Pralsetinib
Mechanism :
Kinase inhibitor of wild-type RET and oncogenic RET fusions and mutations. It is A Selective inhibitor of RET alterations and resistant mutations; specifically designed to spare VEGFR2 and other kinases that have the potential to cause off-target toxicity.
It’s Antitumor activity was observed in cultured cells and animal tumour implantation models containing oncogenic RET fusions or mutations.
Indication :
- Medullary thyroid cancer treatment.
Dosing :
In children more than 12 years of age - 400 mg PO every day for 12 years. Continue until the illness gets worse or there is intolerable toxicity.
Dose modifications is to be done according to adverse effects:
First dose reduction: 300 mg PO once daily. Second dose reduction: 200 mg PO once daily. Third dose reduction: 100 mg PO once daily. discontinue forever.
ILD/pneumonitis: Interstitial lung disease - Grade 1 or 2: Wait until the issue is resolved, then resume at a lower dose. Recurrent ILD/pneumonitis or grade 3 or 4: discontinue forever.
Hypertension - Grade 3: Withhold due to chronic Grade 3 hypertension while receiving adequate antihypertensive medication; reintroduce at a lower dose after hypertension is under control. Fourth grade: Stop.
Hepatoxicity - Grades 3 or 4: Defer AST/ALT testing until Grade 1 until resolution. Restart with a lower dose. Discontinue if Grade 3 hepatotoxicity occurs once more.
Haemorrhagic situations- Withhold until baseline recovery or Grade 1 for grades 3 or 4.For severe or life-threatening haemorrhagic episodes, discontinue.
Other negative effects- Grade 3 or 4: Delay until Grade 2 recovery, then resume at a lower dose. Grade 4 recurring: permanently discontinued.
Adverse Effect :
when used for thyroid cancer treatment - the major side effects are - Decreased calcium, increased AST and ALT, decreased lymphocytes, haemoglobin, albumin, platelets. Fatigue, diarrhoea, oedema, headache, rash, dysgeusia, dry mouth, nausea, stomatitis, tumour lysis syndrome, cough dysponea, musculoskeletal pain, hypertension, constipation.
Interaction :
Pralsetinib is a CYP3A4 inhibitor of high potency
• Strong CYP3A inhibitors - increase pralsetinib exposure and risk of toxicity. Hence they shouldn’t be coadministered
• Combined P-gp and strong CYP3A inhibitors- Avoid coadministration; if this is not possible, reduce the pralsetinib dose. Pralsetinib plasma concentrations and effects are increased when P-gp and strong CYP3A inhibitors are combined.
• CYP3A4 inducers of high potency - Avoid coadministration; if this is not possible, increase the pralsetinib dose. Strong CYP3A inducers reduce pralsetinib exposure.
Lactation :
No information is available. Women are advised not to breastfeed while receiving therapy and for one week after the last dose.
Hepatic Dose :
No dosage change is required for mild (total bilirubin ULN and AST >ULN OR total bilirubin >1-1.5x ULN with any AST).
Moderate-to-severe: Not researched (total bilirubin >1.5x ULN and any AST).
Pregnanacy :
Given its mode of action and results from animal studies, this medication should not be given to pregnant women.