Epidermal growth factor receptor (EGFR) with activating mutations (e.g., exon 19 deletions, L858R) and the T790M resistance mutation. [1]

In HCC827 cells expressing EGFRDEL19 (IC50=9.2 nM) and H1975 cells expressing EGFRL858R/T790M (IC50=10 nM), olmutinib potently suppresses EGFR. By contrast, olmutinib's IC50 against EGFRWT-expressing cells is 2225 nM [1].

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In a proliferation assay using human non-small cell lung cancer (NSCLC) cell lines, Olmutinib demonstrated potent inhibitory activity against cells harboring EGFR mutations. The half-maximal growth inhibition concentration (IC50) was 9.2 nmol/L for HCC827 cells expressing EGFR exon 19 deletion (DEL19) and 10 nmol/L for H1975 cells expressing the EGFR L858R/T790M double mutation. In contrast, the IC50 against cells expressing wild-type EGFR (EGFR WT) was 2225 nmol/L, indicating high selectivity for mutant forms over the wild-type receptor. [1]
In a separate pharmacodynamic study, Olmutinib potently inhibited EGFR phosphorylation in H1975 cells (EGFR L858R/T790M) with an IC50 of 18 nmol/L, while the IC50 in H358 cells (EGFR WT) was 2000 nmol/L, further confirming its selective inhibition of mutant EGFR signaling. [1]

In long-term tumor xenograft models derived from multiple NSCLC cell lines, including HCC827 (EGFR DEL19) and H1975 (EGFR L858R/T790M), oral administration of Olmutinib at doses of 200 or 400 mg/kg/day for 3 months induced prolonged tumor shrinkage compared to vehicle-treated control groups. [1]

The article mentions studies in tumor xenograft models. Mice bearing tumors derived from NSCLC cell lines (e.g., HCC827, H1975) were treated orally with Olmutinib at doses of 200 or 400 mg/kg/day for a duration of 3 months. T [1]

Absorption, Distribution and Excretion
The time to peak concentration (tmax) after oral administration is 3–4 hours. Data is unavailable. Data is unavailable. Data is unavailable. Metabolites/Metabolites Data is unavailable. Biological half-life 8–11 hours. In patients with EGFR mutation-positive non-small cell lung cancer (NSCLC) who have failed prior EGFR-TKI therapy, oral olotutinib is well absorbed. The median time to reach maximum plasma concentration (Tmax) ranged from 2.5 to 5.9 hours across multiple dose levels. [1] Peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC, exposure) generally increased with increasing dose over a dose range of 75 to 1200 mg/day. [1]
In these patients, the mean elimination half-life (t½) of omamotinib ranged from 8.1 to 18.3 hours. [1]

Protein Binding

Data unavailable.

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In a phase I/II clinical trial (data cutoff date February 29, 2016) involving 76 patients with T790M mutation-positive non-small cell lung cancer (NSCLC), patients received 800 mg olotitinib daily. The most common treatment-related adverse events of any grade were diarrhea (59% of patients), pruritus (42%), rash (41%), and nausea (39%). [1]
The most common grade 3 treatment-related adverse events were rash (5% of patients) and pruritus (1%). Serious treatment-related adverse events occurred in 14% of patients. 5% of patients discontinued treatment due to treatment-related adverse events, including epigastric pain, vomiting, peripheral neuropathy, interstitial lung disease, and skin desquamation. [1]

[1]. Olmutinib: First Global Approval. Drugs. 2016 Jul;76(11):1153-7.

[2]. Detection and characterization of olmutinib reactive metabolites by LC‐MS/MS: Elucidation of bioactivation pathways. Journal of Separation science. 18 November 2019.

Olmutinib is an orally administered, potent epidermal growth factor receptor (EGFR) inhibitor used to treat T790M mutation-positive non-small cell lung cancer. It is marketed under the brand name Olita and manufactured by Hanmi Pharmaceutical. Olmutinib was jointly developed by Hanmi Pharmaceutical and Boehringer Ingelheim. In December 2015, ozOlmutinib received Breakthrough Therapy Designation in the United States and was approved for marketing in South Korea in May 2016. Olmutinib is an orally administered, small-molecule, mutation-selective inhibitor of epidermal growth factor receptor (EGFR) with potential anti-tumor activity. Olmutinib binds to and inhibits the activity of EGFR mutants, leading to the death of EGFR-expressing tumor cells. Due to its selectivity for EGFR mutants, its toxicity may be reduced compared to non-selective EGFR inhibitors that also inhibit wild-type EGFR. Drug Indications: For the treatment of metastatic T790M mutation-positive non-small cell lung cancer. Mechanism of Action Olmutinib covalently binds to cysteine residues near the genotype EGFR kinase domain, thereby preventing receptor phosphorylation. Since phosphorylation is essential for the recruitment of signaling cascade proteins, this drug inhibits receptor signaling. Pharmacodynamics Olmutinib selectively and irreversibly binds to and inhibits epidermal growth factor receptor (EGFR) carrying the T790M activating mutation. EGFR is frequently overexpressed in lung cancer and promotes the activation of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways, both of which promote cell survival and proliferation. Olmutinib attenuates the activation of these pro-tumorigenic pathways by inhibiting EGFR activation. Olmutinib (Olita™) is an oral, third-generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) used to treat non-small cell lung cancer (NSCLC). It was first approved in South Korea in May 2016 for the treatment of patients with locally advanced or metastatic EGFR T790M mutation-positive NSCLC who had previously received EGFR TKI therapy. [1] In December 2015, the U.S. FDA granted olmutinib Breakthrough Therapy Designation for the treatment of non-small cell lung cancer (NSCLC). [1] Its mechanism of action is through the covalent and irreversible binding of the Michael receptor to cysteine residues in the domain of mutant EGFR kinases, thereby effectively inhibiting activating mutations (exon 19 deletion, L858R) and T790M resistance mutations, without affecting wild-type EGFR. [1] In a pivotal Phase I/II clinical trial (NCT01588145), olmutinib showed antitumor activity in patients with advanced EGFR mutation-positive NSCLC who had failed prior EGFR-TKI therapy. In T790M-positive patients (n=70, evaluable), at the recommended phase II dose (800 mg once daily), the objective response rate (ORR) was 61% (54% of which were confirmed partial responses), the disease control rate (DCR) was 90%, and the median duration of response was 8.3 months. The median progression-free survival (PFS) was 6.9 months. [1] The maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) determined in the phase I trial were both 800 mg orally once daily. [1]

C26H26N6O2S

486.5886

486.183

1353550-13-6

1842366-97-5 (2HCl);2102670-48-2 (HCl);1353550-13-6;2102714-68-9 (HCl hydrate);

54758501

Light yellow to yellow solid powder

1.3±0.1 g/cm3

1.706

4.95

2

8

7

35

712

0

FDMQDKQUTRLUBU-UHFFFAOYSA-N

InChI=1S/C26H26N6O2S/c1-3-23(33)27-19-5-4-6-21(17-19)34-25-24-22(11-16-35-24)29-26(30-25)28-18-7-9-20(10-8-18)32-14-12-31(2)13-15-32/h3-11,16-17H,1,12-15H2,2H3,(H,27,33)(H,28,29,30)

N-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)thieno[3,2-d]pyrimidin-4-yl)oxy)phenyl)acrylamide

BI 1482694; HM61713; BI-1482694; HM 61713; BI1482694; HM-61713

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~125 mg/mL (~256.89 mM)

Solubility in Formulation 1: ≥ 6.25 mg/mL (12.84 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 62.5 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: 6.25 mg/mL (12.84 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 62.5 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: 6.25 mg/mL (12.84 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 62.5 mg/mL clear DMSO stock solution to 900 μL corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)