Gilteritinib

Gilteritinib (as fumarate) is an inhibitor of the receptor tyrosine kinases FLT3 and AXL. FLT3 is frequently mutated in acute myeloid leukaemia: internal tandem duplications (ITD) and tyrosine kinase domain (TKD) mutations keep the receptor switched on and drive the growth of leukaemic cells. Roughly 30% of patients with AML carry an activated FLT3, and the ITD form is associated with a poorer outcome. Gilteritinib is active against both ITD and TKD mutations.

Mechanism of Action

• FLT3 inhibition: gilteritinib inhibits FLT3 receptor signalling and proliferation in cells expressing FLT3, including FLT3-ITD, FLT3-D835Y and FLT3-ITD-D835Y. It also blocks phosphorylation of FLT3 and of downstream signalling proteins such as STAT5, ERK and AKT.
• Cell death: it induces apoptosis in leukaemic cells that express FLT3-ITD.
• AXL inhibition: AXL is a related receptor kinase that can modulate FLT3 activity in AML and is linked to resistance to treatment. Laboratory data also show inhibition of ALK.
• Effect in patients: in patients with relapsed or refractory AML taking 120 mg, FLT3 phosphorylation was inhibited by more than 90% within 24 hours of the first dose, and the inhibition was sustained (measured with an ex vivo plasma inhibitory activity assay).
• Cardiac electrophysiology: the QTcF interval rose in a concentration-related way across doses of 20 to 450 mg. At the mean steady-state peak concentration for 120 mg daily (282.0 ng/mL), the predicted mean change from baseline was 4.96 ms (upper 1-sided 95% confidence limit 6.20 ms).

Pharmacokinetics

• Absorption: the median time to peak concentration is about 4 to 6 hours in healthy volunteers and in patients. Absorption is first-order, with an absorption rate constant of 0.43 per hour and a lag time of 0.34 hours (population modelling). At 120 mg once daily, the median steady-state Cmax is 282.0 ng/mL and the AUC over 24 hours is 6,180 ng·h/mL. Steady state is reached within 15 days, with about 10-fold accumulation. A high-fat meal lowered Cmax by about 26% and AUC by less than 10% and delayed the median time to peak by 2 hours (single 40 mg dose in healthy adults).
• Distribution: the central and peripheral volumes of distribution are about 1,092 L and 1,100 L, so gilteritinib distributes extensively outside the plasma. Protein binding in humans is about 90%, mainly to albumin.
• Metabolism: mainly by CYP3A4 (in vitro data). The main human metabolites are M17 (formed by N-dealkylation and oxidation), and M16 and M10 (both formed by N-dealkylation); none exceeds 10% of the exposure to the parent drug, and their activity against FLT3 and AXL is unknown. Gilteritinib is a substrate of P-gp and BCRP in vitro.
• Elimination: after a single dose of radiolabelled gilteritinib, 64.5% of the dose was recovered in the faeces and about 16.4% in the urine as unchanged drug and metabolites. Plasma concentrations fall in two phases, with a population mean half-life of about 113 hours.
• Special populations: no dose adjustment is needed in patients aged 65 or over, or in mild or moderate hepatic impairment. Exposure may be higher in severe renal impairment or end-stage renal disease.

• Relapsed or refractory AML: Xospata is indicated as monotherapy for adults who have relapsed or refractory acute myeloid leukaemia (AML) with a FLT3 mutation. The mutation (ITD or TKD) must be confirmed with a validated test before treatment.

• Hypersensitivity to gilteritinib or to any of the excipients.

The safety of Xospata was evaluated in 319 patients with relapsed or refractory AML who had received at least one 120 mg dose. The most frequent reactions were raised ALT (82.1%), raised AST (80.6%), raised blood alkaline phosphatase (68.7%), raised blood creatine phosphokinase (53.9%), diarrhoea (35.1%), fatigue (30.4%), nausea (29.8%), constipation (28.2%), cough (28.2%), peripheral oedema (24.1%), dyspnoea (24.1%), dizziness (20.4%), hypotension (17.2%), pain in the limbs (14.7%), asthenia (13.8%), arthralgia (12.5%) and myalgia (12.5%). The most frequent serious reactions were acute kidney injury (6.6%), diarrhoea (4.7%), raised ALT (4.1%), dyspnoea (3.4%), raised AST (3.1%) and hypotension (2.8%). Other clinically significant serious reactions were differentiation syndrome (2.2%), QT prolongation (0.9%) and posterior reversible encephalopathy syndrome (0.6%).

The percentages below are for all grades. The frequencies of the raised liver enzymes, creatine phosphokinase and alkaline phosphatase are based on centralised laboratory values.

Very common (≥1/10): raised ALT (82.1%), raised AST (80.6%), raised blood alkaline phosphatase (68.7%), raised blood creatine phosphokinase (53.9%), diarrhoea (35.1%), fatigue (30.4%), nausea (29.8%), constipation (28.2%), cough (28.2%), peripheral oedema (24.1%), dyspnoea (24.1%), dizziness (20.4%), hypotension (17.2%), pain in the limbs (14.7%), asthenia (13.8%), arthralgia (12.5%), myalgia (12.5%).

Common (≥1/100 to <1/10): acute kidney injury (6.6%), QT prolongation on the ECG (8.8%), pericardial effusion (4.1%), pericarditis (1.6%), heart failure (1.3%), differentiation syndrome (3.4%), anaphylactic reaction (1.3%), musculoskeletal pain (4.1%), malaise (4.4%).

Uncommon (≥1/1,000 to <1/100): posterior reversible encephalopathy syndrome (0.6%).

Grade 3 or higher events were most often raised ALT (12.9%), raised AST (10.3%), hypotension (7.2%), raised creatine phosphokinase (6.3%) and dyspnoea (4.4%). Differentiation syndrome, QT prolongation, posterior reversible encephalopathy syndrome and pancreatitis need prompt action (see Special Instructions).

Gilteritinib is mainly metabolised by CYP3A enzymes, which many other medicines induce or inhibit.

• Strong CYP3A/P-gp inducers (phenytoin, rifampicin, St John’s wort): avoid. Rifampicin 600 mg at steady state lowered the mean Cmax of a single 20 mg dose of gilteritinib by 27% and the AUC by 70%, so efficacy may be lost.
• Strong inhibitors of CYP3A, P-gp and/or BCRP (voriconazole, itraconazole, posaconazole, clarithromycin, erythromycin, captopril, carvedilol, ritonavir, azithromycin): they can raise gilteritinib levels. Itraconazole raised the mean Cmax of a single 10 mg dose by about 20% and the AUC 2.2-fold in healthy subjects; in patients with AML, exposure rose about 1.5-fold with a strong inhibitor. Consider alternatives that do not strongly inhibit these pathways; if none exist, monitor closely for toxicity.
• Medicines acting on the 5HT2B or sigma non-specific receptors: based on laboratory data, gilteritinib may reduce their effect. The SmPC names the selective serotonin reuptake inhibitors escitalopram, fluoxetine and sertraline. Avoid combining them with gilteritinib unless the patient’s care requires it.
• Substrates of P-gp, BCRP and OCT1: gilteritinib inhibits these transporters in vitro, and there are no clinical data. Caution is advised with substrates of P-gp (digoxin, dabigatran etexilate), BCRP (mitoxantrone, methotrexate, rosuvastatin) and OCT1 (metformin).
• No effect on CYP3A4 or MATE1: in patients, gilteritinib did not inhibit or induce CYP3A4 or inhibit MATE1; a sensitive CYP3A4 substrate and a MATE1 substrate were not significantly affected.
• Hormonal contraceptives: it is unknown whether gilteritinib lowers their effectiveness, so women using them should add a barrier method.
• Food and herbal products: grapefruit and grapefruit juice inhibit CYP3A and may raise gilteritinib levels, so avoid them. Avoid St John’s wort, which induces CYP3A4 and P-gp. The tablets can be taken with or without food.

Treatment should be started and supervised by a physician experienced in anti-cancer therapy. Before treatment, the FLT3 mutation (ITD or TKD) must be confirmed with a validated test. The tablets are taken by mouth, with or without food, swallowed whole with water, at about the same time each day; they must not be broken or crushed. Xospata may be restarted after haematopoietic stem cell transplantation (HSCT).

Recommended Dose

• 120 mg (three 40 mg tablets) once daily as the starting dose.
• Treatment continues until the patient no longer benefits clinically or toxicity becomes unacceptable. Response may be delayed, so continuing at the prescribed dose for up to 6 months should be considered to allow time for a response.
• If there is no response (composite complete remission, CRc) after 4 weeks, the dose can be increased to 200 mg (five 40 mg tablets) once daily, if tolerated or clinically warranted.

Monitoring During Treatment

• Blood chemistry, including creatine phosphokinase: before starting, on day 15 and then monthly for the whole treatment.
• ECG: before starting, on days 8 and 15 of cycle 1, and before the start of each of the next three months of treatment.
• Pregnancy test: for females of reproductive potential, within 7 days before starting treatment.

Dose Interruption, Reduction and Discontinuation

• Differentiation syndrome: if suspected, give corticosteroids and start haemodynamic monitoring. Interrupt gilteritinib if severe signs or symptoms persist for more than 48 hours after corticosteroids are started. Resume at the same dose when signs and symptoms improve to grade 2 or lower.
• Posterior reversible encephalopathy syndrome: discontinue gilteritinib.
• QTcF interval above 500 ms: interrupt gilteritinib. Resume at a reduced dose (80 mg or 120 mg) when the QTcF returns to within 30 ms of baseline or to 480 ms or less.
• QTcF increase of more than 30 ms on the day 8 ECG of cycle 1: confirm with an ECG on day 9. If confirmed, consider reducing the dose to 80 mg.
• Pancreatitis: interrupt gilteritinib until it has resolved, then resume at a reduced dose (80 mg or 120 mg).
• Other grade 3 or higher toxicity considered related to treatment: interrupt until the toxicity resolves or improves to grade 1, then resume at a reduced dose (80 mg or 120 mg).
• Planned HSCT: interrupt gilteritinib one week before the conditioning regimen. Treatment can be resumed 30 days after the transplant if engraftment was successful, there was no grade 2 or higher acute graft-versus-host disease and the patient is in CRc.

A reduced daily dose means 80 mg instead of 120 mg, or 120 mg instead of 200 mg. Grade 1 is mild, grade 2 moderate, grade 3 severe and grade 4 life-threatening.

Special Populations

• Elderly: no dose adjustment in patients aged 65 or over.
• Hepatic impairment: no adjustment in mild (Child-Pugh A) or moderate (Child-Pugh B) impairment. Not recommended in severe (Child-Pugh C) impairment because safety and efficacy have not been evaluated.
• Renal impairment: no adjustment in mild, moderate or severe impairment, but exposure may be higher in severe impairment or end-stage renal disease, so monitor closely for toxicity.
• Children and adolescents: safety and efficacy under 18 years have not been established, and no data are available. Because gilteritinib binds the 5HT2B receptor in vitro, there is a potential effect on heart development in patients under 6 months of age.

Missed or Vomited Dose

If a dose is missed or not taken at the usual time, take it as soon as possible on the same day and return to the normal schedule the next day. If vomiting occurs after a dose, do not take another dose; return to the normal schedule the next day.

FLT3 Mutation Testing

Gilteritinib is for patients whose relapsed or refractory AML carries a FLT3 mutation (ITD or TKD). The mutation must be confirmed with a validated test before the first dose is taken.

Differentiation Syndrome

Gilteritinib has been associated with differentiation syndrome, which comes from rapid growth and maturation of myeloid cells and may be life-threatening or fatal if not treated. Symptoms and findings include fever, dyspnoea, pleural effusion, pericardial effusion, pulmonary oedema, hypotension, rapid weight gain, peripheral oedema, rash and kidney dysfunction. If it is suspected, start corticosteroids with haemodynamic monitoring until the symptoms have resolved; interrupt gilteritinib if severe signs persist for more than 48 hours. Corticosteroids can be tapered after the symptoms resolve but should be given for at least 3 days, because symptoms may return if they are stopped too early.

QT Prolongation and ECG Monitoring

Gilteritinib prolongs the QT interval, most often in the first three months of treatment. An ECG is done before starting, on days 8 and 15 of cycle 1 and before each of the next three months (see Administration and Dosage). Take care in patients with a relevant cardiac history. Low potassium or magnesium raises the risk, so correct hypokalaemia and hypomagnesaemia before and during treatment. Interrupt gilteritinib if the QTcF is above 500 ms. The decision to restart after QT prolongation should rest on a careful assessment of benefit and risk; if restarted at a reduced dose, repeat the ECG after 15 days of dosing and before each of the next three months. In clinical studies, 12 patients had a QTcF above 500 ms, and 3 of them interrupted and restarted treatment without recurrence.

Posterior Reversible Encephalopathy Syndrome

PRES is a rare, reversible neurological disorder with rapidly evolving symptoms such as seizure, headache, confusion, and visual and neurological disturbances, with or without hypertension and altered mental state. If suspected, confirm it with brain imaging, preferably MRI. Stopping gilteritinib is recommended if PRES develops.

Pancreatitis

Pancreatitis has been reported. Patients with signs or symptoms suggesting it should be evaluated and monitored. Interrupt gilteritinib and resume at a reduced dose once the pancreatitis has resolved.

Severe Renal Impairment

Exposure to gilteritinib may be higher in severe renal impairment or end-stage renal disease. Monitor these patients closely for toxicity.

Interacting Medicines

Avoid strong CYP3A/P-gp inducers. Use strong inhibitors of CYP3A, P-gp and/or BCRP with caution, and consider alternatives. Avoid medicines that act on the 5HT2B or sigma non-specific receptors unless essential (see Drug Interactions).

Pregnancy, Breastfeeding and Fertility

• Pregnancy test and contraception: females of reproductive potential should have a pregnancy test within 7 days before starting. Women of childbearing potential should use effective contraception (methods with a pregnancy rate below 1%) during treatment and for up to 6 months after it ends. Women using hormonal contraceptives should add a barrier method. Males with female partners of reproductive potential should use effective contraception during treatment and for at least 4 months after the last dose.
• Pregnancy: gilteritinib can cause foetal harm. There are few or no data in pregnant women; in rats it suppressed foetal growth and caused embryo-foetal deaths and malformations. It is not recommended in pregnancy or in women of childbearing potential who are not using effective contraception.
• Breastfeeding: it is unknown whether gilteritinib or its metabolites pass into human milk; they pass into the milk of lactating rats and reach the tissues of infant rats. A risk to breast-fed children cannot be excluded. Breastfeeding should be stopped during treatment and for at least two months after the last dose.
• Fertility: there are no data on the effect of gilteritinib on human fertility.

Effect on Driving

Gilteritinib has a minor influence on the ability to drive and use machines. Dizziness has been reported and should be considered when assessing whether a patient can drive or use machines.

Xospata needs no special temperature conditions. Keep the tablets in the original package to protect them from light, out of the sight and reach of children. It is supplied in blisters of 21 film-coated tablets, with 84 tablets in each pack.

4 years. Do not use after the expiry date on the pack.

Prescription only (Rx). Xospata is a medicinal product subject to restricted medical prescription, started and supervised by a physician experienced in anti-cancer therapy. It is taken at home as tablets, so it is supplied to the patient or to the treating clinic on prescription. Treatment depends on a confirmed FLT3 mutation, regular ECG and blood chemistry monitoring, and, for females of reproductive potential, a pregnancy test within 7 days before the start.