Brigatinib Research Articles

Soluplus-TPGS Mixed Micelles as a Delivery System for Brigatinib: Characterization and In Vitro Evaluation.

Lung cancer is a major public health concern, with a high incidence and fatality rate. Its treatment is very difficult, as it is mostly diagnosed in advanced stages. Non-small cell lung carcinoma (NSCLC) is the major form of lung carcinoma that persists. Brigatinib (BGT), a powerful small-molecule tyrosine kinase inhibitor, has demonstrated significant therapeutic potential in the treatment of NSCLC with anaplastic lymphoma kinase (ALK) mutations. However, the therapeutic applicability of BGT is hampered by its low solubility and bioavailability. In this study, we developed a mixed micelle system comprising Soluplus and TPGS loaded with BGT. BGT was encapsulated into the mixed micelles using various combinations of Soluplus and TPGS, with encapsulation efficiency (EE%) ranging from 52.43 ± 1.07 to 97.88 ± 2.25%. The dynamic light scattering data showed that the mixed micelles ranged in size from 75.7 ± 0.46 to 204.3 ± 5.40 nm. The selected mixed micelles (F6) showed approximately 38% BGT release in the first 2 h, and subsequently, within 72 h, the release was 94.50 ± 5.90%. The NMR experiment confirmed the formation of micelles. Additionally, the mixed micelles showed significantly higher cellular uptake (p < 0.05) and increased cytotoxicity (p < 0.05) as compared to the free BGT. Specifically, the obtained IC50 values for BGT-loaded Soluplus-TPGS mixed micelles and free BGT were 22.59 ± 6.07 and 61.45 ± 6.35 μg/mL, respectively. The results of the in vitro stability experiment showed that the selected mixed micelle (F6) was stable at both room temperature and 4 °C, with only minor changes in size and PDI. Our results indicate great potential for the developed Soluplus-TPGS mixed micelles as a delivery system for BGT.

Quantitative 31P-NMR for the Purity Determination of the Organophosphorus Compound Brigatinib and Its Method Validation.

The spectrum of 31P-NMR is fundamentally simpler than that of 1H-NMR; consequently identifying the target signal(s) for quantitation is simpler using quantitative 31P-NMR (31P-qNMR) than using quantitative 1H-NMR (1H-qNMR), which has been already established as an absolute determination method. We have previously reported a 31P-qNMR method for the absolute determination of cyclophosphamide hydrate and sofosbuvir as water-soluble and water-insoluble organophosphorus compounds, respectively. This study introduces the purity determination of brigatinib (BR), an organophosphorus compound with limited water solubility, using 31P-qNMR at multiple laboratories. Phosphonoacetic acid (PAA) and 1,4-BTMSB-d4 were selected as the reference standards (RSs) for 31P-qNMR and 1H-qNMR, respectively. The qNMR solvents were chosen based on the solubilities of BR and the RSs for qNMR. CD3OH was selected as the solvent for 31P-qNMR measurements to prevent the influence of deuterium exchange caused by the presence of exchangeable intramolecular protons of BR and PAA on the quantitative values, while CD3OD was the solvent of choice for the 1H-qNMR measurements to prevent the influence of water signals and the exchangeable intramolecular protons of BR and PAA. The mean purity of BR determined by 31P-qNMR was 97.94 ± 0.69%, which was in agreement with that determined by 1H-qNMR (97.26 ± 0.71%), thus indicating the feasibility of purity determination of BR by 31P-qNMR. Therefore, the findings of this study may provide an effective method that is simpler than conventional 1H-qNMR for the determination of organophosphorus compounds.

Safety profile of tyrosine kinase inhibitors used in non-small-cell lung cancer: An analysis from the Italian pharmacovigilance database.

Non-small cell lung cancer (NSCLC) is often caused by molecular alterations that can be detected by predictive biomarkers including mutations or amplifications of several genes. Several tyrosine kinase inhibitors (TKIs) have been approved in Europe by the European Medicines Agency (EMA) for NSCLC. The aim of this study was to analyze the onset of adverse drug reactions (ADRs) related to TKIs in NSCLC through a spontaneous reporting system (SRS) database. All ADR reports having as suspected drug afatinib (AFT), alectinib (ALEC), brigatinib (BRG), ceritinib (CER), crizotinib (CRIZ), erlotinib (ERL), gefitinib (GEF), lorlatinib (LORL), nintedanib (NTB), and osimertinib (OSI) recorded into the Report Reazioni Avverse dei Medicinali (RAM) system database for national data and into the Italian SRS database for Sicilian data and collected from 2006 to 2021 have been evaluated. A descriptive analysis of basal demographic and drug-related characteristics was performed. A case-by-case methodology was conducted paying particular attention to all serious ADR reports collected in Sicily, focusing on type of seriousness, age, sex, concomitant drugs, and comorbidities. Of the 3,048 Italian reports, most of ADRs were related to ERL (n = 1,448), followed by AFT (n = 435) and GEF (n = 366). ADR reports were slightly more frequent in females (52.2%) and in the age group >65 years (53.0%). A higher number of cases were related to skin disorders (n = 1,766; 57.9%), followed by gastrointestinal disorders (n = 1,024; 33.6%), general disorders and administration site conditions (n = 536; 17.6%), and infections (n = 483; 15.8%). The case-by-case assessment of Sicilian ADRs showed that 33 cases were serious (12.5%) and mainly involved ERL (n = 17; 51.5%), occurring in males with a higher onset of respiratory diseases (30.3%) such as respiratory failure, interstitial lung disease and dyspnea. The analysis of spontaneous ADR reports of TKIs confirmed, in general, well-known risks, which often include skin, gastrointestinal, general, liver, and respiratory diseases as well as infections. However, more attention should be paid to the occurrence of serious life-threatening ADRs including respiratory failure, interstitial lung disease, and cardiogenic shock, especially in young patients.

319O ALTA-3: A randomized trial of brigatinib (BRG) vs alectinib (ALC) in crizotinib (CRZ)-refractory advanced ALK+ NSCLC

In patients (pts) with ALK+ NSCLC, resistance to the first-generation ALK TKI CRZ eventually develops, with CNS progression and/or ALK-acquired resistance mutations. ALC and BRG are CNS-active, next-generation ALK TKIs with differing selectivity vs these mutations. Single-arm post-CRZ trials with ALC reported median PFS (mPFS) <12 mo, while BRG showed mPFS >16 mo (16.3–16.7). ALTA-3 (NCT03596866) was designed to test whether BRG efficacy is superior to ALC in ALK+ NSCLC that progressed on CRZ. We report results of the preplanned interim analysis (IA).

1156P Quality-adjusted survival with brigatinib (BRG) versus crizotinib (CRZ) in ALK-positive (ALK+) non-small cell lung cancer (NSCLC): Results from the ALTA-1L trial

The ALTA-1L phase III trial showed BRG significantly improved blinded independent review committee (BIRC)-assessed progression-free survival (PFS) (hazard ratio [HR]=0.48, 95% confidence interval [CI] [0.35-0.66]) and investigator (INV)-assessed PFS (HR=0.43, 95% CI [0.31-0.58]) vs CRZ in patients with ALK+ NSCLC. This study examined the treatment differences on the quality of survival of BRG vs CRZ using a quality-adjusted time without symptoms and toxicity (Q-TWiST) method based on the ALTA-1L trial.

Association of depth of target lesion response to brigatinib with outcomes in patients with ALK inhibitor-naive ALK+ NSCLC in ALTA-1L.

9072 Background: In patients (pts) with crizotinib (CRZ)-refractory advanced ALK+ NSCLC in the phase 2 ALTA trial (NCT02094573), the depth of target lesion response to brigatinib (BRG) correlated with PFS and OS. Here, we examine the association of maximum decrease in target lesions with PFS and OS in ALTA-1L (NCT02737501), a randomized phase 3 trial of BRG vs CRZ in pts with ALK inhibitor-naive advanced ALK+ NSCLC. Methods: Pts were randomized 1:1 to receive BRG 180 mg qd (7-day lead-in at 90 mg; n=137) or CRZ 250 mg bid (n=138). Pts with target lesion assessment by blinded independent review committee (BIRC) were grouped based on greatest decrease from baseline per RECIST v1.1: none–50%, 51%–75%, and 76%–100% shrinkage. Outcomes in the ≤50% target lesion shrinkage group served as the comparator for outcomes in the 51%–75% and 76%–100% groups. Results: At study end (last pt contact: Jan 29, 2021), 124/137 pts in the BRG arm and 125/138 pts in the CRZ arm had ≥1 evaluable target lesion assessment; female (BRG/CRZ), 51%/59%; median age, 57.5/60.0 years. Median follow-up was 40.8/15.7 months. In BRG/CRZ arms, 76%-100% shrinkage was observed in 56%/34% of pts, 51%-75% shrinkage in 27%/30%, and ≤50% shrinkage in 16%/35%, respectively. BRG was associated with significantly more pts with target lesion shrinkage &gt;75% vs CRZ ( P=0.0005), and a Cochran-Armitage trend analysis demonstrated significantly deeper response across all shrinkage groups for BRG compared with CRZ ( P&lt;0.0001). A majority of pts in the BRG arm experienced 76%–100% target lesion shrinkage in all subgroups analyzed. Pts treated with BRG or CRZ with target lesion shrinkage &gt;50% had lower risk of a PFS event (BRG HR [95% CI]: 51%–75% shrinkage, 0.58 [0.29–1.18]; 76%–100%, 0.23 [0.12–0.46]; CRZ: 51%–75% shrinkage, 0.68 [0.41–1.12]; 76%–100%, 0.26 [0.15–0.45]) or an OS event (BRG: 51%–75% shrinkage, 0.39 [0.17–0.89]; 76%–100%, 0.15 [0.07–0.35]; CRZ: 51%–75% shrinkage, 0.43 [0.21–0.85]; 76%–100%, 0.23 [0.10–0.50]) than pts with ≤50% shrinkage. Longer median time to PFS and OS and higher 4-year estimated OS rates were associated with depth of response in both arms (Table). Conclusions: In this exploratory post hoc analysis, BRG demonstrated significantly deeper target lesion response vs CRZ. Pts with &gt;75% shrinkage had significantly reduced risk of a PFS or OS event vs pts with ≤50% target lesion shrinkage. Clinical trial information: NCT02737501. [Table: see text]

29P Brigatinib (BRG) vs crizotinib (CRZ) in anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor-naive ALK+ non-small cell lung cancer (NSCLC): ALTA-1L final results

In ALTA-1L planned interim analyses, BRG progression-free survival (PFS) by blinded independent review committee (BIRC) was superior to CRZ. We report final ALTA-1L (NCT02737501) results. Patients (pts) were randomized 1:1 to BRG 180 mg qd (7-day lead-in at 90 mg) or CRZ 250 mg bid. Primary endpoint: PFS by BIRC. Secondary endpoints included intracranial PFS (iPFS; BIRC), overall survival (OS), safety, quality of life (QoL). 275 pts randomized (BRG/CRZ, n=137/138); median age 58/60 y; prior chemotherapy (CT) 26%/27%; median CT duration, 71/73 days; baseline brain metastases (BL BM) 29%/30%. As of 29 Jan 2021 (last patient contact), median follow-up was 40.4/15.2 mo, with 166 (73/93) PFS events. BIRC PFS hazard ratio (HR) was 0.48 (95% CI: 0.35–0.66, log-rank P<0.0001); median PFS was 24.0 (95% CI: 18.4–43.2)/11.1 (9.1–13.0) mo; 3-yr PFS rate, 43%/19%. PFS HR by investigator was 0.43 (0.31–0.58; median PFS 30.8 vs 9.2 mo). Median duration of response (DoR) was 33/14 mo by BIRC and 37/11 mo by investigator. Median OS was not reached in either group (events: 41/51; HR 0.81 [0.53–1.22]; 3-yr OS 71%/68%. In pts with BL BM, PFS HR 0.25 (0.14–0.46); OS HR 0.43 (0.21–0.89; Table). Most common grade ≥3 treatment-emergent adverse events (AE): BRG: increased creatine phosphokinase (26%) and lipase (15%), hypertension (14%); CRZ: increased alanine aminotransferase (10%), lipase, (8%), aspartate aminotransferase (7%). Any-grade interstitial lung disease/pneumonitis: 5.9%/2.2%; discontinuation due to AE: 13.2%/8.8%. Median time to worsening in pt-reported global health status/QoL was 26.7/8.3 mo; HR 0.69 (0.49–0.98).Table: 29PEfficacyaBRGCRZPBL brain metastasesMeasurable, n1823Confirmed iORR, %78 (52–94b)26 (10–48b)0.0014cMedian iDoRd, mo28 (6–NEb)9 (4–NEb)Any, n40e41ePFS events, n (%)24 (60)31 (76)HR0.25 (0.14–0.46b)<0.0001fOS events, n (%)11 (28)22 (54)3-yr OS, %74 (57–85b)55 (38–69b)HR0.43 (0.21–0.89b)0.0199f47a49aiPFS events, n (%)27 (57)35 (71)HR0.29 (0.17–0.51b)<0.0001fNone, n97e97ePFS events, n (%)49 (51)62 (64)HR0.62 (0.43–0.91b)0.0131fOS events, n (%)30 (31)29 (30)3-yr OS, %70 (59–78b)73 (62–81b)HR1.16 (0.69–1.93b)0.6027f90a89aiPFS events, n (%)25 (28)23 (26)HR0.70 (0.39–1.26b)0.2410fa BIRC; b 95% CI; c CMH test; d Confirmed responders; e Investigator; f Log-rank Open table in a new tab a BIRC; b 95% CI; c CMH test; d Confirmed responders; e Investigator; f Log-rank BRG demonstrated durable overall and intracranial efficacy with manageable tolerability with extended treatment, confirming BRG as a standard of care in treatment-naive ALK+ NSCLC.

Formulation of Chitosan-Coated Brigatinib Nanospanlastics: Optimization, Characterization, Stability Assessment and In-Vitro Cytotoxicity Activity against H-1975 Cell Lines.

The purpose of the current study was to develop Brigatinib (BGT)-loaded nanospanlastics (BGT-loaded NSPs) (S1-S13) containing Span 60 with different edge activators (Tween 80 and Pluronic F127) and optimized based on the vesicle size, zeta potential (ZP), and percent entrapment efficiency (%EE) using Design-Expert® software. The optimum formula was recommended with desirability of 0.819 and composed of Span-60:Tween 80 at a ratio of 4:1 and 10 min as a sonication time (S13). It showed predicted EE% (81.58%), vesicle size (386.55 nm), and ZP (−29.51 mv). The optimized nanospanlastics (S13) was further coated with chitosan and further evaluated for Differential Scanning Calorimetry (DSC), X-ray Diffraction (XRD), in vitro release, Transmission Electron Microscopy (TEM), stability and in-vitro cytotoxicity studies against H-1975 lung cancer cell lines. The DSC and XRD revealed complete encapsulation of the drug. TEM imagery revealed spherical nanovesicles with a smooth surface. Also, the coated formula showed high stability for three months in two different conditions. Moreover, it resulted in improved and sustained drug release than free BGT suspension and exhibited Higuchi kinetic release mechanism. The cytotoxic activity of BGT-loaded SPs (S13) was enhanced three times in comparison to free the BGT drug against the H-1975 cell lines. Overall, these results confirmed that BGT-loaded SPs could be a promising nanocarrier to improve the anticancer efficacy of BGT.

1195P Brigatinib (BRG) vs crizotinib (CRZ) in ALK TKI–naive ALK+ NSCLC: Final results from ALTA-1L

1195P Brigatinib (BRG) vs crizotinib (CRZ) in ALK TKI–naive ALK+ NSCLC: Final results from ALTA-1L

Brigatinib loaded poly(d,l-lactide-co-glycolide) nanoparticles for improved anti-tumoral activity against non-small cell lung cancer cell lines

Objective The aim of the current investigation was to develop poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) to sustain the brigatinib (BTB) release for prolong time period and to examine the antitumor effect of the optimized NPs. Significance Optimized PLGA-based NPs of BTB could be potentially used as a promising nanocarrier for the treatment of non-small cell lung cancer. Methods BTB-loaded NPs were fabricated with core-shell of PLGA by solvent evaporation technique using different proportions of PLGA polymer and poly-vinyl alcohol (PVA) stabilizer. The prepared NPs were evaluated for particle characterizations; size, polydispersity index (PDI), zeta-potential, entrapment efficiency (EE), and drug loading (DL), Fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), and X-ray diffraction studies. The optimized NPs (BN5) were further evaluated for morphology, stability, and cytotoxicity studies against A549 cell-lines. Results Among the nine different NPs formulae (BN1–BN9), BN5 was optimized with composition of BTB (30 mg), PLGA (75 mg), PVA (0.55% w/v), represents an average particle size of (267.1 ± 1.01 nm), PDI (0.101 ± 0.007), and zeta potential (–42.1 ± 0.75 mV), high EE (66.83 ± 0.06%), and DL (6.17 ± 0.69%). SEM image of selected NPs was spherical with smooth surface. In vitro drug release profile in phosphate buffers (pH 5 and pH 7.4) showed a biphasic release with initial burst phase followed by sustained release for prolong time. Furthermore, optimized NPs (BN5) exhibited excellent cytotoxic activity against A549 cell-lines with IC50 value of 5.25 ± 0.23 µg/mL. Conclusion The overall results suggest that BTB-loaded PLGA NPs could be a potential nanocarrier for lung cancer treatment.

Brigatinib

Brigatinib

Brigatinib (BRG) in ALK+ crizotinib (CRZ)-refractory non-small cell lung cancer (NSCLC): Final results of the phase 1/2 and phase 2 (ALTA) trials.

9071 Background: BRG is a kinase inhibitor approved for the treatment of patients (pts) with ALK+ metastatic NSCLC; specific details for BRG use vary by indication and country. We report long-term efficacy and safety results of the Phase 1/2 and Phase 2 (ALTA) trials of BRG. Methods: The Phase 1/2 study was a single-arm, open-label trial (NCT01449461) of BRG 30–300 mg/d in pts with advanced malignancies. ALTA (NCT02094573) randomized pts with CRZ-refractory ALK+ NSCLC to receive BRG at 90 mg qd (arm A) or 180 mg qd with 7-d lead-in at 90 mg (arm B). For the Phase 1/2 study, investigator assessments of confirmed objective response rate (cORR; RECIST v1.1), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety in pts with ALK+ NSCLC are reported. The primary endpoint of ALTA was cORR per investigator; secondary endpoints included cORR per independent review committee (IRC), DoR, PFS, and OS. Results: In the Phase 1/2 study, 137 pts received BRG; of these, 79 pts had ALK+ NSCLC (71/79 had prior CRZ; 28/79 received 180 mg qd [7-d lead-in at 90 mg]; 14/79 received 90 mg qd). In ALTA, 222 pts with CRZ-refractory ALK+ NSCLC were randomized (n = 112/110, arm A/B). At the end of the Phase 1/2 study (Feb 18, 2020), with median 27.7 mo follow-up (̃67 mo after last pt enrolled), 4 pts remained on BRG. At the end of ALTA (Feb 27, 2020), with median 19.6/28.3 mo follow-up in arm A/B (̃53 mo after last pt enrolled), 10/17 pts in arm A/B were still on treatment. Table shows efficacy results from final analyses with long-term follow-up. In ALTA, the IRC-assessed intracranial cORR in pts with measurable baseline brain metastases was 50% (13/26) in arm A and 67% (12/18) in arm B; Kaplan-Meier (KM) estimated median intracranial DoR was 9.4 mo (95% CI, 3.7, not reached [NR]) in arm A and 16.6 mo (3.7, NR) in arm B. With long-term follow-up, no new safety signals were identified. Treatment-emergent adverse events led to dose interruption (Phase 1/2: 59%; ALTA arm A/B: 49%/61%), dose reduction (13%; 8%/33%), or discontinuation (10%; 4%/13%). Conclusions: BRG showed sustained long-term activity, PFS, and manageable safety in pts with CRZ-refractory ALK+ NSCLC. The 180 mg/d dose after 7-d lead-in at 90 mg/d led to numerically higher median PFS and OS. Final results are similar to those reported for other approved ALK tyrosine kinase inhibitors in this setting. Clinical trial information: NCT01449461, NCT02094573. [Table: see text]

Novel spectrofluorimetric determination of brigatinib in bulk powder and human urine samples via ion-pair complex formation using eosin Y

The developed spectrofluorimetric method was successfully applied to the analysis of brigatinib (BRG) in its bulk powder form, and human urine sample.It is based on the investigation of the fluorescence spectrum behavior of the BRG-eosin Y complex. The relative fluorescence intensity (RFI) was recorded at 560 nm after excitation at 480 nm. The principle of the proposed method was thoroughly explained. All experimental parameters affecting method development were optimized. Moreover, the obtained results were fully discussed and statistically analyzed. The molar ratio method was applied to study the stoichiometric relationship between BRG and eosin Y complex. The method revealed a ratio of 1:3 for BRG-eosin Y afforded the highest RFI. The developed method was validated over the concentration range of 62.5–4000 ng mL−1. The results were compared positively with the reported method.

EPID-05. COMPARATIVE EFFICACY OF FIRST-LINE ALK-INHIBITORS IN ALK+ LUNG CANCER BRAIN METASTASES: A NETWORK META-ANALYSIS

Abstract BACKGROUND Lung cancer has been the leading cause of cancer death for both men and women worldwide. Non-small-cell lung cancer (NSCLC) displays an array of molecular abnormalities most commonly involving ALK and EGFR pathways. NSCLC with ALK rearrangements comprises close to 5% of cases. Several ALK inhibitors (ALKI) have been approved with activity in brain metastases. However, there have been limited comparative studies exploring their relative efficacies. This meta-analysis was conducted to compare the relative efficacy of ALKIs against ALKI-naïve ALK+ lung cancer brain metastases. METHODS A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; diagnosis of ALKI-naïve ALK+ lung cancer trials with brain metastases; treatment with Crizotinib (CRZ), Alectinib (ALC), Brigatinib (BRG), and Ceritinib (CER); and comparative studies reporting brain metastases specific responses/events. A Bayesian and a frequentists network meta-analysis were conducted using netmeta package and the random-effects model. RESULTS Eight studies comprising a total of 665 participants with ALKI-naive ALK+ lung cancer brain metastases were included. When compared pair-wise to CRZ, ALC (RR=0.49;95%CI:0.36–0.66), BRG (RR=0.39;95%CI:0.24–0.64), and CER (RR=0.36;95%CI:0.19–0.68) demonstrated significantly superior response rates in patients with untreated or previously treated lung cancer brain metastases. When the efficacy of each ALKI was compared to each other, BRG and CER were ranked the highest, followed by ALC and CRZ in decreasing order. CONCLUSIONS This network meta-analysis is the first to compare and rank approved ALKIs used in treating metastatic ALK+ lung cancer. It indicates that BRG, CER, and ALC are better therapeutic options for patients with ALK-naive ALK+ lung cancer brain metastases when compared to CRZ.

Development and characterization of Brigatinib loaded solid lipid nanoparticles: In-vitro cytotoxicity against human carcinoma A549 lung cell lines

Brigatinib (BG) is a tyrosine kinase receptor inhibitor act as an antineoplastic agent by blocking the action of an abnormal protein that causes cancer cells to multiply. In the current study, nine formulae of BG loaded solid lipid nanoparticles (SLNs) were developed using 32 factorial design. SLNs were prepared by the solvent emulsification technique using stearic acid as lipid and soya- lecithin as a surfactant, both of these act as independent variables, whereas Particle size, polydispersity index (PDI), zeta potential, entrapment efficiency (EE) and drug loading (DL) were selected as responses. The particle size was found to be in the nano range (176−787 nm), fairly monodisperse (PDI indices 0.19−0.5), interparticle electrical stability was supported by zeta-potential (+1.78 mV to -15.4 mV), whereas EE and DL were in the range of (61.31–87.87 %) (3.35–31.01 %), respectively. Differential scanning calorimetry (DSC) thermograms indicated the amorphous state of BG in the SLN. Fourier transform infrared spectroscopy (FTIR) spectrums confirm non-interaction between drug and polymer while nuclear magnetic resonance (NMR) spectroscopy study revealed BG incorporation in the SLN. A scanning electron microscope (SEM) image exhibit a spherical shape of SLN. The in-vitro release profile demonstrates a sustained release pattern for the selected BS5 SLNs. MTT assay was performed on the optimized SLNs (BS5) and the results are indicative that BG loaded SLN (BS5) showed better cytotoxicity against A349 lung cell lines while compared to BG suspension and blank SLN. Thus, BG loaded SLNs can find Its better place in the non-small cell lung cancer treatment.

Solubility determination, computational modeling, Hansen solubility parameters and apparent thermodynamic analysis of brigatinib in (ethanol + water) mixtures

Abstract The solubility and various thermodynamic parameters of an antitumor drug brigatinib (BRN) in various ethanol (EtOH) + water (H2O) mixtures were determined in this study. The mole fraction solubility (x e) of BRN in various (EtOH + H2O) mixtures including pure EtOH and pure H2O was obtained at T = 298.2–323.2 K and p = 0.1 MPa by adopting a saturation shake flask method. Hansen solubility parameters (HSPs) of BRN, pure EtOH, pure H2O and (EtOH + H2O) mixtures free of BRN were also computed. The x e values of BRN were correlated using Van’t Hoff, Apelblat, Yalkowsky–Roseman, Jouyban–Acree and Jouyban–Acree–Van’t Hoff models with mean errors of &lt;2.0%. The maximum and minimum x e value of BRN was obtained in pure EtOH (1.43 × 10−2 at T = 323.2 K) and pure H2O (3.08 × 10−6 at T = 298.2 K), respectively. The HSP of BRN was also found more closed with that of pure EtOH. The x e value of BRN was obtained as increasing significantly with the rise in temperature and increase in EtOH mass fraction in all (EtOH + H2O) mixtures including pure EtOH and pure H2O. The data of apparent thermodynamic analysis showed an endothermic and entropy-driven dissolution of BRN in all (EtOH + H2O) mixtures including pure EtOH and pure H2O.

Development and characterization of ethyl cellulose nanosponges for sustained release of brigatinib for the treatment of non-small cell lung cancer

Abstract Non-small cell lung cancer (NSCLC) contributes to about 85% of lung cancer. By 2040, lung cancer cases estimated to rise to 3.6 million globally. Brigatinib (BG) acts as tyrosine kinase inhibitors that target the epidermal growth factor receptor of the epithelial lung cancer cells. BG loaded nanosponges (NSs) were prepared by the emulsion solvent evaporation technique using ethylcellulose (EC) and polyvinyl alcohol (PVA) as a stabilizer. Eight formulations were developed by varying the concentration of the drug (BG), EC and PVA followed by optimization through particle characterization; size, polydispersity index (PDI), zeta potential (ZP), drug entrapment and loading efficiency. The optimized formulation BGNS5 showed particles size (261.0 ± 3.5 nm), PDI (0.301) and ZP(−19.83 ± 0.06 Mv) together with entrapment efficiency (85.69 ± 0.04%) and drug loading (17.69 ± 0.01%). FTIR, DSC, XRD, and SEM showed drug-polymer compatibility, entrapment of drug in EC core, non-crystallinity of BG in NS and confirm spherical porous nature of the NS. BGNS5 reflects drug release in a sustained manner, 86.91 ± 2.12% for about 12 h. BGNS5 significantly decreased the cell viability of A549 human lung cancer cell lines with less hemolytic ratio compared to pure drug BG and EC. Based on the aforementioned results BGNS5 could be used in the effective treatment of NSCLC.

1304P Brigatinib (BRG) vs crizotinib (CRZ) in Asian vs non-Asian patients (pts): Update from ALTA-1L

1304P Brigatinib (BRG) vs crizotinib (CRZ) in Asian vs non-Asian patients (pts): Update from ALTA-1L

1300P Intracranial efficacy of brigatinib (BRG) vs crizotinib (CRZ): Updated results from the ALTA-1L trial

1300P Intracranial efficacy of brigatinib (BRG) vs crizotinib (CRZ): Updated results from the ALTA-1L trial

1305P Health-related quality of life (HRQoL) in a phase III study of first-line brigatinib (BRG) vs crizotinib (CRZ) in NSCLC: Updated results from ALTA-1L

1305P Health-related quality of life (HRQoL) in a phase III study of first-line brigatinib (BRG) vs crizotinib (CRZ) in NSCLC: Updated results from ALTA-1L