Midostaurin

L01X - Other antineoplastic agents ATC L01XE39 Small molecule approved 2017 Oral First-in-class Natural product Orphan

JFDA label: Rydapt

Mechanism of Action

Inhibitor of Receptor-type tyrosine-protein kinase FLT3 — Tyrosine-protein kinase receptor FLT3 inhibitor; Inhibitor of Mast/stem cell growth factor receptor Kit — Stem cell growth factor receptor inhibitor; Inhibitor of Platelet-derived growth factor receptor — Platelet-derived growth factor receptor inhibitor; Inhibitor of Protein kinase C (PKC) — Protein kinase C (PKC) inhibitor; Inhibitor of Vascular endothelial growth factor receptor 2 — Vascular endothelial growth factor receptor 2 inhibitor

Target	Action	Gene / class
Mast/stem cell growth factor receptor Kit efficacy	INHIBITOR	KIT
Platelet-derived growth factor receptor efficacy	INHIBITOR
Protein kinase C (PKC) efficacy	INHIBITOR
Receptor-type tyrosine-protein kinase FLT3 efficacy	INHIBITOR	FLT3
Vascular endothelial growth factor receptor 2 efficacy	INHIBITOR	KDR

Indications

Approved

Acute myeloid leukemia, FLT3-positive
Mast cell leukemia
Systemic mastocytosis

Contraindications

Source: Lexicomp

Hypersensitivity to midostaurin or any component of the formulation Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (9)

Very Common Edema · prolonged Q-T interval on ECG

Common cardiac failure · hypertension · Hypotension · ischemia · myocardial infarction · pericardial effusion · thrombosis

Nervous system disorders (8)

Very Common dizziness · fatigue · Headache · insomnia

Common chills · Disturbance in attention · mental status changes · vertigo

Hepatobiliary disorders (4)

Very Common hyperbilirubinemia · increased serum alkaline phosphatase · Increased serum ALT · increased serum AST

Renal and urinary disorders (3)

Very Common Increased serum creatinine · renal insufficiency · Urinary tract infection

Blood and lymphatic system disorders (10)

Very Common anemia · Febrile neutropenia · leukopenia · lymphocytopenia · neutropenia · petechia · prolonged partial thromboplastin time · thrombocytopenia

Common Bruise · hematoma

Immune system disorders (1)

Common Hypersensitivity

Metabolism and nutrition disorders (13)

Very Common Hyperglycemia · hyperkalemia · hypernatremia · hyperuricemia · hypoalbuminemia · hypocalcemia · hypokalemia · hypomagnesemia · hyponatremia · hypophosphatemia · increased gamma-glutamyl transferase

Common hypercalcemia · Weight gain

Gastrointestinal disorders (12)

Very Common abdominal pain · constipation · diarrhea · gastrointestinal hemorrhage · hemorrhoids · increased serum amylase · increased serum lipase · mucositis · Nausea · vomiting

Common Dyspepsia · gastritis

Skin and subcutaneous tissue disorders (5)

Very Common Hyperhidrosis · skin rash

Common cellulitis · erysipelas · Xeroderma

Musculoskeletal and connective tissue disorders (3)

Very Common arthralgia · Musculoskeletal pain

Common Tremor

Eye disorders (1)

Common Eyelid edema

Infections and infestations (4)

Very Common Localized infection

Common fungal infection · Herpes virus infection · sepsis

General disorders and administration site conditions (1)

Very Common Fever

Respiratory, thoracic and mediastinal disorders (11)

Very Common cough · dyspnea · epistaxis · pleural effusion · Upper respiratory tract infection

Common bronchitis · interstitial pulmonary disease · oropharyngeal pain · Pneumonia · pneumonitis · pulmonary edema

Dosing

Source: Lexicomp

Note: Administer prophylactic antiemetics prior to midostaurin therapy. Acute myeloid leukemia (AML), FLT3-positive: Oral: 50 mg twice daily on days 8 to 21 of each induction cycle (in combination with daunorubicin and cytarabine) and on days 8 to 21 of each consolidation cycle (in combination with high-dose cytarabine) Mast cell leukemia: Oral: 100 mg twice daily until disease progression or unacceptable toxicity (Gotlib 2016) Systemic mastocytosis (aggressive systemic mastocytosis or systemic mastocytosis with associated hematological neoplasm): Oral: 100 mg twice daily until disease progression or unacceptable toxicity (Gotlib 2016) Missed doses: If a dose is missed or vomited, do not make up the dose; take the next dose at the usually scheduled time.

Refer to adult dosing.

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling; however, the pharmacokinetics of midostaurin and active metabolites were not significantly altered. CrCl 15 to 29 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Mild (total bilirubin >1 to 1.5 times ULN or AST > ULN) or moderate (total bilirubin 1.5 to 3 times ULN and any AST) impairment: There are no dosage adjustments provided in the manufacturer's labeling; however, the pharmacokinetics of midostaurin and active metabolites were not significantly altered. Severe impairment (total bilirubin >3 times ULN and any AST): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Warnings & Precautions

Source: Lexicomp

Bone marrow suppression

Lymphopenia, leukopenia, neutropenia, thrombocytopenia and anemia have been commonly observed in patients with systemic mastocytosis. Although the incidence of hematologic toxicity in acute myeloid leukemia (AML) may be confounded by concomitant chemotherapy, febrile neutropenia was reported at a slightly higher incidence in patients with AML receiving chemotherapy plus midostaurin (compared to chemotherapy plus placebo). Monitor blood counts.

GI toxicity

Nausea and vomiting commonly occur; premedicate with antiemetics prior to administration. Diarrhea, abdominal pain, and constipation also occur frequently. Mucositis has also been reported. · ·

Hypersensitivity

Hypersensitivity reactions, including anaphylactic shock, angioedema, dyspnea, chest pain and flushing have been observed.

Pulmonary toxicity

Interstitial lung disease and pneumonitis have been reported with midostaurin (either as monotherapy or in combination with other chemotherapy), some cases have been fatal. Monitor for pulmonary symptoms; discontinue in patients who develop signs/symptoms of interstitial lung disease or pneumonitis (without an infectious etiology). Concurrent drug therapy issues:

Drug-drug/drug-food interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Other warnings/precautions:

FLT3 mutation positivity

In the treatment of acute myeloid leukemia, midostaurin is approved for use only in patients who are FLT3 mutation-positive (as detected by an approved test).

Pregnancy & Lactation

Pregnancy

Adverse events were observed in animal reproduction studies with doses providing less than the human exposure at the recommended dose based on AUC. Based on the mechanism of action, midostaurin may cause fetal harm if used in pregnant women. Pregnancy status should be verified within 7 days prior to therapy initiation. Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during therapy and for at least 4 months after the last dose. Based on animal data, treatment with midostaurin may impair fertility in males and females.

Lactation

Avoid

It is not known if midostaurin is present in breast milk. Due to the potential for adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for at least 4 months after the last dose.

Monitoring

Clinical pearl	FLT3 mutation status (in AML); CBC with differential (in patients with systemic mastocytosis: at least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter or as clinically indicated); pregnancy status within 7 days of therapy initiation in women of reproductive potential; signs/symptoms of pulmonary toxicity (interstitial lung disease and pneumonitis); consider ECG for QT interval assessment in patients on concurrent medications that may prolong the QT interval.

Clinical pearl

FLT3 mutation status (in AML); CBC with differential (in patients with systemic mastocytosis: at least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter or as clinically indicated); pregnancy status within 7 days of therapy initiation in women of reproductive potential; signs/symptoms of pulmonary toxicity (interstitial lung disease and pneumonitis); consider ECG for QT interval assessment in patients on concurrent medications that may prolong the QT interval.

Chemistry & Properties

Formula	C35H30N4O4
Molecular weight	570.65 g/mol
IUPAC name	N-[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-N-methylbenzamide
CAS	120685-11-2
PubChem CID	9829523
InChIKey	`BMGQWWVMWDBQGC-IIFHNQTCSA-N`
logP	5.91 (XLogP 4.8)
Polar surface area	77.73 Å²
H-bond acceptors / donors	6 / 1
Drug-likeness (QED)	0.29
Lipinski violations	2

SMILES

CO[C@@H]1[C@H](N(C)C(=O)c2ccccc2)C[C@H]2O[C@]1(C)n1c3ccccc3c3c4c(c5c6ccccc6n2c5c31)C(=O)NC4

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	0.947 h
Volume of distribution	1.625 L/kg
Protein binding	99.1%
BBB penetrant	Yes

Enzyme interactions

Enzyme	Role	Detail
CYP2B6	Inhibitor	—
CYP2C19	Inhibitor	—
CYP2C19	Substrate	—
CYP2C8	Inhibitor	—
CYP2C9	Inhibitor	—
CYP3A4	Inhibitor	—
CYP3A4	Substrate	—

Receptor binding (top 4)

Target	Action	Affinity
fms related receptor tyrosine kinase 3 (FLT3)	Inhibitor	pKd 8.0
fms related receptor tyrosine kinase 3 (FLT3)	Inhibitor	pIC50 6.3
large tumor suppressor kinase 1 (LATS1)	Inhibitor	pKd 6.0
large tumor suppressor kinase 2 (LATS2)	Inhibitor	pKd 5.7

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OAT1 (Inhibitor)OAT3 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)MDR1 (Substrate)MRP2 (Substrate)P-gp (Substrate)Transporter(unspecified) (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Adalimumab	major
Amiodarone	major
Amisulpride	major
Anagrelide	major
Apalutamide	major
Arsenic trioxide	major
Atazanavir	major
Bacillus calmette-guerin substrain tice live antigen	major
Baricitinib	major
Bedaquiline	major
Bepridil	major
Boceprevir	major
Cabozantinib	major
Carbamazepine	major
Ceritinib	major
Certolizumab pegol	major
Chloroquine	major
Cisapride	major
Citalopram	major
Cladribine	major
Clarithromycin	major
Clozapine	major
Cobicistat	major
Colchicine	major
Conivaptan	major
Crizotinib	major
Deferiprone	major
Delavirdine	major
Disopyramide	major
Dofetilide	major
Dolasetron	major
Dronedarone	major
Droperidol	major
Edoxaban	major
Enzalutamide	major
Escitalopram	major
Etanercept	major
Fingolimod	major
Fosphenytoin	major
Gatifloxacin	major

Showing 40 of 100+.

Registered Products (2)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Rydapt	Capsule 25 mg	112 cap pack varies	The Jordan Drugstore Co	—
Rydapt	Capsule 25 mg	56 cap pack varies	The Jordan Drugstore Co	—