t 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 μM) and MRP2 (IC50 = 43.5 μM) and a potent inhibitor of MRP3 (IC50 < 0.3 μM).
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.
Excretion
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 intravenous push over 3-5minutes 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 intravenous push over 3-5 minutes. In a population pharmacokinetic analysis drug clearance decreased with decreasing creatinine clearance [see Warnings and Precautions (5.7)].
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.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Carcinogenicity studies have not been performed with pralatrexate.
Mutagenesis
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.
Impairment of Fertility
No fertility studies have been performed.
14 CLINICAL STUDIES
Peripheral T-cell Lymphoma (PTCL)
The safety and efficacy of FOLOTYN was eva luated in an open-label, single-arm, multi-center, international trial that enrolled 115patients with relapsed or refractory PTCL. One hundred and eleven patients were treated with FOLOTYN at 30 mg/m2 once weekly by IV push over 3-5 minutes for 6 weeks in 7-week cycles until disease progression or unacceptable toxicity. Of the 111 patients treated, 109 patients were eva luable for efficacy. eva luable 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 Cr
