Pharmacokinetic Study In Rats Research Articles

Preparation and evaluation of oral enteric sustained-release liquid formulations of aspirin.

To develop an enteric sustained-release nanoparticle formulations of aspirin for applicability to a broader population. Aspirin-loaded nanoparticles were prepared using poly(lactic-co-glycolic acid) (PLGA) and the enteric polymer Eudragit L100-55 through an optimized oil-in-water emulsification solvent evaporation method. The nanoparticles were subjected to comprehensive physicochemical characterization, including particle size, zeta potential, and morphological analysis. Additionally, their stability, in vitro drug release profile, cytotoxicity, intestinal absorption, and in vivo pharmacokinetics were systematically evaluated. The nanoparticles exhibited well-defined spherical morphology, uniform particle size, and favorable surface charge, demonstrating excellent biocompatibility. In the in vitro drug release study, AS-PLGA@NPs exhibited pronounced enterolysis effect. The morphology of the nanoparticles was confirmed by scanning electron microscopy (SEM) at different release stages. In vivo intestinal absorption and pharmacokinetic studies in rats demonstrated that AS-PLGA-EL@NPs enhanced drug absorption, prolonged drug release, and showed higher bioavailability compared to conventional enteric-coated tablets. The development and preparation of an oral enteric sustained-release nanoparticle delivery system for aspirin has the potential to serve a broader population, with promising applications in various therapeutic contexts.

Thermosensitive, mucoadhesive brivaracetam nasal gel: a promising strategy for targeted relief of epilepsy.

This study aimed to develop a mucoadhesive thermosensitive in situ nasal gel of brivaracetam (BRIVA-gel) to treat epilepsy. A BRIVA-gel was statistically optimized using 32 factorial design varying amounts of Poloxamer 407 and Carbopol 934. The formulation was subjected to nasal ciliotoxicity studies. A comparative pharmacokinetic and brain distribution study was also conducted on BRIVA-gel and oral-marketed tablets in rats. The final BRIVA-gel was clear in the sol form and transformed into a gel at 32-34°C with a gelling time between 49 and 154s. The drug release studies demonstrated the sustained release of BRIVA-gel up to 4h. Stability studies confirmed the BRIVA-gel was stable over a 3-month testing period at refrigerated conditions. BRIVA-gel did not show any nasal toxicity and was considered safe for intranasal delivery. The pharmacokinetic study in rats exhibited a twofold increase in AUC by BRIVA-gel (25.907µg/mL.h) than the oral-marketed tablets (11.844ng/mL.h). The brain biodistribution revealed significantly improved drug content in the brain by nasal BRIVA-gel than oral tablets. These findings suggested that thermosensitive in situ nasal BRIVA-gel has the potential to serve as a targeted delivery system to the brain, overcoming the challenges of first-pass metabolism and gastric degradation.

Abstract 7463: A linker platform for antibody drug conjugates (ADCs): expanding the therapeutic window

Abstract Although ADCs have demonstrated great clinical promise, their therapeutic window remains limited due to the complexity of this drug format. Factors contributing to this narrow safety window include the instability of the linkers, accelerated plasma clearance due to the hydrophobicity of the ADCs, and off-target toxicity caused by nonspecific uptake by non-antigen expression healthy cells, free payload pre-release in the circulation system, low tumor retention due to heterogeneity of tumor antigen level and ADC DAR value By preserving the essential functions of the antibody and the payload, an optimized linker can significantly enhance ADC therapeutic window by increasing hydrophilicity and stability while reducing non-specific endocytosis by non-tumor cells. We have designed a panel of novel linkers focused on improving hydrophilicity and stability of ADC, with a particular emphasis on reducing its off-target endocytosis. A key feature of our linkers is the inclusion of a negative charged side chain and hydrophilic chaperone, which not only minimizes non-specific uptake by non-tumor cells but also greatly enhances its hydrophilicity. The side chain linker with this special architecture allows efficient enzymatic cleavage to ensure rapid payload release intracellularly, and lead to superior bystander cell killing effect than the ADC with GGFG-Dxd linker system. One example exploiting the proprietary linker is Trastuzumab-BL-001-exatecan with a drug-to-antibody ratio (DAR) of 8, demonstrated hydrophilicity comparable to Trastuzumab-GGFG-Dxd (biosimilar) in HIC analysis, with no aggregation detected by analytical SEC. This ADC exhibited excellent stability, maintaining high solubility, and cytotoxicity under stressed conditions. It also resisted deconjugation in the presence of high concentration of N -acetylcysteine and showed exceptional stability in human and mouse plasma. Pharmacokinetic studies in rats indicated favorable pharmacokinetic properties, while efficacy testing in the NCI-N87 tumor model revealed comparable performance to Trastuzumab-GGFG-Dxd. Additionally, BLB-101 ADC, featuring the same linker, was well tolerated in non-human primates following repeated administration. In conclusion, our novel linker designs offer significant advantages, with features that could expand the therapeutic window of current ADCs by improving their stability, reducing off-target effects, increasing bystander activity, and maintaining efficacy. We are also expanding the utility of this class of linkers to enable ubiquitous design of dual-payload-ADC Degrader-Antibody-Conjugates. Citation Format: David Yi, Wen Zhang, John Liu, Suk Lee, Alice Chen. A linker platform for antibody drug conjugates (ADCs): expanding the therapeutic window [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7463.

Abstract 323: Preclinical evaluation of SDV2102, a novel PSMA-targeting DAR1 ADC for mCRPC treatment

Abstract Metastatic castration-resistant prostate cancer (mCRPC) presents a significant therapeutic challenge due to limited treatment options. Prostate-specific membrane antigen (PSMA) is overexpressed in mCRPC tumors, making it a viable target for antibody-drug conjugates (ADCs). We developed SDV2102, a novel PSMA-targeting ADC designed to enhance tumor penetration and efficacy. SDV2102 utilizes a novel anti-PSMA antibody, D10, selected for its superior antigen-binding properties. The D10 antibody is conjugated with monomethyl auristatin E (MMAE), a tubulin-binding cytotoxic agent to which mCRPC tumors are inherently more sensitive than to topoisomerase I inhibitors. Notably, SDV2102 has a drug-to-antibody ratio (DAR) of 1, allowing for higher dosing and increased efficacy without proportional increases in systemic toxicity, thereby improving the therapeutic index. In vivo efficacy was assessed using the C4-2 cell-derived xenograft (CDX) model, characterized by high PSMA expression. SDV2102 demonstrated significantly greater anti-tumor efficacy than classical DAR4 ADCs constructed with either the generic J591 antibody or the D10 antibody when administered at equivalent doses of MMAE. Additionally, SDV2102 showed potent activity in patient-derived xenograft (PDX) models with low to moderate PSMA expression levels, with some tumors expressing as few as 25, 000 receptors per cell. This indicates that SDV2102 may be effective across a spectrum of PSMA expression in mCRPC tumors. Pharmacokinetic studies in rats revealed that SDV2102 has a favorable profile, closely mirroring that of the unconjugated D10 antibody, suggesting maintained antibody-like characteristics in circulation. Dose-response studies in the C4-2 model identified a minimum effective dose of 2.5 mg/kg. Toxicology studies in non-human primates showed no major toxicities at doses up to 24 mg/kg, with the maximum tolerated dose (MTD) not reached, indicating a wide therapeutic window. SDV2102 achieved a therapeutic index of 38, representing a substantial safety margin. These preclinical results support the advancement of SDV2102 into clinical trials as a promising therapeutic candidate for the treatment of mCRPC. Citation Format: Damien Dattler, Fabian Schlimpen, Constantin Semenchenko, Oleksandr Koniev, Sergii Kolodych. Preclinical evaluation of SDV2102, a novel PSMA-targeting DAR1 ADC for mCRPC treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 323.

The discovery and preclinical pharmacology of JNJ-10450232 (NTM-006), a centrally penetrant, non-opioid structural analog of acetaminophen with comparable analgesic and anti-pyretic properties but no evidence of hepatotoxicity.

The discovery and preclinical pharmacology of JNJ-10450232 (NTM-006), a centrally penetrant, non-opioid structural analog of acetaminophen with comparable analgesic and anti-pyretic properties but no evidence of hepatotoxicity.

Costunolide nanosuspension loaded in dissolvable microneedle arrays for atopic dermatitis treatment.

Costunolide nanosuspension loaded in dissolvable microneedle arrays for atopic dermatitis treatment.

Variable pore size of mesoporous silica in improving physical stability and oral bioavailability of insoluble drugs.

Variable pore size of mesoporous silica in improving physical stability and oral bioavailability of insoluble drugs.

Hyaluronate-incorporated edaravone nanostructured lipid carriers for nose-to-brain targeting- biphasic DoE optimization, pharmacokinetic, and brain distribution studies.

Hyaluronate-incorporated edaravone nanostructured lipid carriers for nose-to-brain targeting- biphasic DoE optimization, pharmacokinetic, and brain distribution studies.

Bioanalytical considerations for quantification of ondansetron in rat microdialysis study using LC-MS/MS.

Ondansetron is an anti-emetic drug and has been recently identified as a therapeutic for neuropathic pain. Permeability of ondansetron into the nervous system may be impacted by the presence of P-glycoprotein (Pgp) at the blood brain barrier, since ondansetron is a substrate of Pgp, which means it may not easily cross into the brain. In order to determine a drug concentration within the brain, microdialysis can be used, which measures unbound analyte concentrations in tissues or body fluids. The purpose of this study was to develop and validate an LC-MS/MS method to measure ondansetron concentrations in serum and brain microdialysates for pharmacokinetic studies in rats. To the best of our knowledge, a fully validated method for the quantification of ondansetron in brain microdialysis studies has not been reported so far. Chromatographic separation was achieved at a flow rate of 0.6 mL/min using the Gemini C18 column (5 μm; 50 × 4.6 mm) and a mobile phase consisting of 10 mM ammonium formate with 0.1 % formic acid in water and 0.1 % formic acid in acetonitrile (55:45, v/v). Serum samples were prepared by protein precipitation; for microdialysate, no specific cleaning procedure was needed, they were only diluted with the internal standard solution. The presented method requires only a small volume of serum (2.5 μL) and microdialysate (15-20 μL), which allows for frequent sampling in animals. Moreover, it enables high throughput due to a short run time and straightforward sample preparation. Artificial cerebrospinal fluid (aCSF) was confirmed to be useful as a surrogate matrix for brain microdialysate. The lower limit of quantitation for ondansetron was 0.01 μg/mL for serum and 0.025 ng/mL for microdialysate. A significant ion suppression for ondansetron was observed in brain microdialysate and aCSF, but the IS-normalized matrix factor was close to 1.0. The developed LC-MS/MS method met the FDA and EMA validation criteria and was successfully applied to the in vivo pilot pharmacokinetic study. It was sensitive enough to capture the low ondansetron concentrations in brain microdialysate and universal enough to measure high ondansetron concentrations in rat serum.

DMC-BH derivative DMC-GF inhibits the growth of glioma stem cells by targeting the TRIM33/SLC25A1/mitochondrial oxidative phosphorylation pathway

Glioma stem cells (GSCs) exhibit significant resistance to conventional radiotherapy and chemotherapy, contributing to high recurrence rates in gliomas. Addressing this critical clinical need, we developed DMC-GF, a novel GLUT1-based curcumin derivative, to enhance brain specificity and metabolic stability compared to its predecessor DMC-BH. Pharmacokinetic studies in rats demonstrated that DMC-GF achieved an 8.5-fold increase in brain-to-blood concentration ratio two hours post-intravenous administration, markedly superior to the 0.2-fold increase observed with DMC-BH. In vitro assays showed that DMC-GF exerted a more substantial inhibitory effect on GSC proliferation than DMC-BH (p < 0.01), as assessed by Cell Counting Kit-3D and EdU assays. Mechanistic analysis via the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway indicated that DMC-GF’s anti-GSC activity is associated with disruption of mitochondrial oxidative phosphorylation. Treatment with DMC-GF at a concentration of 4 µM caused a notable decrease in mitochondrial membrane potential and maximal mitochondrial oxygen consumption. Additionally, exposure to 8 µM DMC-GF led to a marked (> 70%) reduction in SLC25A1, a mitochondrial citrate transporter, protein levels (p < 0.01). Overexpression of SLC25A1 attenuated both the decreased proliferation and enhanced apoptosis caused by DMC-GF (p < 0.01). Furthermore, the proteasome inhibitor MG132 (10 µM) and TRIM33, an E3 ubiquitin ligase involved in proteasome-mediated protein degradation, knockdown via shRNA both abrogated the DMC-GF-mediated decrease in SLC25A1 protein levels (p < 0.05). These findings underscore the potential of DMC-GF as an efficacious targeted therapeutic against GSCs, offering enhanced brain specificity and stability, and elucidating its mechanism involving mitochondrial dysfunction and SLC25A1 degradation.

Ezetimibe oral solid lipid nanoparticle by effervescent dispersion method: in vitro characterization and in vivo pharmacokinetic study in rats

Ezetimibe (EZT) is a class II drug of the Biopharmaceutics classification system (BCS), with limited aqueous solubility and high permeability. This study aims to enhance the solubility and oral bioavailability of EZT by developing EZT solid lipid nanoparticles (SLNs). EZT-SLNs were developed through the effervescent dispersion technique. Different amounts of Tween-80, Compritol ATO 888, and mannitol as cryoprotectant were used. F11 was the optimum formula with 154 nm in size and 90.26% entrapment efficiency. It demonstrates significant enhancements in solubility across various pH values. In addition, F11 shows a significantly higher drug release than pure EZT at all time points, and that’s related to the reduction in the particle size and increasing its surface area along with the transformation from a crystalline state to an amorphous state. The powder X-ray diffraction and Differential Scanning Calorimetry tests confirmed this conversion from crystalline form to amorphous. The in vivo animal study demonstrated that the Cmax and AUC 0 ∞ of the EZT-SLNs group were significantly higher than the pure EZT group, after oral administration. In conclusion, EZT-SLNs with enhanced in vitro and in vivo properties were successfully developed using the effervescent dispersion technique.

Investigation of flurbiprofen pharmacokinetics in rats following dermal administration of optimized cyclodextrin-based nanogel.

Investigation of flurbiprofen pharmacokinetics in rats following dermal administration of optimized cyclodextrin-based nanogel.

CANNABINOID MEDICINAL CHEMISTRY HAS VAST IMPACT ON PHARMACOLOGY IN MOUSE AND RAT MODELS OF INFLAMMATORY BOWEL DISEASE (IBD)

Abstract Natural cannabinoids are experiencing a renaissance in pharmacological research. With over 400 studies reported on clinicaltrials.gov, cannabidiol (CBD) and cannabigerol (CBG) are among the most extensively studied. Despite the potential of cannabinoids, few drugs have been approved. Due to low oral bioavailability clinically investigated cannabinoids must be administered at remarkably high doses, which can lead to complications including severe hepatic impairment. Recently, a rare THC molecule with a seven-term alkyl side chain was found to bind CB receptors up to 66 times more effectively than THC. From our previous work we determined the primary site of metabolism of CBG was at the hydroxyl sites. Consequently, we sought to explore Structure Activity Relationships (SAR) focusing on the alkyl side chain and the hydroxyl sites. To our knowledge, cannabinoid derivatives have not been specifically developed for targeting IBD. Seventeen derivatives were characterized in vitro for their potential to inhibit pro-inflammatory cytokines. Subsequently, we screened 10 derivatives in a mouse model of Trinitrobenzenesulfonic Acid (TNBS)-induced colitis. While CBG was ineffective, we found two compounds—(1’R,2’R)-4-heptyl-6-methoxy-5’-methyl-2’-(prop-1-en-2-yl)-1’,2’,3’,4’-tetrahydro-[1’,1’-biphenyl]-2-ol and (E)-2-(3,7-dimethylocta-2,6-dien-1-yl)-1,3-dimethoxy-5-pentylbenzene - DM350-P, and DM300 respectively—to be highly efficacious. Subsequently, in an Indomethacin-induced Crohn’s Disease (CD) model in rats, both DM300 and DM350-P were highly effective at reducing inflammation and necrosis in the small bowel when administered orally. An oral rat pharmacokinetic (PK) study revealed that the derivatives had bioavailability up to 15 times higher than natural cannabinoids, as determined by the area under the plasma concentration versus time curve (AUC) calculation. Additionally, we employed the BioMAP Diversity Plus panel of 12 human primary cell-based systems modeling complex human tissue and disease biology. The derivatives shared common threads in anti-inflammatory, immunomodulatory, and tissue remodeling activities. The BioMAP panel corroborated our in vivo data. DM350-P was the most active and potent, while DM300 was active with moderate potency. These data support that DM300 and DM350-P may have potential to prevent NSAID induced gastrointestinal injury and treat IBD while presenting safer profiles than natural cannabinoids due to improved bioavailability. Our cannabinoid SAR studies have identified promising lead candidates derived from just two out of more than 130 known natural cannabinoids. While we plan to advance these candidates, extending our cannabinoid SAR research by utilizing AI-assisted design and learning, may establish a new paradigm for discovering orally available small molecules to treat IBD. Figure 1: Mouse TNBS colitis histopathology scores. †p&amp;lt; 0.05, vs sham control. *p&amp;lt; 0.05, vs vehicle control; two-way ANOVA followed by Bonferroni test. Figure 2: Representative H&amp;E staining photomicrographs of Jejunum sections of small intestine. Normal group has no lesions. Vehicle group has marked inflammation and necrosis (arrow). Dexamethasone group has minimal inflammation and necrosis (arrow). DM350-P and DM300 groups have very minimal inflammation and no evidence of necrosis.

Application of microarray patches for the transdermal administration of psychedelics drugs in micro-doses

Application of microarray patches for the transdermal administration of psychedelics drugs in micro-doses

Advantages of the refined developability classification system in early discovery.

Advantages of the refined developability classification system in early discovery.

Silybin Cocrystals with Improved Solubility and Bioavailability.

Backgroud/Objectives: Silymarin, an extract from milk thistle, is widely recognized for its therapeutic potential in treating liver disorders. However, its clinical utility is limited by the poor solubility and low bioavailability of its key active ingredient, Silybin. In this study, we sought to address this issue through the development of a novel cocrystal of Silyin. Methods: Silybin-L-proline cocrystal was synthesized and the physicochemical properties of the cocrystal were characterized by PXRD, TGA, DSC, and FTIR. Dissolution tests were conducted in various pH solutions, and the impact of precipitation inhibitors was evaluated. Furthermore, pharmacokinetic study in rats were performed to assess the bioavailability. Results: The dissolution studies demonstrated that the cocrystal has a significant improvement in dissolution performance, particularly in acidic environments. Furthermore, the use of precipitation inhibitors, such as PVP, prolonged the supersaturation period for adequate absorption. Pharmacokinetic studies in rats revealed that the cocrystal exhibited a 16-fold increase in bioavailability compared to the raw Silybin extract, outperforming the commercial Silybin-phosphatidylcholine complex. Conclusions: The Silybin-L-proline cocrystal significantly enhances dissolution and bioavailability, indicating its potential to improve the therapeutic efficacy of Silybin in clinical applications.

Development and Validation of a Robust LC-MS/MS Method for Quantitation of a Novel Kinase Inhibitor, Ritlecitinib, in Rat Plasma: Application in Pharmacokinetic Study

Background Ritlecitinib (RIT) is a novel kinase inhibitor with promising therapeutic applications in the treatment of autoimmune disease alopecia areata. Accurate quantification of RIT in biological matrices is essential for pharmacokinetic studies and drug development. Objectives This study aims to develop and validate a sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantitation of RIT in rat plasma and to apply this method in a pharmacokinetic study. Materials and Methods A sensitive and selective LC-MS/MS method was developed in a AB Sciex QTRAP 5500 coupled with Shimadzu Prominence LC-20AD UFLC (ultra-fast liquid chromatography) System using an C18 column (Xselect HSS T3 2.5 µm, 2.1x150 mm) with a mobile phase consisting of 0.1% formic acid in high-performance liquid chromatography (HPLC) grade water and 0.1% formic acid in acetonitrile (70:30, v:v). RIT ( m/z 286.1 ↓ 105.7) and [ 13 C4]-ritlecitinib (internal standard, IS) ( m/z 290.1 ↓ 109.7) were detected in a positive mode by electrospray ionization (ESI) using multiple reaction monitoring (MRM) and extracted from rat plasma samples through protein precipitation We validated the method according to United States Food and Drug Administration (U.S. FDA) guidelines, assessing parameters such as linearity, accuracy, precision, selectivity, sensitivity, recovery and stability. The validated method was then applied to a pharmacokinetic study in rats following the administration of RIT. Results On rat plasma, the LC-MS/MS method has shown exceptional linearity across the concentration range of 5–100 ng/mL. The FDA’s approved standards of ±15% matched the accuracy and precision measurements. The matrix effect was negligible, and the mean recovery was about 93%, indicating that RIT was fully extracted from plasma. Different experimental conditions found RIT to be stable. RIT is quickly absorbed, with a peak plasma concentration (Cmax) of 43.82 ng/mL occurring 0.5–0.75 hours after the dose. It then drops in concentration in a way that is biexponential, with a half-life at the end of 1.5 hours. Conclusion A highly sensitive and specific LC-MS/MS method for quantitation of RIT in rat plasma was successfully developed and validated. The method was effectively applied to a pharmacokinetic study, providing critical data on the absorption and elimination characteristics of RIT in rats. This established approach may support additional preclinical pharmacokinetic investigations of RIT.

Ezetimibe Loaded Nanostructured Lipid Carriers Tablets: Response Surface Methodology, In-vitro Characterization, and Pharmacokinetics Study in Rats

PurposeThe present study aims to overcome the poor oral bioavailability of ezetimibe (EZ), a selective Biopharmaceutics Classification System (BCS) Class II cholesterol absorption inhibitor drug. EZ-loaded nanostructured lipid carriers (EZ-NLCs) were dried by lyophilization and incorporated in a convenient oral solid dosage form to enhance its dissolution, and absorption and increase patient compliance. Response surface methodology (RSM) was employed to systematically optimize formulation variables, improving the efficiency of disintegration and drug release characteristics.MethodsRSM was adopted to study the effects of (A) increasing the amount of the super-disintegrant, crosscarmelose sodium, (CCS), and (B) varying the ratio between the used drying excipients Avicel and mannitol (A: M) on the disintegration time (R1), and the percentage drug released after 24 h (R2). Thirteen EZ-NLCs tablets were prepared and subjected to pre-compression and post-compression evaluation. Furthermore, a bioequivalence study was conducted by administering EZ-NLCs and ezetrol® tablets to Sprague Dawley male rats.ResultsThe optimized EZ-NLCs tablet (prepared with the ratio of Avicel: mannitol (7.5:0) using 30 mg CCS), revealed a disintegration time of 3.85 ± 0.03 min, and 98 ± 3.09% of the drug were released at the end of the 24 h. EZ-NLCs tablet displayed a maximum concentration (Cmax) of 3.57 ± 0.27 ng/mL and an area under the curve (AUC0− 24) of 22.44 ± 2.68 ng.hr/mL, while those of ezetrol® were 2.79 ± 0.15 ng/mL and 15.36 ± 0.86 ng.hr/mL, respectively.ConclusionThe assessed relative bioavailability demonstrated the superiority of EZ-NLCs tablet over ezetrol® with 1.5 fold improvement which proves that EZ-NLCs tablet could be a good candidate to enhance the oral bioavailability of EZ.Graphical

BIO ANALYTICAL METHOD DEVELOPMENT AND VALIDATION OF FLUPENTIXOL AND NORTRIPTYLINE HCL IN RAT PLASMA AND ITS PHARMACOKINETIC STUDIES BY LCMS

Objective: An easy, quick, precise, active and reproducible Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) technique was developed for the bio-analytical method of flupentixol and nortriptyline HCl using zuclopenthixol as Internal Standard (IS). Methods: This article summarizes the recent progress on bio-analytical LC-MS/MS methods using Luna Phenyl Hexyl column (250x4.6 mm, 5µ) and organic mobile phase of Ammonium acetate pH-3.0/Formic acid and Acetonitrile in 70:30 v/v. 5 min of run time was used in the analysis. Results: The calibration curve was linear in the range of 5.0ng/ml to 200.0ng/ml (r2= 0.99988±0.006) for nortriptyline HCl and 0.25ng/ml to 10.0ng/ml (r2=0.99972±0.007) for flupentixol. Matrix effect, recovery and stability results were within the acceptable limit. An electrospray ionization source was used to study of nortriptyline HCl, flupentixol at m/z 300.8471 →73.2501, m/z 435.5225→103.4247 and m/z 400.9657→142.0087 for zuclopenthixol were ion pairs of mass analysis. Conclusion: The application denotes all the parameters of system suitability, specificity, linearity and accuracy are in good agreement with United States Food and Drug Administration (USFDA) guidelines and applied effectively for the investigation of pharmacokinetic studies in rat.

Solid dispersion of alectinib HCl: preclinical evaluation for improving bioavailability and establishing an IVIVC model

Objective Alectinib HCl (ALB-HCl) is a BCS class IV molecule with low solubility and low oral bioavailability. Owing to its low bioavailability, a high dose of ALB-HCl is recommended with food to meet clinical efficacy. Thus, there is a need for a delivery system to overcome the bioavailability concerns. Methods Three solid dispersion (SD) formulations (I, II, and III) were evaluated for in-vitro dissolution and in-vivo pharmacokinetics (PK) study in Wistar rats. An in-vitro and in-vivo correlation (IVIVC) model was developed to establish a relationship between in-vitro dissolution data and in-vivo PK data. The formulations were subjected to stability studies. Results All formulations showed enhanced dissolution in all the media except Formulation I in FaSSIF media. In-vivo PK studies displayed that Formulation I was inferior to API alone. Formulations II and III (amorphous SD [ASD]) exhibited two-fold higher Cmax and AUC0–last than API alone. Level A IVIVC model was established for Cmax and AUC0–last with an acceptable % prediction error (PE). When evaluated for external predictability, the model was found validated for Cmax (% PE <10%), however, it was inconclusive for AUC0–last (%PE −14.03). Stability studies showed ASD formulations were stable during storage. Conclusion A stable ASD formulation of ALB-HCl was successfully developed with improved bioavailability. Developing an IVIVC model can act as a surrogate to predict in-vivo performance. The selection of formulation components in ASD shall be rationalized for bioavailability and stability before clinical evaluation.