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General Description:

Abametapir, identified by CAS number 1762-34-1, is a notable compound with significant therapeutic applications. Abametapir is a novel pediculicidal metalloproteinase inhibitor used to treat infestations of head lice. The life cycle of head lice (_Pediculus capitis_) is approximately 30 days, seven to twelve of which are spent as eggs laid on hair shafts near the scalp. Topical pediculicides generally lack adequate ovicidal activity, including standard-of-care treatments such as , and many require a second administration 7-10 days following the first to kill newly hatched lice that resisted the initial treatment. The necessity for follow-up treatment may lead to challenges with patient adherence, and resistance to agents like permethrin and / may be significant in some areas. Investigations into novel ovicidal treatments revealed that several metalloproteinase enzymes were critical to the egg hatching and survival of head lice, and these enzymes were therefore identified as a potential therapeutic target. Abemetapir is an inhibitor of these metalloproteinase enzymes, and the first topical pediculicide to take advantage of this novel target. The improved ovicidal activity (90-100% _in vitro_) of abemetapir allows for a single administration, in contrast to many other topical treatments, and its novel and relatively non-specific mechanism may help to curb the development of resistance to this agent. Abametapir was first approved for use in the United States under the brand name Xeglyze on July 27, 2020.

Indications:

This drug is primarily indicated for: Abametapir is indicated, in the context of an overall lice management program, for the topical treatment of head lice infestation in patients 6 months of age and older. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Abametapir undergoes metabolic processing primarily in: The biotransformation of abametapir is extensive and primarily mediated by CYP1A2. It is metabolized first to abametapir hydroxyl and then further to abametapir carboxyl - the latter is cleared slowly from the plasma, resulting in higher systemic concentrations than that of the parent drug. _In vitro_ studies suggest that abametapir carboxyl may act as an inhibitor of CYP3A4, CYP2B6, and CYP1A2, particularly at the relatively high and prolonged concentrations observed following topical administration of abametapir. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Abametapir are crucial for its therapeutic efficacy: In a pharmacokinetic trial with both adult and pediatric patients, the C_max and AUC_0-8h in the adult group were 41 ng/mL and 121 ng.h/mL and the C_max and AUC_0-8h in the pediatric group were 73 ng/mL and 264 ng.h/mL. In general, systemic exposure to abametapir appears to decrease with increasing age. The median T_max of abemetapir is 0.57 - 1.54 hours. Following topical administration, benzyl alcohol was found in detectable quantities in the serum of 7 out of 39 pediatric patients. The C_max of benzyl alcohol in these subjects ranged from 0.52 to 3.57 μg/mL. The predominant circulating metabolite of abemetapir (abemtapir carboxylate) is eliminated slowly from the circulation and is therefore found at higher serum concentrations than its parent drug - based on data collected for 72 hours post-administration, the ratios of serum C_max and AUC_0-72h between abametapir and abametapir carboxylate were approximately 30 and 250, respectively. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Abametapir is an important consideration for its dosing schedule: The elimination half-lives of abametapir and its metabolites have not been well-characterized, but the estimated half-life of abametapir carboxyl is 71 ± 40 hours (or longer) in adults. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Abametapir exhibits a strong affinity for binding with plasma proteins: Both abametapir and abametapir carboxyl are high protein-bound in plasma, although the specific proteins to which they bind are unclear. Following topical administration, abametapir is 91.3-92.3% protein-bound and abametapir carboxyl is 96.0-97.5% protein-bound. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Abametapir from the body primarily occurs through: The clearance and excretion of abametapir has not been examined in patients. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Abametapir is distributed throughout the body with a volume of distribution of: Data regarding the volume of distribution of abametapir are not available. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Abametapir is a critical factor in determining its safe and effective dosage: The clearance and excretion of abametapir has not been examined in patients. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Abametapir exerts its therapeutic effects through: Abametavir has been shown to inhibit all stages of embryo development in both head and body lice by interfering with enzymes critical to this process. It is relatively unique amongst lice treatments in that it requires only a single application, whereas many current therapies require two applications, due to its exceptional potency and unique mechanism. Its predominant metabolite, abametapir carboxyl, has a prolonged residence time in the body, with an estimated half-life of 71 ± 40 hours or longer in adults - as this metabolite has been shown to inhibit cytochrome P450 enzymes _in vitro_, the use of substrates of CYP3A4, CYP2B6, or CYP1A2 should be avoided for two weeks following the administration of abametapir. Abametapir lotion is formulated with , which has been associated with significant toxicity following unintentional systemic exposure, particularly in neonates and low birth weight infants. Benzyl alcohol-containing formulations should not be administered to patients <6 months of age, and should be administered to pediatric patients cautiously and under direct supervision of an adult to mitigate the risk of unintentional oral ingestion. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Abametapir functions by: There are several metalloproteinases (enzymes requiring metal co-factors to function) involved in the process of louse egg hatching and survival. _In vitro_ studies have demonstrated that metal-chelating agents can inhibit the activity of these proteins, and may therefore be valuable pediculicidal agents. Abametapir is a metalloproteinase inhibitor that targets louse metalloproteinases which are critical to their development and hatching. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Abametapir belongs to the class of organic compounds known as bipyridines and oligopyridines. These are organic compounds containing two pyridine rings linked to each other, classified under the direct parent group Bipyridines and oligopyridines. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Pyridines and derivatives class, specifically within the Bipyridines and oligopyridines subclass.

Categories:

Abametapir is categorized under the following therapeutic classes: Antiparasitic Products, Insecticides and Repellents, Cytochrome P-450 CYP1A2 Inhibitors, Cytochrome P-450 CYP1A2 Inhibitors (strength unknown), Cytochrome P-450 CYP1A2 Substrates, Cytochrome P-450 CYP2B6 Inhibitors, Cytochrome P-450 CYP2B6 Inhibitors (strength unknown), Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors, Cytochrome P-450 CYP3A4 Inhibitors (strength unknown), Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Ectoparasiticides, Incl. Scabicides, Ectoparasiticides, Incl. Scabicides, Insecticides and Repellents, Matrix Metalloproteinase Inhibitors, Pediculicides, Pyridines. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.