Plasma Cmax Research Articles

Poly(ethylene glycol)-b-poly(epsilon-caprolactone) nanoparticles as a platform for the improved oral delivery of cannabidiol.

Cannabidiol (CBD), a non-psychoactive constituent of Cannabis, has proven neuroprotective, anti-inflammatory and antioxidant properties though his therapeutic use, especially by the oral route, is still challenged by the poor aqueous solubility that results in low oral bioavailability. In this work, we investigate the encapsulation of CBD within nanoparticles of a highly hydrophobic poly(ethylene glycol)-b-poly(epsilon-caprolactone) block copolymer produced by a simple and reproducible nanoprecipitation method. The encapsulation efficiency is ~ 100% and the CBD loading 11% w/w (high performance liquid chromatography). CBD-loaded nanoparticles show a monomodal size distribution with sizes of up to 100nm (dynamic light scattering), a spherical morphology, and the absence of CBD crystals (high resolution-scanning electron microscopy and cryogenic-transmission electron microscopy) which is in line with a very efficient nanoencapsulation. Then, the CBD release profile from the nanoparticles is assessed under gastric- and intestine-like conditions. At pH 1.2, only 10% of the payload is released after 1h. Conversely, at pH 6.8, a release of 80% is recorded after 2h. Finally, theoral pharmacokinetics is investigated in rats and compared to a free CBD suspension. CBD-loaded nanoparticles lead to a statistically significant ~ 20-fold increase of themaximum drug concentration in plasma (Cmax) and a shortening of the time to the Cmax (tmax) from 4 to 0.3h, indicating a more complete and faster absorption than in free form. Moreover, the area-under-the-curve(AUC), a measure of oral bioavailability, increased by 14 times. Overall results highlight the promise of this simple, reproducible, and scalable nanotechnology strategy to improve the oral performance of CBD with respect to common oily formulations and/or lipid-based drug delivery systems associated with systemic adverse effects.

Pharmacokinetics of SPR206 in Plasma, Pulmonary Epithelial Lining Fluid, and Alveolar Macrophages following Intravenous Administration to Healthy Adult Subjects.

SPR206 is a next-generation polymyxin being developed for the treatment of multidrug-resistant (MDR) Gram-negative infections. This Phase 1 bronchoalveolar lavage (BAL) study was conducted to evaluate SPR206's safety and pharmacokinetics in plasma, pulmonary epithelial lining fluid (ELF), and alveolar macrophages (AM) in healthy volunteers. Subjects received a 100 mg intravenous (IV) dose of SPR206 infused over 1 h every 8 h for 3 consecutive doses. Each subject underwent 1 bronchoscopy with BAL at 2, 3, 4, 6, or 8 h after the start of the third IV infusion. SPR206 concentrations in plasma, BAL, and cell pellet were measured with a validated LC-MS/MS assay. Thirty-four subjects completed the study and 30 completed bronchoscopies. Mean SPR206 peak concentrations (Cmax) in plasma, ELF, and AM were 4395.0, 735.5, and 860.6 ng/mL, respectively. Mean area under the concentration-time curve (AUC0-8) for SPR206 in plasma, ELF, and AM was 20120.7, 4859.8, and 6026.4 ng*h/mL, respectively. The mean ELF to unbound plasma concentration ratio was 0.264, and mean AM to unbound plasma concentration ratio was 0.328. Mean SPR206 concentrations in ELF achieved lung exposures above the MIC for target Gram-negative pathogens for the entire 8-h dosing interval. Overall, SPR206 was well tolerated; 22 subjects (64.7%) reported at least 1 treatment-emergent adverse event (TEAE). Of the 40 reported TEAEs, 34 (85.0%) were reported as mild in severity. The most frequent TEAEs were oral paresthesia (10 subjects [29.4%]) and nausea (2 subjects [5.9%]). This study demonstrates pulmonary penetration of SPR206 and supports further development of SPR206 for the treatment of patients with serious infections caused by MDR Gram-negative pathogens.

A phase 1/2, open-label, parallel group study to evaluate the safety and pharmacokinetics of DARE-HRT1 (80 μg estradiol/4 mg progesterone and 160 μg estradiol/8 mg progesterone intravaginal rings) over 12 weeks in healthy postmenopausal women.

Primary objectives were to evaluate the safety and systemic pharmacokinetics (PK) of DARE-HRT1, an intravaginal ring (IVR), which releases 17β2-Estradiol (E2) with progesterone (P4) for 28 days in healthy postmenopausal women. This was a randomized, open-label, 2-arm, parallel group study in 21 healthy postmenopausal women with an intact uterus. Women were randomized (1:1) to either DARE-HRT1 IVR1 (E2 80 μg/d with P4 4 mg/d) or DARE-HRT1 IVR2 (E2 160 μg/d with P4 8 mg/d). They used the IVR for three 28-day cycles, inserting a new IVR monthly. Safety was measured by treatment emergent adverse events and changes in systemic laboratories and the endometrial bilayer width. Baseline adjusted plasma PK of E2, P4, and estrone (E1) was described. Both DARE-HRT1 IVR were safe. All treatment emergent adverse events were mild or moderate and were distributed similarly among IVR1 versus IVR2 users. Month 3 median maximum plasma (Cmax) P4 concentrations were 2.81 and 3.51 ng/mL and Cmax E2 was 42.95 and 77.27 pg/mL for IVR1 and IVR2 groups, respectively. Month 3 median steady state (Css) plasma P4 concentrations were 1.19 and 1.89 ng/mL, and Css E2 was 20.73 and 38.16 pg/mL for IVR1 and IVR2 users, respectively. Both DARE-HRT1 IVRs were safe and released E2 in systemic concentrations, which were in the low, normal premenopausal range. Systemic P4 concentrations predict endometrial protection. Data from this study support further development of DARE-HRT1 for the treatment of menopausal symptoms.

Plasma and Urine Pharmacokinetics of Oral Fosfomycin Tromethamine in Dogs

Fosfomycin is a broad-spectrum, bactericidal antibiotic with low toxicity. It has been used in human medicine and is a promising candidate for treating infections in veterinary medicine. Different Fosfomycin salts exhibit various degrees of bioavailability. Tromethamine salt is the most commonly used oral form due to its improved bioavailability. However, information regarding its use with dogs is limited. Therefore, this study aimed to investigate the pharmacokinetics of oral Fosfomycin tromethamine in canine plasma and urine using liquid chromatography tandem mass spectrometry (LC-MS/MS). Six healthy male beagles underwent a three-period three-treatment study: treatment 1 and 2 with single oral Fosfomycin tromethamine at 40 and 80 mg/kg (the total doses with tromethamine salt were 75 and 150 mg/kg, respectively), and treatment 3 with intravenously Fosfomycin disodium at 57 mg/kg (the total dose with disodium salt was 75 mg/kg). Dogs receiving oral Fosfomycin tromethamine at 75 and 150 mg/kg, maximal drug concentration (Cmax) in plasma produced results of 34.46 ± 12.52 and 66.40 ± 12.64 µg/mL, oral bioavailability (F) was approximately 38 and 45%, while urine Cmax was 4463.07 ± 2208.88 and 8784.93 ± 2303.46 µg/mL, respectively. No serious adverse effects were reported, except loose stool in some dogs. The tremendously high urine Fosfomycin concentrations indicate that oral Fosfomycin tromethamine is suitable as an alternative treatment for bacterial cystitis in dogs.

Long-Term Intake of Linezolid Elevates Drug Exposure and Reduces Drug Clearance and Elimination in Adults With Drug-Resistant Pulmonary Tuberculosis.

Pharmacokinetic (PK) studies are critical for dose optimization, and there is a paucity of linezolid (LZD) PK data for prolonged use in drug-resistant tuberculosis (DR-TB). Therefore, the authors evaluated the pharmacokinetics of LZD at two-time intervals in DR-TB during long-term use. PK evaluation of LZD was performed at the end of the 8th and 16th weeks of treatment in a randomly selected subset of adult pre-extensively drug-resistant pulmonary tuberculosis patients (n = 18) from a multicentric interventional study (Building Evidence to Advance Treatment of TB/BEAT study; CTRI/2019/01/017310), wherein a daily dose of 600 mg LZD was used for 24 weeks. Plasma LZD levels were measured using a validated high-pressure liquid chromatography (HPLC) method. The LZD median plasma C max was comparable between the 8th and 16th weeks [18.3 mg/L, interquartile range (IQR: 15.5-20.8 and 18.8 mg/L, IQR: 16.0-22.7, respectively)]. However, the trough concentration increased significantly in the 16th week (3.16 mg/L, IQR: 2.30-4.76), compared with the 8th week (1.98 mg/L, IQR: 0.93-2.75). Furthermore, compared with the 8th week, in the 16th week, there was a significant increase in drug exposure (AUC 0-24 = 184.2 mg*h/L, IQR: 156.4-215.8 versus 233.2 mg*h/L, IQR: 187.9-277.2), which corroborated with a longer elimination half-life (6.94 hours, IQR: 5.55-7.99 versus 8.47 hours, IQR:7.36-11.35) and decreased clearance (2.91 L/h, IQR: 2.45-3.33 versus 2.19 L/h, IQR: 1.49-2.78). Long-term daily intake of 600 mg LZD resulted in a significant elevation in trough concentration (>2.0 mg/L) in 83% of the study participants. Furthermore, increased LZD drug exposure may be partly because of decreased clearance and elimination. Overall, the PK data underscore the need for dose adjustment when LZDs are intended for long-term treatment.

Phase 1, randomized, open-label, single-dose, crossover study to evaluate the bioequivalence of four formulations of oral rivoceranib tablets in healthy subjects.

e15122 Background: Rivoceranib is a novel oral tyrosine kinase inhibitor that potently and selectively inhibits VEGFR2. Rivoceranib is being investigated for indications targeted towards solid malignancies as either monotherapy or in combination with other anticancer therapies. Herein, we assessed the bioequivalence of a single dose of rivoceranib administered as 4 different formulations in healthy subjects. Methods: This single-center, open-label, randomized, single-dose, 4-way crossover study evaluated the bioequivalence of 4 different formulations of rivoceranib oral tablets in healthy adults. Each subject participated in 4 treatment periods, where they were randomized to 1 of 4 sequences: ABCD, BDAC, CADB, and DBAC (Formulation A = rivoceranib 250 mg tablet/clinical formulation used in the pivotal phase 3 study, Formulation B = rivoceranib 200 mg tablet/clinical formulation used in early clinical studies, Formulation C = rivoceranib 250 mg tablet/formulation to be developed for future use, Formulation D = rivoceranib 250 mg tablet/to-be-marketed formulation). Results: Of the 60 subjects enrolled, 66.7% were male, 88.3% were white, and median age was 43 years. The median plasma rivoceranib Tmax was similar following all treatments (2 hours post-dose). The 90% CIs around the geometric mean ratios (GMRs) of plasma rivoceranib AUC0-t, AUC0-inf, and Cmax for Formulation B vs. Formulation A and Formulation D vs. Formulation A were within the 80-125% reference interval, demonstrating bioequivalence between Formulation B and Formulation A as well as Formulation D and Formulation A. The 90% CIs around the GMRs of plasma rivoceranib AUC0-t, AUC0-inf, and Cmax for Formulation C vs. Formulation A were slightly outside of the 80%-125% reference interval. Conclusions: Formulations B (clinical formulation used in early clinical studies) and D (to-be-marketed formulation) were bioequivalent to Formulation A (clinical formulation used in the pivotal phase 3 study). Formulation C (formulation to be developed for future use) and Formulation A were similar, but the difference was slightly outside of the bioequivalence criteria. It remains to be evaluated whether the difference in bioavailability between Formulation C and Formulation A is clinically meaningful. Clinical trial information: NCT05287360 . [Table: see text]

Generic Workflow to Predict Medicine Concentrations in Human Milk Using Physiologically-Based Pharmacokinetic (PBPK) Modelling-A Contribution from the ConcePTION Project.

Women commonly take medication during lactation. Currently, there is little information about the exposure-related safety of maternal medicines for breastfed infants. The aim was to explore the performance of a generic physiologically-based pharmacokinetic (PBPK) model to predict concentrations in human milk for ten physiochemically diverse medicines. First, PBPK models were developed for "non-lactating" adult individuals in PK-Sim/MoBi v9.1 (Open Systems Pharmacology). The PBPK models predicted the area-under-the-curve (AUC) and maximum concentrations (Cmax) in plasma within a two-fold error. Next, the PBPK models were extended to include lactation physiology. Plasma and human milk concentrations were simulated for a three-months postpartum population, and the corresponding AUC-based milk-to-plasma (M/P) ratios and relative infant doses were calculated. The lactation PBPK models resulted in reasonable predictions for eight medicines, while an overprediction of human milk concentrations and M/P ratios (>2-fold) was observed for two medicines. From a safety perspective, none of the models resulted in underpredictions of observed human milk concentrations. The present effort resulted in a generic workflow to predict medicine concentrations in human milk. This generic PBPK model represents an important step towards an evidence-based safety assessment of maternal medication during lactation, applicable in an early drug development stage.

Pharmacokinetics and tissue distribution of florfenicol and florfenicol amine in snubnose pompano (Trachinotus blochii) following oral administration.

The present study reports the comparative pharmacokinetic profiles of florfenicol and its metabolite (florfenicol amine, FFA) in Trachinotus blochii under tropical marine conditions (salinity: 35 ± 1.4‰; temperature: 28.8 ± 0.54°C) following a single in-feed oral administration of the recommended dose (15mg/Kg). Furthermore, the study investigated the distribution of these two compounds in nine different tissues. The maximum florfenicol concentrations (Cmax) in plasma and tissues were observed within five hours (Tmax), except for bile. The Cmax ranged from 572 to 1954ng/g or ml and was in the intestine > bile > muscle + skin > liver > gill = heart > plasma > kidney = spleen. The elimination half-life of FFC was significantly slower in the bile (38.25 ± 4.46h). The AUC tissue/plasma was highest for bile (3.77 ± 0.22), followed by intestine > muscle + skin > heart > liver > kidney = gill = spleen. Tmax and t1/2β were slower, and Cmax was lower for FFA than florfenicol in all tissues except Cmax of the kidney and bile. FFA t1/2β was exceptionally slower in the kidney (46.01 ± 8.2h). Interestingly, reaching an apparent distribution rate of > 0.5 was comparatively faster in the kidney, liver, and gills than in other tissues. The highest apparent metabolic rate was in the kidney (0.95 ± 0.01) and the lowest in plasma (0.41 ± 0.01). The generated data can be applied for formulating efficient therapeutic protocols in T. blochii, a promising mariculture species.

Enhanced Pharmacokinetics and Anti-inflammatory Activity of Curcumin Using Dry Emulsion as Drug Delivery Vehicle.

Many naturally available dietary molecules such as curcumin have not seen the market due to poor solubility, bioavailability, and photodegradability. Successful development of a lipid-based dry emulsion may overcome these issues and help in reaching the markets for natural dietary molecules such as curcumin. The current study aims to develop a dry emulsion formulation of curcumin using natural oil and evaluate its dissolution, photostability, pharmacokinetics, and anti-inflammatory activity. Dry emulsions were prepared using emu oil and corn oil as the lipid phase, Caproyl 90 and Cremophor RH 40 as surfactants, and dextrin as a hydrophilic carrier. Microscopic studies showed the formation of spherical porous particles, and solid-state characterization using differential scanning calorimetry and powder X-ray diffraction showed the conversion of curcumin to an amorphous form. About 80% drug release was observed from formulation, whereas pure drug showed only 50% drug release in 30min. Invivo pharmacokinetic studies showed fivefold improvement in the maximum concentration of curcumin in plasma (Cmax) and sevenfold improvement in the area under the concentration-timecurve of curcumin from emu oil formulation compared with pure curcumin. Significant differences were observed in the anti-inflammatory activity of curcumin dry emulsion and plain curcumin. Emu-oil-based formulations showed synergistic anti-inflammatory activity over corn-oil-based formulations with improved photostability. The present study suggests that the dry emulsion may enhance the bioavailability with synergistic anti-inflammatory activity and photostability of curcumin when given orally.

Diurnal Changes in Capecitabine Clock-Controlled Metabolism Enzymes Are Responsible for Its Pharmacokinetics in Male Mice.

The circadian timing system controls absorption, distribution, metabolism, and elimination processes of drug pharmacokinetics over a 24-h period. Exposure of target tissues to the active form of the drug and cytotoxicity display variations depending on the chronopharmacokinetics. For anticancer drugs with narrow therapeutic ranges and dose-limiting side effects, it is particularly important to know the temporal changes in pharmacokinetics. A previous study indicated that pharmacokinetic profile of capecitabine was different depending on dosing time in rat. However, it is not known how such difference is attributed with respect to diurnal rhythm. Therefore, in this study, we evaluated capecitabine-metabolizing enzymes in a diurnal rhythm-dependent manner. To this end, C57BL/6J male mice were orally treated with 500 mg/kg capecitabine at ZT1, ZT7, ZT13, or ZT19. We then determined pharmacokinetics of capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine (5'DFCR), 5'-deoxy-5-fluorouridine (5'DFUR), 5-fluorouracil (5-FU), in plasma and liver. Results revealed that plasma Cmax and AUC0-6h (area under the plasma concentration-time curve from 0 to 6 h) values of capecitabine, 5'DFUR, and 5-FU were higher during the rest phase (ZT1 and ZT7) than the activity phase (ZT13 and ZT19) (p < 0.05). Similarly, Cmax and AUC0-6h values of 5'DFUR and 5-FU in liver were higher during the rest phase than activity phase (p < 0.05), while there was no significant difference in liver concentrations of capecitabine and 5'DFCR. We determined the level of the enzymes responsible for the conversion of capecitabine and its metabolites at each ZT. Results indicated the levels of carboxylesterase 1 and 2, cytidine deaminase, uridine phosphorylase 2, and dihydropyrimidine dehydrogenase (p < 0.05) are being rhythmically regulated and, in turn, attributed different pharmacokinetics profiles of capecitabine and its metabolism. This study highlights the importance of capecitabine administration time to increase the efficacy with minimum adverse effects.

The pharmacokinetics of tilmicosin in plasma and joint dialysate in an experimentally Mycoplasma synoviae infection model

Mycoplasma synoviae (MS) infection is a serious threat to poultry industry in China, thus it is essential to study the pharmacokinetics (PK) in the target site of MS-infected chickens, but there are no relevant reports at present. The aim of this study was to compare the PK of tilmicosin in plasma and joint dialysate in MS-infected chickens. The MS infection model was established by evaluating the influence factors of the susceptibility of chicken species, day age of chicken, infection routes, infection cycle, infection dose, and stress response. The clinical symptoms, pathogen isolation, PCR identification, and ELISA antibody were detected to determine whether the MS infection model has been successfully established. Eight-week-old Mahuang chickens were challenged with MS by joint combined with footpad, 2 mL each time, twice a day for 5 d, then the MS infection model was successfully established. The infection group was orally administrated a single dose of 15 mg/kgbody weight (b. w.) tilmicosin. The joint dialysate was collected by the microdialysis technique, then the concentration of tilmicosin in plasma samples and joint dialysate were determined by triple quadrupole high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). There was no significant difference in elimination half-life (t1/2) and the mean residence time (MRT) of dialysate and plasma. In contrast, the time of the area under the concentration-time curve (AUC) and the (maximum concentration of tilmicosin in plasma) Cmax of tilmicosin in plasma was 2.1 and 1.4 times higher than in dialysate. The distribution coefficient of tilmicosin in joint and plasma (AUCdialysate/AUCplasma) was 0.51. In conclusion, tilmicosin concentration in joints of MS-infected chicken was much lower than that of plasma, which may result in the poor clinical effect and drug resistance. The study could provide a reference for the clinical use of tilmicosin against MS.

Design, Characterization and Pharmacokinetic-Pharmacodynamic Evaluation of Poloxamer and Kappa-Carrageenan-Based Dual-Responsive In Situ Gel of Nebivolol for Treatment of Open-Angle Glaucoma.

This study developed a dual-responsive in situ gel of nebivolol (NEB), a selective β-adrenergic antagonist. The gel could achieve sustained concentrations in the aqueous humor to effectively treat glaucoma. The gel was prepared using a combination of poloxamers (Poloxamer-407 (P407) and Poloxamer-188 (P188)) and kappa-carrageenan (κCRG) as thermo-responsive and ion-sensitive polymers, respectively. Box-Behnken design (BBD) was used to optimize the effect of three critical formulation factors (concentration of P407, P188 and κCRG) on two critical response variables (sol-to-gel transition temperature of 33-35 °C and minimum solution state viscosity) of the in situ gel. A desirability function was employed to find the optimal concentrations of P407, P188 and κCRG that yielded a gel with the desired sol-to-gel transition temperature and solution state viscosity. An NEB-loaded gel was prepared using the optimized conditions and evaluated for in vitro drug release properties and ex vivo ocular irritation studies. Furthermore, ocular pharmacokinetic and pharmacodynamics studies were conducted in rabbits for the optimized formulation. The optimized NEB-loaded gel containing P407, P188 and κCRG had a sol-to-gel transition temperature of 34 °C and exhibited minimum viscosity (212 ± 2 cP at 25 °C). The optimized NEB-loaded gel sustained drug release with 86% drug release at the end of 24 h. The optimized formulation was well tolerated in the eye. Ocular pharmacokinetic studies revealed that the optimized in situ gel resulted in higher concentrations of NEB in aqueous humor compared to the NEB suspension. The aqueous humor Cmax of the optimized in situ gel (35.14 ± 2.25 ng/mL) was 1.2 fold higher than that of the NEB suspension (28.2 ± 3.1 ng/mL), while the AUC0-∞ of the optimized in situ gel (381.8 ± 18.32 ng/mL*h) was 2 fold higher than that of the NEB suspension (194.9 ± 12.17 ng/mL*h). The systemic exposure of NEB was significantly reduced for the optimized in situ gel, with a 2.7-fold reduction in the plasma Cmax and a 4.1-fold reduction in the plasma AUC0-∞ compared with the NEB suspension. The optimized gel produced a higher and sustained reduction in the intra-ocular pressure compared with the NEB suspension. The optimized gel was more effective in treating glaucoma than the NEB suspension due to its mucoadhesive properties, sustained drug release and reduced drug loss. Lower systemic exposure of the optimized gel indicates that the systemic side effects can be significantly reduced compared to the NEB suspension, particularly in the long-term management of glaucoma.

Pharmacokinetics and Comparative Bioavailability of Test or Reference Capecitabine and Discrepant Pharmacokinetics Among Various Tumors in Chinese Solid Cancer Patients.

The main objective of this study was to compare the pharmacokinetic (PK) bioequivalence of two capecitabine tablets and explore the different PK profiles of various tumors in Chinese patients with cancer. All 76 patients with a confirmed cancer diagnosis were included in this study. A single dose of 2000mg of test or reference capecitabine (Xeloda, Hoffmann-La Roche) was orally administered postprandially. After 24hours of washout, the patients were administered the test or the reference capecitabine alternately. PK samples were taken at the time of predose up to 6hours postdose. Bioequivalence evaluation was performed using the geometric mean ratios of peak concentration in plasma (Cmax) , area under the concentration-time curve from time 0 to 6 h (AUC0-t) , and area under the concentration-time curve from time 0 to infinity (AUC0-∞ ) for capecitabine and 5-fluorouracil (5-FU). In this study, 90% confidence intervals of test/reference mean ratios of Cmax , AUC0-t , AUC0-∞ of capecitabine and 5-FU were in the range of 80%-125%. Both the test and reference capecitabine regimens were well tolerated in this study. Furthermore, we found that patients with esophageal-gastrointestinal cancers had higher exposure to capecitabine and a shorter time to Cmax (Tmax) than those with breast cancer. In conclusion, a single oral dose of 2000mg of test capecitabine tablets after postprandial administration was bioequivalent to the reference drug.

Structure-activity relationship read-across and transcriptomics for branched carboxylic acids.

The purpose of this study was to use chemical similarity evaluations, transcriptional profiling, in vitro toxicokinetic data, and physiologically based pharmacokinetic (PBPK) models to support read-across for a series of branched carboxylic acids using valproic acid (VPA), a known developmental toxicant, as a comparator. The chemicals included 2-propylpentanoic acid (VPA), 2-ethylbutanoic acid, 2-ethylhexanoic acid (EHA), 2-methylnonanoic acid, 2-hexyldecanoic acid, 2-propylnonanoic acid (PNA), dipentyl acetic acid or 2-pentylheptanoic acid, octanoic acid (a straight chain alkyl acid), and 2-ethylhexanol. Transcriptomics was evaluated in 4 cell types (A549, HepG2, MCF7, and iCell cardiomyocytes) 6 h after exposure to 3 concentrations of the compounds, using the L1000 platform. The transcriptional profiling data indicate that 2- or 3-carbon alkyl substituents at the alpha position of the carboxylic acid (EHA and PNA) elicit a transcriptional profile similar to the one elicited by VPA. The transcriptional profile is different for the other chemicals tested, which provides support for limiting read-across from VPA to much shorter and longer acids. Molecular docking models for histone deacetylases, the putative target of VPA, provide a possible mechanistic explanation for the activity cliff elucidated by transcriptomics. In vitro toxicokinetic data were utilized in a PBPK model to estimate internal dosimetry. The PBPK modeling data show that as the branched chain increases, predicted plasma Cmax decreases. This work demonstrates how transcriptomics and other mode of action-based methods can improve read-across.

1727. Phase 1b Dose-ranging Study Demonstrates Tolerability and Pharmacokinetics (PK) of Oral Epetraborole at the Predicted Therapeutic Dosage for Mycobacterium avium Complex (MAC) Lung Disease

Abstract Background Epetraborole (EBO) — an orally available bacterial leucyl transfer RNA synthetase inhibitor with potent activity against nontuberculous mycobacteria — is under clinical development for treatment of MAC lung disease. We conducted a Phase 1b dose-ranging study of EBO tablets in healthy adult volunteers, to inform dose selection in the treatment of MAC lung disease. Methods In this double-blind, placebo-controlled trial, EBO or placebo tablets were administered (n=8/cohort, 3:1 randomization) at dosages of 250-1000 mg q24h or 500 mg or 1000 mg q48h for up to 28 days. Standard Ph1 clinical and laboratory evaluations and treatment-emergent adverse events (TEAEs) were assessed. Based on prior human studies using significantly higher EBO daily doses, gastrointestinal (GI) events and anemia were predetermined AEs of special interest (AESIs). Plasma concentrations of EBO were measured by validated LC-MS/MS methods. Plasma PK parameters were determined using non-compartmental methods. Results A total of 43 subjects were enrolled; the 1000 mg q24h cohort was terminated early due to local COVID restrictions. Overall, 80.6% EBO subjects and 83.3% placebo subjects experienced ≥1 TEAE, none of which was serious or severe (Table). Most TEAEs were mild in severity (90%), and the remainder were moderate (10%). No TEAE leading to withdrawal from study was reported. The most frequent types of TEAEs were GI events (48.4% EBO, 41.7% placebo subjects), the most common being mild nausea. Two subjects had premature discontinuation of EBO due to a TEAE (asymptomatic liver enzyme elevations in a 250 mg q24h subject and mild nausea in a 1000 mg q48h subject). One 1000mg q24h subject had a TEAE of anemia. No clinically significant findings or TEAEs were observed for physical examinations, ECGs, or urine laboratory tests. Plasma Cmax and AUC0-∞ of EBO increased in a linear, dose-proportional manner across cohorts. Tmax was observed at ∼1 h post dose; mean t1/2 ranged from 7.63 to 11.1 h. Conclusion Oral EBO administered for 28-day dosing was generally well tolerated at the predicted therapeutic dose (500mg q24h) Predictable PK characteristics facilitate its use in MAC lung disease Further evaluation in a Phase 2/3 treatment-refractory MAC lung disease study is planned Disclosures Paul B. Eckburg, MD, Paratek Pharmaceuticals, Inc.: Safety Review Board|Spero Therapeutics, Inc.: Advisor/Consultant Sanjay Chanda, PhD, AN2 Therapeutics: Stocks/Bonds George Talbot, MD, AN2 Therapeutics, Inc.: Advisor/Consultant|AN2 Therapeutics, Inc.: Co-founder Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics,: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support.

217. A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Multiple Doses of the Lipopeptide QPX9003 in Healthy Adult Subjects

Abstract Background QPX9003 is a fully synthetic lipopeptide with potent activity against MDR Pseudomonas and Acinetobacter spp. This report describes the safety and pharmacokinetics of QPX9003 following single and multiple doses. Methods Twelve healthy subjects were enrolled in 2 cohorts of up to 8 subjects (each cohort randomized to have up to 6 active and 2 placebo) each in the multiple ascending dose phase (100 or 200 mg every 6 hrs). Subjects received a single dose of QPX9003 followed by 48 hours of washout, then were administered QPX9003 q6h for 7 days. All infusions were administered over 1 hour. Intensive plasma sampling was obtained after dosing and assayed for QPX9003 content using validated HPLC/MS methods. Results Single and multiple dose QPX9003 pharmacokinetic parameters (mean +/- SD) are shown below: No subjects discontinued due to AEs and no SAEs were observed. There was no evidence of increasing numbers or severity of AEs with increasing dose, and all AEs were mild or moderate in severity. Conclusion QPX9003 was safe and well tolerated at all doses tested. QPX9003 plasma AUC and Cmax increased with increasing dose. QPX9003 plasma exposure accumulated ∼ 1.5 fold over 7 days of q6h dosing consistent with its plasma half-life. Based on the PK and safety profile, QPX9003 produces plasma exposures that exceed the PK-PD target safely and warrants further clinical development. Disclosures David Griffith, n/a, Qpex Biopharma: Employee Yehuda Carmeli, MD, Allecra Therapeutics: Advisor/Consultant|MSD: Advisor/Consultant|Nabriva: Advisor/Consultant|Pfizer: Advisor/Consultant|Qpex Pharmaceuticals: Advisor/Consultant|Roche: Advisor/Consultant|Shinogi: Advisor/Consultant|Spero Therapeutics: Advisor/Consultant Shawnee Gehrke, n/a, Qpex Biopharma: Employee Elizabeth Morgan, n/a, Qpex Biopharma: Employee Michael Dudley, n/a, ArrePath: Board Member|Qpex Biopharma: Board Member|Qpex Biopharma: Employee Jeff Loutit, MBChB, Qpex Biopharma: Employee.

218. A Phase 1 Study of the Single-Dose Safety, Tolerability, and Pharmacokinetics of the Beta-lactamase inhibitor Xeruborbactam Administered as the Isobutyryloxymethyl Oral Prodrug to Healthy Adult Subjects

Abstract Background Xeruborbactam (XERU) is a member of a new class of cyclic boronic acid β-lactamase inhibitors with inhibitory activity against major members of Class A, B, C, and D beta-lactamases. This report describes the first safety and pharmacokinetic data following oral administration as the isobutyryloxymethyl prodrug in humans. Methods Forty-eight healthy subjects were enrolled into one of 6 cohorts of 8 subjects each in the single ascending doses (100, 200, 400, 600, 800, and 1000 mg). Subjects were randomly assigned with each cohort to XERU oral prodrug (n = 6), or placebo capsule (n = 2). Intensive plasma (total drug) and ultrafiltrate (free drug) sampling was obtained after dosing and assayed for QPX7831 and XERU content using validated HPLC/MS methods. Results XERU PK parameters following oral administration as the prodrug are shown in the table below. Compared to IV XERU doses (data not shown), XERU bioavailability is 90 - 100% orally bioavailable. No subjects discontinued due to AEs and no SAEs were observed. There was no evidence of increasing numbers or severity of AEs with increasing dose. All AEs were mild in severity. Conclusion Orally administered XERU was safe and well tolerated at all doses tested. Plasma XERU AUC and Cmax increased with increasing dose. XERU exposures (24h free AUC) exceed the predicted PK-PD parameter for stasis with once-daily doses of 400 mg or higher and exceed the PK-PD parameter for 1-log of bacterial killing once daily doses of 800 mg or higher. XERU, administered as an oral prodrug, has plasma PK properties that support once-daily administration. Disclosures David Griffith, n/a, Qpex Biopharma: Employee Jason Roberts, BPharm(Hons), PhD, FSHP, FISAC, British Society of Chemotherapy: Grant/Research Support|Cipla: Honoraria|Gilead: Advisor/Consultant|MSD: Advisor/Consultant|MSD: Honoraria|Pfizer: Board Member|Pfizer: Honoraria|Qpex: Grant/Research Support|Sandoz: Board Member|Summit: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant Elizabeth Morgan, n/a, Qpex Biopharma: Employee Michael Dudley, n/a, ArrePath: Board Member|Qpex Biopharma: Board Member|Qpex Biopharma: Employee Jeff Loutit, MBChB, Qpex Biopharma: Employee.

ITK Inhibitor Induces Dose-Dependent Th1 Skewing in Normal T Cells and Is Active in Refractory T Cell Lymphomas

Introduction Interleukin 2 inducible T cell kinase (ITK) is a TEC family tyrosine kinase expressed in T cells with an important role both in T cell receptor (TCR) signaling and T helper cell differentiation. Resting lymphocyte kinase (RLK), a closely related kinase, is redundant to ITK and is involved in the differentiation of naïve T cells into Th1 T cells. ITK-/- mice exhibit defects in Th2 differentiation while retaining the ability to differentiate into Th1 cells that secrete IFNγ; whereas, double ITK/RLK knockout mice exhibit profound defects in T cell function. Th1 cells are needed for various cytotoxic T cell functions such as destruction of tumor cells. CPI-818 is a covalent inhibitor of ITK (KD 2.5nM) with > 100 fold selectivity over RLK and other TEC family kinases. CPI-818 is being evaluated in an ongoing phase 1 trial in patients (pts) with refractory T cell lymphomas (TCL). We now report that selective ITK blockade with CPI-818 induces Th1 skewing of normal T cells and demonstrates anti-tumor activity. Methods Normal human peripheral blood mononuclear cells (PBMC) were stimulated in vitro for 6 days with anti-CD3/CD28 in the presence of CPI-818. Th1 cells were measured by flow cytometry based on ratio of IFNγ:IL4 staining cells. Sezary cells were similarly stimulated in the presence of CPI-818. Peripheral blood and tumor samples were stained with antibodies to CD3, 4, 8, 183, 196, 197 and 45RA to enumerate Th1 and other T cell subsets using multicolor flow cytometry. Successive cohorts of TCL pts were treated in a phase 1 trial until disease progression with continuous oral dosing of CPI-818 100mg, 200mg, 400mg or 600mg given BID. Results T cell receptor stimulated PBMC from 12 healthy donors incubated in vitro with CPI-818 demonstrated Th1 skewing at concentrations of 0.1 to < 10uM (Figure 1). Maximal skewing was seen at 1uM; cell viability was unaffected but, proliferation was inhibited at 10uM. Similar studies using Th2 Sezary cells showed inhibition of proliferation with CPI-818 (0.5-2.5uM). Thirty-three pts with TCL with a median age of 62 yrs and median of 4 prior therapies were enrolled. Histologies included: PTCL-NOS (17), AITL (4), and CTCL (12). The most common (≥ 10%) AEs were nausea, chills, vomiting, fatigue, pyrexia, decreased appetite, pruritus, and rash. Treatment-related Grade 3+ AEs were: anemia (1), lymphocytosis (1), WBC decreased (1) and neutropenia (1). The swimmer plot (Figure 2) shows a dose-dependent relationship with an optimum dose of 200mg (N=10) producing 1 CR 25 mo; 1 PR 2+ mo; 1 nodal CR 16 mo (CTCL); 2 SD; 1 PD; 4 not yet evaluated; 6 pts remain on treatment. Pharmacokinetic and target occupancy studies for the 200mg dose showed mean plasma Cmax of 2.3uM (SD 1.9uM) and ITK target occupancy of >75%. Analysis of blood in 4 of 4 pts treated in this cohort showed increases in Th1 cells (CD3+/CD4+/CD8-/CD183+/CD196-) compared to baseline and increases in terminally differentiated T effector memory cells (TEMRA CD3+/CD4-/CD8+/CD197-/CD45RA+). Tumor biopsy from 1 patient taken during response demonstrated an increase in Th1 (0 to 40%) and TEMRA CD8+ T cells (2.83% to 18.6%). CPI-818 reduced blood eosinophils (Eos) in 3 of 3 pts in this cohort with elevated Eos count, consistent with inhibition of Th2 function. Conclusions This study demonstrates that selective inhibition of ITK, while sparing RLK, induces Th1 skewing. As expected, the effects on T cell differentiation and proliferation are dose dependent: lower doses induce Th1 skewing and higher concentrations in vitro and in vivo lead to inhibition of TCR signaling and proliferation. Tumor responses were observed in several patients receiving 200mg BID, which achieves drug plasma levels consistent with Th1 skewing observed in vitro. The increases in Th1 cells and TEMRA CD8+ cells suggest that anti-tumor activity is due to induction of a host anti-tumor response. This raises the possibility that immunomodulation with ITK blockade could be used for immunotherapy of other cancers. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

EXTH-99. SYSTEMIC AND BRAIN PHARMACOKINETICS OF A GABAA RECEPTOR AGONIST, AMLAL-101, AS AN INVESTIGATIONAL THERAPEUTIC FOR THE TREATMENT OF PRIMARY AND METASTATIC BRAIN CANCERS

Abstract PURPOSE AMLAL-101 is a novel agent which preferentially targets α3, α5 subtypes of ɣ-amino butyric acid receptors and shows anti-tumor activity against disparate cancer types. AMLAL-101 is being advanced as an ‘add-on’ to potentiate treatment of primary and metastatic brain cancers. However, AMLAL-101 must penetrate the blood-brain barrier (BBB) and show sufficient brain retention. The primary purpose of this study was to determine the plasma pharmacokinetics (PK) and quantitative estimate of the BBB permeability of AMLAL-101. METHODS We performed intracranial microdialysis, employing jugular vein cannulated Sprague-Dawley rats which facilitated simultaneous serial blood and brain extracellular fluid (ECF) sampling. AMLAL-101 was injected i.p. at 5 mg/kg and serial blood and brain ECF samples collected up to 10 h post-dosing. Plasma and ECF samples were analyzed by LC/MS-MS and plasma and ECF concentration vs time PK profiles determined. In vivo recovery analysis was performed using retrodialysis and rapid equilibrium dialysis employed to determine the extent of protein binding. RESULTS AMLAL-101 plasma protein binding was 85% and in vivo recovery from ECF was 25%. AMLAL-101 peak concentration (Cmax) in plasma and brain ECF were 15 µM and 13.8 µM, respectively. The plasma and brain ECF area under the concentration (AUC0-10) were 27.5 h.µg/mL and 24.10 h.µg/mL, respectively. The brain partitioning of unbound AMLAL-101 (Kp,uu; determined either as a ratio of brain ECF Cmax:unbound plasma Cmax or brain ECF AUC: unbound plasma AUC), were 6.13 and 4.13, respectively. The elimination half-life of AMLAL-101 was 3 h for both brain ECF and plasma. CONCLUSIONS These results suggest that AMLAL-101 has the requisite BBB permeability required for brain cancer therapeutics. AMLAL-101 shows significant brain retention when compared to a chemically similar agent that does not show anti-cancer activity, which may contribute to efficacy of AMLAL-101 as an anti-tumor agent for treatment of brain cancers.

EXTH-15. DRUG SCREENING ON PATIENT GBM CELL CULTURES IDENTIFIES OMACETAXINE MEPESUCCINATE AS A POTENT ANTI-GLIOMA AGENT WITH THE ABILITY TO CROSS THE BLOOD-BRAIN-BARRIER

Abstract INTRODUCTION Little progress has been made in the development of effective new therapies for glioblastoma (GBM) the past decades. Fresh patient-derived GBM cell culture models have become the gold standard for GBM drug discovery and development. One of the major obstacles in identifying novel candidate drugs against GBM remains the blood-brain barrier (BBB). Therefore, it is crucial to select drugs with favourable physicochemical properties to cross BBB and reach the tumour tissue in therapeutically effective concentrations. In current drug repurposing approach, we evaluated available anti-cancer agents in our patient-derived drug screening platform against GBM. METHODS The FDA-approved Oncology Drug Set II library was tested on 45 primary GBM cell cultures. We developed a drug shortlisting pipeline combining efficacy data with pharmacodynamic and pharmacokinetic characteristics of each compound. The therapeutic efficacy of the selected agent was assessed in an orthotopic mouse PDX model, while penetration into the CNS by LC/MS/MS. RESULTS Omacetaxine mepesuccinate (OMA) was ranked as one of the most promising candidates applying our drug selection approach. In vitro, OMA revealed anti-tumour activity at IC50 values well-below reported Cmax plasma values in approximately 80% of GBM cultures. NanoString nCounter analysis, revealed DNA damage repair as the main pathway involved in OMA’s anti-tumour effect. Activation of caspase 3/7 activity and decrease of glioma cell invasiveness were also linked to its anti-tumour effect. In vivo, 1mg/kg dose of OMA was found to reach the brain tumour tissue in concentrations similar to the reported IC50 values in vitro. No adverse reactions were noted and a survival benefit was observed in a proportion of the treated mice. CONCLUSIONS At 1 mg/kg, OMA reaches the tumour brain tissue in therapeutically effective concentrations in mice while a moderate therapeutic benefit was observed. Additional in vivo experiments are ongoing investigating higher dosages of OMA and longer exposure.