Repotrectinib is a next-generation macrocyclic tyrosine kinase inhibitor (TKI) developed to target ROS1 and TRK family kinases. It is the active pharmaceutical ingredient in AUGTYRO and is used for the treatment of ROS1-positive non-small cell lung cancer. The FDA also approved repotrectinib for certain locally advanced or metastatic solid tumors with NTRK gene fusions.
Repotrectinib has the molecular formula C18H18FN5O2 and molecular weight 355.37 g/mol. It is a white to off-white powder and contains two chiral centers. EMA reports that polymorphism has been observed for the active substance.
Repotrectinib is a potent kinase inhibitor targeting ROS1, TRKA, TRKB and TRKC, with activity against several resistance-associated mutations. Its macrocyclic structure was designed to maintain activity against kinase alterations that can confer resistance to earlier-generation TKIs.
The pharmaceutical API is manufactured as a defined active substance whose regulatory characterization includes appearance, identification, assay, related substances, stereoisomeric purity, residual solvents and particle-size testing. EMA confirms that the active substance specification uses IR and LC identification, RP-UPLC assay and related-substance testing, NP-HPLC for stereoisomers and GC for residual solvents.
| Parameter | Value |
|---|---|
| Chemical Name | (3R,11S)-6-Fluoro-3,11-dimethyl-10-oxa-2,13,17,18,21-pentaazatetracyclo[13.5.2.0⁴,⁹.0¹⁸,²²]docosa-1(21),4,6,8,15(22),16,19-heptaen-14-one |
| CAS Number | 1802220-02-5 |
| Molecular Formula | C18H18FN5O2 |
| Molecular Weight | 355.37 g/mol |
| Chemical Type | Macrocyclic small molecule |
| Drug Class | Tyrosine kinase inhibitor |
| Target | ROS1 / TRK family kinases |
| Physical Form | White to off-white powder |
| Stereochemistry | Two chiral centers |
| Solid-State Property | Polymorphism observed |
| Aqueous Solubility | 0.006–0.008 mg/mL across physiological pH range |
| Development Code | TPX-0005 |
The CAS number, molecular formula and molecular weight are confirmed by PubChem and FDA documentation.
Repotrectinib is indicated for:
The FDA initially approved AUGTYRO for ROS1-positive NSCLC in November 2023 and subsequently expanded its indication to NTRK fusion-positive solid tumors in 2024.
Repotrectinib API quality control requires analytical methods capable of controlling both chemical purity and stereochemical composition.
Important quality attributes include:
EMA specifically confirms RP-UPLC assay and related-substance testing, NP-HPLC stereoisomer testing, GC residual-solvent testing and Ph. Eur. particle-size testing for the active substance.
Repotrectinib API manufacturing requires careful control of stereochemistry, impurities, residual solvents and particle-size characteristics. Because polymorphism has been observed, control of the solid-state form is also important for maintaining consistent API quality.
FDA reports that repotrectinib has pH-independent aqueous solubility of approximately 0.006–0.008 mg/mL across the physiological pH range, confirming its practically insoluble character in water.
Repotrectinib active substance is stable under the validated storage conditions evaluated in the regulatory stability program. EMA reports long-term stability testing at 25°C/60% RH and accelerated testing at 40°C/75% RH, with no significant trends in assay, impurities, chiral impurities, water content or particle-size distribution.
The finished AUGTYRO capsules should be stored according to the applicable approved product labeling.
Typical Repotrectinib API documentation may include:
Repotrectinib is a modern macrocyclic kinase inhibitor requiring controlled chemical purity, stereochemical purity, residual solvents and solid-state characteristics. A robust analytical program should follow validated chromatographic and physicochemical methods consistent with applicable ICH and pharmacopoeial requirements.
| Parameter | Specification |
|---|---|
| Appearance | white to off-white crystalline powder |
| Identification | IR & HPLC compliant |
| Assay (HPLC) | 98.0% – 102.0% |
| Loss on Drying | NMT 0.5% |
| Heavy Metals | NMT 20 ppm |
| pH (1% Solution) | 4.0–10.0 |
| Individual Impurity | NMT 0.10% |
| Total Impurities | NMT 1.0% |
| Water Content | NMT 5.0% |