Systematic studies on the kinetic process of 20(S)-protopanaxadiol in rats and dogs: absorption, distribution, metabolism and excretion.

Background and Objective: Ginseng has been regarded as a precious medicinal herb with miraculous effects in Eastern culture. The primary chemical constituents of ginseng are saponins, and the physiological activities of ginsenosides determine their edible and medicinal value. The aim of this study is to comprehensively and systematically investigate the kinetic processes of 20(S)-protopanaxadiol (PPD) in rats and dogs, in order to promote the rational combination of ginseng as a drug and dietary ingredient. Methods: PPD was administered, and drug concentration in different biological samples were detected by liquid chromatography tandem mass spectrometry (LC/MS/MS) and radioactive tracer methods. Pharmacokinetic parameters such as absorption, bioavailability, tissue distribution, plasma protein binding rate, excretion rate, and cumulative excretion were calculated, along with inference of major metabolites. Results: This study systematically investigated the absorption, distribution, metabolism, excretion (ADME) of PPD in rats and dogs for the first time. The bioavailabilities of PPD were relatively low, with oral absorption nearly complete, and the majority underwent first-pass metabolism. PPD had a high plasma protein binding rate and was relatively evenly distributed in the body. Following oral administration, PPD underwent extensive metabolism, potentially involving one structural transformation and three hydroxylation reactions. The metabolites were primarily excreted through feces and urine, indicating the presence of enterohepatic circulation. The pharmacokinetic processes of PPD following intravenous administration aligned well with a three-compartment model. In contrast, after gastric administration, it fitted better with a two-compartment model, conforming to linear pharmacokinetics and proportional elimination. There were evident interspecies differences between rats and dogs regarding PPD, but individual variations of this drug were minimal within the same species. Conclusion: This study systematically studied the kinetic process of PPD in rats and also investigated the kinetic characteristics of PPD in dogs for the first time. These findings lay the foundation for further research on the dietary nutrition and pharmacological effects of PPD.

Mixed effect estimation in deep compartment models: Variational methods outperform first-order approximations.

This work focusses on extending the deep compartment model (DCM) framework to the estimation of mixed-effects. By introducing random effects, model predictions can be personalized based on drug measurements, enabling the testing of different treatment schedules on an individual basis. The performance of classical first-order (FO and FOCE) and machine learning based variational inference (VI) algorithms were compared in a simulation study. In VI, posterior distributions of the random variables are approximated using variational distributions whose parameters can be directly optimized. We found that variational approximations estimated using the path derivative gradient estimator version of VI were highly accurate. Models fit on the simulated data set using the FO and VI objective functions gave similar results, with accurate predictions of both the population parameters and covariate effects. Contrastingly, models fit using FOCE depicted erratic behaviour during optimization, and resulting parameter estimates were inaccurate. Finally, we compared the performance of the methods on two real-world data sets of haemophilia A patients who received standard half-life factor VIII concentrates during prophylactic and perioperative settings. Again, models fit using FO and VI depicted similar results, although some models fit using FO presented divergent results. Again, models fit using FOCE were unstable. In conclusion, we show that mixed-effects estimation using the DCM is feasible. VI performs conditional estimation, which might lead to more accurate results in more complex models compared to the FO method.

Transporter-mediated drug-drug interactions: regulatory guidelines, in vitro and in vivo methodologies and translation, special populations, and the blood-brain barrier.

This review, part of a special issue on drug-drug interactions (DDIs) spearheaded by the International Society for the Study of Xenobiotics (ISSX) New Investigators, explores the critical role of drug transporters in absorption, disposition, and clearance in the context of DDIs. Over the past two decades, significant advances have been made in understanding the clinical relevance of these transporters. Current knowledge on key uptake and efflux transporters that affect drug disposition and development is summarized. Regulatory guidelines from the FDA, EMA, and PMDA that inform the evaluation of potential transporter-mediated DDIs are discussed in detail. Methodologies for preclinical and clinical testing to assess potential DDIs are reviewed, with an emphasis on the utility of physiologically based pharmacokinetic (PBPK) modeling. This includes the application of relative abundance and expression factors to predict human pharmacokinetics (PK) using preclinical data, integrating the latest regulatory guidelines. Considerations for assessing transporter-mediated DDIs in special populations, including pediatric, hepatic, and renal impairment groups, are provided. Additionally, the impact of transporters at the blood-brain barrier (BBB) on the disposition of CNS-related drugs is explored. Enhancing the understanding of drug transporters and their role in drug disposition and toxicity can improve efficacy and reduce adverse effects. Continued research is essential to bridge remaining gaps in knowledge, particularly in comparison with cytochrome P450 (CYP) enzymes.

Safety and Pharmacokinetics of a Combined Antioxidant Therapy against Myocardial Reperfusion Injury: A Phase I Randomized Clinical Trial in Healthy Humans.

Myocardial reperfusion injury (MRI) accounts for up to 50% of the final size in acute myocardial infarction and other conditions associated with ischemia-reperfusion. Currently, there is still no therapy to prevent MRI, but it is well known that oxidative stress has a key role in its mechanism. We previously reduced MRI in rats through a combined antioxidant therapy (CAT) of ascorbic acid, N-acetylcysteine, and deferoxamine. This study determines the safety and pharmacokinetics of CAT in a Phase I clinical trial. Healthy subjects (n = 18) were randomized 2:1 to CAT or placebo (NaCl 0.9% i.v.). Two different doses/infusion rates of CATs were tested in a single 90-minute intravenous infusion. Blood samples were collected at specific times for 180 minutes to measure plasma drug concentrations (ascorbic acid, N-acetylcysteine, and deferoxamine) and oxidative stress biomarkers. Adverse events were registered during infusion and followed for 30 days. Both CAT1 and CAT2 significantly increased the CAT drug concentrations compared to placebo (P < .05). Most of the pharmacokinetic parameters were similar between CAT1 and CAT2. In total, 6 adverse events were reported, all nonserious and observed in CAT1. The ferric-reducing ability of plasma (an antioxidant biomarker) increased in both CAT groups compared to placebo (P < .001). The CAT is safe in humans and a potential treatment for patients with acute myocardial infarction undergoing reperfusion therapy.

Methotrexate accumulation in target intestinal mucosa and white blood cells differs from non-target red blood cells of patients with Crohn's disease.

BACKGROUND: Intracellular methotrexate polyglutamates (MTX-PGs) concentrations are measurable in red blood cells (RBCs) during MTX treatment. MTX-PG3 concentrations correlate with efficacy in patients with Crohn's disease (CD). Since RBCs are not involved in pathogenesis of CD and lack extended MTX metabolism, we determined MTX-PGs accumulation in peripheral blood mononuclear cells (PBMCs: effector cells) and intestinal mucosa (target cells) and compared those with RBCs as a potential more precise biomarker. METHODS: In a multicentre prospective cohort study, blood samples of patients with CD were collected during the first year of MTX therapy. Mucosal biopsies were obtained from non-inflamed rectum and/or inflamed intestine. MTX-PGs concentrations in mucosa, PBMCs and RBCs were measured by liquid chromatography-tandem mass spectrometry. RESULTS: From 80 patients with CD, a total of 27 mucosal biopsies, 9 PBMC and 212 RBC samples were collected. From 12 weeks of MTX therapy onwards, MTX-PG3 was the most predominant species (33%) in RBCs. In PBMCs, the distribution was skewed towards MTX-PG1 (48%), which accounted for an 18 times higher concentration than in RBCs. Long-chain MTX-PGs were highly present in mucosa: 21% of MTX-PGtotal was MTX-PG5. MTX-PG6 was measurable in all biopsies. CONCLUSIONS: MTX-PG patterns differ between mucosa, PBMCs and RBCs of patients with CD.

Multi-Task ADME/PK prediction at industrial scale: leveraging large and diverse experimentaldatasets.

ADME (Absorption, Distribution, Metabolism, Excretion) properties are key parameters to judge whether a drug candidate exhibits a desired pharmacokinetic (PK) profile. In this study, we tested multi-task machine learning (ML) models to predict ADME and animal PK endpoints trained on in-house data generated at Boehringer Ingelheim. Models were evaluated both at the design stage of a compound (i. e., no experimental data of test compounds available) and at testing stage when a particular assay would be conducted (i. e., experimental data of earlier conducted assays may be available). Using realistic time-splits, we found a clear benefit in performance of multi-task graph-based neural network models over single-task model, which was even stronger when experimental data of earlier assays is available. In an attempt to explain the success of multi-task models, we found that especially endpoints with the largest numbers of data points (physicochemical endpoints, clearance in microsomes) are responsible for increased predictivity in more complex ADME and PK endpoints. In summary, our study provides insight into how data for multiple ADME/PK endpoints in a pharmaceutical company can be best leveraged to optimize predictivity of ML models.

Auditory N1 event-related potential amplitude is predictive of serum concentration of BPN14770 in fragile x syndrome.

Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5' untranslated region of the FMR1 gene, leading to intellectual disability and cognitive difficulties, including in the domain of communication. A recent phase 2a clinical trial testing BPN14770, a phosphodiesterase 4D inhibitor, showed improved cognition in 30 adult males with FXS on drug relative to placebo. The initial study found significant improvements in clinical measures assessing cognition, language, and daily functioning in addition to marginal improvements in electroencephalography (EEG) results for the amplitude of the N1 event-related potential (ERP) component. EEG results suggest BPN14770 improved neural hyperexcitability in FXS. The current study investigated the relationship between BPN14770 pharmacokinetics (PK) and the amplitude of the N1 ERP component from the initial data. Consistent with the original group-level finding in period 1 of the study, participants who received BPN14770 in the period 1 showed a significant correlation between N1 amplitude and serum concentration of BPN14770. These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS.

Differentiation between primary central nervous system lymphomas and gliomas according to pharmacokinetic parameters derived from dynamic contrast-enhanced magnetic resonance imaging.

Purpose: It is difficult to differentiate between primary central nervous system lymphoma and primary glioblastoma due to their similar MRI findings. This study aimed to assess whether pharmacokinetic parameters derived from dynamic contrast-enhanced MRI could provide valuable insights for differentiation. Methods: Seventeen cases of primary central nervous system lymphoma and twenty-one cases of glioblastoma as confirmed by pathology, were retrospectively analyzed. Pharmacokinetic parameters, including Ktrans, Kep, Ve, and the initial area under the Gd concentration curve, were measured from the enhancing tumor parenchyma, peritumoral parenchyma, and contralateral normal parenchyma. Statistical comparisons were made using Mann-Whitney U tests for Ve and Matrix Metallopeptidase-2, while independent samples t-tests were used to compare pharmacokinetic parameters in the mentioned regions and pathological indicators of enhancing tumor parenchyma, such as vascular endothelial growth factor and microvessel density. The pharmacokinetic parameters with statistical differences were evaluated using receiver-operating characteristics analysis. Except for the Wilcoxon rank sum test for Ve, the pharmacokinetic parameters were compared within the enhancing tumor parenchyma, peritumoral parenchyma, and contralateral normal parenchyma of the primary central nervous system lymphomas and glioblastomas using variance analysis and the least-significant difference method. Results: Statistical differences were observed in Ktrans and Kep within the enhancing tumor parenchyma and in Kep within the peritumoral parenchyma between these two tumor types. Differences were also found in Matrix Metallopeptidase-2, vascular endothelial growth factor, and microvessel density within the enhancing tumor parenchyma of these tumors. When compared with the contralateral normal parenchyma, pharmacokinetic parameters within the peritumoral parenchyma and enhancing tumor parenchyma exhibited variations in glioblastoma and primary central nervous system lymphoma, respectively. Moreover, the receiver-operating characteristics analysis showed that the diagnostic efficiency of Kep in the peritumoral parenchyma was notably higher. Conclusion: Pharmacokinetic parameters derived from dynamic contrast-enhanced MRI can differentiate primary central nervous system lymphoma and glioblastoma, especially Kep in the peritumoral parenchyma.

Icanbelimod (CBP-307), a next-generation Sphingosine-1-phosphate receptor modulator, in healthy men: pharmacokinetics, pharmacodynamics, safety, and tolerability in a randomized trial in Australia.

Background: Icanbelimod (formerly CBP-307) is a next-generation S1PR modulator, targeting S1PR1. In this first-in-human study, icanbelimod was investigated in healthy men in Australia. Methods: Participants were randomized 3:1, double-blind, to icanbelimod or placebo in four single-dose cohorts (0.1 mg, 0.25 mg, 0.5 mg [n=8 per cohort], 2.5 mg [n=4]) or for 28-days once-daily treatment in two cohorts (0.15 mg, 0.25 mg [n=8 per cohort]). Participants in the 0.25-mg cohort received 0.1 mg on Day 1. Treatments were administered orally after fasting; following one-week washout, icanbelimod was administered after breakfast in the 0.5-mg cohort. Results: Icanbelimod exposure increased rapidly and dose-dependently with single and multiple dosing (Tmax 4-7 hours). Lymphocyte counts decreased rapidly after single (-11%, 0.1 mg; -40%, 0.25 mg; -71%, 0.5 mg; -77%, 2.5 mg) and multiple doses (-49%, 0.15 mg; -75%, 0.25 mg), and recovered quickly, 7 days after dosing. After single-dose 0.5 mg, although a high-fat breakfast versus fasting did not affect maximal decrease, lymphocyte counts tended to be lower after breakfast across most timepoints up to 72 hours. Twenty-eight participants (63.6%) experienced mainly mild treatment-emergent adverse events (TEAEs). After single-dose icanbelimod, the most common TEAEs were headache (28.6%, n=6) and dizziness (19.0%, n=4). Three participants experienced transient bradycardia, with one serious, following single-dose 2.5 mg icanbelimod. After multiple-dose icanbelimod, the most common TEAEs were headache (50.0%, n=6) and lymphopenia (41.7%, n=5), and two participants withdrew due to non-serious TEAEs. Up-titration attenuated heart rate reductions. Conclusion: Icanbelimod was well-tolerated up to 0.5 mg and effectively reduced lymphocyte counts. Clinical trial registration: ClinicalTrials.gov, identifier NCT02280434.b.

Pharmacokinetics of Human Plasma-Derived Antithrombin in Pediatric Patients Supported on Extracorporeal Membrane Oxygenation.

Extracorporeal membrane oxygenation (ECMO) support of critically ill pediatric patients is associated with increased risk of thromboembolic events, and unfractionated heparin is used commonly for anticoagulation. Given reports of acquired antithrombin (AT) deficiency in this patient population and associated concern for heparin resistance, AT activity measurement and off-label AT replacement have become common in pediatric ECMO centers despite limited optimal dosing regimens. We conducted a retrospective cohort study of pediatric ECMO patients (0 to <18 years) at a single academic center to characterize the pharmacokinetics (PK) of human plasma-derived AT. We demonstrated that a two-compartment turnover model appropriately described the PK of AT, and the parameter estimates for clearance, central volume, intercompartmental clearance, peripheral volume, and basal AT input under non-ECMO conditions were 0.338 dL/h/70 kg, 38.5 dL/70 kg, 1.16 dL/h/70 kg, 40.0 dL/70 kg, and 30.4 units/h/70 kg, respectively. Also, ECMO could reduce bioavailable AT by 50% resulting in 2-fold increase of clearance and volume of distribution. To prevent AT activity from falling below predetermined thresholds of 50% activity in neonates and 80% activity in older infants and children, we proposed potential replacement regimens for each age group, accompanied by therapeutic drug monitoring.

Preclinical pharmacokinetic characterization of amdizalisib, a novel PI3Kδ inhibitor for the treatment of hematological malignancies.

Amdizalisib, also named HMPL-689, a novel selective and potent PI3Kδ inhibitor, is currently under Phase II clinical development in China for treating hematological malignancies. The preclinical pharmacokinetics (PK) of amdizalisib were extensively characterized in vitro and in vivo to support the further development of amdizalisib. We characterized the plasma protein binding, blood-to-plasma partition ratio, cell permeability, hepatic microsomal metabolic stability, and drug-drug interaction potential of amdizalisib using in vitro experiments. In vivo PK assessment was undertaken in mice, rats, dogs, and monkeys following a single intravenous or oral administration of amdizalisib. The tissue distribution and excretion of amdizalisib were evaluated in rats. The PK parameters (CL and Vss) of amdizalisib in preclinical species (mice, rats, dogs, and monkeys) were utilized for the human PK projection using the allometric scaling (AS) approach. Amdizalisib was well absorbed and showed low-to-moderate clearance in mice, rats, dogs, and monkeys. It had high cell permeability without P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) substrate liability. Plasma protein binding of amdizalisib was high (approximately 90%). It was extensively distributed but with a low brain-to-plasma exposure ratio in rats. Amdizalisib was extensively metabolized in vivo, and the recovery rate of the prototype drug was low in the excreta. Amdizalisib and/or its metabolites were primarily excreted via the bile and urine in rats. Amdizalisib showed inhibition potential on P-gp but not on BCRP and was observed to inhibit CYP2C8 and CYP2C9 with IC50 values of 30.4 and 10.7 µM, respectively. It exhibited induction potential on CYP1A2, CYP2B6, CYP3A4, and CYP2C9. The preclinical data from these ADME studies demonstrate a favorable pharmacokinetic profile for amdizalisib, which is expected to support the future clinical development of amdizalisib as a promising anti-cancer agent.

Nicotine flux and pharmacokinetics-based considerations for early assessment of nicotine delivery systems.

In the past few years, technological advancements enabled the development of novel electronic nicotine delivery systems (ENDS). Several empirical measures such as "nicotine flux" are being proposed to evaluate the abuse liability potential of these products. We explored the applicability of nicotine flux for clinical nicotine pharmacokinetics (PK) and 52-week quit success from cigarettes for a wide range of existing nicotine delivery systems. We found that the differences in nicotine flux for various nicotine delivery systems are not related to changes in PK, as nicotine flux does not capture key physiological properties such as nicotine absorption rate. Further, the 52-week quit success and abuse liability potential of nicotine nasal sprays (high nicotine flux product), and nicotine inhalers (nicotine flux similar to ENDS) are low, suggesting that nicotine flux is a poor metric for the assessment of nicotine delivery systems. PK indices are more dependable for characterizing nicotine delivery systems, and a nicotine plasma C max T max > 1 could improve 52-week quit success from cigarettes. However, a single metric may be inadequate to fully assess the abuse liability potential of nicotine delivery systems and needs to be further studied. A combination of in vitro and in silico approaches could potentially address the factors influencing the inhaled aerosol dosimetry and resulting PK of nicotine to provide early insights for ENDS assessments. Further research is required to understand nicotine dosimetry and PK for ad libitum product use, and abuse liability indicators of nicotine delivery systems. This commentary is intended to (1) highlight the need to think beyond a single empirical metric such as nicotine flux, (2) suggest potential PK-based metrics, (3) suggest the use of in vitro and in silico tools to obtain early insights into inhaled aerosol dosimetry for ENDS, and (4) emphasize the importance of considering comprehensive clinical pharmacology outcomes to evaluate nicotine delivery systems.

Pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid in rainbow trout (Oncorhynchus mykiss).

BACKGROUND: Although research on the mechanism and control of pain and inflammation in fish has increased in recent years, the use of analgesic drugs is limited due to the lack of pharmacological information about analgesic drugs. Tolfenamic acid is a non-steroidal anti-inflammatory drug and can be used in fish due to its low side effect profile and superior pharmacokinetic properties. OBJECTIVES: The pharmacokinetics, bioavailability and plasma protein binding of tolfenamic acid were investigated following single intravascular (IV), intramuscular (IM) and oral administration of 2 mg/kg in rainbow trout at 13 ± 0.5°C. METHODS: The experiment was carried out on a total of 234 rainbow trout (Oncorhynchus mykiss). Tolfenamic acid was administered to fish via IV, IM and oral route at a dose of 2 mg/kg. Blood samples were taken at 13 different sampling times until the 72 h after drug administration. The plasma concentrations of tolfenamic acid were quantified using high pressure liquid chromatography-ultraviolet (UV) and pharmacokinetic parameters were assessed using non-compartmental analysis. RESULTS: The elimination half-life (t1/2ʎz) of tolfenamic acid for IV, IM and oral routes was 3.47, 6.75 and 9.19 h, respectively. For the IV route, the volume of distribution at a steady state and total body clearance of tolfenamic acid were 0.09 L/kg and 0.03 L/h/kg, respectively. The peak plasma concentration and bioavailability for IM and oral administration were 8.82 and 1.24 µg/mL, and 78.45% and 21.48%, respectively. The mean plasma protein binding ratio of tolfenamic acid in rainbow trout was 99.48% and was not concentration dependent. CONCLUSIONS: While IM route, which exhibits both the high plasma concentration and bioavailability, can be used in rainbow trout, oral route is not recommended due to low plasma concentration and bioavailability. However, there is a need to demonstrate the pharmacodynamic activity of tolfenamic acid in rainbow trout.

Clinical Pharmacokinetics of Semaglutide: A Systematic Review.

Purpose: The aim of this review was to provide all the pharmacokinetic data for semaglutide in humans concerning its pharmacokinetics after subcutaneously and oral applications in healthy and diseased populations, to provide recommendations for clinical use. Methodology: The PubMed and Embase databases were searched to screen studies associated with the pharmacokinetics of semaglutide. The pharmacokinetic parameters included area under the curve plasma concentrations (AUC), maximal plasma concentration (Cmax), time to Cmax, half-life (t1/2), and clearance. The systematic literature search retrieved 17 articles including data on pharmacokinetic profiles after subcutaneously and oral applications of semaglutide, and at least one of the above pharmacokinetic parameter was reported in all included studies. Results: Semaglutide has a predictable pharmacokinetic profile with a long t1/2 that allows for once-weekly subcutaneous administration. The AUC and Cmax of both oral and subcutaneous semaglutide increased with dose. Food and various dosing conditions including water volume and dosing schedules can affect the oral semaglutide exposure. There are limited drug-drug interactions and no dosing adjustments in patients with upper gastrointestinal disease, renal impairment or hepatic impairment. Body weight may affect semaglutide exposure, but further studies are needed to confirm this. Conclusion: This review encompasses all the pharmacokinetic data for subcutaneous and oral semaglutide in both healthy and diseased participants. The existing pharmacokinetic data can assist in developing and evaluating pharmacokinetic models of semaglutide and will help clinicians predict semaglutide dosages. In addition, it can also help optimize future clinical trials.

Drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics.

Background: The present study aimed to investigate the drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics. Research design and methods: A total of 119 patients with schizophrenia treated with aripiprazole were included to build an aripiprazole population pharmacokinetic model using nonlinear mixed effects. Results: The weight and concomitant medication of fluoxetine influenced aripiprazole clearance. Under the same weight, the aripiprazole clearance rates were 0.714:1 in patients with or without fluoxetine, respectively. In addition, without fluoxetine, for the once-daily aripiprazole regimen, dosages of 0.3 and 0.2 mg kg-1 day-1 were recommended for patients with schizophrenia weighing 40-95 and 95-120 kg, respectively, while for the twice-daily aripiprazole regimen, 0.3 mg kg-1 day-1 was recommended for those weighing 40-120 kg. With fluoxetine, for the once-daily aripiprazole regimen, a dosage of 0.2 mg kg-1 day-1 was recommended for patients with schizophrenia weighing 40-120 kg, while for the twice-daily aripiprazole regimen, 0.3 and 0.2 mg kg-1 day-1 were recommended for those weighing 40-60 and 60-120 kg, respectively. Conclusion: This is the first investigation of the effects of fluoxetine on aripiprazole via drug-drug interaction. The optimal aripiprazole initial dosage is recommended in patients with schizophrenia.

More Than a Gut Feeling─A Combination of Physiologically Driven Dissolution and Pharmacokinetic Modeling as a Tool for Understanding Human Gastric Motility.

In vivo studies of formulation performance with in vitro and/or in silico simulations are often limited by significant gaps in our knowledge of the interaction between administered dosage forms and the human gastrointestinal tract. This work presents a novel approach for the investigation of gastric motility influence on dosage form performance, by combining biopredictive dissolution tests in an innovative PhysioCell apparatus with mechanistic physiology-based pharmacokinetic modeling. The methodology was based on the pharmacokinetic data from a large (n = 118) cohort of healthy volunteers who ingested a capsule containing a highly soluble and rapidly absorbed drug under fasted conditions. The developed dissolution tests included biorelevant media, varied fluid flows, and mechanical stress events of physiological timing and intensity. The dissolution results were used as inputs for pharmacokinetic modeling that led to the deduction of five patterns of gastric motility and their prevalence in the studied population. As these patterns significantly influenced the observed pharmacokinetic profiles, the proposed methodology is potentially useful to other in vitro-in vivo predictions involving immediate-release oral dosage forms.

A sub-pharmacological test dose does not predict individual docetaxel exposure in prostate cancer patients.

PURPOSE: Docetaxel is a cytotoxic drug used for first-line treatment of various malignancies. It has a narrow therapeutic index and shows wide interpatient variability in clearance and toxicity. Tools for individual dose optimization are needed to maximize efficacy and avoid toxicity. METHODS: We performed a proof-of-concept study (EudraCT 2016-003785-77) to evaluate whether pharmacokinetics after a sub-pharmacological test dose of 1000 µg docetaxel (millidose) could be used to predict therapeutic dose exposure. Thirty prostate cancer patients eligible for treatment with docetaxel as part of routine clinical care were included. An intravenous docetaxel millidose was administered 1-7 days prior to therapeutic docetaxel. After both doses plasma docetaxel concentrations were measured by ultra- high performance liquid chromatography-tandem mass spectrometry. The docetaxel clearance was estimated with non-linear mixed effects modeling. RESULTS: Geometric mean docetaxel clearance was 57.9 L/h (GCV 78.6%) after admission of a millidose and 40.3 L/h (GCV 60.7%) after admission of a therapeutic dose. The millidose and therapeutic dose in a single patient were not significantly correlated (Spearman's rho R = 0.02, P = 0.92). CONCLUSION: Docetaxel pharmacokinetics at milli- and therapeutic dose level showed insufficient correlation for individual dose optimization. However, the clearance of a docetaxel millidose and full dose are within the same order of magnitude. Therefore, docetaxel millidose pharmacokinetics could potentially facilitate prediction of docetaxel pharmacokinetics at a population level in situations where therapeutic dose levels are impractical, such as pharmacokinetic drug-drug interaction studies or pediatric studies.

Safety and efficacy of acalabrutinib and obinutuzumab in treatment-naive chronic lymphocytic leukemia: a Japanese phase 1 study.

This report focuses on part 3 of a multicenter, open-label, phase 1 study (NCT03198650) assessing the safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of acalabrutinib plus obinutuzumab in Japanese patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL). Ten patients were included; median age was 68 years. With a median treatment duration of 27.2 months, treatment-emergent adverse events (AEs) occurred in all patients (grade ≥3, 70%), and the most common AEs were anemia and headache (40% each). One patient had a grade 4 AE of neutropenia (the only dose-limiting toxicity). PK results suggested no marked effects of concomitant obinutuzumab treatment on the exposure of acalabrutinib. PD assessment indicated that combination therapy provided >98% Bruton tyrosine kinase (BTK) occupancy. Overall response rate (ORR) was 100% with median duration of response (DoR) and median progression-free survival (PFS) not reached. Treatment with acalabrutinib plus obinutuzumab was generally safe and efficacious in adult Japanese patients with TN CLL.

Discovering interactions in polypharmacy: Impact of metamizole on the metabolism of quetiapine.

AIMS: Metamizole is quite an old drug with analgesic, antipyretic and spasmolytic properties. Recent findings have shown that it may induce several cytochrome P450 (CYP) enzymes, especially CYP3A4 and CYP2B6. The clinical relevance of these properties is uncertain. We aimed to unravel potential pharmacokinetic interactions between metamizole and the CYP3A4 substrate quetiapine. METHODS: Plasma concentrations of quetiapine from a large therapeutic drug monitoring database were analysed. Two groups of 33 patients, either receiving quetiapine as a monotherapy (without CYP modulating comedications) or with concomitantly applied metamizole, were compared addressing a potential impact of metamizole on the metabolism of quetiapine being reflected in differences of plasma concentrations of quetiapine and dose-adjusted plasma concentrations. RESULTS: Patients comedicated with metamizole showed >50% lower plasma concentrations of quetiapine (median 45.2 ng/mL, Q1 = 15.5; Q3 = 90.5 vs. 92.0 ng/mL, Q1 = 52.3; Q3 = 203.8, P = .003). The dose-adjusted plasma concentrations were 69% lower in the comedication group (P = .001). Subgroup analyses did not suggest a dose dependency of the metamizole effect or an influence of quetiapine formulation (immediate vs. extended release). Finally, the comedication group exhibited a significantly higher proportion of patients whose quetiapine concentrations were below the therapeutic reference range (78.8% in the metamizole group vs. 54.4% in the control group, P = .037) indicating therapeutically insufficient drug concentrations. CONCLUSION: The combination of metamizole and quetiapine leads to significantly lower drug concentrations of quetiapine, probably via an induction of CYP3A4. Clinicians must consider the risk of adverse drug reactions, especially treatment failure under quetiapine when adding metamizole.

Potent anti-inflammatory and anti-apoptotic activities of electrostatically complexed C-peptide nanospheres ameliorate diabetic nephropathy.

In the present era of "Diabetic Pandemic", peptide-based therapies have generated immense interest however, are facing odds due to inevitable limitations like stability, delivery complications and off-target effects. One such promising molecule is C-peptide (CPep, 31 amino acid polypeptide with t1/2 30 min); it is a cleaved subunit of pro-insulin, well known to suppress microvascular complications in kidney but has not been able to undergo translation to the clinic till date. Herein, a polymeric CPep nano-complexes (NPX) was prepared by leveraging electrostatic interaction between in-house synthesized cationic, polyethylene carbonate (PEC) based copolymer (Mol. wt. 44,767 Da) and negatively charged CPep (Mol. wt. 3299 Da) at pH 7.4 and further evaluated in vitro and in vivo. NPX exhibited a spherical morphology with a particle size of 167 nm and zeta potential equivalent to +10.3, with 85.70 % of CPep complexation efficiency. The cellular uptake of FITC-tagged CPep NPX was 95.61 % in normal rat kidney cells, NRK-52E. Additionally, the hemocompatible NPX showed prominent cell-proliferative, anti-oxidative (1.8 folds increased GSH; 2.8 folds reduced nitrite concentration) and anti-inflammatory activity in metabolic stress induced NRK-52E cells as well. The observation was further confirmed by upregulation of anti-apoptotic protein BCl2 by 3.5 folds, and proliferative markers (ß1-integrin and EGFR) by 3.5 and 2.3 folds, respectively, compared to the high glucose treated control group. Pharmacokinetic study of NPX in Wistar rats revealed a 6.34 folds greater half-life than free CPep. In in-vivo efficacy study in STZ-induced diabetic nephropathy animal model, NPX reduced blood glucose levels and IL-6 levels significantly by 1.3 and 2.5 folds, respectively, as compared to the disease control group. The above findings suggested that NPX has tremendous potential to impart sustained release of CPep, resulting in enhanced efficacy to treat diabetes-induced nephropathy and significantly improved renal pathology.