Pharmacology: Pharmacodynamics: Mechanism of Action:
Pralatrexate is a folate analog metabolic inhibitor that competitively inhibits dihydrofolate reductase. It is also a competitive inhibitor for polyglutamylation by the enzyme folylpolyglutamyl synthetase. This inhibition results in the depletion of thymidine and other biological molecules the synthesis of which depends on single carbon transfer.
Clinical Studies: Peripheral T-Cell Lymphoma (PTCL):
The safety and efficacy of Folotyn was evaluated in an open-label, single-arm, multi-center, international trial that enrolled 115 patients with relapsed or refractory PTCL. One hundred and eleven (111) patients were treated with Folotyn at 30 mg/m2
once weekly by IV push over 3-5 min for 6 weeks in 7-week cycles until disease progression or unacceptable toxicity. Of the 111 patients treated, 109 patients were evaluable for efficacy. Evaluable patients had histologically confirmed PTCL by independent central review using the revised European-American lymphoma (REAL) World Health Organization (WHO) disease classification and relapsed or refractory disease after at least one prior treatment.
The primary efficacy endpoint was overall response rate (complete response, complete response unconfirmed and partial response) as assessed by international workshop criteria (IWC). The key secondary efficacy endpoint was duration of response. Response assessments were scheduled at the end of cycle 1 and then every other cycle (every 14 weeks). Duration of response was measured from the 1st day of documented response to disease progression or death. Response and disease progression were evaluated by independent central review using the IWC.
The median age of treated patients was 59 years (range 21-85); 68% were male and 32% were female. Most patients were White (72%) and other racial origins including: Black (13%), Hispanic (8%), Asian (5%), other and unknown (<1% each). Patients had an Eastern cooperative oncology group (ECOG) performance status at study entry of 0 (39%), 1 (44%) or 2 (17%). The median time from initial diagnosis to study entry was 15.6 months (range 0.8-322.3).
The median number of prior systemic therapies was 3 (range 1-12). Approximately ¼ of patients (24%, n=27) did not have evidence of response to any previous therapy. Approximately 2
of patients (63%, n=70) did not have evidence of response to their most recent prior therapy before entering the study.
In all evaluable patients (n=109) treated with Folotyn, the response rate, as determined by independent central review by IWC, was 27% (n=29). (See Table1.)
Click on icon to see table/diagram/image
The initial response assessment was scheduled at the end of cycle 1. Of the responders, 66% responded within cycle 1. The median time to 1st response was 45 days (range 37-349 days).
The pharmacokinetics of pralatrexate administered as a single agent at a dose of 30 mg/m2
administered as an intravenous (IV) push over 3-5 min once weekly for 6 weeks in 7-week cycles have been evaluated in 10 patients with PTCL. The total systemic clearance of pralatrexate diastereomers was 417 mL/min (S
-diastereomer) and 191 mL/min (R
-diastereomer). The terminal elimination half-life (t½
) of pralatrexate was 12-18 hrs [coefficient of variance (CV)=62-120%]. Pralatrexate total systemic exposure (AUC) and maximum plasma concentration (Cmax
) increased proportionally with dose (dose range 30-325 mg/m2
, including pharmacokinetics data from high-dose solid tumor clinical studies). The pharmacokinetics of pralatrexate did not change significantly over multiple treatment cycles and no accumulation of pralatrexate was observed.
Pralatrexate diastereomers showed a steady-state volume of distribution of 105 L (S
-diastereomer) and 37 L (R
-diastereomer). In vitro
studies indicate that pralatrexate is approximately 67% bound to plasma proteins. In in vitro
transporter studies, pralatrexate was a low to moderate substrate for BCRP, OATP1B1, MRP2 and MRP3, and a substrate for OATP1B3. Pralatrexate was not a significant substrate for P-gp, OCT2, OAT1 and OAT3. Pralatrexate did not significantly inhibit P-gp, BCRP, OCT2, OAT1, OAT3 and OATP1B3. Pralatrexate was a weak inhibitor of OATP1B1 (35% inhibition at 100 micrometer) and MRP2 (IC50
=43.5 micrometer) and a potent inhibitor of MRP3 (IC50
Metabolism: In vitro
studies using human hepatocytes, liver microsomes and S9 fractions and recombinant human CYP450 isozymes showed that pralatrexate is not significantly metabolized by the phase I hepatic CYP450 isozymes or phase II hepatic glucuronidases. In vitro
studies indicated that pralatrexate has low potential to induce or inhibit the activity of CYP450 isozymes.
A mass balance study has not been performed. The mean fraction of unchanged pralatrexate diastereomers excreted in urine following a pralatrexate dose of 30 mg/m2
administered as an IV push over 3-5 min was 31% (S
-diastereomer) (CV=47%) and 38% (R
-diastereomer) (CV=45%), respectively.
Patients with Renal Impairment:
Approximately 34% of pralatrexate was excreted unchanged into urine following a single dose of 30 mg/m2
administered as an IV push over 3-5 min. In a population pharmacokinetic analysis drug clearance decreased with decreasing creatinine clearance (see Precautions).
Patients with Hepatic Impairment:
Pralatrexate has not been studied in patients with hepatic impairment.
Effects of Age and Gender:
Due to the contribution of renal excretion to overall clearance of pralatrexate, age-related decline in renal function may lead to a reduction in clearance and a commensurate increase in plasma exposure. There was no significant effect of gender on pharmacokinetics.
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis:
Carcinogenicity studies have not been performed with pralatrexate.
Pralatrexate did not cause mutations in the Ames test or the Chinese hamster ovary cell chromosome aberration assay. Nevertheless, these tests do not reliably predict genotoxicity for this class of compounds. Pralatrexate did not cause mutations in the mouse micronucleus assay. However, in the in vitro
chromosomal aberration test, inhibition of mitosis resulted at concentrations far below what is encountered in vivo
in clinical use. Based on the pharmacology of pralatrexate and experience with other folate analogs, an increased risk for genotoxicity from pralatrexate treatment cannot be excluded.
Impairment of Fertility:
No fertility studies have been performed.