FOLOTYN Solution for injection Ref.[10174] Active ingredients: Pralatrexate

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

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 L, 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 FOLOTYN 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.

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 FOLOTYN, 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 (f_e) 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.

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.

The efficacy of FOLOTYN was evaluated in Study PDX-008, an open-label, single-arm, multi-center, international trial that enrolled patients with relapsed or refractory PTCL. One hundred and eleven patients received FOLOTYN 30 mg/m² intravenously over 3 to 5 minutes once weekly by 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 major efficacy outcome measure was overall response rate (complete response, complete response unconfirmed, and partial response) as assessed by International Workshop Criteria (IWC). An additional efficacy outcome measure 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 first 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 was 59 years (range: 21 to 85); 68% were male; 72% were White, 13% were Black, 8% were Hispanic and 5% were Asian. Patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (39%), 1 (44%), or 2 (17%). The median time from initial diagnosis to study entry was 1.3 years (range 24 days to 26.8 years). The median number of prior systemic therapies was 3 (range 1 to 12). Approximately 24% of patients (n=27) did not have evidence of response to any previous therapy. Approximately 63% of patients (n=70) did not have evidence of response to their most recent prior therapy before entering the study.

Efficacy results are provided in Table 5.

Table 5. Efficacy Results for Study PDX-008 per Independent Central Review (IWC):

Fourteen patients went off treatment in cycle 1; 2 patients were unevaluable for response by IWC due to insufficient materials provided to central review.
CR = Complete Response, CRu = Complete Response unconfirmed, PR = Partial Response

The initial response assessment was scheduled at the end of cycle 1. Of the responders, 66% responded within cycle 1. The median time to first response was 45 days (range 37-349 days).