Mitapivat API Manufacturers

General Description:

Mitapivat, identified by CAS number 1260075-17-9, is a notable compound with significant therapeutic applications. Mitapivat is a novel, first-in-class pyruvate kinase activator. It works to increase the activity of erythrocyte pyruvate kinase, a key enzyme involved in the survival of red blood cells. Defects in the pyruvate kinase enzyme in various red blood cells disorders lead to the lack of energy production for red blood cells, leading to lifelong premature destruction of red blood cells or chronic hemolytic anemia. On February 17, 2022, the FDA approved mitapivat as the first disease-modifying treatment for hemolytic anemia in adults with pyruvate kinase (PK) deficiency, a rare, inherited disorder leading to lifelong hemolytic anemia. Mitapivat has also been investigated in other hereditary red blood cell disorders associated with hemolytic anemia, such as sickle cell disease and alpha- and beta-thalassemia.

Indications:

This drug is primarily indicated for: Mitapivat is indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Mitapivat undergoes metabolic processing primarily in: According to _in vitro_ studies, mitapivat is primarily metabolized by CYP3A4. It is also a substrate of CYP1A2, CYP2C8, and CYP2C9. Following a single oral dose administration of 120 mg of radiolabeled mitapivat in healthy subjects, unchanged mitapivat was the major circulating component in plasma. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Mitapivat are crucial for its therapeutic efficacy: The absolute bioavailability of mitapivat after a single dose is approximately 73%. Mitapivat exposure increases dose-proportionally. Following twice-daily oral administration of mitapivat at the dose of 5 mg, 20 mg, and 50 mg, the mean (CV%) C_max at steady state were 101.2 (17%) ng/mL, 389.9 (18%) ng/mL, and 935.2 (18%) ng/mL, respectively. The mean (CV%) AUC were 450.4 (28%) ng x h/mL, 1623.8 (28%) ng x h/mL, and 3591.4 (28%) ng x h/mL, respectively. The median T_max values at steady state were 0.5 to 1.0 hour post-dose across the dose range of 5 mg to 50 mg twice daily. In healthy subjects, a high-fat meal did not affect the drug exposure but reduced the rate of mitapivat absorption, with a 42% reduction in C_max and a delay in T_max of 2.3 hours when compared to dosing under fasted conditions. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Mitapivat is an important consideration for its dosing schedule: In patients with pyruvate kinase deficiency receiving multiple doses of 5 mg mitapivat twice daily to 20 mg twice daily, the mean effective half-life (t_1/2) of mitapivat ranged from 3 to 5 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Mitapivat exhibits a strong affinity for binding with plasma proteins: Mitapivat is 97.7% bound to plasma proteins, with an RBC-to-plasma ratio of 0.37. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Mitapivat from the body primarily occurs through: Mitapivat is primary eliminated via hepatic metabolism. After a single oral administration of radiolabeled mitapivat in healthy subjects, the total recovery of administered radioactive dose was 89.2%. About 49.6% of radioactivity was recovered in the urine with 2.6% excreted as unchanged mitapivat. About 39.6% of radioactivity was recovered in the feces with less than 1% being the unchanged drug. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Mitapivat is distributed throughout the body with a volume of distribution of: The mean volume of distribution at steady state (V_ss) was 42.5 L. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Mitapivat is a critical factor in determining its safe and effective dosage: Population pharmacokinetics derived median CL/F at steady state was 11.5, 12.7, and 14.4 L/h for the 5 mg twice daily, 20 mg twice daily, and 50 mg twice daily regimens, respectively. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Mitapivat exerts its therapeutic effects through: Mitapivat is a pyruvate kinase activator that works to increase the activity of erythrocyte pyruvate kinase, an enzyme responsible for energy production for and survival of red blood cells. It is effective in upregulating the activity of both wild-type and mutant forms of erythrocyte pyruvate kinase. Interestingly, mitapivat is a mild-to-moderate inhibitor of the aromatase enzyme (CYP19A1), which is an enzyme involved in biosynthesis of estrogens from androgen precursors. Inhibition of aromatase is associated with bone density loss, as estrogen mediates suppressive, antiresorptive effects on osteoclasts and generally favours bone formation over resorption. Thus, low estrogen levels can increase bone turnover and osteoclast activity, resulting in net bone loss and decreased bone quality. Inhibition of aromatase by mitapivat may have some clinical implications, as patients with pyruvate kinase deficiency have considerably high rate of osteopenia and osteoporosis. The long-term effect of mitapivant on bond mineral density requires further investigation. One study suggests that this off-target effect may have negligible clinical effects on adults, but may potentially have some clinical implications in developing children. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Mitapivat functions by: The pyruvate kinase enzyme is an ATP-generating enzyme involved in the Embden–Meyerhof glycolytic pathway: it catalyzes the conversion of phosphoenolpyruvate to pyruvate in the final step of glycolysis, generating adenosine triphosphate (ATP), which is critical for cellular maintenance and survival. One of the four isoforms of pyruvate kinase - erythrocyte pyruvate kinase or PKR - is dedicated to red blood cells (RBCs). Compared to most human cells, RBCs lack the metabolic machinery required for aerobic metabolism of glucose and generation of ATP; thus, they rely on anaerobic glycolysis for ATP production. The deficiency of ATP due to glycolytic enzyme defects leads to shortened lifespan and premature destruction of RBCs in the form of chronic hemolytic anemia and ineffective erythropoiesis. Pyruvate kinase deficiency is a rare hereditary disorder affecting RBC glycolysis, caused by mutations in _PKLR_, the gene encoding the RBC (PKR) and liver-specific isoforms (PKL) of pyruvate kinase. Pyruvate kinase deficiency is associated with a build-up of 2,3-disphosphoglycerate (2,3-DPG), an upstream metabolite in glycolysis, and deficient ATP levels. Erythrocyte pyruvate kinase is an allosterically regulated homotetrameric enzyme that is normally activated by fructose bisphosphate (FBP) in an allosteric fashion. Mitapivat is also an allosteric pyruvate kinase activator but binds to a different allosteric site from FBP on the PKR tetramer. This allows for the activation of both wild-type and mutant forms of erythrocyte pyruvate kinase, including those not induced by FBP. Upon binding to pyruvate kinase, mitapivat stabilizes the active tetrameric form of the enzyme and enhances its affinity for its substrate, phosphoenolpyruvate. Mitapivat upregulates erythrocyte pyruvate kinase activity, increases ATP production, and reduces levels of 2,3-DPG. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Mitapivat is categorized under the following therapeutic classes: Cytochrome P-450 CYP1A2 Substrates, Cytochrome P-450 CYP2B6 Inducers, Cytochrome P-450 CYP2B6 Inducers (strength unknown), Cytochrome P-450 CYP2C19 Inducers, Cytochrome P-450 CYP2C19 Inducers (strength unknown), Cytochrome P-450 CYP2C8 Inducers, Cytochrome P-450 CYP2C8 Inducers (strength unknown), Cytochrome P-450 CYP2C8 Substrates, Cytochrome P-450 CYP2C9 Inducers, Cytochrome P-450 CYP2C9 Inducers (strength unknown), Cytochrome P-450 CYP2C9 Substrates, Cytochrome P-450 CYP3A Inducers, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Inducers, Cytochrome P-450 CYP3A4 Inducers (strength unknown), Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Substrates, Enzyme Activators, Genito Urinary System and Sex Hormones, Gynecological Antiinfectives and Antiseptics, Heterocyclic Compounds, Fused-Ring, P-glycoprotein inhibitors, P-glycoprotein substrates, Sulfonamides, Sulfones, UGT1A1 Inducers. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.