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General Description:

Fosdenopterin, identified by CAS number 150829-29-1, is a notable compound with significant therapeutic applications. Molybdenum cofactor deficiency (MoCD) is an exceptionally rare autosomal recessive disorder resulting in a deficiency of three molybdenum-dependent enzymes: sulfite oxidase (SOX), xanthine dehydrogenase, and aldehyde oxidase. Signs and symptoms begin shortly after birth and are caused by a build-up of toxic sulfites resulting from a lack of SOX activity. Patients with MoCD may present with metabolic acidosis, intracranial hemorrhage, feeding difficulties, and significant neurological symptoms such as muscle hyper- and hypotonia, intractable seizures, spastic paraplegia, myoclonus, and opisthotonus. In addition, patients with MoCD are often born with morphologic evidence of the disorder such as microcephaly, cerebral atrophy/hypodensity, dilated ventricles, and ocular abnormalities. MoCD is incurable and median survival in untreated patients is approximately 36 months - treatment, then, is focused on improving survival and maintaining neurological function. The most common subtype of MoCD, type A, involves mutations in _MOCS1_ wherein the first step of molybdenum cofactor synthesis - the conversion of guanosine triphosphate into cyclic pyranopterin monophosphate (cPMP) - is interrupted. In the past, management strategies for this disorder involved symptomatic and supportive treatment, though efforts were made to develop a suitable exogenous replacement for the missing cPMP. In 2009 a recombinant, E. coli-produced cPMP was granted orphan drug designation by the FDA, becoming the first therapeutic option for patients with MoCD type A. Fosdenopterin was approved by the FDA on Februrary 26, 2021, for the reduction of mortality in patients with MoCD type A, becoming the first and only therapy approved for the treatment of MoCD. By improving the three-year survival rate from 55% to 84%, and considering the lack of alternative therapies available, fosdenopterin appears poised to become a standard of therapy in the management of this debilitating disorder. In July 2022, the EMA's Committee for Medicinal Products for Human Use (CHMP) recommended fosdenopterin be granted marketing authorization under exceptional circumstances for the treatment of patients with molybdenum cofactor deficiency (MoCD) Type A. In September 2022, the EMA approved the use of fosdenopterin.

Indications:

This drug is primarily indicated for: Fosdenopterin is indicated to reduce the risk of mortality in patients with molybdenum cofactor deficiency (MoCD) type A. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Fosdenopterin undergoes metabolic processing primarily in: Fosdenopterin metabolism occurs mainly via non-enzymatic degradation into Compound Z, which is a pharmacologically inactive product of endogenous cyclic pyranopterin monophosphate. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Fosdenopterin are crucial for its therapeutic efficacy: In healthy adult subjects, the observed C_max and AUC_0-inf following the intravenous administration of 0.68 mg/kg (0.76x the maximum recommended dose) were 2800 ng/mL and 5960 ng*h/mL, respectively. Both C_max and AUC_0-inf appear to increase proportionally with increasing doses. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Fosdenopterin is an important consideration for its dosing schedule: The mean half-life of fosdenopterin ranges from 1.2 to 1.7 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Fosdenopterin exhibits a strong affinity for binding with plasma proteins: Plasma protein binding ranges from 6 to 12%, though the specific proteins to which fosdenopterin binds have not been elucidated. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Fosdenopterin from the body primarily occurs through: Renal clearance of fosdenopterin accounts for approximately 40% of total clearance. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Fosdenopterin is distributed throughout the body with a volume of distribution of: The volume of distribution of fosdenopterin is approximately 300 mL/kg. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Fosdenopterin is a critical factor in determining its safe and effective dosage: Total body clearance of fosdenopterin ranges from 167 to 195 mL/h/kg. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Fosdenopterin exerts its therapeutic effects through: Fosdenopterin replaces an intermediate substrate in the synthesis of molybdenum cofactor, a compound necessary for the activation of several molybdenum-dependent enzymes including sulfite oxidase (SOX). Given that SOX is responsible for detoxifying sulfur-containing acids and sulfites such as S-sulfocysteine (SSC), urinary levels of SSC can be used as a surrogate marker of efficacy for fosdenopterin. Long-term therapy with fosdenopterin has been shown to result in a sustained reduction in urinary SSC normalized to creatinine. Animal studies have identified a potential risk of phototoxicity in patients receiving fosdenopterin - these patients should avoid or minimize exposure to sunlight and/or artificial UV light. If sun exposure is necessary, use protective clothing, hats, and sunglasses, in addition to seeking shade whenever practical. Consider the use of a broad-spectrum sunscreen in patients 6 months of age or older. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Fosdenopterin functions by: Molybdenum cofactor deficiency (MoCD) is a rare autosomal-recessive disorder in which patients are deficient in three molybdenum-dependent enzymes: sulfite oxidase (SOX), xanthine dehydrogenase, and aldehyde dehydrogenase. The loss of SOX activity appears to be the main driver of MoCD morbidity and mortality, as the build-up of neurotoxic sulfites typically processed by SOX results in rapid and progressive neurological damage. In MoCD type A, the disorder results from a mutation in the _MOCS1_ gene leading to deficient production of MOCS1A/B, a protein that is responsible for the first step in the synthesis of molybdenum cofactor: the conversion of guanosine triphosphate into cyclic pyranopterin monophosphate (cPMP). Fosdenopterin is an exogenous form of cPMP, replacing endogenous production and allowing for the synthesis of molybdenum cofactor to proceed. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Categories:

Fosdenopterin is categorized under the following therapeutic classes: Alimentary Tract and Metabolism, Biological Factors, Cyclic Pyranopterin Monophosphate, Heterocyclic Compounds, Fused-Ring, MATE 1 Substrates, MATE 2 Inhibitors, MATE inhibitors, MATE substrates, OAT1/SLC22A6 inhibitors, Photosensitizing Agents, Pteridines, Various Alimentary Tract and Metabolism Products. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.