Plasma Pharmacokinetics Research Articles

Comparative pharmacokinetics of six components in normal and rheumatoid arthritis rats after intragastrical administration of Qianghuo Shengshi Decoction granules by LC-MS/MS

ObjectiveTo investigate the plasma pharmacokinetics of six representative components (nodakenin, osthole, 5-O-methylvisammioside, ferulic acid, liquiritigenin, and liquiritin), which were the ingredients of Qianghuo Shengshi Decoction (QSD) granules, in normal and rheumatoid arthritis (RA) rats administrated QSD granules intragastrically. MethodsA rapid and accurate ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of six components in plasma, and it showed a good specificity, linearity, intra-day and inter-day precision, intra-day and inter-day accuracy, extraction recovery, stability, and the less matrix effect. ResultsThe validated LC-MS/MS method was successfully used to compare the plasma pharmacokinetics of six ingredients between normal and RA rats after intragastrical administration of QSD granules and differences in the pharmacokinetics were found in two types of rats. The absorption rate in the RA rats was lower for nodakenin, osthole, 5-O-methylvisammioside, liquiritigenin and liquiritin than in the normal group, while the absorption rate of ferulic acid remained constant in two groups. Incomparisonwith the normal rats, the exposure concentration of nodakenin was higher and that of other five components except for nodakenin was lower under pathological conditions. Additionally, the absorptive amount of nodakenin, osthole, 5-O-methylvisammioside and liquiritin was increased and that of ferulic acid and liquiritigenin was reduced in the RA rats than in the normal rats. Compared with the normal rats, the retention time of nodakenin, ferulic acid and liquiritin was reduced in vivo, whereas the retention time of osthole, 5-O-methylvisammioside and liquiritigenin was raised in the body for the RA rats. In contrast to the normal rats, the data demonstrated an increase in the elimination velocity of nodakenin and a decrease in the elimination velocity of the other five components except for nodakenin in the pathological state. ConclusionThis study showed that the pharmacokinetic behavior of the six components, nodakenin, osthole, 5-O-methylvisammioside, ferulic acid, liquiritigenin, and liquiritin, is different in vivo between normal and pathological states of rats, and this research provided the necessary experimental data to explain the pharmacokinetics of QSD granules in both normal and pathological states and provide some references for its clinical application at some level.

Comprehensive ocular and systemic pharmacokinetics of dexamethasone after subconjunctival and intravenous injections in rabbits

Even though subconjunctival injections are used in clinics, their quantitative pharmacokinetics has not been studied systematically. For this purpose, we evaluated the ocular and plasma pharmacokinetics of subconjunctival dexamethasone in rabbits. Intravenous injection was also given to enable a better understanding of the systemic pharmacokinetics. Dexamethasone concentrations in plasma (after subconjunctival and intravenous injections) and four ocular tissues (iris-ciliary body, aqueous humour, neural retina and vitreous) were analysed using LC-MS/MS.Population pharmacokinetic modelling for plasma data from both injection routes were used, and for first time the constant rate of absorption of dexamethasone from the subconjunctival space into plasma was estimated (ka,plasma = 0.043 min−1, i.e. absorption half-life of 17.3 min). Non-compartmental analysis was used for the ocular data analysis and resulting in ocular drug exposure of iris-ciliary body (AUC0-∞= 41984 min·ng/g) > neural retina (AUC0-∞= 25511 min·ng/g) > vitreous (AUC0-∞= 7319 min·ng/mL) > aqueous humour (AUC0-∞= 6146 min·ng/mL). The absolute bioavailability values after subconjunctival injection, reported for the first time, were 0.74 % in aqueous humour (comparable to topical dexamethasone suspensions), and 0.30 % in vitreous humour (estimated to be higher than in topical administration).These novel and comprehensive pharmacokinetic data provide valuable information on the potential for exploiting this route in ocular drug development for treating both, anterior and posterior segment ocular diseases. Moreover, the new generated dexamethasone-parameters are a step-forward in building predictive pharmacokinetic models to support the design of new subconjunctival dexamethasone formulations, which may sustain drug effect for longer period of time.

Impact of loperamide on the pharmacokinetics and tissue disposition of ritonavir-boosted oral docetaxel therapy; a preclinical assessment.

An oral docetaxel formulation boosted by the Cytochrome P450 (CYP) 3A inhibitor ritonavir, ModraDoc006/r, is currently under clinical investigation. Based on clinical data, the incidence of grade 1-2 diarrhea is increased with this oral docetaxel formulation compared to the conventional intravenous administration. Loperamide, a frequently used diarrhea inhibitor, could be added to the regimen as symptomatic treatment. However, loperamide is also a substrate of the CYP3A enzyme, which could result in competition between ritonavir and loperamide for this protein. Therefore, we were interested in the impact of coadministered loperamide on the pharmacokinetics of ritonavir-boosted oral docetaxel. We administered loperamide simultaneously or with an 8-hour delay to humanized CYP3A4 mice (with expression in liver and intestine) receiving oral ritonavir and docetaxel. Concentrations of docetaxel, ritonavir, loperamide and two of its active metabolites were measured. The plasma exposure (AUC and Cmax) of docetaxel was not altered during loperamide treatment, nor were the ritonavir plasma pharmacokinetics. However, the hepatic and intestinal dispositions of ritonavir were somewhat changed in the simultaneous, but not 8-hour loperamide treatment groups, possibly due to loperamide-induced delayed drug absorption. The pharmacokinetics of loperamide itself did not seem to be influenced by ritonavir. These results suggest that delayed loperamide administration can be added to ritonavir-boosted oral docetaxel treatment, without affecting the overall systemic exposure of docetaxel.

Physiologically Based Pharmacokinetic Modeling to Unravel the Drug-gene Interactions of Venlafaxine: Based on Activity Score-dependent Metabolism by CYP2D6 and CYP2C19 Polymorphisms.

Venlafaxine (VEN) is a commonly utilized medication for alleviating depression and anxiety disorders. The presence of genetic polymorphisms gives rise to considerable variations in plasma concentrations across different phenotypes. This divergence in phenotypic responses leads to notable differences in both the efficacy and tolerance of the drug. A physiologically based pharmacokinetic (PBPK) model for VEN and its metabolite O-desmethylvenlafaxine (ODV) to predict the impact of CYP2D6 and CYP2C19 gene polymorphisms on VEN pharmacokinetics (PK). The parent-metabolite PBPK models for VEN and ODV were developed using PK-Sim® and MoBi®. Leveraging prior research, derived and implemented CYP2D6 and CYP2C19 activity score (AS)-dependent metabolism to simulate exposure in the drug-gene interactions (DGIs) scenarios. The model's performance was evaluated by comparing predicted and observed values of plasma concentration-time (PCT) curves and PK parameters values. In the base models, 91.1%, 94.8%, and 94.6% of the predicted plasma concentrations for VEN, ODV, and VEN + ODV, respectively, fell within a twofold error range of the corresponding observed concentrations. For DGI scenarios, these values were 81.4% and 85% for VEN and ODV, respectively. Comparing CYP2D6 AS = 2 (normal metabolizers, NM) populations to AS = 0 (poor metabolizers, PM), 0.25, 0.5, 0.75, 1.0 (intermediate metabolizers, IM), 1.25, 1.5 (NM), and 3.0 (ultrarapid metabolizers, UM) populations in CYP2C19 AS = 2.0 group, the predicted DGI AUC0-96h ratios for VEN were 3.65, 3.09, 2.60, 2.18, 1.84, 1.56, 1.34, 0.61, and for ODV, they were 0.17, 0.35, 0.51, 0.64, 0.75, 0.83, 0.90, 1.11, and the results were similar in other CYP2C19 groups. It should be noted that PK differences in CYP2C19 phenotypes were not similar across different CYP2D6 groups. In clinical practice, the impact of genotyping on the in vivo disposition process of VEN should be considered to ensure the safety and efficacy of treatment.

Abstract B112: A dose escalation and cohort expansion study of the CDK9 inhibitor KB-0742 in relapsed, refractory ovarian cancer and transcriptionally addicted relapsed or refractory solid tumors

Abstract Ovarian cancer is responsible for more female cancer deaths than any other female reproductive malignancy. MYC deregulation is a hallmark of ovarian cancer and is associated with poor clinical outcome. In a real-world cohort (n=1,667), the MYC family of genes is overexpressed and/or genomically amplified in up to 87% of ovarian cancer. Although MYC remains undrugged, targeting of its cofactors has emerged as an attractive strategy to inhibit MYC oncogenic activity. Cyclin-dependent kinase 9 (CDK9) is a critical regulator of oncogenic MYC expression and activity. KB-0742 is an orally bioavailable, highly selective, long half-life (~24 hours) CDK9 inhibitor that demonstrates promising preclinical activity against ovarian cancer and is currently being evaluated in a phase 1/2 dose escalation and cohort expansion study in patients with ovarian cancer and other transcriptionally addicted tumors (NCT04718675). The phase 1/2 study is being conducted in two parts: dose escalation (part 1) and cohort expansion (part 2). Part 2 is comprised of cohort A (solid tumors with high prevalence of MYC overexpression including ovarian cancer, non-small cell lung cancer, and triple negative breast cancer) and cohort B (other transcriptionally addicted tumor types including sarcomas, adenoid cystic carcinoma, nut midline carcinoma and small cell lung cancer). KB-0742 is dosed orally once daily for 3 consecutive days, followed by 4 days off, on a weekly basis in 28-day cycles until unacceptable toxicity or disease progression. It is estimated that up to 170 patients will be enrolled in the study. Part 1 dose escalation is open to patients with relapsed or refractory solid tumors or non-Hodgkin’s lymphoma. Part 2 is defined by tumor indications as described in cohorts A and B. Eligibility criteria include age > 18 years (≥ 12 years old and with a body weight ≥ 40 kg in part 2, cohort B), acceptable organ function, and ECOG PS < 2. Primary objectives include evaluation of pharmacokinetics (PK), pharmacodynamics (PD), safety, tolerability, and preliminary anti-tumor activity, with the goal of identifying a maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Plasma PK measurements include Cmax, tmax, AUC0-last, accumulation ratio (Racc) and t1/2. Safety data will be evaluated per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. Dose escalation and MTD identification is guided by a Modified Continuous Reassessment Method (mCRM) (Goodman et al., Stat Med 1995). RP2D is informed by PD in peripheral blood mononuclear cells using assays to evaluate phosphorylation of the CDK9 substrate serine 2 on the RNA Polymerase II C-terminal domain (pSER2) and CDK9-responsive gene expression. Radiographic tumor response is assessed using RECIST 1.1 criteria. Exploratory objectives include assessment of KB-0742 PD in tumor tissue and profiling of treatment-related genomic, transcriptomic, and proteomic changes. Enrollment continues in the United States with sites in Spain, France, and UK expected to open. Citation Format: Miguel Villalona-Calero, Monica Mita, Alain Mita, Noah Federman, Drew Rasco, David Spigel, Jia Luo, Gregory M. Cote, Richard E. Cutler, Pavan Kumar, Crystal J. MacKenzie, Charles Lin, Jorge F. DiMartino, Elizabeth A. Olek, Brian Van Tine. A dose escalation and cohort expansion study of the CDK9 inhibitor KB-0742 in relapsed, refractory ovarian cancer and transcriptionally addicted relapsed or refractory solid tumors [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B112.

Effects of tetramethylpyrazine on pharmacokinetics in plasma and brain dialysate and neuropathic pain in rat model of spared sciatic nerve injury

This study aims to explore the effects of tetramethylpyrazine(TMP) on pharmacokinetics in plasma and brain dialysate and neuropathic pain in the rat model of partial sciatic nerve injury(SNI), and to investigate the correlation between the analgesic effect of TMP and its concentrations in the plasma and brain dialysate. Male SD rats were randomized into Sham, SNI, and SNI+TMP groups. Mechanical stimulation with von frey filaments and cold spray method were employed to evaluate the mechanical sensitivity and cold sensitivity of rats. Another two groups, Sham+TMP and SNI+TMP, were used to intubate the common jugular vein and implant microdialysis probes into the anterior cingulate gyrus(ACC), respectively.After intraperitoneal injection of TMP at a dose of 80 mg·kg~(-1), automatic blood collection and intracerebral microdialysis(perfusion rate of 1 μL·min~(-1)) systems were used to collect the blood and brain dialysate for 24 h. HSS T3 C_(18) reversed-phase chromatographic column(2.1 mm×50 mm, 2.5 μm) was used for liquid chromatographic separation. Gradient elution was carried out with the mobile phase of methanol-water(containing 0.005% formic acid) at a flow rate of 0.25 mL·min~(-1). Electrospray ion source was used for mass spectrometry, and the scanning mode was multi-reaction monitoring under the positive ion mode. The ion pairs for quantitative analysis were TMP m/z 137/122 and aspirin m/z 179/137, respectively. DAS 2.11 was used to calculate the pharmacokinetic parameters. The optimal time of TMP to exert the analgesia effect and inhibit cold pain sensitivity was 60 min after treatment. The TMP in the plasma and brain dialysate of SNI rats showed the T_(max) of 15 min and 30 min, the C_(max) of(2 866.43±135.39) and(1 462.14±197.38) μg·L~(-1), the AUC_(0-t) of(241 463.30±28 070.31) and(213 115.62±32 570.07) μg·min·L~(-1), the MRT_(0-t) of(353.13±47.73) and(172.16±12.72) min, and the CL_Z of 0.73 and 0.36 L·min·kg~(-1), respectively. The analgesic effect of TMP had a significant correlation with the blood drug concentration in the ACC, which indicated that this method was suitable for the detection of TMP in rat plasma and brain dialysate. The method is accurate, reliable, and sensitive and can realize the important value of the application of correlation analysis theory of "automatic blood collection-microdialysis/PK-PD" in the research on neuropathic pain.

Comparative safety, pharmacokinetics, and off-target assessment of 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane in mouse and dog: implications for therapeutic development.

The modified phytochemical derivative, 1,1-bis(3'-indolyl)-1-(p-chlorophenyl) methane (C-DIM12), has been identified as a potential therapeutic platform based on its capacity to improve disease outcomes in models of neurodegeneration and cancer. However, comprehensive safety studies investigating pathology and off-target binding have not been conducted. To address this, we administered C-DIM12 orogastrically to outbred male CD-1 mice for 7days (50mg/kg/day, 200mg/kg/day, and 300mg/kg/day) and investigated changes in hematology, clinical chemistry, and whole-body tissue pathology. We also delivered a single dose of C-DIM12 (1mg/kg, 5mg/kg, 25mg/kg, 100mg/kg, 300mg/kg, 1,000mg/kg) orogastrically to male and female beagle dogs and investigated hematology and clinical chemistry, as well as plasma pharmacokinetics over 48-h. Consecutive in-vitro off-target binding through inhibition was performed with 10μM C-DIM12 against 68 targets in tandem with predictive off-target structural binding capacity. These data show that the highest dose C-DIM12 administered in each species caused modest liver pathology in mouse and dog, whereas lower doses were unremarkable. Off-target screening and predictive modeling of C-DIM12 show inhibition of serine/threonine kinases, calcium signaling, G-protein coupled receptors, extracellular matrix degradation, and vascular and transcriptional regulation pathways. Collectively, these data demonstrate that low doses of C-DIM12 do not induce pathology and are capable of modulating targets relevant to neurodegeneration and cancer.

Advanced Model-based Approach to Evaluate Human Plasma, Cerebrospinal Fluid, and Neuronal mTORC1 Activation Biomarkers After NV-5138 Administration in Healthy Volunteers

NV-5138 ([S]-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid) is an orally bioavailable, small-molecule activator of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in development for treatment-resistant depression. The authors established a model to describe the relationship between plasma and cerebrospinal fluid (CSF) concentrations of NV-5138 and between CSF concentrations and potential biomarkers thought to be associated with mTORC1 activity (ie, orotic acid, N-acetylmethionine, and N-formylmethionine). Data were collected from a randomized, double-blind, placebo-controlled, tolerability, and pharmacokinetic (PK) parameter study of 5 ascending (400, 800, 1600, 2400, and 3000 mg), once-daily oral doses of NV-5138 in healthy subjects. NV-5138 plasma PK parameter samples were collected at 15 time points over 24 hours on days 1 and 7, and at pre dose on days 2-6 for all doses. NV-5138 CSF PK parameter and CSF biomarker samples were collected on days 1 and 7 at pre dose and 4, 8, and 12 hours post dose for all doses except 3000 mg. A model-based approach was used to develop and validate a model that describes the relationship between NV-5138 in CSF and biomarker concentrations. Twenty-four of the 42 enrolled subjects had simultaneous plasma and CSF measurements of NV-5138 and CSF biomarker concentrations and were included in the PK parameter and pharmacodynamic (PD) analyses. A 2-compartment plasma and CSF PK parameter, with indirect PD effects, model was developed and validated. NV-5138 plasma concentrations were positively correlated with those in CSF, although CSF concentrations lagged slightly behind those in plasma, as indicated by a counterclockwise hysteresis effect. Similarly, the relationship between the PD measures of mTORC1 activation and NV-5138 was also characterized by counterclockwise hysteresis, when the increase in CSF biomarker concentrations lagged behind those of NV-5138, consistent with a signaling intermediary/cascade, such as mTORC1. Maximal biomarker activation was achieved at NV-5138 CSF concentrations of approximately 3 µg/mL, which were associated with daily doses of 1600 mg NV-5138. The safety profile analysis (n = 42) found that most of the reported adverse events were mild in severity, with no severe, serious, unusual, or unexpected adverse events or any dissociative effects; 2 subjects (400-mg cohort) discontinued due to adverse events that were judged to be unrelated to study medication. The model will be used for designing future efficacy and tolerability studies. Consecutive daily doses of NV-5138 were well tolerated in this healthy volunteer study.

TADALAFILA: AN APPROACH TO THE TREATMENT OF ERECTILE DYSFUNCTION

Introduction: Erectile dysfunction is the persistent inability to achieve and/or maintain an erection sufficient to allow satisfactory sexual intercourse. Objective: To evaluate the effectiveness of Tadafila as the main treatment option for erectile dysfunction, providing a comprehensive analysis of its effectiveness and safety in managing this condition. Methodology: This is a qualitative bibliographical research, which searched for articles published between the years 2013 and 2023, after the searches, 43 references were selected. Development: Throughout the study, general aspects of the disease and the medication were addressed, from its effectiveness, time of use, dosage, absorption and distribution, plasma concentration, contraindications, side effects, pharmacodynamics and pharmacokinetics. Final Considerations: It is concluded that tadalafil is the most effective treatment against erectile dysfunction, as it acts on the PDE5 enzyme, which contributes to a longer-lasting and safer effect for the client undergoing treatment.

In vivo pharmacodynamic characterization of a next-generation polyene, SF001, in the invasive pulmonary aspergillosis mouse model.

SF001 is a next-generation polyene antifungal drug in development, designed to have increased specificity to fungal ergosterol, which is absent in humans, and decreased binding to cholesterol. SF001 demonstrates long-acting, potent, broad-spectrum fungicidal activity. The goal of the current study was to determine the pharmacodynamic index and target of SF001 in an immunocompromised mouse model of invasive pulmonary aspergillosis against six Aspergillus fumigatus isolates. Minimum inhibitory concentration (MIC) values ranged from 0.5 to 2.0 mg/L. Plasma and epithelial lining fluid (ELF) pharmacokinetics were performed following single intraperitoneal doses of 1, 4, 16, and 64 mg/kg. Treatment efficacy was assessed with each of the six fungal isolates using daily doses of SF001 ranging from 0.25 to 64 mg/kg/day over a 96-h treatment duration. Efficacy was assessed by A. fumigatus quantitative PCR of conidial equivalents from lung homogenates. Nonlinear regression analysis using the Hill equation demonstrated that the 24-h exposure-response relationships for both plasma and ELF area under the concentration/MIC and Cmax/MIC ratios were strong and relatively similar [coefficient of determination (R2) = 0.74-0.75). Exposure-response relationships included a median plasma 24-h Cmax/MIC target for stasis and 1-log kill endpoint of 0.5 and 0.6, respectively. The present studies demonstrated in vitro and in vivo SF001 potency against A. fumigatus. These results have potential relevance for SF001 clinical dose selection and evaluation of susceptibility breakpoints.

A Phase I Clinical Study of the Pharmacokinetics and Safety of Prusogliptin Tablets in Subjects with Mild to Moderate Hepatic Insufficiency and Normal Liver Function.

Prusogliptin is a potent and selective DPP-4 inhibitor. In different animal models, Prusogliptin showed potential efficacy in the treatment of type 2 diabetes. However, the knowledge of its pharmacokinetics and safety in patients with liver dysfunction is limited. The present study evaluated the pharmacokinetics and safety of Prusogliptin in subjects with mild or moderate hepatic impairment compared with healthy subjects. According to the liver function of the subjects, we divided them into a mild liver dysfunction group, a moderate liver dysfunction group and a normal liver function group. All subjects in three groups received a single oral dose of Prusogliptin 100-mg tablets. Pharmacokinetics and safety index collection was carried out before and after taking the drug. Plasma pharmacokinetics of Prusogliptin were evaluated, and geometric least- -squares mean (GLSM) and associated 90% confidence intervals for insufficient groups versus the control group were calculated for plasma exposures. After a single oral administration of 100 mg of Prusogliptin tablets, the exposure level of Prusogliptin in subjects with mild liver dysfunction was slightly higher than that in healthy subjects. The exposure level of Prusogliptin was significantly increased in subjects with moderate liver dysfunction. There were no adverse events in this study. The exposure level of Prusogliptin in subjects with liver dysfunction was higher than that in healthy subjects. No participant was observed of adverse events. Prusogliptin tablets were safe and well tolerated in Chinese subjects with mild to moderate liver dysfunction and normal liver function.

A pilot study investigating plasma pharmacokinetics and tolerance of oral capecitabine in carcinoma-bearing dogs

BackgroundCapecitabine is an oral prodrug of the active metabolite 5-fluorouracil, which has been used effectively in human colorectal, head and neck, and mammary carcinomas. Capecitabine has several properties that make it an attractive treatment option for dogs: (i) it is relatively inexpensive, (ii) it has a short half-life in humans, allowing for rapid plasma concentration changes to be achieved with dosage adjustments, (iii) it is effective for treating carcinomas in humans, for which there are no widely-effective oral chemotherapy options in dogs, and (iv) it is thought to preferentially target cancer cells due to different expression of thymidine phosphorylase, thereby decreasing the risk of off-target side effects. However, capecitabine has not been widely explored as a chemotherapy agent for dogs. The goal of this study was to determine the plasma disposition of capecitabine in dogs following a single oral dose and to document any adverse events associated with capecitabine administration over the course of 5 weeks.ResultsCapecitabine was well tolerated throughout the 5-week study period when administered to 5 dogs with naturally occurring carcinomas at 750 mg/m2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$^2$$\\end{document} by mouth once daily for 14 consecutive days in a 3-week cycle. No dogs withdrew from the study due to adverse events or other causes. The median AUC0-last\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$_{\ ext {0-last}}$$\\end{document} was 890 h·\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\cdot$$\\end{document}ng/ml (range 750-1100 h·\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\cdot$$\\end{document}ng/ml); however, the maximum blood concentration and time to reach that concentration of capecitabine was highly variable after a single dose.ConclusionsCapecitabine appears well-tolerated as an oral chemotherapy agent for dogs with carcinomas, although individualized dosing may be necessary, and further studies are warranted.

Pharmacokinetic Modeling to Guide Preclinical Development of an Islatravir-Eluting Reservoir-Style Biodegradable Implant for Long-Acting HIV PrEP.

Long-acting injectable cabotegravir is more effective than daily oral PrEP at preventing HIV transmission due to improved adherence, but requires bi-monthly large-volume intramuscular injections. Subcutaneous (SC) contraceptive implants can be formulated with antiretrovirals for extended-duration HIV PrEP. Islatravir (ISL) is a first-in-class, investigational antiretroviral with pharmacologic properties well-suited for implant delivery. We performed preclinical studies for the development of a reservoir-style, poly(ε-caprolactone) ISL-eluting implant by conducting a single-dose SC ISL dose-ranging pharmacokinetic (PK) study of 0.1, 0.3, and 1 mg/kg in adult Wistar rats. Non-compartmental analysis was conducted, and dose proportionality assessed for ISL plasma and intracellular islatravir-triphosphate (ISL-tp). Population PK models estimated ISL's unit impulse response to deconvolve ISL-implant in vivo absorption rate (mg/day) and cumulative mass (mg) from published rat plasma PK (n = 10). Drug release was interpreted using four kinetic models. Dose proportionality was affirmed for ISL and ISL-tp. A first-order, two-compartment model fitted the SC ISL bolus data. Mean (SD) absorption rate from 0 to 154 days was 0.072 ± 0.024 mg/day, and cumulative mass at 154 days was 8.67 ± 3.22 mg. ISL absorption was well-described by zero-order (r2 = 0.95) and Ritger-Peppas (r2 = 0.98). Our zero-order ISL-release poly(ε-caprolactone) implant is projected to achieve clinical PK above ISL-tp's PrEP efficacy threshold. Continued development for HIV PrEP applications is warranted.

Ocular and Plasma Pharmacokinetics of Enavogliflozin Ophthalmic Solution in Preclinical Species.

An enavogliflozin ophthalmic solution (DWRX2008) is being developed to treat diabetic retinopathy and macular edema. This study evaluated the ocular distribution and plasma pharmacokinetics (PKs) of enavogliflozin in animal species. A sample of [14C] enavogliflozin was ocularly administered to two rabbits per time point at single doses of 600 μg/eye to evaluate ocular PK, which was evaluated using autoradiography until 48 h post-dose. Plasma concentrations after ocular administration in six rabbits, three rats, and three beagle dogs with single doses of 400 μg, 25 μg, and 100 μg, respectively, were investigated for 24 h. The retinal concentration of [14C] enavogliflozin reached Cmax at 2.0 h with an elimination half-life of 32.5 h, which remained above the IC50 value of sodium-dependent glucose transporter 2 until 24 h post-dose. In the plasma of rabbits, the fastest Tmax of 0.5 h and a 3.6 h half-life were observed among animal species. The relative bioavailability in rabbits after ocular administration was 3.4 compared to oral administration. Ocular administration of enavogliflozin could be a potential therapeutic route for diabetic retinal complications, based on relative bioavailability and effective delivery to the posterior ocular segment. DWRX2008 would be applicable to humans with favorable PK profiles and minimal systemic adverse effect.

Effect of Dexketoprofen on the Disposition Kinetics of Moxifloxacin in Plasma and Lung in Male and Female Rats.

The simultaneous use of NSAIDs and antibiotics is recommended for bacterial diseases in human and veterinary medicine. Moxifloxacin (MFX) and dexketoprofen (DEX) can be used simultaneously in bacterial infections. However, there are no studies on how the simultaneous use of DEX affects the pharmacokinetics of MFX in rats. The aim of this study was to determine the effect of DEX on plasma and lung pharmacokinetics of MFX in male and female rats. A total of 132 rats were randomly divided into 2 groups: MFX (n=66, 33 males/33 females) and MFX+DEX (n=66, 33 females/33 males). MFX at a dose of 20 mg/kg and DEX at a dose of 25 mg/kg were administered intraperitoneally. Plasma and lung concentrations of MFX were determined using the highperformance liquid chromatography-UV and pharmacokinetic parameters were evaluated by noncompartmental analysis. Simultaneous administration of DEX increased the plasma and lung area under the curve from 0 to 8 h (AUC0-8) and peak concentration (Cmax) of MFX in rats, while it significantly decreased the total body clearance (CL/F). When female and male rats were compared, significant differences were detected in AUC0-8, Cmax, CL/F and volume of distribution. The AUC0-8lung/AUC0-8plasma ratios of MFX were calculated as 1.68 and 1.65 in female rats and 5.15 and 4.90 in male rats after single and combined use, respectively. MFX was highly transferred to the lung tissue and this passage was remarkably higher in male rats. However, DEX administration increased the plasma concentration of MFX in both male and female rats but did not change its passage to the lung. However, there is a need for a more detailed investigation of the difference in the pharmacokinetics of MFX in male and female rats.

Population pharmacokinetics and dosing simulations of total and unbound temocillin in the plasma and CSF of neurocritically ill patients with external ventricular drain-related cerebral ventriculitis.

Cerebral ventriculitis might be caused by Gram-negative bacteria, including ESBL producers. Temocillin may be a useful treatment option in this scenario; however, no consistent data are available regarding its penetration into the CSF. To describe the population pharmacokinetics of temocillin in plasma and CSF and to determine the probability for different simulated dosing regimens to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets in the CSF. Ten post-neurosurgical critically ill adult patients requiring continuous drainage of CSF were included in this monocentric, prospective, open-label, non-randomized study. They received 2 g loading dose temocillin over 30 min IV infusion, followed by a 6 g continuous infusion over 24 h. Total and unbound concentrations were measured in plasma (n = 88 and 86) and CSF (n = 88 and 88) samples and used to build a population PK model. Monte Carlo simulations were performed to estimate the PTA at 100% Css>MIC (steady state concentration above the MIC) in CSF. All patients were infected with Enterobacterales with temocillin MICs ≤8 mg/L. The median (min-max) temocillin penetration in CSF was 12.1% (4.3-25.5) at steady state. Temocillin unbound plasma pharmacokinetics were best described by a one-compartment model. PTA for the applied dosing regimen was >90% for bacteria with MIC ≤ 4 mg/L. The currently approved dose of 6 g by continuous infusion may be adequate for the treatment of ventriculitis by Enterobacterales with MIC ≤ 4 mg/L if considering 100% Css>MIC as the PK/PD target to reach. Higher maintenance doses could help covering higher MICs, but their safety would need to be assessed.

Functionalisation of brush polyethylene glycol polymers with specific lipids extends their elimination half-life through association with natural lipid trafficking pathways

Polymeric prodrugs have been applied to control the delivery of various types of therapeutics. Similarly, conjugation of peptide therapeutics to lipids has been used to prolong systemic exposure. Here, we extend on these two approaches by conjugating brush polyethylene glycol (PEG) polymers with different lipid components including short-chain (1C2) or medium-chain (1C12) monoalkyl hydrocarbon tails, cholesterol (Cho), and diacylglycerols composed of two medium-chain (2C12) or long-chain (2C18) fatty acids. We uniquely evaluate the integration of these lipid-polymers into endogenous lipid trafficking pathways (albumin and lipoproteins) and the impact of lipid conjugation on plasma pharmacokinetics after intravenous (IV) and subcutaneous (SC) dosing to cannulated rats. The IV and SC elimination half-lives of Cho-PEG (13 and 22 h, respectively), 2C12-PEG (11 and 17 h, respectively) and 2C18-PEG (12 h for both) were prolonged compared to 1C2-PEG (3 h for both) and 1C12-PEG (4 h for both). Interestingly, 1C2-PEG and 1C12-PEG had higher SC bioavailability (40 % and 52 %, respectively) compared to Cho-PEG, 2C12-PEG and 2C18-PEG (25 %, 24 % and 23 %, respectively). These differences in pharmacokinetics may be explained by the different association patterns of the polymers with rat serum albumin (RSA), bovine serum albumin (BSA) and lipoproteins. For example, in pooled plasma (from IV pharmacokinetic studies), 2C18-PEG had the highest recovery in the high-density lipoprotein (HDL) fraction. In conclusion, the pharmacokinetics of brush PEG polymers can be tuned via conjugation with different lipids, which can be utilised to tune the elimination half-life, biodistribution and effect of therapeutics for a range of medical applications. Statement of significanceLipidation of therapeutics such as peptides has been employed to extend their plasma half-life by promoting binding to serum albumin, providing protection against rapid clearance. Here we design and evaluate innovative biomaterials consisting of brush polyethylene glycol polymers conjugated with different lipids. Importantly, we show for the first time that lipidated polymeric materials associate with endogenous lipoprotein trafficking pathways and this, in addition to albumin binding, controls their plasma pharmacokinetics. We find that conjugation to dialkyl lipids and cholesterol leads to higher association with lipid trafficking pathways, and more sustained plasma exposure, compared to conjugation to short and monoalkyl lipids. Our lipidated polymers can thus be utilised as delivery platforms to tune the plasma half-life of various pharmaceuticals.

A First-in-Human, Open-Label, Phase I Dose Escalation Trial of Daily Oral Nmt Inhibitor Zelenirstat in Patients with Relapsed/Refractory B-Cell Lymphomas and Advanced Solid Tumors

Background Myristoylation, the N-terminal modification of proteins with the fatty acid myristate, regulates multiple membrane-bound signal transduction pathways driving cancer cell biology. This modification is catalyzed by two N-myristoyltransferases (NMT), NMT1 and NMT2. Aberrant NMT expression has been identified in cancer cells and inhibition of myristoylation represents a novel anticancer treatment strategy. Zelenirstat (PCLX-001) is an oral, highly bioavailable, small molecule NMT inhibitor with strong affinity for both NMT1 and NMT2 proteins (IC 50 of 5nM and 8nM, respectively). In vitro hematologic cancer cell lines were exquisitely sensitive to zelenirstat. Zelenirstat regressed subcutaneous tumors in xenograft models derived from lymphoma cell lines, as well as in a refractory DLBCL patient (pt) derived xenograft model. Zelenirstat also demonstrated anticancer activity in multiple solid tumor xenograft models. Based on pre-clinical data, we conducted a phase I dose escalation trial to determine safety, tolerability, maximum tolerated dose (MTD), and pharmacokinetics (PK) of zelenirstat. Methods Pts with relapsed/refractory (R/R) B-cell lymphomas and advanced solid tumors were enrolled in a multicenter, open label, standard phase I dose escalation trial of once daily (OD) oral zelenirstat, administered in 28-day cycles until progressive disease or unacceptable toxicity. Seven dose levels were studied: 20 mg, 40 mg, 70 mg, 100 mg, 140 mg, 210 mg, and 280 mg. Dose limiting toxicity (DLT), attributable to zelenirstat during cycle 1, was defined as: grade (Gr) 4 thrombocytopenia, Gr 3 thrombocytopenia with bleeding, Gr 4 neutropenia ≥ 7 days, febrile neutropenia, clinically significant > Gr 3 non-hematologic toxicity, or any significant toxicity warranting a hold of zelenirstat. Plasma PK were obtained on C1D1, C1D15, and trough concentrations C1D2, C1D16 and prior to each subsequent cycle. Response assessments occurred every 2 cycles to determine best overall response. Results Between Sept 2021 and Jul 2023, 21 DLT-evaluable pts [4 R/R B-cell lymphoma (3 DLBCL, 1 FL grade 3b); 17 advanced solid tumor (7 colorectal, 2 pancreas, 2 ovarian, 1 each of sarcoma, NSCLC, pleural mesothelioma, melanoma, CUP, bladder)] received zelenirstat at doses ranging from 20 mg OD to 280 mg OD. Dose escalation occurred without DLT until the 280 mg cohort where two DLTs were reported: a bladder carcinoma pt who developed nausea, vomiting, and drug-induced fever necessitating a hold of zelenirstat and a colorectal cancer (CRC) pt who had Gr 3 dehydration from nausea, vomiting, diarrhea, and oral mucositis. The maximal administered dose was 280 mg OD and the presumptive MTD was 210 mg OD. Drug compliance was high, and of 3 pts within the 210 mg cohort, none required dose reduction. Common treatment-emergent all-grade adverse events (AEs) at doses up to the 210 mg cohort were gastrointestinal and reported in 29% of pts. These were primarily diarrhea, nausea, or vomiting. Gr 2 thrombocytopenia occurred in 17% of patients. No other AEs were seen at a frequency of > 5%. There were no AEs of neuropathy, alopecia, or QT interval prolongation. Noncompartmental PK analyses demonstrated rapid oral absorption, a terminal half-life of approximately 10 hrs, rapid achievement of steady state, and no induction of metabolism. Zelenirstat trough plasma concentrations at 100 mg, 140 mg, and 210 mg doses markedly exceeded the EC 90 required to inhibit cultured cancer cells. Stable disease as best response was seen in five patients (pancreas at 40 mg; CRC at 140 mg; and two ovarian and one CRC at 210 mg). At the 210 mg dose, one of the ovarian cancer pts had a corresponding reduction of CA-125 (20%) while the CRC pt had a reduction in CEA (50%). Conclusions Zelenirstat is safe and well tolerated up to the 210 mg OD dose, which we have established as the presumptive MTD. Additional pts, including a phase IIA study in pts with R/R B-cell NHL, are accruing at this dose for further safety and activity exploration. The absence of severe toxicities, attainment of plasma concentrations highly active in preclinical models, and early evidence of antitumor activity support the ongoing development of zelenirstat for pts with R/R B-cell lymphomas and advanced solid tumors.

A Phase I/II Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Preliminary Antitumor Activity of BTK Inhibitor HZ-a-018 in Adult Patients with Relapsed and/or Refractory Central Nervous System Lymphoma

Background: HZ-A-018 is a highly selective and potent covalent BTK inhibitor with CNS-penetrating profile, which was previously reported (Abstract 5501, ASH 2022). Phase I/II study is ongoing in China, and here we present preliminary results of HZ-A-018 monotherapy of the phase I part in central nervous system lymphoma. Methods: HZ-A-018-102 is an ongoing phase I/II study (CTR20210181) to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of HZ-A-018 in central nervous system lymphoma. The primary objective for phase I monotherapy was to determine the safety and tolerability and the recommended phase 2 dose (RP2D), and secondary objectives included preliminary antitumor activity and pharmacokinetics in patients with relapsed/refractory primary/secondary CNS lymphoma (R/R PCNSL/SCNSL) and primary vitreoretinal lymphoma (PVRL) who had received ≥1 prior therapy. HZ-A-018 was administered orally once daily in 28-day cycles until disease progression or unacceptable toxicity. Results: At the data cutoff date of 30 May 2023, 21 pts from the phase I monotherapy were analyzed, including 18 R/R PCNSL and 3 R/R SCNSL. 3 pts received 300mg/d, 12 pts received 450mg/d and 6 pts received 600mg/d. 600mg was the highest dose pre-defined in the study and MTD was not reached. Pts were with a median age of 62 years (range: 36-80), median KPS 80 (range: 60-90) and a median of 2 prior systemic therapies (range: 1-5). 20 pts (95.2%) presented with brain parenchyma, and 1 pt (4.8%) presented with intraocular (IO) involvement. All patients had received HD-MTX based chemotherapy, 19 pts (90.5%) had received rituximab and 1 pt had received whole brain radiation therapy (WBRT). 16 of 21 pts (76.2%) experienced a treatment related adverse event (TRAE). The most common TRAEs (≥10%) were thrombocytopenia (42.9%), neutropenia (23.8%), leukopenia (23.8%), and hypokalemia (14.3%), majority of which were grade 1 to 2. DLTs occurred in 1 pt at 450 mg/d and 1 pt at 600 mg/d. 4 pts (19.0%) had dose interruption, no pts had dose reductions, and no pts discontinued from the study due to TRAEs. The plasma and cerebrospinal fluid (CSF) pharmacokinetics showed HZ-A-018 was rapidly absorbed and could cross the blood-brain barrier with CSF HZ-A-018 concentration ranged from 5.94 to 17.5 ng/mL two hours post-dose. Of 19 pts available for tumor assessment (16 PCNSL with brain parenchyma, 1 PCNSL with IO and 2 SCNSL with brain parenchyma) and 2 pts not evaluable (1 PCNSL with brain parenchyma, and 1 SCNSL with brain parenchyma), the overall response rate (ORR) was 52.4% (95%CI: 29.8, 74.3), including 23.8% (5 pts) complete response(CR)/unconfirmed complete response(CRu), 28.6% (6 pts) partial response (PR), and 19.0% (4 pts) stable disease (SD), contributing to an 71.4% (95%CI: 47.8, 88.7) disease control rate (DCR). At 600mg/d, all 6 pts had achieved high and deep responses, contributing to 100% ORR and 50% CRR, with the 3-month duration of response (DOR) rate not reached. Dose expansion was ongoing at 600mg QD. Conclusions: These results demonstrated that HZ-A-018 was efficacious and well-tolerated in CNS lymphoma patients with high CNS penetrating profile. The monotherapy RP2D for R/R PCNSL was determined as 600 mg QD and a phase 2 R/R PCNSL registration study in China is currently planned.

Pharmacokinetics and Biodistribution of 16,16 dimethyl Prostaglandin E2 in Non-Irradiated and Irradiated Mice and Non-Irradiated Non-Human Primates.

Exposure to high-dose ionizing radiation can lead to life-threatening injuries and mortality. Bone marrow is the most sensitive organ to radiation damage, resulting in the hematopoietic acute radiation syndrome (H-ARS) with the potential sequelae of infection, hemorrhage, anemia, and death if untreated. The development of medical countermeasures (MCMs) to protect or mitigate radiation injury is a medical necessity. In our well-established murine model of H-ARS we have demonstrated that the prostaglandin E2 (PGE2) analog 16,16 dimethyl-PGE2 (dmPGE2) has survival efficacy as both a radioprotectant and radiomitigator. The purpose of this study was to investigate the pharmacokinetics (PK) and biodistribution of dmPGE2 when used as a radioprotector in irradiated and non-irradiated inbred C57BL/6J mice, PK in irradiated and non-irradiated Jackson Diversity Outbred (JDO) mice, and the PK profile of dmPGE2 in non-irradiated non-human primates (NHPs). The C57BL/6J and JDO mice each received a single subcutaneous (SC) dose of 35 ug of dmPGE2 and were randomized to either receive radiation 30 min later or remain non-irradiated. Plasma and tissue PK profiles were established. The NHP were dosed with 0.1 mg/kg by SC administration and the PK profile in plasma was established. The concentration time profiles were analyzed by standard non-compartmental analysis and the metrics of AUC0-Inf, AUC60-480 (AUC from 60-480 min), Cmax, and t1/2 were evaluated. AUC60-480 represents the postirradiation time frame and was used to assess radiation effect. Overall, AUC0-Inf, Cmax, and t1/2 were numerically similar between strains (C57BL/6J and JDO) when combined, regardless of exposure status (AUC0-Inf: 112.50 ng·h/ml and 114.48 ng·h/ml, Cmax: 44.53 ng/ml and 63.96 ng/ml; t1/2: 1.8 h and 1.1 h, respectively). PK metrics were numerically lower in irradiated C57BL/6J mice than in non-irradiated mice [irradiation ratio: irradiated values/non-irradiated values = 0.71 for AUC60-480 (i.e., 29% lower), and 0.6 for t1/2]. In JDO mice, the radiation ratio was 0.53 for AUC60-480 (i.e., 47% lower), and 1.7 h for t1/2. The AUC0-Inf, Cmax, and t1/2 of the NHPs were 29.20 ng·h/ml, 7.68 ng/ml, and 3.26 h, respectively. Despite the numerical differences seen between irradiated and non-irradiated groups in PK parameters, the effect of radiation on PK can be considered minimal based on current data. The biodistribution in C57BL/6J mice showed that dmPGE2 per gram of tissue was highest in the lungs, regardless of exposure status. The radiation ratio for the different tissue AUC60-480 in C57BL/6J mice ranged between 0.5-1.1 (50% lower to 10% higher). Spleen, liver and bone marrow showed close to twice lower exposures after irradiation, whereas heart had a 10% higher exposure. Based on the clearance values from mice and NHP, the estimated allometric scaling coefficient was 0.81 (95% CI: 0.75, 0.86). While slightly higher than the current literature estimates of 0.75, this scaling coefficient can be considered a reasonable estimate and can be used to scale dmPGE2 dosing from animals to humans for future trials.