"Sabahaddin Akman, owner of the Istanbul, Turkey, firm Ozay Pharmaceuticals, has pleaded guilty to charges of smuggling misbranded and adulterated cancer treatment drugs into the United States.
Akman pleaded guilty in the U.S. District Court"...
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.
The pharmacokinetics of pralatrexate administered as a single agent at a dose of 30 mg/m² administered as an intravenous push over 3-5 minutes 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 of pralatrexate was 12-18 hours (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 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.
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 3-5 minutes 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 Use In Specific Populations].
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.
In vitro studies indicated that pralatrexate does not induce or inhibit the activity of CYP450 isozymes at concentrations of pralatrexate that can be reasonably expected clinically.
In vitro, pralatrexate is a substrate for the breast cancer resistance protein (BCRP), MRP2, multidrug resistanceassociated protein 3 (MRP3), and organic anion transport protein 1B3 (OATP1B3) transporter systems at concentrations of pralatrexate that can be reasonably expected clinically. Pralatrexate is not a substrate of the P glycoprotein (P-gp), organic anion transport protein 1B1 (OATP1B1), organic cation transporter 2 (OCT2), organic anion transporter 1 (OAT1), and organic anion transporter 3 (OAT3) transporter systems.
In vitro, pralatrexate inhibits MRP2 and MRP3 transporter systems ([I]/IC50 > 0.1) at concentrations of pralatrexate that can be reasonably expected clinically. MRP3 is a transporter that may affect the transport of etoposide and teniposide.
In vitro, pralatrexate did not significantly inhibit the P-gp, BCRP, OCT2, OAT1, OAT3, OATP1B1, and OATP1B3 transporter systems at concentrations of pralatrexate that can be reasonably expected clinically.
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 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 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 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 of treated patients was 59.0 years (range 21-85); 68% were male and 32% were female. Most patients were White (72%) and other racial origins included: 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 one-fourth of patients (24%, n = 27) did not have evidence of response to any previous therapy. Approximately two-thirds 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) (Table 5).
Table 5 : Response Analysis per Independent Central
|Evaluable Patients (N=109)||Median Duration of Response||Range of Duration of Response|
|N (%)||95% CI|
|CR+CRu+PR||29 (27)||19, 36||287 days (9.4 months)||1-503 days|
|Responses ≥ 14 weeks|
|CR+CRu+PR||13 (12)||7, 20||Not Reached||98-503 days|
|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).
Last reviewed on RxList: 6/7/2012
This monograph has been modified to include the generic and brand name in many instances.
Additional Folotyn Information
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