doxecitine/doxribtimine

Action and Spectrum

Action and spectrum:    

Actions:  

Doxecitine and doxribtimine are pyrimidine nucleoside analogs that serve as precursors for mitochondrial DNA synthesis. After oral administration, they are converted within cells into their active phosphorylated forms. These active metabolites replenish depleted mitochondrial deoxynucleotide pools and promote mitochondrial DNA replication and repair. By restoring mitochondrial DNA copy number, the drugs help improve mitochondrial function, energy production, and overall muscle strength in patients with TK2D. 

Drug Interaction

Adverse Reaction

Frequency Defined    

1-10% 

AST increased, adult (7%) 

Vomiting, adult (7%) 

>10% 

ALT increased, adult (13%) 

Vomiting, pediatric (21%) 

AST increased, pediatric (22%) 

Abdominal pain (23%) 

ALT increased, pediatric (25%) 

Diarrhea (72%) 

Black Box Warning

Black Box Warning   

None   

Contraindication / Caution

Contraindication/Caution:    

Contraindication  

None 

Cautions 

Gastrointestinal adverse reactions 

Elevated liver transaminase levels 

Pregnancy / Lactation

Pregnancy Warnings:    

Pregnancy category: N/A    

Lactation: Excretion in human breastmilk is unknown    

Pregnancy categories:    

Category A: Satisfactory and well-controlled studies show no evidence of risk to the fetus in the first trimester or in the later trimester.    

Category B: No evidence of risk to fetus found in animal reproduction studies and there are not enough studies on pregnant women.    

Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women.    

Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category clearly outweigh risks over benefits. These category drugs should be prohibited for pregnant women.     

Category N: There is no data available for the drug under this category.     

Pharmacology

Pharmacology:    

Doxecitine and doxribtimine are synthetic pyrimidine nucleosides designed to restore mitochondrial DNA (mtDNA) synthesis in patients with thymidine kinase 2 deficiency (TK2D). TK2D is a mitochondrial disorder that impairs the phosphorylation of deoxynucleosides, leading to depletion of the mitochondrial deoxynucleotide (dNTP) pool and subsequent mtDNA depletion. 

Pharmacokinetics:     

Absorption 

The peak plasma concentration occurs approximately 2 hours after administration for doxecitine and about 4 hours after administration for doxribtimine. 

Distribution 

Both doxecitine and doxribtimine exhibit less than 10% protein binding. The volume of distribution is approximately 0.23 mcg/mL for doxecitine and 23 mcg/mL for doxribtimine. 

Metabolism 

Doxecitine and doxribtimine are primarily metabolized by cytidine deaminase and thymidine phosphorylase, respectively, yielding their corresponding nucleobases and a 2-deoxy-α-D-ribose 1-phosphate moiety. The intermediate metabolites of doxecitine include deoxyuridine, uracil, and dihydrouracil, which are further broken down into the end products β-alanine, ammonia, and carbon dioxide (CO₂). 

Excretion and Elimination 

The elimination half-life of doxecitine is approximately 1 hour, while that of doxribtimine is about 5 hours. Both compounds are excreted primarily through non-renal pathways, with less than 1% of the administered dose of intact doxecitine and doxribtimine recovered in the urine. 

Adminstartion

Administration:    

Before each oral administration, the tightly closed mixing bottle should be gently inverted back and forth at least three times to ensure uniform suspension of the solution. The medication should be administered using one of the two provided methods, either the dosing cup or the oral syringe included in the ZX2000 administration kit. 

Patient Information Leaflet

Patient information leaflet    

Generic Name:   doxecitine/doxribtimine 

Why do we use doxecitine/doxribtimine?

Doxecitine and doxribtimine are indicated for the treatment of thymidine kinase 2 deficiency (TK2D) in both adult and pediatric patients who developed symptoms at or before 12 years of age. TK2D is a rare, progressive mitochondrial DNA depletion syndrome that primarily affects skeletal muscle, leading to muscle weakness, respiratory insufficiency, and motor decline. The goal of therapy is to restore mitochondrial DNA synthesis and improve muscle function.