Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
In MoCD Type A, the lack of effective SOX leads to elevated levels of the neurotoxic sulfite, S-sulfocysteine (SSC). Treatment with NULIBRY resulted in a reduction in the level of urinary SSC normalized to creatinine and the reduction was sustained with long-term treatment with NULIBRY [see Clinical Studies (14)].
Cardiac Electrophysiology
At the maximum approved recommended dose, Nulibry did not prolong the QT interval to any clinically relevant extent.

Pharmacokinetic Properties

12.3 Pharmacokinetics
The pharmacokinetics of fosdenopterin in healthy adult subjects following a single intravenous NULIBRY infusion are summarized in Table 3. The area under the plasma concentration-time curve (AUC) and the maximum plasma concentration (Cmax) of fosdenopterin increased in an approximately proportional manner with increasing doses.

Table 3         Mean (SD) Pharmacokinetic Parameters Following A Single Intravenous Dose of Fosdenopterin in Healthy Subjects
Parameter                        0.075 mg/kg1              0.24 mg/kg1              0.68 mg/kg1 
Cmax (ng/mL)                     285 (57)                  873 (99)                 2800 (567) AUC0-inf (ng*h/mL)               523 (75)                  1790 (213)               5960 (1820) 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 (Vd) of fosdenopterin was approximately 300 mL/kg. The plasma protein binding of fosdenopterin ranged from 6 to 12%.
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.
Metabolism
Fosdenopterin is predominantly metabolized through nonenzymatic degradation processes to Compound Z, an inactive oxidation product of endogenous cPMP.
Excretion
Renal clearance of fosdenopterin accounts for approximately 40% of total body clearance.
Specific Populations
The effect of renal and hepatic impairment on the pharmacokinetics of fosdenopterin is unknown.
Pediatric Patients
Pharmacokinetic properties of fosdenopterin in pediatric MoCD Type A patients are similar to healthy adult subjects.
Drug Interaction Studies
In Vitro Studies
Cytochrome P450 (CYP) Enzymes: Fosdenopterin does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5. Fosdenopterin does not induce CYP1A2, CYP2B6, or CYP3A4.
Transporter Systems: Fosdenopterin is a weak inhibitor of MATE2-K and OAT1, but does not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT3, and MATE1.
Fosdenopterin is a weak substrate for MATE1, but is not a substrate of P-gp, BCRP, OATP1B1, OATP1B3, OCT2, OAT1, OAT3, or MATE2-K.