Fosdenopterin

Patients with MoCD Type A have mutations in the Molybdenum Cofactor Synthesis 1 (MOCS1) gene leading to deficient MOCS1A/B dependent synthesis of the intermediate substrate, cPMP. Substrate replacement therapy with fosdenopterin provides an exogenous source of cPMP, which is converted to molybdopterin. Molybdopterin is then converted to molybdenum cofactor, which is needed for the activation of molybdenum-dependent enzymes, including sulphite oxidase (SOX), an enzyme that reduces levels of neurotoxic sulphites.

The pharmacokinetics of fosdenopterin in healthy adult subjects following a single intravenous administration of fosdenopterin are summarised in the table below. The area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (C_max) of fosdenopterin increased in an approximately proportional manner with increasing doses.

Mean (SD) pharmacokinetic parameters following a single intravenous dose of fosdenopterin in healthy subjects:

¹ 0.075 mg/kg, 0.24 mg/kg, and 0.68 mg/kg doses are 0.08, 0.27, and 0.76 times the recommended maximum dose, respectively.

Distribution

The volume of distribution (V_d) of fosdenopterin was approximately 300 mL/kg. The plasma protein binding of fosdenopterin ranged from 6 to 12%.

Biotransformation

Fosdenopterin is predominantly metabolised through nonenzymatic degradation processes to an inactive oxidation product of endogenous cPMP.

Investigation of potential for drug interaction

The potential for drug-drug interactions based on cytochrome P450 (CYP) and/or transporter interactions was studied in a number of in vitro studies.

Fosdenopterin does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 isozymes when tested in vitro in human liver microsomes. There was little or no direct time-dependent or metabolism-dependent inhibition of these isozymes, and the half maximal inhibitory concentration (IC₅₀) values were reported as >500 µM. Fosdenopterin did not demonstrate induction of CYP1A2, CYP2B6, or CYP3A4. Treatment of cultured human hepatocytes with up to 100 µM fosdenopterin produced little or no increase in CYP1A2, CYP2B6, or CYP3A4 mRNA and enzyme activity levels.

Fosdenopterin does not inhibit efflux or uptake transporters. Inhibition of P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1 (20 μM), OAT3, MATE1, and MATE2-K (20 μM) was reported as <10% at 200 μM, while cPMP demonstrated slight inhibition of MATE2-K (25%) and OAT1 (33%) at 200 μM. Fosdenopterin is not a substrate of P-gp, BCRP, OAT1, OAT3, OATP1B1, OATP1B3, OCT2, or MATE2-K, and is possibly a weak substrate for MATE1.

Elimination

The mean total body clearance (CL) of fosdenopterin ranged from 167 to 195 mL/h/kg. The mean half-life of fosdenopterin ranged from 1.2 to 1.7 hours.

Renal clearance of fosdenopterin accounts for approximately 40% of total body clearance.

Specific populations

Studies have not been conducted to evaluate the pharmacokinetics of fosdenopterin in specific patient populations, identified by race, age, or the presence of renal or hepatic impairment. The effect of renal and hepatic impairment on the pharmacokinetics of fosdenopterin is unknown.

Paediatric population

Pharmacokinetic properties of fosdenopterin in paediatric MoCD Type A patients are similar to healthy adult subjects.

Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity in juvenile animals, and genotoxicity.

Carcinogenicity

Carcinogenicity studies have not been conducted with fosdenopterin.

Reproductive and developmental toxicity

Reproductive and developmental toxicity studies have not been conducted with fosdenopterin.

Phototoxicity

Fosdenopterin was phototoxic in vitro and in vivo. In rats, cutaneous skin reactions (erythema, oedema, flaking, and eschar) and ophthalmic and histopathologic changes were observed after UV radiation.