Pharmacokinetic profile of isavuconazole
Pharmacokinetic profile of isavuconazole
Predictable and consistent pharmacokinetic (PK) profile in adult patients1
Dose-proportional pharmacokinetics following administration of CRESEMBA1
- No significant association between area under the curve (AUC) or drug concentration and efficacy in patients treated for invasive aspergillosis in a controlled trial1
| Steady-state pharmacokinetic parameters of isavuconazole following administration of CRESEMBA 186 mg capsules1 | ||
|---|---|---|
| Parameter | CRESEMBA 2 capsules* (n=37) |
CRESEMBA 6 capsules* (n=32) |
| Cmax (mg/L) | ||
| Mean | 7.5 | 20.0 |
| SD | 1.9 | 3.6 |
| CV % | 25.2 | 17.9 |
| tmax (h) | ||
| Median | 3.0 | 4.0 |
| Range | 2.0–4.0 | 2.0–4.0 |
| AUC (mg•h/L) | ||
| Mean | 121.4 | 352.8 |
| SD | 35.8 | 72.0 |
| CV % | 29.5 | 20.4 |
*Each capsule contains the equivalent of 100 mg of isavuconazole.Cmax=maximum plasma concentration; CV=coefficient of variation; SD=standard deviation; Tmax=time to reach Cmax.
- Dose-proportional pharmacokinetics following PO administration of CRESEMBA® (isavuconazonium sulfate) capsules at doses up to the equivalent of 600 mg/day of isavuconazole (6 capsules)1
- Mean plasma half-life was 130 hours based on a population pharmacokinetics analysis of healthy subjects and patients in clinical trials1
- A single dose administration of two 186 mg CRESEMBA capsules and five 74.5 mg CRESEMBA capsules exhibited a mean (SD) Cmax and AUC of 3.3 (0.6) mg/L and 112.2 (30.3) mg·h/L, respectively, and 3.3 (0.6) mg/L and 118.0 (33.1) mg·h/L, respectively1
- No relevant pharmacokinetic differences between healthy subjects and patients with invasive fungal infections†2
†Based on a 2-compartment model developed using data from Phase 1 subjects and Phase 3 trial patients administered single and multiple, oral (PO) and intravenous (IV) doses of CRESEMBA.2
CRESEMBA offers bioequivalent IV and PO formulations1
Absorption1
- 98% absolute bioavailability following PO administration
- CRESEMBA can be taken with or without food
- Reaches Cmax 2–3 hours after single and multiple PO dosing
- Nasogastric (NG) tube administration provides exposure similar to the oral capsule
Distribution1
- Extensively distributed with a mean steady state volume of distribution of ~450 L
- Highly protein bound (>99%) predominantly to albumin
Metabolism1
- Isavuconazonium sulfate is rapidly hydrolyzed in blood to isavuconazole by esterases
- Isavuconazole is a substrate of cytochrome P450 enzymes 3A4 and 3A5
- In vivo studies indicate that CYP3A4, CYP3A5, and subsequently uridine diphosphate-glucuronosyltransferases (UGT) are involved in the metabolism of isavuconazole
Excretion1
-
Mean total radioactive dose of radio-labeled CRESEMBA (isavuconazonium sulfate)‡:
- 46.1% was recovered in the feces
- 45.5% was recovered in the urine
- Renal excretion of isavuconazole itself was <1% of the dose administered
‡Following PO administration in healthy volunteers.
No dose adjustments required in specific populations based on1:
-
Mild, moderate, or severe renal impairment, including end-stage renal disease
- Of the 403 patients who received CRESEMBA in the Phase 3 trials, 79 (20%) patients had an estimated glomerular filtration rate (GFR) <60 mL/min/1.73 m2
- CRESEMBA is not removed by hemodialysis
-
Mild to moderate hepatic impairment
- CRESEMBA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Monitoring for CRESEMBA-related adverse reactions is recommended when treating these patients
- Gender
Predictable pharmacokinetics in pediatric patients
§Estimated AUCss values of 15 mg/kg that were derived from existing values of pediatric patients that received 10 mg/kg of CRESEMBA for injection administered intravenously. ||CRESEMBA for injection administered intravenously. ¶CRESEMBA for injection administered intravenously or CRESEMBA capsules administered orally.
- The pharmacokinetics of isavuconazole were evaluated in two clinical studies (N = 73) in pediatric patients 1 to <18 years of age which included 28 patients with at least possible invasive aspergillosis or possible invasive mucormycosis1
Drug Interactions with CRESEMBA
Learn about the potential drug interactions with CRESEMBA and co-administered drugs.
Recommended Dosing for CRESEMBA
Review recommended dosing regimen for CRESEMBA injection and PO formulations.
IMPORTANT SAFETY INFORMATION AND USE OF CRESEMBA
CONTRAINDICATIONS
- CRESEMBA is contraindicated in persons with known hypersensitivity to isavuconazole
- Coadministration of strong CYP3A4 inhibitors, such as ketoconazole or high-dose ritonavir (400 mg every 12 hours), with CRESEMBA is contraindicated because strong CYP3A4 inhibitors can significantly increase the plasma concentration of isavuconazole
- Coadministration of strong CYP3A4 inducers, such as rifampin, carbamazepine, St. John’s wort, or long acting barbiturates with CRESEMBA is contraindicated because strong CYP3A4 inducers can significantly decrease the plasma concentration of isavuconazole
- CRESEMBA shortened the QTc interval in a concentration-related manner. CRESEMBA is contraindicated in patients with familial short QT syndrome
WARNINGS AND PRECAUTIONS
Hepatic Adverse Drug Reactions (e.g., elevations in ALT, AST, alkaline phosphatase, total bilirubin) have been reported in clinical trials and were generally reversible and did not require discontinuation of CRESEMBA. Cases of severe hepatic adverse drug reactions including hepatitis, cholestasis or hepatic failure including death have been reported in patients with serious underlying medical conditions (e.g., hematologic malignancy) during treatment with azole antifungal agents, including CRESEMBA. Evaluate liver tests at the start and during therapy. Monitor patients who develop liver abnormalities during CRESEMBA therapy for severe hepatic injury. Discontinue if clinical signs and symptoms consistent with liver disease develop that may be attributable to CRESEMBA.
Infusion-Related Reactions including hypotension, dyspnea, chills, dizziness, paresthesia, and hypoesthesia were reported during intravenous administration of CRESEMBA. Discontinue the infusion if these reactions occur.
Hypersensitivity Reactions: Anaphylactic reactions, with fatal outcome, have been reported during treatment with CRESEMBA. Serious skin reactions, such as Stevens Johnson syndrome, have been reported during treatment with other azole antifungal agents. Discontinue CRESEMBA if anaphylactic or serious skin reactions occur, and initiate supportive treatment as needed.
Embryo-Fetal Toxicity: During pregnancy, CRESEMBA may cause fetal harm when administered, and CRESEMBA should only be used if the potential benefit to the patient outweighs the risk to the fetus. Women who become pregnant while receiving CRESEMBA are encouraged to contact their physician.
Drug Interactions: Coadministration of CRESEMBA with strong CYP3A4 inhibitors such as ketoconazole or high-dose ritonavir and strong CYP3A4 inducers such as rifampin, carbamazepine, St. John’s Wort, or long acting barbiturates is contraindicated.
Drug Particulates: Following dilution, CRESEMBA intravenous formulation may form precipitate from the insoluble isavuconazole. Administer CRESEMBA through an in-line filter.
ADVERSE REACTIONS
In adult patients, the most frequently reported adverse reactions among CRESEMBA-treated patients were nausea (26%), vomiting (25%), diarrhea (22%), headache (17%), elevated liver chemistry tests (16%), hypokalemia (14%), constipation (13%), dyspnea (12%), cough (12%), peripheral edema (11%), and back pain (10%).
In adult patients, the adverse reactions which most often led to permanent discontinuation of CRESEMBA therapy during the clinical trials were confusional state (0.7%), acute renal failure (0.7%), increased blood bilirubin (0.5%), convulsion (0.5%), dyspnea (0.5%), epilepsy (0.5%), respiratory failure (0.5%), and vomiting (0.5%).
In pediatric patients, the most frequently reported adverse reactions were diarrhea (26%), abdominal pain (23%), vomiting (21%), elevated liver chemistry tests (18%), rash (14%), nausea (13%), pruritus (13%), and headache (12%).
In general, adverse reactions in pediatric patients (including serious adverse reactions and adverse reactions leading to permanent discontinuation of CRESEMBA) were similar to those reported in adults.
INDICATIONS AND USAGE
CRESEMBA (isavuconazonium sulfate) is an azole antifungal indicated for the treatment of invasive aspergillosis and invasive mucormycosis as follows:
- CRESEMBA for injection: adults and pediatric patients 1 year of age and older
- CRESEMBA capsules: adults and pediatric patients 6 years of age and older who weigh 16 kg and greater
Specimens for fungal culture and other relevant laboratory studies (including histopathology) to isolate and identify causative organism(s) should be obtained prior to initiating antifungal therapy. Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.
INDICATIONS AND USAGE
CRESEMBA (isavuconazonium sulfate) is an azole antifungal indicated for the treatment of invasive aspergillosis and invasive mucormycosis as follows:
- CRESEMBA for injection: adults and pediatric patients 1 year of age and older
- CRESEMBA capsules: adults and pediatric patients 6 years of age and older who weigh 16 kg and greater
Specimens for fungal culture and other relevant laboratory studies (including histopathology) to isolate and identify causative organism(s) should be obtained prior to initiating antifungal therapy. Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.
Please see full Prescribing Information for CRESEMBA (isavuconazonium sulfate).