Pacritinib API Manufacturers

General Description:

Pacritinib, identified by CAS number 937272-79-2, is a notable compound with significant therapeutic applications. Myelofibrosis (MF) is a rare disorder characterized by hematopoietic abnormalities and fibrosis within the bone marrow. The underlying cause of primary MF is unknown, but secondary MF can arise in patients with a history of polycythemia vera or essential thrombocythemia. While some patients may remain asymptomatic, typical symptoms of MF arise from abnormalities in blood cell production and may therefore include various cytopenias, infections, splenomegaly, and general systemic symptoms such as fever. Approximately 50% of patients with primary MF have a mutation of the _JAK2_ gene, which is also commonly mutated in patients with polycythemia vera or essential thrombocythemia. JAK2 signaling is important for hematopoiesis and proper immune functioning, and while the precise role it plays in the pathogenesis of MF remains unclear, its clear association with MF has made it a desirable therapeutic target in MF treatment. Pacritinib is an inhibitor of both wild-type and mutant (V617F) JAK2, as well as FMS-like tyrosine kinase 3 (FLT3), which was granted accelerated approval by the FDA in February 2022 for the treatment of both primary and secondary MF in patients with platelet counts < 50 x 10⁹/L. It provides a treatment option for patients who have MF with severe thrombocytopenia, which occurs in approximately one-third of MF patients and carries with it a particularly poor prognosis.

Indications:

This drug is primarily indicated for: Pacritinib is indicated for the treatment of adults with intermediate or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 x 10⁹/L. This indication is approved under accelerated approval based on spleen volume reduction. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Pacritinib undergoes metabolic processing primarily in: Pacritinib metabolism is mediated primarily by CYP3A4. While it undergoes extensive metabolism to at least four identified metabolites - M1, M2, M3, and M4 - parent drug is the major circulating component in plasma and is responsible for the pharmacologic activity. The two major metabolites, M1 and M2, represent 9.6% and 10.5% of parent drug exposure, respectively. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Pacritinib are crucial for its therapeutic efficacy: Following oral administration of 200mg pacritinib twice daily, the mean C_max and AUC_0-12 at steady-state were 8.4 mg/L and 95.6 mg*h/L, respectively. The T_max is approximately 4-5 hours post-dose. Co-administration with food does not significantly impact the pharmacokinetics of pacritinib. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Pacritinib is an important consideration for its dosing schedule: The mean effective half-life of pacritinib is 27.7 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Pacritinib exhibits a strong affinity for binding with plasma proteins: Pacritinib is 98.8% protein-bound in plasma. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Pacritinib from the body primarily occurs through: Following oral administration of radiolabeled pacritinib, approximately 87% of the radioactivity was recovered in feces and 6% was recovered in urine. Unchanged parent drug was not present in the feces and accounted for only 0.12% of the radioactivity excreted in the urine. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Pacritinib is distributed throughout the body with a volume of distribution of: The mean apparent volume of distribution of pacritinib at steady-state is 229 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Pacritinib is a critical factor in determining its safe and effective dosage: The mean apparent clearance of pacritinib is 2.09 L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Pacritinib exerts its therapeutic effects through: Pacritinib is administered orally twice daily, with or without food. It should not be used in patients with moderate or severe (Child-Pugh B or C) hepatic impairment, nor in patients with significant renal impairment (eGFR <30 mL/min). Patients taking pacritinib may experience a prolonged QTc interval - while no cases of torsades de pointes have been reported in clinical trials, QTc prolongations to >500 msec and/or increases in baseline QTc by >60 msec were observed in some patients during clinical trials. A baseline QTc interval should be obtained prior to initiating therapy and regular monitoring (including for risk factors, e.g. hypokalemia) should continue throughout therapy. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Pacritinib functions by: While the pathogenesis of myelofibrosis (MF) is still poorly understood, both primary and secondary (i.e. post-polycythemia vera or post-essential thrombocythemia) myelofibrosis have been associated with mutations of _JAK2_. Signaling pathways initiated by JAK2 generate a number of cytokines and growth factors responsible for hematopoiesis and immune functioning, and its dysregulation is thought to be a driver of MF pathogenesis. Pacritinib is thought to exert its pharmacologic activity via inhibition of wild-type JAK2, mutant JAK2^V617F, and FMS-like tyrosine kinase 3 (FLT3). It has a greater inhibitory potency towards JAK2 than related proteins (e.g. JAK3, TYK2), and does not inhibit JAK1 at clinically relevant concentrations. Pacritinib also exhibits some inhibitory activity against other cellular kinases (e.g. CSF1R and IRAK1), although the clinical significance of this activity is unknown. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Pacritinib belongs to the class of organic compounds known as phenol ethers. These are aromatic compounds containing an ether group substituted with a benzene ring, classified under the direct parent group Phenol ethers. This compound is a part of the Organic compounds, falling under the Benzenoids superclass, and categorized within the Phenol ethers class, specifically within the None subclass.

Categories:

Pacritinib is categorized under the following therapeutic classes: Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, BCRP/ABCG2 Inhibitors, Cytochrome P-450 CYP1A2 Inducers, Cytochrome P-450 CYP1A2 Inducers (strength unknown), Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 CYP1A2 Inhibitors (strength unknown), Cytochrome P-450 CYP2C19 Inhibitors, Cytochrome P-450 CYP2C19 inhibitors (strength unknown), Cytochrome P-450 CYP3A Inducers, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inducers, Cytochrome P-450 CYP3A4 Inducers (strength unknown), Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (strength unknown), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Janus Kinase 2, antagonists & inhibitors, Janus-associated kinase (JAK) inhibitors, Kinase Inhibitor, OCT1 inhibitors, OCT2 Inhibitors, P-glycoprotein inhibitors, Potential QTc-Prolonging Agents, Protein Kinase Inhibitors, QTc Prolonging Agents, Tyrosine Kinase Inhibitors. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.