Superior Pharmacokinetic Profile Research Articles

Factors associated with subtherapeutic levels of oral posaconazole tablet: a detailed analysis from a tertiary care center in India

ObjectivesPosaconazole is a broad-spectrum triazole antifungal, with activity against various clinically important fungi. The delayed release (DR) tablet of posaconazole has been shown to have a superior pharmacokinetic profile in comparison with the oral suspension. MethodsWe retrospectively analyzed the factors associated with posaconazole levels <1.25 μg/ml in 164 patients receiving the DR tablet for therapeutic purposes. ResultsOf the 164 patients, 53 (32.3%) showed subtherapeutic trough levels of posaconazole. The use of proton pump inhibitors (95% CI 1.41-3.91; P-value = 0.028) and the presence of diarrhea (95% CI 1.95-6.93; P-value = 0.001) were significantly associated with subtherapeutic levels. A total of 13 of the 21 patients receiving posaconazole tablets through a nasogastric tube had therapeutic levels. ConclusionThis is the largest study from India that analyzed factors associated with subtherapeutic levels of the DR tablet of posaconazole. These findings reinforce the importance of therapeutic drug monitoring. Unlike in previous studies, obesity and hypoalbuminemia were not found to be significant factors in our settings. The use of proton pump inhibitors and diarrhea remained significant factors, as found in previous studies. Administering the DR tablet of posaconazole through a nasogastric tube may be a viable option.

Pharmacological characterization of linzagolix, a novel, orally active, non-peptide antagonist of gonadotropin-releasing hormone receptors.

Control of gonadotropin-releasing hormone (GnRH) signalling is an effective strategy for the treatment of sex hormone-dependent diseases. GnRH analogues have been widely used for treating these diseases; however, initial stimulation or complete suppression of GnRH signalling by GnRH analogues results in the occurrence of several distinct adverse effects. Accordingly, we aimed to discover small molecule GnRH antagonists with superior pharmacokinetic and pharmacodynamic profiles. Linzagolix is a potent, orally available, and selective GnRH antagonist. Here, we reported the pharmacological characterization of linzagolix in vitro and in vivo. Linzagolix selectively binds to the GnRH receptor and inhibits GnRH-stimulated signalling, in a manner comparable to cetrorelix, a peptide GnRH antagonist. Because the inhibitory effect of the gonad axis is useful for the treatment of gynaecological conditions such as endometriosis and uterine fibroids, we investigated the effect of orally administrated linzagolix on the gonadal axis in ovariectomized and intact cynomolgus monkeys. In ovariectomized monkeys, linzagolix immediately suppressed the serum luteinizing hormone concentration at doses over 1mg/kg, indicating dose-dependent inhibition that correlated with serum linzagolix concentrations. In intact female monkeys, repeated linzagolix administration suppressed hormone surges and ceased or prolonged menstrual cycles. Furthermore, all animals presenting arrested menstrual cycles following linzagolix treatment showed recovery of hormone secretion and regular menstrual cycles after administration periods ended. Our results demonstrated that linzagolix has potential as a novel agent for reproductive-age women suffering from sex hormone-dependent diseases.

Abstract 1147: A novel anti-Galectin-3 antibody therapeutic for the treatment of triple negative breast cancer

Abstract About 43,600 women in the U.S. are expected to die in 2021 from breast cancer. Triple negative breast cancer (TNBC), which accounts for approximately 15% of all breast cancers, is diagnosed by exclusion of expression and/or amplification of three biomarkers (estrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2]).Characterized by a high risk of relapse (one half of patients with early stages experience recurrence), short overall survival and progression-free survival (life expectancy of few months after failure of first-line chemotherapy), TNBC represents a high unmet medical need. Galectin-3 plays multiple roles in tumor initiation and development via a variety of cellular processes, spanning from angiogenesis to tumor migration. Galectin-3 (Gal3) expression is induced in TNBC patients and highly correlates with poor survival, as shown by our and others’ bioinformatics analysis from public database. We recently discovered and patented a series of antibodies with high specificity and affinity for Gal3, one of which is currently tested in human volunteers. This clinical candidate has shown superior pharmacokinetic properties and clean toxicity profile in GLP studies on non-human primates. Here, we show that anti-Gal3 inhibit both anchorage dependent and independent growth of TNBC cells, as well as Gal3-induced escape from NK cell killing. Also, anti-Gal3 proved to be efficacious in in vivo studies, where TNBC cells were implanted in mammary fat pads of mice and tumor progression, measured as growth of primary mass and presence of metastatic nodules in the lungs, was followed during the two months of treatment. The results presented herein support the conclusion that our therapeutic modality could offer an alternative promising treatment of TNBC. Citation Format: Li Zhang, Heng Wu, Karyssa Palopo, Jie Hu, Marvin Cadiente, Anh Nguyen, Teodelinda Mirabella, Dongxu Sun. A novel anti-Galectin-3 antibody therapeutic for the treatment of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1147.

Targeted Cancer Immunotherapy by Nanoparticle T Cell Engagers

IntroductionAcute myeloid leukemia (AML) is the most common type of leukemia. Emerging immunotherapies such as chimeric antigen receptor T (CAR‐T) cells and T cell engagers (TCEs), have the potential to enhance T cell recognition and response against cancers, but come with serious limitations such as short half‐life, complex production, high cost, and inability to customize for another antigen. To overcome these limitations, we previously developed a nanoparticle‐based T cell engagers (nanoTCEs) technology that has a longer half‐life (60h vs 2h for TCEs), is convenient to make, easily customizable, and robustly activates T cells for cancer killing. In this study, we hypothesized that nanoTCEs targeting CD33/CD3 would effectively activate T cell response in an AML disease model.Material and MethodsLiposomes were produced via the thin‐film hydration method with cholesterol, DPPC, and DSPE‐PEG200 at a molar ratio of 30:65:5 respectively (Figure 1A). CD33/CD3 nanoTCEs were created by conjugating anti‐CD3 and anti‐CD33 monoclonal antibodies (mAbs) on liposome surface with streptavidin‐biotin chemistry. Liposome binding to human T cells and AML cell lines was performed with fluorescently labeled nanoTCEs for 2 hours. The activation of T cell subsets and killing of AML cell lines was analyzed by flow cytometry after 4 days in a 3D culture model. For in vivo efficacy, immunodeficient NCG mice were inoculated with AML cell line and received Isotype/CD3 or CD33/CD3 nanoTCEs injections (0.5 mg/mouse) weekly and monitored for tumor progression and survival.ResultsAML cell lines (K052, MOLM‐14. NOMO‐1, and THP‐1) exhibited high expression of CD33 compared to controls. CD33/CD3 nanoTCEs bound to human T cells and AML cell lines with higher specificity than isotype controls. In addition, the CD33/CD3 nanoTCEs induced increased activation of both CD4+ and CD8+ T cells (Figure 1B, 1C) and achieved greater AML killing compared to the untreated and Isotype/CD3 groups (Figure 1D). Lastly, our in vivo results showed that weekly CD33/CD3 nanoTCE injections extended survival and decreased tumor progression of AML bearing mice compared to Isotype/CD3 nanoTCEs treated mice. By day 66 of the in vivo study, none of the Isotype/CD3 cohort was alive, while 100% of the CD33/CD3 cohort remained living (Figure 2).Discussion and ConclusionThis study shows that nanoTCEs are a promising novel platform for immunotherapy in AML. CD33/CD3 nanoTCEs demonstrated specific engagement of T cells to AML cells, which induced T cell activation and AML cell killing both in vitro and in vivo. It not only circumvented the limitations of traditional T cell engagers, but also presented numerous advantages such as short production time, low cost, and superior pharmacokinetic profile. Moreover, this technology is highly customizable and can be tailored to target multiple cancer antigens simultaneously. The current findings provide a strong preclinical basis for future first‐in‐human clinical trials of CD33/CD3 nanoTCEs as a novel AML immunotherapy.

Superior Pharmacokinetic Profile of an Innovative, Next Generation Curcumin Formula

IntroductionCurcumin is the major bioactive component of turmeric or Curcuma longa L., a widely used spice, food colorant, preservative as well as medicinal agent in Indian and Chinese remedies. Numerous studies have demonstrated its potential benefits for heart health, immunity, diabetes, arthritis as well as joint health and mobility. Currently, curcumin‐based products in capsules, ointments, tablets, and cosmetics are marketed worldwide. One important drawback of using curcumin is its poor bioavailability and hence the need to use it at high doses to achieve measurable plasma levels and efficacy – this limits both consumer compliance and product formulation. Curcumin’s poor solubility, low absorption from the gut, rapid metabolism and rapid systemic elimination contributes to its poor bioavailability. To help overcome this major limitation of curcumin, we developed a proprietary curcumin formulation (Curcuwin Ultra+) (CU+) to enhance its bioavailability. We hypothesized that the formulation would protect the curcuminoids from degradation at intestinal alkaline pH conditions, and through this mechanism, significantly increase the availability of curcuminoids in blood and at the tissue level.GoalOur goal was to measure the pharmacokinetic profile of CU+ vs. a standard turmeric extract (STE).MethodA randomized, double‐blind, crossover study design involving 24 healthy volunteers under fasting conditions was implemented. Subjects received a single dose of 250 mg CU+, 500 mg CU+ and 1900 mg of STE. Blood samples before dosing, and at various time points post dosing up to 24 hours were collected. Total curcuminoids were measured using a validated LC‐MS/MS method. Formulations were compared based on Cmax, AUC0‐6, AUC0‐24, Tmax, t1/2, and relative absorption.ResultsMaximum serum concentration (Cmax) and total systemic exposure (AUC0‐6 and AUC0‐24) for total curcuminoids were significantly higher (p&lt;0.05) for both doses of CU+ vs. STE. For example, AUC0‐6 was 144 and 149 times greater for CU+ at 250 mg and 500 mg respectively compared to 1900 mg of STE. Additionally, CU+ showed 40% faster absorption as measured by Tmax vs. the STE (p&lt;0.05). No adverse events were observed.ConclusionsThese pharmacokinetic data demonstrates the ability of this curcumin formulation to deliver superior bioavailability vs. STE, and, at doses that are considerably lower than STE and several other commercially available curcumin products. This has important relevance to consumer compliance in terms of lowering curcumin dose and frequency of dosing. Since maximizing bioavailability influences the therapeutic effects of a compound, the next phase of our research program is to determine if this enhanced bioavailability can be translated to an efficacious benefit of CU+.

Potent Hydrazide-Based HDAC Inhibitors with a Superior Pharmacokinetic Profile for Efficient Treatment of Acute Myeloid Leukemia In Vivo.

As "Michael acceptors" may induce promiscuous responses in mammalian cells by reacting with various proteins, we modified the cinnamamide of our previous hydrazide-based HDAC inhibitors (HDACIs) to deactivate the Michael reaction. Representative compound 11h is 2-5 times more potent than lead compound 17 in both HDAC inhibitory activity (IC50 = 0.43-3.01 nM) and cell-based antitumor assay (IC50 = 19.23-61.04 nM). The breakthrough in the pharmacokinetic profile of 11h (oral bioavailability: 112%) makes it a lead-in-class oral active agent, validated in the in vivo anti-AML study (4 mg/kg p.o., TGI = 78.9%). Accumulated AcHH3 and AcHH4 levels in tumor tissue directly correlate with the in vivo efficacy, as panobinostat with lower AcHH3 and AcHH4 levels than 11h displays limited activity. To the best of our knowledge, this work contributes the first report of in vivo antitumor activity of hydrazide-based HDACIs. The outstanding pharmacokinetic/pharmacodynamic and antitumor activity of 11h could potentially extend the clinical application of current HDACIs.

Design of Experiment Approach to Assess the Effect of Formulation Variables on Extrusion and Spheronization of Telmisartan and Cilostazol Loaded Pellets and its Pharmacokinetic Study

Background: Solubility is an important parameter that affects the availability of drug in systemic circulation. Drugs having poor solubility belonging to BCS class II eventually result in lower dissolution and bioavailability. Hence, improvement of solubility is a challenging task. Hence the present work focuses on using solid dispersion and inclusion complex approach for both telmisartan and cilostazol belonging to BCS Class II drugs. Objective: The present study was carried out to improve apparent solubility of telmisartan and cilostazol (BCS-Class II drugs) and optimization as pellets along with its pharmacokinetic study. Methods: Phase solubility study was carried out to screen the excipients such as, PVPK30, PVA, HPMC E5 and β-CD. Solvent evaporation method was adopted to prepare the solid dispersions and inclusion complex of both drugs. Pellets were optimized by extrusion spheronization method using 32 factorial design and characterized by morphology, drug content, DSC, FTIR, XRD, SEM, in- -vitro studies and drug content study. Results: Phase solubility study showed improved apparent solubility of telmisartan with HPMC E5 (1:3) by solid dispersion and cilostazol with β-CD (1:3) using inclusion complexation method. Drug characterization did not reveal any incompatibility. Formulation was optimized on the basis of acceptable pellet properties, including acceptable spherical shape and micromeritics properties. The percent friability of all batches was found to be less than 1%. The optimized pellets of both drugs prepared with micro crystalline cellulose provided desirable maximum release with acceptable release profile. Conclusion: The formulated pellets when studied in vivo showed superior pharmacokinetic profile. The drawback associated with apparent solubility and bioavailability of both drugs can thus be alleviated by use of novel pellet formulation.

A Novel Allosteric HIPK2 Inhibitor Attenuates Renal Fibrosis with Superior Pharmacokinetic, Selectivity, and Safety Profiles

A Novel Allosteric HIPK2 Inhibitor Attenuates Renal Fibrosis with Superior Pharmacokinetic, Selectivity, and Safety Profiles

The possibility of short-term hypothalamic-pituitary-adrenal axis suppression with high-volume, high-dose nasal mometasone irrigation in postsurgical patients with chronic rhinosinusitis.

Medically refractory chronic rhinosinusitis (CRS) is often treated with functional endoscopic sinus surgery (FESS) and high-volume steroid nasal irrigation. While budesonide is the most common steroid irrigation for this indication, mometasone has a superior pharmacokinetic profile, which may allow dose escalation. The safety and efficacy of mometasone at higher concentrations than previously used in treating CRS have not been explored. Patients were recruited from a tertiary level clinic between June 2018 and December 2019. Inclusion criteria included adults (>18 years); CRS diagnosis; previous FESS; pre-treatment morning cortisol within normal range; minimum of twice daily high-volume sinonasal mometasone irrigations (total dose of 4 mg) for 12 weeks; and post-treatment morning cortisol measured within 2 weeks following the study period. Patients with potential for endogenous or exogenous disruption of the HPA axis were excluded. 14 patients were enrolled in this prospective cohort study. In all but one patient, pre- and post-treatment morning cortisol levels were not significantly different and were within normal limits (6.7-25.4 μg/dL). Following an uninterrupted 12-week treatment course, no evidence of HPA axis suppression was found (P = 0.915). The single patient who was found to have a low (1.3 μg/dL) post-treatment morning serum cortisol level reportedly received an intraarticular steroid shot several days prior to the blood draw. She remained asymptomatic and her rechecked serum cortisol was within normal limits at 12.3 μg/dL. High-volume 2 mg twice daily sinonasal mometasone irrigations did not cause HPA axis suppression in a representative sample of patients with refractory CRS post-FESS with normal baseline cortisol levels.

Pterostilbene is more efficacious than hydroxystilbenes in protecting liver fibrogenesis in a carbon tetracholride-induced rat model

Stilbene compounds existing in edible berries have attracted much attention due to their efficacious health-promoting properties such as antioxidant, anti-aging, modulation of metabolic diseases and cancer prevention among others. Pterostilbene has superior pharmacokinetic profile over hydroxylated stilbenes such as resveratrol and oxyresveratrol. Hence, the current study was to evaluate the anti-hepatic fibrosis effects of pterostilbene in direct comparison to two hydroxylated stilbene compounds. In a carbon tetrachloride (CCl4) stimulated hepatic fibrosis model, rats were co-administrated with pterostilbene and hydroxystilbene via gavage feeding. Results revealed that stilbenes exerted significant efficacious protective effects against rat liver fibrosis, by reducing the expression levels of α-SMA, desmin, MMP2 and MMP9 and down-regulating the expression ofTGF-β1, phosphorylated Smad1/2 and ERK1/2 in the liver tissue, among which pterostilbene demonstrated much potent preventive activity than the hydroxylated stilbenes.

Abstract 1842: CD79b targeting ADC with superior pharmacokinetic profile and anti-tumor activity

Abstract Araris' site-specific conjugation technology is improving the safety and efficacy of ADCs without antibody engineering. Our technology is using transglutaminase for site-specific enzymatic payload conjugation to ‘off-the-shelf' antibodies, i.e., without the need to reduce or engineer the antibody. The functionalization takes place site-specifically and stoichiometrically (drug-to-antibody ratio, DAR = 2) at the glutamine residue Q295 in the Fc-part of antibodies. The resulting ADCs show favorable biophysical properties such as high solubility and stability. Additionally, initial data show that linker conjugation does not interfere with Fc-gamma receptor and FcRn binding. Using native polatuzumab (non-engineered, same antibody sequence as present in approved polatuzumab-vedotin) as the targeting antibody and monomethyl auristatin E (MMAE) as payload, we generated within 24 hours highly homogeneous and pure ADCs with a well-defined DAR of 1.9 (LC-MS). Size exclusion chromatography analysis showed a highly monomeric ADC product (&amp;gt; 96% monomer content) that remained stable under stressed conditions at elevated temperatures. In in-vitro assays our ADCs demonstrated potent cytotoxicity in four tested cell-lines, similar to the approved polatuzumab-vedotin (Polivy®). Moreover, our anti-CD79b ADC (termed ARC-01) is highly stable in mouse, cynomolgus and human sera and is resistant to mouse Ces1c cleavage but is cleaved by the lysosomal human Cathepsin B. Most importantly, the resulting ADC is extremely stable as shown in pharmacokinetic studies in mice demonstrating a very long exposure comparable to the unmodified polatuzumab antibody and twice as long as the approved polatuzumab-vedotin (half-life 10d vs 5d). Most importantly, the in vivo efficacy of our ARC-01 (DAR 1.9) as compared with approved polatuzumab-vedotin (DAR 3.5) was assessed in the Granta-519 tumor model. Animals received a single injection of 0.53 or 2.1 mg/kg polatuzumab-vedotin (Polivy®) and either 0.53, 1 or 2.1 mg/kg of ARC-01. ARC-01 provided equal tumor growth inhibition and survival at about half the payload dose relative to polatuzumab-vedotin (comparison of the 2mg/kg doses and 0.53 mg/kg doses). At an approximately equal payload dose, ARC-01 treatment led to a greater antitumor efficacy and a considerable survival advantage with 6/8 complete tumor remissions over polatuzumab-vedotin with 0/8 complete tumor remission (comparison of the 0.53mg/kg dose of polatuzumab-vedotin and 1mg/kg dose of ARC-01). These encouraging results obtained so far indicate that our linker technology a) allows for fast (&amp;lt; 24 hours) and straightforward manufacturing of ADCs without protein engineering efforts, b) results in ADCs with favorable biophysical properties and a clear defined drug-to-antibody ratio, and c) enables the generation of highly potent and stable, thus safer, next-generation ADCs. Citation Format: Philipp René Spycher, Philipp Probst, Romain Bertrand, Ramona Stark, Roger Santimaria, Dragan Grabulovski, Isabella Attinger-Toller. CD79b targeting ADC with superior pharmacokinetic profile and anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1842.

In Vitro and In Vivo Efficacies of the Linear and the Cyclic Version of an All-d-Enantiomeric Peptide Developed for the Treatment of Alzheimer's Disease.

Multiple sources of evidence suggest that soluble amyloid β (Aβ)-oligomers are responsible for the development and progression of Alzheimer’s disease (AD). In order to specifically eliminate these toxic Aβ-oligomers, our group has developed a variety of all-d-peptides over the past years. One of them, RD2, has been intensively studied and showed such convincing in vitro and in vivo properties that it is currently in clinical trials. In order to further optimize the compounds and to elucidate the characteristics of therapeutic d-peptides, several rational drug design approaches have been performed. Two of these d-peptides are the linear tandem (head-to-tail) d-peptide RD2D3 and its cyclized form cRD2D3. Tandemization and cyclization should result in an increased in vitro potency and increase pharmacokinetic properties, especially crossing the blood–brain-barrier. In comparison, cRD2D3 showed a superior pharmacokinetic profile to RD2D3. This fact suggests that higher efficacy can be achieved in vivo at equally administered concentrations. To prove this hypothesis, we first established the in vitro profile of both d-peptides here. Subsequently, we performed an intraperitoneal treatment study. This study failed to provide evidence that cRD2D3 is superior to RD2D3 in vivo as in some tests cRD2D3 failed to show equal or higher efficacy.

Pharmacokinetics of bilirubin-10-sulfonate and biliverdin in the rat

Background and purposeBiliverdin (BV) administration induces antioxidant and anti-inflammatory effects, with previous reports also identifying anti-anaphylactic potential. Interestingly however, intra-duodenal administration of BV in rats leads to the formation of bilirubin-10-sulfonate (BRS), which might be responsible for BV's purported effects. Experimental approachThis study aimed to assess the intravenous, intraperitoneal and intraduodenal pharmacokinetics of BRS and BV in order to assess their therapeutic potential in future studies. Bile and venous blood were intermittently collected before and after administration, which was subsequently analysed using liquid chromatography-mass spectrometry for quantification of bile pigment concentrations. Key resultsInterestingly, i.p. BRS administration led to a greater circulating concentration and had a reduced excretion rate, which resulted in a substantially elevated AUC180 when compared to BV administration. Furthermore, BRS was excreted intact in the bile, in contrast to BV which was excreted after chemical reduction and conjugation. Intraperitoneal and intraduodenal administration substantially increased blood BRS concentrations (p<0.05), however, the bioavailability of BV was higher than BRS following i.p. administration (i.p. BV 28.4%, BRS 15.5%) but lower following i.d. administration (i.d. BV 0.04%, BRS 0.07%), over 180 minutes. When BRS was administered i.v., BRS had a significantly (p<0.05) longer distribution (191.9 vs 54.1 minutes) half-life compared to BV, and significantly reduced (p<0.05) volume of distribution (0.026 vs 0.145 L kg−1). As a consequence, intraperitoneal and intraduodenal administration resulted in significantly greater blood concentrations of BRS (p<0.05) over 180 minutes. Therefore, BRS may be more likely to induce antioxidant or molecular effects, when compared to BV, due to greater concentrations and a longer half-life. Conclusions and implicationsCumulatively, these data demonstrate that BRS has a superior pharmacokinetic profile when compared to BV, which is a result of its resistance to hepatic metabolism and excretion. These data therefore provide a basis to explore the capacity of BRS to protect from inflammatory pathology.

Enhanced oral bioavailability and biodistribution of atractylodin encapsulated in PLGA nanoparticle in cholangiocarcinoma.

Atractylodes lancea (Thunb) DC. and its bioactive compound atractylodin (ATD), have been shown to exert promising anticancer activity against cholangiocarcinoma (CCA) both in vitro and in vivo. However, the clinical development of ATD could be hindered due to hydrophobicity and poor pharmacokinetic properties, and thus, the requirement of high dose administration and the risk of toxicity. In the present study, ATD-loaded in PLGA nanoparticles (ATD-PLGA) and that coated with chitosan (ATD-PLGA-CS) were developed using nanoprecipitation and single emulsification methods, respectively. The optimized ATD-PLGA formulation provided superior physical and pharmaceutical properties over ATD-PLGA-CS. The antiproliferative activity of ATD-PLGA against the two CCA cell lines, HuCCT1 and CL6, and the normal cell line (OUMS-36T-1F) was evaluated using MTT assay. Results showed that normal epithelial cell was less sensitive to ATD-PLGA compared to both CCA cell lines. In mice, the radiolabelled 99m Tc-ATD-PLGA showed superior pharmacokinetic profile over free 99m Tc-ATD, as evidenced by a 2.7-fold increase of area under plasma concentration-time curve (AUC0-∞ ), maximum plasma concentration (Cmax ), time to Cmax (tmax ), and mean residence time (MRT). Higher accumulation of 99m Tc-ATD-PLGA was observed in vital organs/tissues such as blood, liver, heart, and kidney, compared with free 99m Tc-ATD-PLGA. Altogether, the results suggest that PLGA NPs could be a suitable drug delivery carrier for ATD in CCA.

Development and characterization of 5-fluorouracil nanofibrous film for the treatment of stomach cancer

The purpose of the present exposition was to develop 5-fluorouracil (5-FU) loaded gastro retentive nanofibrous film, to improve the chemotherapeutic performance in gastric cancer. 5-FU loaded Eudragit S-100 composite nanofibers have been prepared and optimized using a single nozzle electrospinning technique. The prepared nanofibers were evaluated for inclusive pharmaceutical aspects including drug encapsulation, physical properties, surface morphology, buoyancy, tensile strength, thermal properties, and in-vitro release. The developed formulation shows high % drug encapsulation (>90%), superior thermal stability, and released 90% of encapsulated therapeutic after 12 h. The optimized formulation was subjected to in-vivo antitumor performance against Ehrlich Ascites Carcinoma (EAC) induced orthotopic xenograft models. The developed nanofiber formulation exhibits superior tumor regression potential and pharmacokinetic profile compared to the plain drug. Experimental findings suggest that a nanofiber-based gastro retentive drug delivery system offers a potential strategy for the localized treatment of gastric cancer with improved chemotherapeutic performance.

Potency-Adjusted Analyses of a Head-to-Head Pharmacokinetic Study of Damoctocog Alfa Pegol (BAY 94-9027) and Efmoroctocog Alfa (rFVIIIFc) in Patients with Severe Hemophilia A

Potency-Adjusted Analyses of a Head-to-Head Pharmacokinetic Study of Damoctocog Alfa Pegol (BAY 94-9027) and Efmoroctocog Alfa (rFVIIIFc) in Patients with Severe Hemophilia A

Targeting ALK2: An Open Science Approach to Developing Therapeutics for the Treatment of Diffuse Intrinsic Pontine Glioma.

Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we adopted an open science approach to develop a series of potent type I inhibitors of ALK2 which are orally bio-available and brain-penetrant. Initial efforts resulted in the discovery of M4K2009, an analogue of the previously reported ALK2 inhibitor LDN-214117. Although highly selective for ALK2 over the TGF-βR1 receptor ALK5, M4K2009 is also moderately active against the hERG potassium channel. Varying the substituents of the trimethoxyphenyl moiety gave rise to an equipotent benzamide analogue M4K2149 with reduced off-target affinity for the ion channel. Additional modifications yielded 2-fluoro-6-methoxybenzamide derivatives (26a–c), which possess high inhibitory activity against ALK2, excellent selectivity, and superior pharmacokinetic profiles.

Copper-64 Labeled PEGylated Exosomes for In Vivo Positron Emission Tomography and Enhanced Tumor Retention.

Exosomes have attracted tremendous attention due to their important role in physiology, pathology, and oncology, as well as promising potential in biomedical applications. Although great efforts have been dedicated to investigating their biological properties and applications as natural cancer drug-delivery systems, the systemic biodistribution of exosomes remains underexplored. In addition, exosome-based drug delivery is inevitably hindered by the robust liver clearance, leading to suboptimal tumor retention and therapeutic efficiency. In this study, we report one of the first examples using in vivo positron emission tomography (PET) for noninvasive monitoring of copper-64 (64Cu)-radiolabeled polyethylene glycol (PEG)-modified exosomes, achieving excellent imaging quality and quantitative measurement of blood residence and tumor retention. PEGylation not only endowed exosomes with a superior pharmacokinetic profile and great accumulation in the tumor versus traditionally reported native exosomes but also reduced premature hepatic sequestration and clearance of exosomes, findings that promise enhanced therapeutic delivery efficacy and safety in future studies. More importantly, this study provides important guidelines about surface engineering, radiochemistry, and molecular imaging in obtaining accurate and quantitative biodistribution information on exosomes, which may benefit future exploration in the realm of exosomes.

Optimization of an Antibody Light Chain Framework Enhances Expression, Biophysical Properties and Pharmacokinetics.

Efficacy, safety, and manufacturability of therapeutic antibodies are influenced by their biopharmaceutical and biophysical properties. These properties can be optimized by library approaches or rationale protein design. Here, we employed a protein engineering approach to modify the variable domain of the light chain (VL) framework of an oxidized macrophage migration inhibitory factor (oxMIF)-specific antibody. The amendment of the antibody sequence was based on homology to human germline VL genes. Three regions or positions were identified in the VL domain—L1-4, L66, L79—and mutated independently or in combination to match the closest germline V gene. None of the mutations altered oxMIF specificity or affinity, but some variants improved thermal stability, aggregation propensity, and resulted in up to five-fold higher expression. Importantly, the improved biopharmaceutical properties translated into a superior pharmacokinetic profile of the antibody. Thus, optimization of the V domain framework can ameliorate the biophysical qualities of a therapeutic antibody candidate, and as result its manufacturability, and also has the potential to improve pharmacokinetics.

Mechanism of Reductive Metabolism and Chiral Inversion of Proton Pump Inhibitors.

Racemic proton pump inhibitors (PPIs) have been developed into pure enantiomers given superior pharmacokinetic profiles. However, after doses of single enantiomer PPIs, different degrees of chiral inversion were observed. We investigated the relationship between chiral inversion and reductive metabolism of PPIs, as well as the mechanism of reductive metabolism. In liver microsomes and Sprague-Dawley rats, PPI thioethers were stereoselectively oxidized to (R)- and (S)-PPIs, indicating that thioethers could be the intermediates of chiral inversion. By comparing the area under the plasma concentration-time curve ratios of thioether to rabeprazole under different routes of administration and blood sampling site, it was determined that thioether was mainly formed in the liver rather than the intestine. The formation rate of PPI thioethers in liver subcellular fractions was significantly higher than that in buffers. Sulfhydryl-blocking agents, such as N-ethylmaleimide, menadione, and ethacrynic acid, inhibited the reductive metabolism of PPIs in vitro, and their corresponding glutathione conjugates were observed. Similar amounts of thioethers were formed in glutathione solutions as in liver subcellular fractions, indicating that biologic reducing agents, instead of reductases, accelerated the reductive metabolism of PPIs. The reduction rates in glutathione solutions were ordered as follows: rabeprazole > omeprazole > lansoprazole > pantoprazole, which was consistent with the natural bond orbital charges of sulfur atoms in these compounds. In conclusion, PPIs were transformed into thioethers by biologic reducing agents in liver, and thioethers continued to be oxidized to two enantiomers, leading to chiral inversion. Furthermore, inhibiting oxidative metabolism of PPIs enhanced reductive metabolism and chiral inversion.