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Ponatinib – Uses, Dosage, Side Effects, Interaction

Mechanism of Action

Ponatinib is a multi-target kinase inhibitor. Its primary cellular target is the Bcr-Abl tyrosine kinase protein which is constitutively active and promotes the progression of CML. This protein arises from the fused Bcr and Abl genes- what is commonly known as the Philadelphia chromosome. Ponatinib is unique in that it is especially useful in the treatment of resistant CML because it inhibits the tyrosine kinase activity of Abl and T315I mutant kinases. The T315I mutation confers resistance in cells as it prevents other Bcr-Abl inhibitors from binding to the Abl kinase. Other targets that ponatinib inhibits are members of the VEGFR, PDGFR, FGFR, EPH receptors, and SRC families of kinases, and KIT, RET, TIE2, and FLT3. A decrease in tumor size expressing native or T315I mutant BCR-ABL has been observed in rats.

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Ponatinib is a kinase inhibitor. Ponatinib inhibited the in vitro tyrosine kinase activity of ABL and T315I mutant ABL with IC50 concentrations of 0.4 and 2.0 nM, respectively. Ponatinib inhibited the in vitro activity of additional kinases with IC50 concentrations between 0.1 and 20 nM, including members of the VEGFR, PDGFR, FGFR, EPH receptors, and SRC families of kinases, and KIT, RET, TIE2, and FLT3. Ponatinib inhibited the in vitro viability of cells expressing native or mutant BCR-ABL, including T315I. In mice, treatment with ponatinib reduced the size of tumors expressing native or T315I mutant BCR-ABL when compared to controls.

Gain-of-function mutations of membrane receptor tyrosine kinase KIT especially gate-keeper D816V point mutation in KIT render kinase auto-activation, disease progression, and poor prognosis. D816V KIT is found in -80% of the patients of systemic mastocytosis (SM) and is resistant to the first and second generations of tyrosine kinase inhibitors (TKIs). The purpose of this investigation was aimed at explore whether ponatinib (AP24534), a novel effective TKI against T315I Bcr-Abl was active against D816V KIT. /The researchers/ discovered that ponatinib abrogated the phosphorylation of KIT harboring either V560G (sensitive to imatinib) or D816V mutation (resistant to imatinib) and the downstream signaling transduction. Ponatinib inhibited the growth of D816V KIT-expressing cells in culture and nude mouse xenografted tumors. Ponatinib triggered apoptosis by inducing the release of cytochrome c and AIF, downregulation of Mcl-1. Furthermore, ponatinib abrogated the phosphorylation of beta-catenin at site Y654, suppressed the translocation of beta-catenin, inhibited the transcription and DNA binding of TCF and the expression of its targets (e.g. Axin2, c-Myc, and cyclin D1). Moreover, ponatinib was highly active against xenografted D816V KIT tumors in nude mice and significantly prolonged the survival of mice with aggressive SM or mast cell leukemia by impeding the expansion and infiltration of mast cells with imatinib-resistant D814Y KIT.

Indications

  • Ponatinib is indicated for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.
  • Iclusig is indicated in adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation.
  • Iclusig is indicated in adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukaemia (CML) who are resistant to dasatinib or nilotinib; who are intolerant to dasatinib or nilotinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) who are resistant to dasatinib; who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate; or who have the T315I mutation.
  • Treatment of acute lymphoblastic leukaemia, Treatment of chronic myeloid leukaemia
  • Ponatinib is a novel Bcr-Abl tyrosine kinase inhibitor that is especially effective against the T315I mutation for the treatment of chronic myeloid leukemia.
  • Accelerated phase chronic myologenic leukemia
  • Acute Lymphoblastic Leukemia (ALL)
  • Myeloid Leukemia, Chronic, Chronic Phase
  • Blast phase Chronic myelocytic leukemia

Contraindications

Dosage

Strengths: 30 mg; 45 mg; 15 mg; 10 mg

Chronic Myelogenous Leukemia

Chronic phase chronic myeloid leukemia (CP-CML):

Accelerated phase chronic myeloid leukemia (AP-CML), blast phase chronic myeloid leukemia (BP-CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL):

Acute Lymphoblastic Leukemia

Chronic phase chronic myeloid leukemia (CP-CML):

Accelerated phase chronic myeloid leukemia (AP-CML), blast phase chronic myeloid leukemia (BP-CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL):

Liver Dose Adjustments

ANY LEVEL OF LIVER DYSFUNCTION (CHILD-PUGH A, B, OR C):

IF HEPATOTOXICITY DEVELOPS DURING TREATMENT:
Elevation of liver transaminase greater than 3 times the upper limit of normal (ULN) and if:

Dose Adjustments

DOSAGE MODIFICATION FOR COADMINISTRATION OF STRONG CYP450 3A INHIBITORS/INDUCERS:

RECOMMENDED DOSE REDUCTION FOR ADVERSE REACTIONS:

HEPATOTOXICITY:
Elevation of liver transaminase greater than 3 times the upper limit of normal (ULN) and if:

ELEVATED LIPASE/PANCREATITIS:

MYELOSUPPRESSION:

ARTERIAL OCCLUSIVE EVENTS:
Cardiovascular or Cerebrovascular:

Peripheral vascular and other or venous thromboembolic events:

HEART FAILURE:

OTHER NON-HEMATOLOGIC ADVERSE REACTIONS:

Administration Advice:

Monitoring:

Patient Advice:

Side Effects

The Most Common

More common

Rare

Drug Interactions

Pregnancy and Lactation

AU TGA pregnancy category D

Pregnancy

Based on its mechanism of action and findings in animals, Iclusig can cause fetal harm when administered to a pregnant woman [see Data]. There are no available data on Iclusig use in pregnant women. In animal reproduction studies, oral administration of ponatinib to pregnant rats during organogenesis caused adverse developmental effects at doses lower than human exposures at the recommended human dose [see Data]. Advise pregnant women of the potential risk to a fetus

Lactation

No information is available on the clinical use of ponatinib during breastfeeding. Because ponatinib is more than 99% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is about 24 hours and it might accumulate in the infant. National Comprehensive Cancer Network guidelines recommend avoiding breastfeeding during ponatinib therapy and the manufacturer recommends withholding breastfeeding for 6 days following the last dose.[1]

How should this medicine be used?

Ponatinib comes as a tablet to take by mouth. It is usually taken once a day with or without food. Take ponatinib at around the same time every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take ponatinib exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

Swallow the tablets whole; do not split, chew, or crush them. Your doctor may need to delay your treatment, adjust your dose, or permanently stop your treatment of ponatinib depending on your response to treatment and any side effects that you experience. Talk to your doctor about how you are feeling during your treatment. Continue to take ponatinib even if you feel well. Do not stop taking ponatinib without talking to your doctor.

What special precautions should I follow?

Before taking ponatinib,

  • tell your doctor and pharmacist if you are allergic to ponatinib, any other medications, lactose, or any of the ingredients in ponatinib tablets. Ask your pharmacist or check the Medication Guide for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: ketoconazole (Nizoral); medications to reduce stomach acid, such as lansoprazole (Prevacid); and rifampin (Rifadin, Rimactane, in Rifamate, in Rifater). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with ponatinib, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
  • tell your doctor if you have or have ever had a bleeding problem; diabetes; pancreatitis (swelling of the pancreas, a gland behind the stomach that produces substances to help with digestion); or if you are lactose intolerant (inability to digest dairy products). Also, tell your doctor if you drink or have ever drunk large amounts of alcohol.
  • you should know that ponatinib may decrease fertility in women. However, you should not assume that you or your partner cannot become pregnant. Tell your doctor if you are pregnant or plan to become pregnant. If you are female, you will need to take a pregnancy test before you start treatment. You should use birth control to prevent pregnancy during your treatment with ponatinib and for 3 weeks after you stop taking the medication. Talk to your doctor about the types of birth control that will work for you. If you become pregnant while taking ponatinib, call your doctor immediately. Ponatinib may harm the fetus.
  • tell your doctor if you are breastfeeding or plan to breastfeed. You should not breastfeed while taking ponatinib and for 6 days after your final dose.
  • if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking ponatinib. If you are scheduled to have surgery, your doctor will tell you to stop taking ponatinib for at least 7 days before the surgery or procedure. Your doctor will tell you when to start taking ponatinib again after your surgery.
  • you should know that your blood pressure may increase during your treatment with ponatinib. Your doctor will probably monitor your blood pressure during your treatment.

 

References
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