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Pralatrexate | CAS No: 146464-95-1 | GMP-certified suppliers
A medication that treats relapsed or refractory peripheral T-cell lymphoma by providing targeted antineoplastic activity with a narrow therapeutic index requiring high-quality API sourcing.
Therapeutic categories
AntimetabolitesAntineoplastic AgentsAntineoplastic and Immunomodulating AgentsBCRP/ABCG2 SubstratesDrugs that are Mainly Renally ExcretedFolic Acid Analogues
Generic name
Pralatrexate
Molecule type
small molecule
CAS number
146464-95-1
DrugBank ID
DB06813
Approval status
Approved drug, Investigational drug
ATC code
L01BA05
Primary indications
- Pralatrexate is indicated for the treatment of relapsed or refractory peripheral T-cell lymphoma
Product Snapshot
- Pralatrexate is an injectable small molecule formulation administered intravenously
- It is primarily used for the treatment of relapsed or refractory peripheral T-cell lymphoma
- The product holds approved status in the US and Canada, with both approved and investigational indications
Clinical Overview
Pralatrexate (CAS Number 146464-95-1) is an antifolate antineoplastic agent primarily indicated for the treatment of relapsed or refractory peripheral T-cell lymphoma. It addresses a clinical need due to suboptimal responses observed with standard therapies for peripheral T-cell lymphomas compared to B-cell malignancies.
Pharmacologically, pralatrexate is a folate analog that inhibits folate metabolism, a critical pathway for the synthesis of nucleic acids and amino acids in rapidly proliferating cancer cells. It exerts cytotoxic effects by selectively targeting cancer cells that overexpress the reduced folate carrier protein-1 (RFC-1). Pralatrexate has an approximately tenfold higher affinity for RFC‐1 than methotrexate, facilitating enhanced cellular uptake. Once inside the cell, it competitively inhibits dihydrofolate reductase (DHFR) and undergoes polyglutamylation by folylpolyglutamate synthase (FPGS), which increases intracellular retention and further impedes folate metabolism.
Key pharmacodynamic parameters include a Kₘ value for RFC-1 of 0.3 μmol/L compared to 4.8 μmol/L for methotrexate and a Kₘ for FPGS of 5.9 μmol/L versus 32.3 μmol/L for methotrexate, reflecting pralatrexate’s enhanced potency and retention in tumor cells.
Absorption, distribution, metabolism, and excretion (ADME) data indicate primary renal excretion, with pralatrexate classified among drugs mainly renally eliminated. Safety considerations focus on toxicities common to antifolates, most notably mucositis, which may necessitate dose modification. Cardiac safety has been evaluated in supratherapeutic dosing scenarios showing no clinically relevant prolongation of the QT interval or hERG channel inhibition, suggesting a low risk of cardiac repolarization abnormalities at therapeutic doses.
Since its FDA approval in 2009, pralatrexate has also been investigated in other malignancies, including non-small-cell lung cancer, breast cancer, and bladder cancer, although peripheral T-cell lymphoma remains its primary approved indication.
For pharmaceutical development and API sourcing, attention to stringent quality standards is essential due to pralatrexate’s narrow therapeutic index and complex synthesis pathway. Ensuring consistency in purity, polymorphic form, and impurity profiles aligns with regulatory requirements and supports safe formulation development and patient use globally.
Pharmacologically, pralatrexate is a folate analog that inhibits folate metabolism, a critical pathway for the synthesis of nucleic acids and amino acids in rapidly proliferating cancer cells. It exerts cytotoxic effects by selectively targeting cancer cells that overexpress the reduced folate carrier protein-1 (RFC-1). Pralatrexate has an approximately tenfold higher affinity for RFC‐1 than methotrexate, facilitating enhanced cellular uptake. Once inside the cell, it competitively inhibits dihydrofolate reductase (DHFR) and undergoes polyglutamylation by folylpolyglutamate synthase (FPGS), which increases intracellular retention and further impedes folate metabolism.
Key pharmacodynamic parameters include a Kₘ value for RFC-1 of 0.3 μmol/L compared to 4.8 μmol/L for methotrexate and a Kₘ for FPGS of 5.9 μmol/L versus 32.3 μmol/L for methotrexate, reflecting pralatrexate’s enhanced potency and retention in tumor cells.
Absorption, distribution, metabolism, and excretion (ADME) data indicate primary renal excretion, with pralatrexate classified among drugs mainly renally eliminated. Safety considerations focus on toxicities common to antifolates, most notably mucositis, which may necessitate dose modification. Cardiac safety has been evaluated in supratherapeutic dosing scenarios showing no clinically relevant prolongation of the QT interval or hERG channel inhibition, suggesting a low risk of cardiac repolarization abnormalities at therapeutic doses.
Since its FDA approval in 2009, pralatrexate has also been investigated in other malignancies, including non-small-cell lung cancer, breast cancer, and bladder cancer, although peripheral T-cell lymphoma remains its primary approved indication.
For pharmaceutical development and API sourcing, attention to stringent quality standards is essential due to pralatrexate’s narrow therapeutic index and complex synthesis pathway. Ensuring consistency in purity, polymorphic form, and impurity profiles aligns with regulatory requirements and supports safe formulation development and patient use globally.
Identification & chemistry
| Generic name | Pralatrexate |
|---|---|
| Molecule type | Small molecule |
| CAS | 146464-95-1 |
| UNII | A8Q8I19Q20 |
| DrugBank ID | DB06813 |
Pharmacology
| Summary | Pralatrexate is a folate analog metabolic inhibitor targeting dihydrofolate reductase (DHFR) and thymidylate synthase to disrupt folate-dependent nucleotide and amino acid synthesis in cancer cells. It selectively enters cells via high-affinity binding to the reduced folate carrier protein-1 (RFC-1) and undergoes polyglutamylation by folylpolyglutamate synthase (FPGS), enhancing intracellular retention and sustained enzymatic inhibition. This dual mechanism impedes tumor cell proliferation, particularly in relapsed or refractory peripheral T-cell lymphoma. |
|---|---|
| Mechanism of action | Pralatrexate is a folate analog metabolic inhibitor that competitively inhibits dihydrofolate reductase (DHFR) selectively in cancer cells overexpressing the reduced folate carrier protein-1 (RFC-1). Folate is a water-soluble vitamin required for DNA synthesis and maintenance as well as DNA, RNA, and protein methylation. As cancer cells are rapidly replicating, they require a lot of folates to accommodate an accelerated cell division and DNA and protein modification for cellular transformation.[A246654, A246659] Therefore, interruption with folate metabolism can inhibit tumor growth. Additionally, pralatrexate also undergoes polyglutamylation catalyzed by folyopolyglutamate synthase (FPGS). This reaction both increases cellular retention of pralatrexate for extended drug action and impedes the uptake of folate, also a substrate of FPGS, to further inhibit folate metabolism in cancer cells. |
| Pharmacodynamics | Pralatrexate is a folate analog that inhibits folate metabolism, thus impeding the synthesis of amino acids and nucleic acid. Additionally, pralatrexate also competes for enzymatic processing by folyopolyglutamate synthase (FPGS)with folate to increase cellular retention. Compared to methotrexate, pralatrexate binds to the reduced folate carrier protein-1 (RFC-1) for cellular uptake with 10-times the affinity and is a more potent substrate for FPGS. The K<sub>m</sub> value for RFC-1 was calculated to be 0.3 μmol/L and 4.8 μmol/L for pralatrexate and methotrexate respectively, while the K<sub>m</sub> value for FPGS was estimated to be 5.9 and 32.3 µmol/l for pralatrexate and methotrexate respectively. As a result, pralatrexate is more cytotoxic and better retained in cancer cells. Due to its anti-folate activity, pralatrexate's main toxicity is manifested as mucositis that can require dose interruption or reduction. In 5 patients with non-small-cell lung carcinoma receiving a supratherapeutic dose of 230 mg/m<sup>2</sup>, the mean change from pre-injection QTcF interval at the end of infusion was 6.1 ms (90%CI: -0.6, 12.7), and at 1-hour post-injection was 7.8 ms (90%CI: 3.0, 12.6). However, no patient exceeded a QTcF of 470 msec and exhibited an absolute increase from baseline in QTcF exceeding 30 msec. As well, the study dose far exceeded the target dose for patients with peripheral T-cell lymphoma and pralatrexate does not inhibit the human ether-a-go-go-related gene (hERG) K<sup>+</sup> channel. Therefore, pralatrexate uses are unlikely to cause cardiac repolarization delays.[A246678, L41559]. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Dihydrofolate reductase | Humans | substrate, inhibitor |
| Thymidylate synthase | Humans | substrate, inhibitor |
| Folylpolyglutamate synthase, mitochondrial | Humans | substrate |
ADME / PK
| Absorption | With an intravenous formulation, pralatrexate has complete bioavailability. Pralatrexate demonstrates a dose-proportional and linear pharmacokinetics over a dose range of 30-325 mg/m<sup>2</sup>. Upon an intravenous push over 3 to 5 minutes of a starting dose of 30 mg/m<sup>2</sup> racemic pralatrexate for dose 1 of cycle 1, C<sub>max</sub> and AUC<sub>0-∞</sub> was estimated to be 5,815 ng/mL and 267,854 ng/mL.min respectively using a noncomparmental pharmacokinetics analysis.Both pralatrexate diastereomers demonstrates a multiphase decline in plasma concentration with a rapid initial fall followed by a slow terminal phase. The initial fall is thought to reflect the clearance of pralatrexate by renal and non-renal mechanism , while the slow terminal phase likely represents the return of pralatrexate from deep intracellular compartments, enterohepatic circulation, or after deglutamination. |
|---|---|
| Half-life | The terminal elimination half-life of pralatrexate was 12-18 hours (coefficient of variance [CV] = 62-120%). |
| Protein binding | The protein binding of pralatrexate is approximately 67% in vitro. |
| Metabolism | While the liver has been shown to metabolize pralatrexate to some extent, pralatrexate is not significantly metabolized by any CYP450 isozymes or glucuronidases in vitro. |
| Route of elimination | Following a single dose of FOLOTYN 30 mg/m<sup>2</sup>, 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. |
| Volume of distribution | The steady-state volume of distribution of pralatrexate S- and R-diastereomers is 105 L and 37 L, respectively. |
| Clearance | The total systemic clearance of pralatrexate diastereomers was 417 mL/min (S-diastereomer) and 191 mL/min (R-diastereomer). |
Formulation & handling
- Pralatrexate is a small molecule API primarily intended for intravenous administration in solution or injection form.
- The compound exhibits low water solubility, necessitating careful consideration in formulation to ensure adequate solubilization for injection.
- Handling should account for its chemical class as a glutamic acid derivative, with standard precautions for stability and storage under recommended conditions.
Regulatory status
| Lifecycle | The active pharmaceutical ingredient (API) has key patent protection in the United States expiring between July 2022 and May 2025. It is marketed in the US and Canada, with the US market approaching increased generic competition following patent expirations. |
|---|
| Markets | US, Canada |
|---|
Supply Chain
| Supply chain summary | Pralatrexate is primarily supported by a limited number of originator companies with branded products available in the US and Canadian markets. Existing patents in the United States extend until 2025, indicating that generic competition may currently be limited but could increase following patent expirations. No data indicates a significant presence in EU or other global markets. |
|---|
Safety
| Toxicity | Mucositis is dose-limiting toxicity. Folic acid and vitamin B12 supplements do not prevent mucositis from happening. No specific information is available on the treatment of overdosage of pralatrexate. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating healthcare provider. Based on pralatrexate's mechanism of action, consider the prompt administration of [leucovorin]. Carcinogenicity studies and fertility studies have not been performed with pralatrexate.Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], pralatrexate can cause fetal harm when administered to a pregnant woman. There are insufficient data on pralatrexate use in pregnant women to evaluate for a drug-associated risk. Pralatrexate was embryotoxic and fetotoxic in rats and rabbits when administered during organogenesis at doses about 1.2% (0.012 times) of the clinical dose on an mg/m<sup>2</sup> basis. Advise pregnant women of the potential risk to a fetus. 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. |
|---|
High Level Warnings:
- Dose-limiting toxicity includes mucositis
- Folic acid and vitamin B12 supplementation do not mitigate this risk
- Overdosage management lacks specific antidotes
Pralatrexate is a type of Antimetabolites
Antimetabolites are a prominent category of pharmaceutical active pharmaceutical ingredients (APIs) utilized in the treatment of various diseases, particularly cancer. These compounds are structurally similar to naturally occurring metabolites essential for cellular processes such as DNA and RNA synthesis. By mimicking these metabolites, antimetabolites interfere with the normal functioning of cellular pathways, leading to inhibition of cancer cell growth and proliferation.
One of the widely used antimetabolites is methotrexate, a folic acid antagonist that inhibits the enzyme dihydrofolate reductase, disrupting the production of DNA and RNA. This disruption impedes the growth of rapidly dividing cancer cells. Another common antimetabolite is 5-fluorouracil (5-FU), which inhibits the enzyme thymidylate synthase, thereby interfering with DNA synthesis and inhibiting cancer cell proliferation.
Antimetabolites can be classified into several subcategories based on their mechanism of action and chemical structure. These include purine and pyrimidine analogs, folic acid antagonists, and pyrimidine synthesis inhibitors. Examples of antimetabolites in these subcategories include azathioprine, cytarabine, and gemcitabine.
Despite their effectiveness, antimetabolites can exhibit certain side effects due to their interference with normal cellular processes. These side effects may include gastrointestinal disturbances, myelosuppression (reduced production of blood cells), and hepatotoxicity.
In conclusion, antimetabolites are a vital category of pharmaceutical APIs used in the treatment of various diseases, especially cancer. By mimicking natural metabolites and disrupting crucial cellular processes, these compounds effectively inhibit cancer cell growth and proliferation. However, their usage should be carefully monitored due to potential side effects.
Pralatrexate API manufacturers & distributors
Compare qualified Pralatrexate API suppliers worldwide. We currently have 2 companies offering Pralatrexate API, with manufacturing taking place in 1 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| Dr. Sahu's Laboratories | Producer | India | India | BSE/TSE, CEP, CoA, FDA, GMP, MSDS | 70 products |
| Hetero Labs | Producer | India | India | CoA, GMP, USDMF, WC | 90 products |
When sending a request, specify which Pralatrexate API quality you need: for example EP (Ph. Eur.), USP, JP, BP, or another pharmacopoeial standard, as well as the required grade (base, salt, micronised, specific purity, etc.).
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