Search

The phosphatidylinositol 3‑kinase/protein kinase B (PI3K/AKT) signaling pathway is critically active in many cell types, both normal and neoplastic. Many small-molecule inhibitors targeting different levels of the PI3K/AKT pathway have been developed for cancer therapy, but their efficacy is reduced by compensatory pathway re-activation mechanisms, and their tolerability by toxic side effects. We studied this problem using cell lines representing diffuse large B-cell lymphoma (SUDHL-4 and OCI-Ly7), a genetically-encoded live-cell reporter of AKT activity, and 3 small-molecule inhibitors targeting different levels of the pathway: idelalisib (PI3Kδ), GSK2334470 (PDPK1), and ipatasertib (AKT). Half-maximal (IC50) concentrations of these inhibitors for AKT activity inhibition at 1 h, when used individually, were much lower than their IC50 values for reduction of viable cell number after 4 days. Time-course studies explained this discrepancy: AKT activity in the continuous presence of the inhibitors returned to normal after 24 h, and was supranormal after inhibitor removal. Combining all 3 inhibitors produced sustained inhibition of AKT activity, was broadly synergistic at reducing viable cell number, enabled substantially lower doses of each inhibitor to be used, and was enhanced further by the mTOR inhibitor rapamycin. Moreover, combined PDPK1 and AKT inhibition showed synergy with multiple different PI3K inhibitors. In a syngeneic mouse cell line model of lymphoma (A20), the triple combination showed antitumor activity and no evidence of toxicity. Our findings provide proof of concept suggesting further study of the safety and efficacy of low-dose multilevel PI3K/AKT pathway inhibition, for lymphoma and perhaps other cancers. [ABSTRACT FROM AUTHOR]

This study aimed to develop and validate a stability-indicating reverse-phase high-performance liquid chromatography (RP-HPLC) method for the quantitative analysis of idelalisib, a potent phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, in pharmaceutical formulations. An RP-HPLC method was developed using an Agilent C18 column (5 μm, 4.6 × 250 mm) and a mobile phase consisting of a mixture of methanol/0.05% ortho-phosphoric acid (75:25) at a flow rate of 0.7 ml/min with UV detection at 269 nm. Forced degradation studies were conducted to evaluate the method's stability-indicating capability. Validation parameters—including linearity, precision, accuracy, specificity, robustness, and system suitability—were assessed according to ICH guidelines. The developed RP-HPLC method demonstrated excellent linearity over a wide concentration range, with a correlation coefficient (r) of >0.999 with respect to the peak area in a concentration range of 5–250 gmL-1. The method exhibited high precision, with relative standard deviations (RSD) for repeatability and intermediate precision well within acceptable limits. Accuracy was confirmed through recovery studies, and the RSD ranged from 0.13% to 0.94%. Forced degradation studies revealed the method's ability to separate and quantify idelalisib from its degradation products. The actual percentage degradation ranged between 0.16% to 6.29%. The limits of detection and quantification were 0.066 μg/ml and 0.2 μg/ml, respectively. Precision was established whereby the mean interday and intraday RSD were 0.58% and 0.45%, respectively. The method's robustness was confirmed through deliberate variations in method parameters, which had negligible effects on the assay results (.4% RSD). The method was applied to commercially available tablets, yielding an average (SD) idelalisib recovery of 101.45% (0.08) with a % RSD of 0.08%. The developed RP-HPLC method is a stability-indicating assay for idelalisib with excellent specificity, linearity, precision, and accuracy. It is suitable for routine analysis of idelalisib in pharmaceutical formulations and can be employed for stability studies and quality control purposes, ensuring the drug's quality and efficacy throughout its shelf life. [ABSTRACT FROM AUTHOR]

Idelalisib is a phosphatidylinositol 3-kinase delta inhibitor approved by the FDA and the EMA for the treatment of lympholytic lymphoma, B cell non-Hodgkin lymphoma, and lymphocytic lymphoma. The present report describes the validation of a simple, rapid, sensitive, and cost-effective zero-order and first-order derivative spectrophotometric method for the estimation of idelalisib in bulk and in its marketed formulation. Preliminary spectrophotometric analysis of the drug was carried out in methanol and a total of 12 parametric variations were considered. Three selected method variants employing peak-zero and peak-peak techniques were assessed for their stability indicating potential in stress degraded solutions of the drug. The developed method was validated with respect to linearity, accuracy, precision, and robustness. Excellent linearity was observed within the concentration range 1.0–60.0 μg/mL with a correlation coefficient of 0.9997. The limits of assay detection values were found for the range 0.42–3.11 μg/mL, and quantitation limits ranged from 1.29 to 9.42 μg/mL for the proposed method variants. The proposed method was used to quantify the drug in its marketed tablet formulation, and good recoveries ranging from 95.98 to 98.81% were obtained. [ABSTRACT FROM AUTHOR]

A simple and a sensitive liquid chromatography–tandem mass spectrometry method was developed and validated for the quantification of gedatolisib in mouse plasma. The extraction technique involved a simple precipitation method to extract gedatolisib and idelalisib (internal standard) from mouse plasma. A clean chromatographic separation of gedatolisib and the internal standard was achieved on an Atlantis dC18 column using an isocratic mobile phase (10 mm ammonium formate and acetonitrile; 30:70% v/v, both supplemented with 0.1% formic acid) delivered at a flow rate of 0.7 ml/min. The total run time was 2.0 min, and gedatolisib and idelalisib were eluted at 0.80 and 0.95 min, respectively. Gedatolisib was monitored at m/z 616.40 → 488.20 and idelalisib at 416.05 → 176.10. All the required parameters for the method validation were performed as per US Food and Drug Administration guidelines, and the results were within the acceptance criteria. The method was accurate and proved to be precise at a linearity range of 1.33–2667 ng/ml. The accuracy for gedatolisib in mouse plasma was in the ranges 0.99–1.06% (intra‐day) and 0.96–1.04% (inter‐day). Gedatolisib appeared to be stable in a series of stability conditions. Gedatolisib showed a good intravenous profile when administered through a solution formulation. [ABSTRACT FROM AUTHOR]

This data report, published in Frontiers in Pharmacology, discusses leniolisib, a drug used to treat activated phosphoinositide 3-kinase delta (APDS) syndrome. Leniolisib inhibits the PI3Kδ pathway and has shown positive results in reducing lymphoproliferation and improving immune cell subsets in APDS patients. The report provides information on the development, synthesis, and physicochemical properties of leniolisib. It also mentions that leniolisib is being studied for its potential use in treating other autoimmune diseases associated with overactive PI3Kδ activity. The document also includes references to studies on the role of PI3Kδ in B cell development, the design of inhibitors for the PI3K signaling pathway, and the clinical spectrum and features of APDS. It also provides information on the availability of raw data, author contributions, funding, conflicts of interest, and a disclaimer regarding the views expressed in the article. [Extracted from the article]

Abstract Background Acute myeloid leukaemia (AML) remains difficult to treat despite the development of novel formulations and targeted therapies. Activating mutations in the FLT3 gene are common among patients and make the tumour susceptible to FLT3 inhibitors, but resistance to such inhibitors develops quickly. Methods We examined combination therapies aimed at FLT3+-AML, and studied the development of resistance using a newly developed protocol. Combinations of FLT3, CDK4/6 and PI3K inhibitors were tested for synergism. Results We show that AML cells express CDK4 and that the CDK4/6 inhibitors palbociclib and abemaciclib inhibit cellular growth. PI3K inhibitors were also effective in inhibiting the growth of AML cell lines that express FLT3-ITD. Whereas resistance to quizartinib develops quickly, the combinations overcome such resistance. Conclusions This study suggests that a multi-targeted intervention involving a CDK4/6 inhibitor with a FLT3 inhibitor or a pan-PI3K inhibitor might be a valuable therapeutic strategy for AML to overcome drug resistance. Moreover, many patients cannot tolerate high doses of the drugs that were studied (quizartinib, palbociclib and PI3K inhibitors) for longer periods, and it is therefore of high significance that the drugs act synergistically and lower doses can be used.

Graphical AbstractIC50 = 11 nM (PI3Kδ); 244 nM (PI3Kα); 424 nM (PI3Kβ), 2,230 nM (PI3Kγ).

Objectives: We examined the efficacy and toxicity of the PI3Kδ inhibitor idelalisib in combination with rituximab salvage therapy in consecutively identified Swedish patients with chronic lymphocytic leukemia (CLL). Methods and Results: Thirty-seven patients with relapsed/refractory disease were included. The median number of prior lines of therapy was 3 (range 1-11); the median age was 69 years (range 50-89); 22% had Cumulative Illness Rating Scale (CIRS) >6 and 51% had del(17p)/TP53 mutation. The overall response rate was 65% (all but one was partial response [PR]). The median duration of therapy was 9.8 months (range 0.9-44.8). The median progression-free survival was 16.4 months (95% CI: 10.4-26.3) and median overall survival had not been reached (75% remained alive at 24 months of follow-up). The most common reason for cessation of therapy was colitis (n = 8, of which seven patients experienced grade ≥3 colitis). The most common serious adverse event was grade ≥3 infection, which occurred in 24 patients (65%). Conclusions: Our real-world results suggest that idelalisib is an effective and relatively safe treatment for patients with advanced-stage CLL when no other therapies exist. Alternative dosing regimens and new PI3K inhibitors should be explored, particularly in patients who are double-refractory to inhibitors of BTK and Bcl-2. [ABSTRACT FROM AUTHOR]

Idelalisib in combination with rituximab is an efficacious treatment for patients suffering from chronic lymphocytic leukemia (CLL) with known limitations due to toxicities. However, the benefit after prior Bruton tyrosine kinase inhibitor (BTKi) therapy remains unclear. For this analysis, 81 patients included in a non-interventional registry study of the German CLL study group (registered at www.clinicaltrials.gov as # NCT02863692) meeting the predefined criteria of a confirmed diagnosis of CLL and being treated with idelalisib containing regimens outside clinical trials were considered. 11 patients were treatment naïve (13.6%) and 70 patients (86.4%) pretreated. Patients had median of one prior therapy line (range 0–11). Median treatment duration with idelalisib was 5.1 months (range 0–55.0 months). Of 58 patients with documented treatment outcome, 39 responded to idelalisib containing therapy (67.2%). Patients treated with the BTKi ibrutinib as last prior treatment prior to idelalisib responded in 71.4% compared to a response rate of 61.9% in patients without prior ibrutinib. Median event free survival (EFS) was 15.9 months with a 16 versus 14 months EFS in patients with ibrutinib as last prior treatment or not, respectively. Median overall survival was 46.6 months. In conclusion, treatment with idelalisib appears to have a valuable impact in patients being refractory to prior ibrutinib therapy even though there are limitations in our analysis due to the low number of patients included. [ABSTRACT FROM AUTHOR]

Idelalisib is a phosphatidylinositol 3-kinase delta inhibitor approved by the USFDA and EMA for the treatment of lympholytic lymphoma, B-cell non-Hodgkin lymphoma and lymphocytic lymphoma. The present report describes the validation of simple, rapid, sensitive, and cost-effective spectrofluorimetric methods based on the native fluorescence of the drug in an acidic medium. Fluorescence characteristics of the drug were found to significantly differ in absolute ethanol (λex = 330 and λem = 595 nm) and HCl (λex = 270 and λem = 350 nm) and both methods were validated as per ICH guidelines. The two methods were extremely sensitive, precise and accurate demonstrating excellent linearity in concentration ranges from 0.1–2.0 μg/mL (absolute ethanol) and 0.1–20 μg/mL (HCl). The LOD and LOQ values were found to be 0.015 and 0.045 μg/mL (ethanol) and 0.1615 and 0.4894 μg/mL (HCl). The proposed methods were used to quantify the drug in its marketed tablet formulation with good recoveries, suggesting their applicability to routine analysis of the drug in bulk as well as in formulation. [ABSTRACT FROM AUTHOR]

Epilepsy results from abnormal brain function and is one of the most common neurological diseases in the world. The phosphatidylinositol-3-kinase (PI3K) signaling pathway has been extensively studied in epilepsy pathogenesis. Idelalisib (IDE) is a selective inhibitor of PI3K. In the present study, IDE was evalu-ated for its potential to reduce convulsions caused by pentylenetetrazole (PTZ). Male Wistar rats (200–250 g, 8 weeks old) were injected intraperitoneally (IP) with IDE at different doses of 40 and 80 mg/kg, or vehicle 30 min prior to PTZ (70 mg/kg, IP) treatment. Racine's scale was used to measure behavioral seizures. The results showed that pretreatment with IDE decreased the seizure stages according to the Racine scale, significantly prolonged the duration of general tonic-clonic seizure (GTCS) and reduced the number of myoclonic jerks (p < 0.05). In conclusion, we found that the PI3K antagonist IDE had a reducing effect on PTZ-induced seizures, suggesting that inhibition of the PI3K signaling pathway by IDE exerts an anticonvulsant effect. [ABSTRACT FROM AUTHOR]

Serious phosphatidylinositol 3 kinase (PI3K) inhibitor-related pneumonitis has raised clinical concerns, and integrated data for this condition are lacking. Randomized controlled trials (RCTs) comparing PI3K inhibitor therapy with control treatments from electronic databases and registrations were searched from inception to 1 April 20231 April 2023seven1 April 2023. The outcomes of our study were the incidence and risk of all-grade and grade ≥ 3 PI3K inhibitor-associated pneumonitis compared with controls. The meta-analysis included 13 studies comprising 3916 patients. The incidence of all-grade and grade ≥ 3 pneumonitis was 3.7% (82/2210) and 3.0% (35/1162) in patients treated with PI3K inhibitors. PI3K inhibitors significantly increased the risk of all-grade and grade ≥ 3 pneumonitis compared with controls (RR 5.63, 95% CI [2.97, 10.65], P < 0.00001; RR 6.85, 95% CI [2.45, 19.11], P = 0.0002, respectively) with no significant heterogeneity across studies. In terms of different PI3K inhibitors, copanlisib and idelalisib significantly increased the risk of pneumonitis compared to controls (RR 4.99, 95% CI [1.19, 21.01], P = 0.03; RR 5.53, 95% CI [2.35, 13.01], P < 0.0001, respectively). PI3K inhibitors significantly increased the risk of pneumonitis compared with controls, and most cases are severe or even life-threatening. CRD42022318878 [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukaemia (AML) remains difficult to treat despite the development of novel formulations and targeted therapies. Activating mutations in the FLT3 gene are common among patients and make the tumour susceptible to FLT3 inhibitors, but resistance to such inhibitors develops quickly. Methods: We examined combination therapies aimed at FLT3+-AML, and studied the development of resistance using a newly developed protocol. Combinations of FLT3, CDK4/6 and PI3K inhibitors were tested for synergism. Results: We show that AML cells express CDK4 and that the CDK4/6 inhibitors palbociclib and abemaciclib inhibit cellular growth. PI3K inhibitors were also effective in inhibiting the growth of AML cell lines that express FLT3-ITD. Whereas resistance to quizartinib develops quickly, the combinations overcome such resistance. Conclusions: This study suggests that a multi-targeted intervention involving a CDK4/6 inhibitor with a FLT3 inhibitor or a pan-PI3K inhibitor might be a valuable therapeutic strategy for AML to overcome drug resistance. Moreover, many patients cannot tolerate high doses of the drugs that were studied (quizartinib, palbociclib and PI3K inhibitors) for longer periods, and it is therefore of high significance that the drugs act synergistically and lower doses can be used. [ABSTRACT FROM AUTHOR]

Summary: Idelalisib (idela), a phosphatidylinositol 3‐kinase inhibitor, and ibrutinib, a Bruton tyrosine kinase inhibitor, were the first oral targeted agents approved for relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL). However, no randomised trials of idelalisib plus rituximab (R‐idela) versus ibrutinib have been conducted. Therefore, we performed a real‐world retrospective analysis of patients with R/R CLL treated with R‐idela (n = 171) or ibrutinib (n = 244). The median age was 70 versus 69 years, with a median of two previous lines. There was a trend towards higher tumour protein p53 (TP53) aberrations and complex karyotype in the R‐idela group (53% vs. 44%, p = 0.093; 57% vs. 46%, p = 0.083). The median progression‐free survival (PFS) was significantly longer with ibrutinib (40.5 vs. 22.0 months; p < 0.001); similarly to overall survival (OS; median 54.4 vs. 37.7 months, p = 0.04). In multivariate analysis, only PFS but not OS remained significantly different between the two agents. The most common reasons for treatment discontinuation included toxicity (R‐idela, 39.8%; ibrutinib, 22.5%) and CLL progression (27.5% vs. 11.1%). In conclusion, our data show significantly better efficacy and tolerability of ibrutinib over R‐idela in patients with R/R CLL treated in routine practice. The R‐idela regimen may still be considered a reasonable option in highly selected patients without a suitable treatment alternative. [ABSTRACT FROM AUTHOR]

Objective: The infection risk in patients receiving ibrutinib, idelalisib or venetoclax for chronic lymphocytic leukaemia (CLL) or B‐cell lymphoma treated outside of clinical trials is incompletely defined. We sought to identify the severe infection rate and associated risk factors in a 'real‐world' cohort. Methods: We conducted a retrospective cohort study of adult patients with CLL or lymphoma treated with ibrutinib, idelalisib or venetoclax. Results: Of 67 patients identified (ibrutinib n = 53, idelalisib n = 8 and venetoclax n = 6), 32 (48%) experienced severe infection. Severe infection occurred at a rate of 65 infections per 100 person‐years, with a median of 17.8 months of therapy. Median time to first infection (IQR) was 5.4 months (1.4–15.9). Poor baseline Eastern Cooperative Oncology Group (ECOG) performance status and high Charlson Comorbidity Index (CCI) score associated with increased risk of severe infection [hazard ratios (95% CI) 1.57 (1.07–2.31, p =.018) and 1.3 (1.05–1.62, p =.016) respectively]. Conclusion: The severe infection rate for patients receiving ibrutinib, idelalisib or venetoclax for lymphoma and CLL exceeded those reported in clinical trials. Patients with poor ECOG or high CCI should be closely monitored for early signs of infection and prevention strategies actively pursued. Further prospective research is required to define optimal antimicrobial prophylaxis recommendations. [ABSTRACT FROM AUTHOR]