Clinical Pharmacokinetics and Pharmacodynamics of Isavuconazole

McCarthy, Matthew W; Moriyama, Brad; Petraitienė, Rūta; Walsh, Thomas J.; Petraitis, Vidmantas

doi:10.1007/s40262-018-0673-2

Cited by 35 publications

(35 citation statements)

References 55 publications

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“…The reason for the lower clearance in Asians has not been established, although it is unlikely to be due to CYP2D6 or CYP2C19, as ISAV is not a substrate for either isoenzyme (16). It may be related to allelic polymorphisms in CYP3A4 and CYP3A5, which previously were not considered to be active in altered drug metabolism (32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients

Arrieta

Neely

Day

et al. 2021

Antimicrob Agents Chemother

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Isavuconazole, administered as the water-soluble prodrug isavuconazonium sulfate, is a new triazole agent used to treat invasive fungal infections. This phase 1 study evaluated the pharmacokinetics (PK), safety, and tolerability of isavuconazole in 46 immunocompromised pediatric patients, stratified by age (1 to <6 [intravenous (IV) only], 6 to <12, and 12 to <18 years), receiving 10 mg/kg (maximum 372 mg) isavuconazonium sulfate either IV or orally. A population PK model using weight-based allometric scaling was constructed with the pediatric IV and oral data plus IV data from a phase 1 study in adults. The best model was a 3-compartment model with combined zero-order and first-order input, with linear elimination. Stepwise covariate modeling was performed in Perl-speaks-NONMEM, version 4.7.0. None of the covariates examined, including age, sex, race, and body mass index, were statistically significant for any of the PK parameters. The area under the concentration–time curve at steady state (AUCSS) was predicted for pediatric patients using 1000 Monte Carlo simulations per age cohort for each administration route. The probability of target attainment (AUCSS range 60–233 μg·h/mL) was estimated; this target range was derived from plasma drug exposures in adults receiving the recommended clinical dose. Predicted plasma drug exposures were within the target range for >80% and >76% of simulated pediatric patients following IV or oral administration, respectively. IV and oral administration of isavuconazonium sulfate at the studied dosage of 10 mg/kg was well tolerated and resulted in exposure in pediatric patients similar to that in adults.

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Section: Discussionmentioning

confidence: 99%

Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients

Arrieta

Neely

Day

et al. 2021

Antimicrob Agents Chemother

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“…Gerade mit Blick auf Immunsuppressiva wie Tacrolimus oder Sirolimus weisen aktuelle Daten darauf hin, dass eine Dosisanpassung dieser Substanzen unter Therapie mit Isavuconazol nicht unbedingt notwendig ist. Es scheint unter Isavuconazol nur zu einem kurzfristigen Anstieg der Plasmakonzentrationen von Tacrolimus oder Sirolimus zu kommen, die dann aber auf normale Werte sinken [100,101]. Routinemäßige Spiegelbestimmungen sind also nicht notwendig.…”

Section: Isavuconazolunclassified

Pilzinfektionen in der Intensivmedizin

Richter¹,

Lichtenstern²,

Brinkmann³

et al. 2021

Krankenhaushygiene up2date

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“…33 In contrast, fluconazole and isavuconazole are more water-soluble. 34,35 Moreover, the systemic azoles are substrates and inhibitors of CYP isoforms to various degrees. [36][37][38] Some azoles are also substrates and/or inhibitors of drug transporters.…”

Section: Isavuconazolementioning

confidence: 99%

Antifungal Therapy: New and Evolving Therapies

Nivoix

Ledoux

Herbrecht

2020

Semin Respir Crit Care Med

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Invasive fungal diseases primarily occur in immunocompromised patients. Immunosuppression has become more prevalent due to novel treatments, and this has led to a rise in the incidence of invasive fungal diseases. The antifungal armamentarium has long been insufficient and has taken quite some time to become diverse. Antifungal spectrum, tolerability, and toxicity are critical issues. Amphotericin B and its lipid formulations still have the widest spectrum, but, in spite of the better tolerance of the lipid formulations, toxicity remains a drawback, mostly with regard to renal function. Azoles constitute a heterogeneous antifungal class, in which newer molecules have an improved spectrum of activity. The main concern for the clinician when using azoles relates to the management of their many potential drug–drug interactions in an often fragile patient population. Echinocandins are better tolerated but possess a narrower antifungal spectrum and lack an oral route of administration. Still, their fungicidal activity makes them a weapon of first choice against Candida species. For certain uncommon fungal infections, antifungals such as flucytosine and terbinafine can also be useful. This article will give an overview of the mechanisms of action of currently used antifungals, as well as their spectrum of activity, clinically relevant pharmacological features, drug–drug interactions, and frequent side effects, all of which should drive the clinician's choice of agent when managing invasive fungal infections.

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Clinical Pharmacokinetics and Pharmacodynamics of Isavuconazole

Cited by 35 publications

References 55 publications

Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients

Safety, Tolerability, and Population Pharmacokinetics of Intravenous and Oral Isavuconazonium Sulfate in Pediatric Patients

Pilzinfektionen in der Intensivmedizin

Antifungal Therapy: New and Evolving Therapies

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