Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
Pralatrexate exposure-response relationship and the time course of pharmacodynamics responses are unknown.

Pharmacokinetic Properties

12.3 Pharmacokinetics
Pralatrexate is a racemic mixture of S- and R-diastereomers. The pharmacokinetics of pralatrexate at the recommended dosage of 30 mg/m2 once weekly have been evaluated in 10 patients with PTCL. Pralatrexate total systemic exposure (AUC) and maximum plasma concentration (C max) increased proportionally over a dose range 30 to 325 mg/m2 (10.8 times the approved recommended dosage). No accumulation of pralatrexate was observed.

Distribution
Steady-state volume of distribution of pralatrexate S- and R-diastereomers is 105 L and 37 respectively Protein binding of pralatrexate is approximately 67% in vitro.

Elimination
The total systemic clearance of pralatrexate diastereomers was 417 mL/min (S-diastereomer) and 191 mL/min (R-diastereomer). The terminal elimination half-life of pralatrexate was 12-18 hours (coefficient of variance [CV] = 62-120%).

Metabolism
Pralatrexate is not significantly metabolized by CYP450 isozymes or glucuronidases in vitro.

Excretion
Following a single dose of Difolta 30 mg/m2 , approximately 34% of the pralatrexate dose was excreted unchanged into urine. Following a radiolabeled pralatrexate dose, 39% (CV = 28%) of the dose was recovered in urine as unchanged pralatrexate and 34% (CV = 88%) in feces as unchanged pralatrexate and/or any metabolites. 10% (CV = 95%) of the dose was exhaled over 24 hours.

Pharmacokinetics in-Specific Populations

No clinically meaningful effect on the pharmacokinetics of pralatrexate was observed based on sex. The effect of hepatic impairment on the pharmacokinetics of pralatrexate has not been studied.
Patients with Renal Impairment
Following administration of a single dose of Difolta, mean exposures of the pralatrexate S-diastereomer and R- diastereomer were comparable in patients with mild to moderate (eGFR 30 to 59 mL/min/1.73 m2 based on MDRD) renal impairment as compared with severe (eGFR 15 to 29 mL/min/1.73 m2) renal impairment. The mean fraction of the administered dose excreted as unchanged diastereomers in urine (fe) decreased with declining renal function [see Use in Specific Populations (8.6)].
Drug Interaction Studies
Clinical Studies
Coadministration of probenecid (an inhibitor of multidrug resistance-associated protein 2 [MRP2] in vitro) resulted in delayed clearance of pralatrexate.
In Vitro Studies
Cytochrome P450 (CYP) Enzymes: Pralatrexate does not induce or inhibit CYP enzymes.
Transporter Systems: Pralatrexate is a substrate for BCRP, MRP2, MRP3, and OATP1B3, but is not a substrate of P-gp, OATP1B1, OCT2, OAT1, or OAT3.
Pralatrexate inhibits MRP2 and MRP3, but does not inhibit P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B1, or OATP1B3. MRP3 is a transporter that may affect the transport of etoposide and teniposide.