^1,17

9.5

Nafcillin

Nafcillin is a moderate inducer of CYP3A4/5, which may significantly reduce the concentrations of isavuconazole. Thus, the concurrent use of isavuconazole and nafcillin is contraindicated.¹

9.6

Rifampicin

Rifampicin is a potent inducer of CYP3A4/5, capable of reducing the AUC and Cmax of isavuconazole by 90% and 75%, respectively. Therefore, the concurrent use of isavuconazole and rifampicin is contraindicated.^1,17

While it has been noted that less potent CYP3A4 inducers than rifampicin may be used in conjunction with isavuconazole in patients with diminished CYP3A5 activity (CYP3A53/3), it is important to know that may result in a substantial decline in isavuconazole plasma concentrations. Consequently, extreme caution is advised.

9.7

Rifabutin

Rifabutin is also a potent inducer of CYP3A4/5, which may significantly reduce the concentrations of isavuconazole. Consequently, their concomitant administration is contraindicated.¹

10

Antineoplastic agents

10.1

Vinca alkaloids (vincriste, vinblastine)

Vinca alkaloids are substrates for P-gp and likely for CYP3A4 as well. When administered together with isavuconazole, the concentration of vinca alkaloids may increase. It is important to closely monitor any instance of drug toxicity, and, if needed, the dose of vinca alkaloids can be reduced.¹

10.2

Cyclophosphamide

This antineoplastic agent is a substrate of CYP2B6. Since its concentration may decrease when coadministered with isavuconazole, it is advisable to proceed with caution and monitor its efficacy closely.¹

10.3

Methotrexate

Methotrexate is a substrate for BCRP; OAT1 and OAT3 reduce the Cmax and AUC of methotrexate by 11% and 3%, respectively. Additionally, they slightly increase the concentration of its metabolite, 7-hydroxymetabolite, by 15–29%. No dose adjustment is necessary.^1,24

Other antineoplastic agents are daunorubicin, doxorubicin, imatinib, irinotecan, lapatinib, mitoxantrone, and topotecan, all substrates of BCRP. As a result, the concentrations of these drugs may increase. It is important to closely monitor for drug toxicity and consider dose reduction if necessary.¹ Tyrosine kinase inhibitors, which include but are not limited to axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, and ribociclib, may be affected by isavuconazole. Although not specifically studied, isavuconazole could potentially increase the plasma concentrations of tyrosine kinase inhibitors that are metabolized by CYP3A4. If the concurrent use of these medications is unavoidable, it is advisable to reduce the dose of the tyrosine kinase inhibitor and to conduct close clinical monitoring.¹

11

Antitussives

Dextromethorphan is a substrate of CYP2D6. It has been reported that there is an increase of 18% in Cmax and 17% in AUC. No dose adjustment is necessary.^1,23

12

Anti-ulcers

Esomeprazole is a substrate of CYP2C19 and acts as a gastric pH reducer. There is no risk of interaction with isavuconazole.¹ Similarly, omeprazole is also a substrate of CYP2C19 and reduces gastric pH. It has been reported that omeprazole's AUC and Cmax are reduced by 11% and 23%, respectively. No dose adjustment is required for either isavuconazole or omeprazole.¹

13

Cardiovascular drugs

Digoxin is a substrate of P-gp, and the presence of isavuconazole increases the Cmax of digoxin by 33% and the AUC by 25%. While the risk of toxicity is minimal, it is important to monitor serum digoxin concentrations for appropriate dose adjustments.^1,24

14

Corticosteroids

Prednisone acts as both a substrate and a moderate inducer of CYP3A4/5. Increases in the AUC and Cmax of prednisolone, the active metabolite of prednisone, have been reported at 8% and 4%, respectively. Additionally, isavuconazole concentrations may decrease. Exercise caution when coadministering these medications unless the potential benefits outweigh the risks.^1,5

15

Immunosuppressants

Isavuconazole leads to an increase in the Cmax and AUC of cyclosporine by 6% and 29%, respectively.^1,5 Generally, no dose adjustment is required; however, monitoring of plasma levels is recommended.¹

Additionally, isavuconazole increases the Cmax and AUC of tacrolimus by 40% and 65%, respectively.^{5,6,10–12,15,19} There is no consensus on whether an empirical reduction in the immunosuppressant dose is necessary. Some authors argue that it is not needed,¹¹ while others suggest reducing the initial dose by factors of 1.3 times,¹⁵ 18%,⁷ or 21%.⁴ While an initial dose adjustment may not be necessary, monitoring plasma concentration is advisable.¹

Mycophenolate mofetil (MMF) is a substrate of UGT and is slightly inhibited by isavuconazole. As a result, the Cmax and AUC of the immunosuppressant increase by 11% and 35%, respectively. There is no need to adjust the dose of isavuconazole; however, it is recommended to monitor for potential MMF-related toxicity.^1,5

The bioavailability of sirolimus increased when combined with isavuconazole treatment.⁵ During the first week of concurrent treatment with isavuconazole, the concentration-to-dose ratio of sirolimus rose by 1.56-fold, which was statistically significant.¹⁰ While an initial dose adjustment may not be necessary, monitoring plasma concentration could be important.¹

16

Anti-lipids

Atorvastatin, simvastatin, lovastatin, and rosuvastatin are substrates of CYP3A4. Increases in the Cmax and AUC of atorvastatin have been reported, with increases of 3% and 37%, respectively. No dose adjustment is required.^1,24

17

Opioids

Fentanyl and its derivatives, alfentanil and sufentanil, are substrates of CYP3A4/5. Therefore, an increase in opioid concentrations may occur, necessitating careful monitoring for any sign of drug toxicity, especially if a dose reduction is required.¹

Methadone is a substrate of CYP3A4/5, 2B6, and 2C9. A 35% reduction in AUC and a 1% increase in Cmax of the S isomer have been observed, although it is inactive. No dose adjustment for methadone is necessary.^1,23

18

Other situations

Caffeine is a substrate of CYP1A2. The increase in Cmax and AUC when combined with isavuconazole is minimal, at 4% and 1% respectively, so no dose adjustment is necessary.^1,23 However, St. John's wort is a strong inducer of CYP3A4/5, which may significantly reduce isavuconazole concentrations. Therefore, the concurrent use of isavuconazole and St. John's wort is contraindicated.¹

Regarding QT interval, isavuconazole does not prolong it; instead, it actually shortens it.^10,13 As a result, it is contraindicated in patients with familial short QT syndrome, but not in those with long QT syndrome. In a study examining QT syndrome in healthy human subjects, isavuconazole was found to shorten the QTc interval in a concentration-dependent manner.¹ For the 200 mg dosage regimen, the mean difference from placebo was 13.1 ms, measured 2 h after dosing [90% CI: 17.1, 9.1 ms]. When the dose was increased to 600 mg, the difference from placebo rose to 24.6 ms, also measured 2 h post-dosing [90% CI: 28.7, 20.4 ms].¹ This unique characteristic, unlike that of other azoles, means that isavuconazole is not contraindicated in situations that may lead to QT prolongation, thus eliminating the risk of Torsades de Pointes. In fact, it has been used safely in such contexts.^9,13,18 Any of the drugs listed in Table 1 can be administered without special precautions, which clearly sets isavuconazole apart from other azole medications.

Table 1.

Medications and QT prolongation.

Drugs	At risk of prolonging QT	With possible risk of QT prolongation	At risk only under certain circumstances*
Anesthetics	PropofolSevoflurane
Anxiolytics	CitalopramEscitalopram
Anticholinesterases	Donepezil		Galantemine
Antidepressants	AgomelatineMaprotiline	ClomipramineImipramineMirtazapineNortriptilineSertralineTrimipramineVenlafaxine	AmitriptilineDoxepinFluoxetineFluvoxamineParoxetineSertralineTrazodone
Anti-infectives	AzitromyicinChloroquineClarithromycinCiprofloxacinDarunavirSpiramycineErithromycineFluconazoleLevofloxacinLopinavirMoxifloxacinPentamidineRoxitrromycine	EfavirenzNorfloxacinOfloxacinRilpivirineSaquinavir	AmantadineAmphotericin BAtazanavirKetoconazoleMetronidazoleHidroxichloroquineItraconazolePosaconazoleRitonavirTelithromycinVoriconazole
Antihistamines	DesloratadineEbastineMizolastineMequitazideRupatadine		Diphenhydramine
Antineoplastics	AnagrelideArsenato trioxideOxaliplatinVinflunine	BedamustineBortezomibCapecitabineCrizotinibDabrafenibDasatinibDegarelixErbulineFingolimodLapatinibLevantinibLeuprorelineNilotinibPazopanibSorafenibSunitinibTamoxifenVemurafenib
Antipsychotics	HaloperidolChlorpromazineFluphenazineLevomepromazinePimozideSulpiride	AsenapineAripiprazoleFlupentixolClozapineRisperidonePaliperidonePerphenazineSertindoleTiaprideZiprasidone	AmisulprideOlanzapineQuetiapine
Bronchodilators	BambuterolFormoterolIndacaterolSalbutamolSalmeterolTerbutaline
Cardiovascular	AdenosineAmiodaroneCilostazolDisoporamideDronedaroneFlecainideProcainamideQuinidineSotalol	Nicardipine	IvravadinRanolazine
Digestive	DomperidoneLevosulprideOndansetronPalonosentronPrucalopride	FamotidineGranisetron	LansopazoleEsomeprazoleLoperamideMetoclopramideOmeprazolePantoprazole
Diuretics			BendreflumethazineIndapamideFurosemideHydrochlorothiazideTorasemide
Genitourinary	AlfuzosinFesoterodineSildenafilTadalafinTrospium	MifepristoneMirabegronTolterodineVardalafil	Solifenacin
Hormones	Terlipressin
Immunosuppressants		Tacrolimus
Opioids	Methadone	Buprenorphine
Others	LithiumHydroxyzine	AtomoxetinePromethazineRetigabine	Tizanidine

*

QT prolongation in special circumstances: high dose, inhibition of metabolism, sum of effects.

In conclusion, isavuconazole offers a favorable interaction profile compared to other azole antifungals. It demonstrates a capacity to modify various transporter proteins and CYP450 isoenzymes to a lesser extent than its counterparts, making it a viable option when other drugs within this antifunfal class may pose challenges.

Funding

The publication of this article has been funded by Pfizer. Pfizer has neither taken part, nor intervened in the content of this article.

Conflict of interest

The author has collaborated in consulting tasks with the following companies: Andrómaco, Angelini, Astellas, Astra Zeneca, Baxter, Boehringer, Bial, Biogen, Bioibérica, Cassen, Cinfa, Eisai, Esteve, Ferrer, Geiser, GSK, Gilead, Idifarma, Leo, Menarini, MSD, Merck, Norgine, Novartis, Nycomed, Ojer, Pfizer, Recordati, Robi, Roche, Sanofi, Seagen, Shionogi, UCB, Zambon.