Plasma Drug Concentrations Research Articles

Neurocognitive effect of biased µ-opioid receptor agonist oliceridine, a utility function analysis and comparison with morphine.

Oliceridine (Olinvyk®) is a μ-opioid receptor agonist that in contrast to conventional opioids preferentially engages the G-protein-coupled signaling pathway. We determined the utility function of oliceridine versus morphine based on neurocognitive tests and cold pressor test. The study had a randomized, double-blind, placebo-controlled, partial block 3-way crossover design. Experiments were performed in 20 male and female volunteers. Subjects received intravenous oliceridine (1 or 3 mg; cohorts of 10 subjects/dose), morphine (5 or 10 mg; cohorts of 10 subjects/dose) or placebo on three separate occasions. Prior to and following dosing, neurocognitive tests, cold pressor test and plasma drug concentrations were obtained at regular intervals. Population pharmacokinetic-pharmacodynamic analyses served as basis for construction of a utility function, which is an objective function of probability of benefit minus probability of harm. Antinociception served as measure of benefit, slowing of saccadic peak velocity and increased body sway as measures of neurocognitive harm. The oliceridine and morphine C50's, i.e. the effect-site concentrations causing 50% effect, were: antinociception 13±2 and 23±7 ng/mL, saccadic peak velocity 90±14 and 54±15 ng/mL, and body sway 10±2 and 5.6±0.8 ng/mL, respectively. The ratio oliceridine/morphine of the therapeutic indices, C50(benefit)/C50(harm), were 0.34 (95% CI 0.17-0.7; p<0.01) for saccadic peak velocity and 0.33 (0.16-0.50; p<0.01) for body sway. The oliceridine utility was positive across the effect-site concentration 5-77 ng/mL, indicative of a greater probability of benefit than harm. The morphine utility was not significantly different from zero from 0-100 ng/mL. Over the concentration range 15-50 ng/mL the oliceridine utility was superior to that of morphine (p < 0.01). Similar observations were made for body sway. These data indicate that over the clinical concentration range, oliceridine is an analgesic with a favorable safety profile over morphine when considering analgesia and neurocognitive function.

Anesthetic drug concentrations and placental transfer rate in fetus between term and preterm infants, twins, and singletons.

Objective: This study aims to determine the drug concentration of etomidate, remifentanil, and rocuronium bromide for general anesthesia in fetus as well as the placental transport rate between term and preterm delivery, twins, and singleton. Study design: Sixty parturients with 72 fetuses undergoing cesarean section under general anesthesia were included. According to whether the fetus was a twin or premature, parturients were divided into Group I (term singleton), Group II (premature singleton), Group III (term twins), and Group IV (premature twins). The preoperative demographic characteristics and laboratory examination of parturients, hemodynamic indicators, the Apgar score of neonates at 1, 5, and 10min after delivery and at specific assigned values, umbilical artery blood gas analysis results, neonatal weight, and resuscitative measures were recorded. Anesthetic drug concentrations in maternal arterial (MA), umbilical arterial (UA), and umbilical venous (UV) blood were detected by Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). Result: No significant differences were observed in the concentrations of etomidate, remifentanil, and rocuronium bromide in MA, UV, and UA blood, or in the UV/MA and UA/UV ratios between term and preterm infants, twins, and singletons. Moreover, there was no variation in the anesthetic drug concentration among each pair of twins. Additionally, no correlation was found between the neonatal weight and the plasma concentrations of anesthetic drugs in UV and UA blood, except for remifentanil in UA blood. Conclusion: Preterm or twin deliveries do not affect the neonatal concentration of etomidate, remifentanil, and rocuronium bromide used in general anesthesia for cesarean sections. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR2100046547.

Pharmacokinetics of cefpirome following intravenous and intramuscular administrations in healthy and febrile sheep (Ovis aries)

Cefpirome is fourth generation cephalosporin class of drug, which facilitates rapid penetration through the outer membrane of Gram-negative bacteria and results in potent activity against Gram-negative pathogens. As fever is one of the most common manifestations in bacterial diseases, the study was undertaken to investigate pharmacokinetics of single dose intravenous and intramuscular administrations of cefpirome (10 mg/kg of body weight) in healthy and lipopolysaccharide (LPS) induced febrile sheep and to perform PK-PD analysis using MIC values reported in previous studies and the pharmacokinetic parameters obtained in this study. Following intravenous and intramuscular administrations of cefpirome in healthy sheep, the plasma drug concentration was detected up to 12 h, while plasma drug concentration was detected up to 18 h following intravenous and intramuscular administrations in febrile sheep. Induction of febrile state significantly altered pharmacokinetic profile of cefpirome following intravenous and intramuscular administrations in sheep. Based on pharmacokinetic- pharmacodynamic integration, an optimal intramuscular dosage regimen of 10 mg/kg once daily for cefpirome in febrile sheep was predicted for targeted average MIC of ≤ 0.25 µg/mL.

Population Pharmacokinetic Modeling and Stochastic Simulations to Support Pediatric Dose Selection of Pimavanserin.

Pimavanserin is a selective serotonin-modulating agent with inverse agonist/antagonist activity at the 5-hydroxytryptamine2A (5-HT2A ) receptor. The safety and efficacy of pimavanserin 34mg once daily were studied in adults with hallucinations and delusions associated with Parkinson's disease psychosis and other neuropsychiatric conditions. This analysis used model-based simulations of pimavanserin steady-state exposures to identify a dose that generated pediatric exposures comparable with adult exposures achieved with 34mg pimavanserin. A population pharmacokinetics model was developed using pooled plasma drug concentration (ie, actual) data from 13 clinical studies, including a phase1 study of adolescent pediatric patients (aged 13-17years) with various psychiatric conditions. Stochastic simulations were performed to predict exposures in a virtual (ie, simulated) group of pediatric patients (aged 5-17years). Steady-state measures of the area under the plasma concentration-time curve (AUC) and maximum drug concentration (Cmax ) were simulated for relevant age and weight stratifications and compared with simulated exposures in adults (aged 18-49years). The simulated mean AUC ranged from 47.41 to 54.73ng d/mL and the mean Cmax ranged from 41.13 to 50.07ng/mL in adults receiving pimavanserin 34mg. The simulated mean (SD) Cmax of 56.54(24.58)ng/mL with pimavanserin 34mg in patients aged 10-17years was similar to that in adults. Pimavanserin 20mg yielded a mean (SD) Cmax of 45.30(21.31)ng/mL in patients aged 5-9years and 49.18(22.91)ng/mL in the pediatric patient weight group of 14-25kg, which are values close to the Cmax in adults treated with 34mg. Pimavanserin 20 and 34mg in pediatric patients aged 5-9 and 10-17years, respectively, yielded exposures similar to daily pimavanserin 34mg in adults aged 18-49years.

Absolute and Relative Bioavailability of Oral Solid Dosage Formulations of Deucravacitinib in Humans.

itinib is an oral, selective, allosteric inhibitor of tyrosine kinase 2, an intracellular signaling kinase involved in the pathogenesis of immune-mediated inflammatory diseases. The absolute and relative bioavailability (BA) were evaluated in phase 1, open-label studies in healthy adults to assess (1) the absolute BA of the deucravacitinib tablet formulation following single oral administration of a 12-mg tablet and an intravenous microdose infusion of 0.1-mg carbon-13 and nitrogen-15-labeled deucravacitinib ([13 C2 , 15 N3 ] deucravacitinib) solution in 8 subjects, and (2) the relative oral BA of deucravacitinib tablet and capsule formulations at the 3- and 12-mg dose levels in 20 subjects. The absolute oral availability of deucravacitinib in the tablet formulation was near complete at approximately 99%. The total clearance (254mL/min) was low relative to hepatic blood flow, and volume of distribution (∼140L) was greater than total body water, indicating extravascular distribution. Deucravacitinib systemic exposure (maximum plasma concentration, area under the plasma drug concentration curve from time zero to the time of the last quantifiable nonzero concentration, and area under the plasma drug concentration-time curve from time zero extrapolated to infinity) after administration of the tablet formulation were similar to the capsule at the tested 3- and 12-mg doses. In both studies, deucravacitinib was safe with no clinically relevant changes in laboratory values, electrocardiogram parameters, or vital signs.

Development and optimization of Ropinirole loaded self-nanoemulsifying tablets

BackgroundThe present research work aims to develop a Ropinirole-loaded self-Nanoemulsifying Drug Delivery system. Ropinirole has limited oral bioavailability due to substantial first-pass metabolism, which ultimately results in poor oral bioavailability and reduces plasma drug concentration and an overall reduction in therapeutic effects. Avoiding hepatic first-pass metabolism by increasing lymphatic uptake is the goal of the creation of the Ropinirole Self-NanoEmulsifying System. The solvent system for the liquid Self-NanoEmulsifying Drug Delivery System (SNEDDS) was optimized using Box-Behnken Design, where the concentration of oil(X1), surfactant (X2), and co-surfactant(X3) were taken as independent variables. The formulated liquid SNEDDS were then converted into solid SNEDDS by the adsorption method for improving patient compliance.ResultsThe obtained mean droplet size of the formulated SNEDDS was 96.71 nm, and the rate of emulsification was 22 s. Liquid SNEDDS was converted into solid SNEDDS using Syloid 244 FP as adsorbent. Scanning Electron Microscopy (SEM) study shows well-separated particles adsorbed on Syloid 244 FP. In vitro drug release studies show better release from solid and liquid SNEDDS when compared to pure suspension.ConclusionsRopinirole-loaded SNEDDS can be a better option for reducing the extensive first-pass metabolism associated with Ropinirole.

Pharmacokinetics of robenacoxib after a single intramuscular dose in smooth dogfish (Mustelus canis).

To determine the pharmacokinetics of robenacoxib after a single intramuscular dose (4.0 mg/kg) in smooth dogfish (Mustelus canis). 8 healthy adult male smooth dogfish in human care within the same habitat. All sharks received a single intramuscular dose of robenacoxib (4.0 mg/kg) in the right caudolateral epaxial musculature. Blood samples were collected under manual restraint from the ventral tail vessel at 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after drug administration. Plasma drug concentrations were determined by HPLC followed by noncompartmental pharmacokinetic analysis of the data. A maximum plasma concentration of 1.24 µg/mL was reached at a mean time of 30 minutes following robenacoxib administration with a plasma elimination half-life of 3.79 hours. Plasma concentrations did not fall below the lower limit of quantification (0.1 µg/mL) at the time points sampled in this study. Intramuscular administration of a single dose (4.0 mg/kg) of robenacoxib in smooth dogfish resulted in rapid absorption to a maximum concentration at approximately 30 minutes after administration and persisted above levels considered to be therapeutic in domestic species for at least 8 hours.

A randomized, single-blind, single-dose, parallel-group study in healthy subjects to demonstrate the pharmacokinetic equivalence of trastuzumab and its biosimilar

ABSTRACT Background Trastuzumab is a humanized anti-HER2 monoclonal antibody used in the treatment of breast cancer. This study compared the pharmacokinetics (PK), immunogenicity and safety of trastuzumab (Roche Pharma AG) and its biosimilar (Chia Tai Tianqing Pharmaceutical Group Co. Ltd) in healthy Chinese subjects. Research design and methods A randomized, parallel, double-blind, single-dose study was conducted. Healthy male subjects were randomized to receive trastuzumab (n = 43) or its biosimilar (n = 43) intravenously at a dose of 4 mg. Plasma drug concentrations were detected by enzyme-linked immunosorbent assay (ELISA), and PK parameters were statistically analyzed. Safety and immunogenicity were also evaluated. Results The geometric mean ratios (GMRs) of AUC0-t, Cmax and AUC0-∞ for trastuzumab and its biosimilar were 92.3%, 100.77% and 92.2%, respectively. The 90% CIs were all within 80%-125%, meeting the bioequivalence standards. No serious adverse events or immunogenicity were reported, and all the adverse events reported were mild and similar between the two treatment groups. Conclusions Trastuzumab was well tolerated, showed a similar safety profile to its biosimilar, and demonstrated PK equivalence. Clinical trial registration This trial was registered at the [anonymized].

Evaluation of the impact of vindoline, an active components of Catharanthus roseus, on rat hepatic cytochrome P450 enzymes by using a cocktail of probe drugs.

The objection of this study was to investigate the effects of vindoline(VDL) on the cytochrome P450 (CYP 450) isoforms (CYP1A2, 2B, 2C11, 2D1 and 3A) in rats. Firstly, the rats were randomly divided into VDL pretreatment group and blank group, each group had six rats. VDL pretreatment group was administrated VDL (20 mg·kg-1) by oral gavage for fifteen days consecutively, and the equivalent CMC-Na solution without VDL was given to the blank group by gavage. Secondly, a cocktail of caffeine, bupropion, diclofenac, dextromethorphan and midazolam was then administered on the sixteenth day. Finally, blood samples were collected at the specified time point, and the plasma concentration of the probe drug was determined by UHPLC-QTOF-MS/MS. The effects of VDL on the activity of these CYP enzymes in rats were evaluated by pharmacokinetic parameters. VDL pretreatment group compared with the blank group, accelerated the metabolism of diclofenac, and weakened the metabolism of caffeine. These results suggested that VDL could induce the activity of CYP2C11, and inhibits the activity of CYP1A2, but had no significant effects on CYP2B, CYP2D1 and CYP3A. The results in this study can provide beneficial information for the later clinical application of VDL.

Population Pharmacokinetic Modeling and Determination of Individual Exposure to Avalglucosidase Alfa in Adolescent and Adult Patients With Late-Onset Pompe Disease: Analysis of Pooled Data From Phase I to III Clinical Trials.

Pompe disease is a rare genetic disorder caused by a deficiency of a lysosomal enzyme called acid alpha-glucosidase and is classified into infantile and late-onset forms. Since 2006, an enzyme replacement therapy involving alglucosidase alfa has been available. In 2021, a new enzyme replacement therapy involving avalglucosidase alfa demonstrated improved clinical benefits. In this article, the authors describe the pharmacokinetics of avalglucosidase alfa using a population pharmacokinetic approach. The population pharmacokinetic model was developed using a data set that included 75 patients and 2042 plasma drug concentrations determined through enzymatic activity assay from 3 studies (phases I/II and III) and involved 3 dose levels (5, 10, and 20 mg/kg). The analysis was performed using NONMEM software. Two sequences were observed in the plasma drug concentration profile: the first kinetic driving exposure, and after 12 hours postdose, a slight rebound addressing very low concentrations that lasted up to 2 weeks. Following model screening, a model with a central compartment with parallel linear and nonlinear elimination and 2 concatenated peripheral compartments was proposed. A putative back-redistribution of a marginal fraction of the drug from the second peripheral compartment to the central compartment may explain the slight rebound in concentration. The final model's mean bias and precision for individual predictions were -2.66% and 30.7%, respectively, and -0.433% and 38.9%, respectively, for population predictions. A concatenated 3-compartment model was developed to describe the avalglucosidase alfa concentrations in patients with late-onset Pompe disease. None of the covariates tested could explain the interindividual variability.

Semisolid Enteral Nutrients Alter the Pharmacokinetics of Orally Administered Levetiracetam in Rats.

Enteral nutrients (ENs) affect the plasma drug concentration of orally co-administered drugs, particularly those of antiepileptic drugs, such as phenytoin and carbamazepine. However, few studies have reported the interactions of levetiracetam (LEV), an upcoming antiepileptic drug, with ENs. In this study we aimed to investigate the pharmacokinetics of LEV in 55 rats after oral co-administration of LEV with liquid or semisolid ENs. Compared with the control group, co-administration with Terumeal ® Soft significantly decreased the plasma LEV concentration at 0.5, 1, and 2 h and area under the plasma concentration-time curve from 0 to 3 h (AUC0→3h) (P < 0.01). However, the AUC0→3h of LEV remained unchanged following the administration of Terumeal ® Soft 2 h after the initial LEV administration. Moreover, co-administration with semisolid Racol® NF delayed the absorption of LEV without decreasing the AUC0→3h, whereas liquid Racol ® NF did not alter LEV pharmacokinetics. Thus, co-administration of LEV with Terumeal® Soft reduced the absorption of LEV from the gastrointestinal tract, which was prevented by administering Terumeal ® Soft 2 h after LEV administration. Semisolid Racol ® NF altered LEV pharmacokinetics without decreasing its gastrointestinal absorption. Our findings suggested that careful monitoring of the plasma LEV levels is necessary when co-administering LEV with Terumeal ® Soft, semisolid Racol ® NF, or any other semisolid ENs, to prevent the inadvertent effects of the interaction between LEV and ENs.

Effects of orally administered pimobendan on platelet function in healthy adult cats.

Several phosphodiesterase inhibitors have demonstrable antiplatelet actions when administered to human patients. Concentration-dependent inhibition of feline platelet aggregation by pimobendan has been previously demonstrated in vitro. However, there are no published reports characterizing the effect of oral pimobendan, administered at therapeutic doses, on platelet function in cats. This study aimed to evaluate the effect of orally administered pimobendan on platelet function in healthy adult cats. 6 healthy purpose-bred adult cats. Cats were administered pimobendan orally at a dosage of 0.625 mg/cat (low-dose) twice daily for 1 week, followed by 1.25 mg/cat (high-dose) twice daily for 1 week. Venous blood sampling for platelet testing and plasma drug concentration occurred at baseline, 1 hour postdose on the eighth day of treatment with low-dose pimobendan, 1 hour postdose on the eighth day of treatment with high-dose pimobendan, and after a 1-week washout period. Platelet function was assessed by whole blood aggregometry and by use of a platelet function analyzer (PFA-100®). Friedman tests were used to compare platelet function parameters among the 4 sampling timepoints. After 1 week of treatment, median (range) plasma pimobendan concentrations were 15.1 ng/mL (6.89-20.2 ng/mL) and 32.8 ng/mL (23.3-44.8 ng/mL) in cats receiving low-dose and high-dose pimobendan, respectively. No significant differences in PFA closure time or any aggregometry variable were found among the treatment conditions. Pimobendan was not associated with measurable inhibition of platelet function when administered orally to healthy adult cats at 2 clinically relevant dosages.

Controlled release of MT-1207 using a novel gastroretentive bilayer system comprised of hydrophilic and hydrophobic polymers

In the present study, novel gastroretentive bilayer tablets were developed that are promising for the once-a-day oral delivery of the drug candidate MT-1207. The gastroretentive layer consisted of a combination of hydrophilic and hydrophobic polymers, namely polyethylene oxide and Kollidon® SR. A factorial experiment was conducted, and the results revealed a non-effervescent gastroretentive layer that, unlike most gastroretentive layers reported in the literature, was easy to prepare, and provided immediate tablet buoyancy (mean floating lag time of 1.5 s) that lasted over 24 h in fasted state simulated gastric fluid (FaSSGF) pH 1.6, irrespective of the drug layer, thereby allowing a 24-hour sustained release of MT-1207 from the drug layer of the tablets. Furthermore, during in vitro buoyancy testing of the optimised bilayer tablets in media of different pH values (1.0, 3.0, 6.0), the significant difference (one-way ANOVA, p < 0.001) between the respective total floating times indicated that stomach pH effects on tablet buoyancy are important to be considered during the development of non-effervescent gastroretentive formulations and the choice of dosing regimen. To the best of our knowledge, this has not been reported before, and it should probably be factored in when designing dosing regimens. Finally, a pharmacokinetic study in Beagle dogs indicated a successful in vivo 24-hour sustained release of MT-1207 from the optimised gastroretentive bilayer tablet formulations with the drug plasma concentration remaining above the estimated minimum effective concentration of 1 ng/mL at the 24-hour timepoint and also demonstrated the gastroretentive capabilities of the hydrophilic and hydrophobic polymer combination. The optimised formulations will be forwarded to clinical development.

High-concentration buprenorphine exceeds target plasma concentrations for extended periods following subcutaneous administration in American flamingos (Phoenicopterus ruber).

To determine the pharmacokinetic parameters of a high-concentration buprenorphine formulation after a single SC dose in American flamingos (Phoenicopterus ruber). 6 healthy adult American flamingos (3 males and 3 females). A single dose of high-concentration buprenorphine (1.8 mg/kg) was administered SC to all birds. Blood samples were collected at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours after drug administration between October 14 and October 18, 2022. Plasma buprenorphine concentrations were determined by liquid chromatography-tandem mass spectrometry and a noncompartmental analysis was used to determine pharmacokinetic parameters. Mean ± SD peak plasma drug concentration (Cmax) was 195.1 ± 187.4 ng/mL, the mean time to peak plasma concentration (Tmax) was 0.32 ± 0.31 hours, the mean area under the concentration-vs-time curve from time 0 to the last measured concentration (AUC0-last) was 881.4 ± 205.4 ng/mL, and mean terminal half-life (t1/2) was 12.6 ± 3.86 hours. Mean plasma buprenorphine concentrations were >1 ng/mL for at least 48 hours after drug administration. No clinically significant adverse effects were observed. High-concentration buprenorphine dosed at 1.8 mg/kg SC in American flamingos rapidly exceeded plasma drug concentrations reported to have analgesic effects in other avian species and maintained these levels for extended periods. Sedative effects were similar to those reported for other species. Additional studies are needed to evaluate the clinical efficacy of high-concentration buprenorphine at this dose in American flamingos.

Blood microsampling in cynomolgus monkey and evaluation of plasma PK parameters in comparison to conventional sampling

Microsampling, a reduced volume sampling method, has successfully gained attention at the International Conference on Harmonization (ICH) level and established benefits support its use in Toxicokinetic (TK) studies. These improved sampling techniques are less invasive and in large animal species improve animal welfare (refinement). To evaluate if the plasma concentrations of drugs were influenced by the blood sampling method, the traditional method from femoral vein and microsampling from tail vein in Cynomolgus monkeys were compared. The pharmacokinetic parameters (Cmax, Tmax and AUC) of four drugs (selected based on acid-base and volume of distribution properties) in non-human primate were correlated. The plasma samples were quantified using standard LC-MS/MS methods, qualified to evaluate the precision and accuracy before the analysis of real samples.The results reported in this work demonstrated the suitability of microsampling in supporting PK/TK studies in non-human primates. The data show that the exposure of drugs tested after blood collection using standard procedure from femoral vein and microsampling from tail vein is correlated and is not influenced by acid-base characteristics and volume of distribution.

Liquid-like Oral Sustained-Release System Based on Acid-Sensitive in situ Hydrogel for Alleviate Gastrointestinal Side Effects of Indobufen

Commonly, most oral non-steroidal anti-inflammatory drugs (NSAIDs) have known gastric adverse reactions due to their long-term and high dose administration. In this study, a novel liquid sustained-release system based on multiple-unit in situ hydrogel beads was designed to address this issue. The system is composed of sodium alginate (SA), gellan gum (GG), zinc oxide (ZnO), and magnesium oxide (MgO). Furthermore, indobufen was loaded into the system to evaluate its gastric mucosal protection effect. This effect can be attributed to the topical antacid, pepsin inhibition, and sustained drug release properties of the system. It was proven that the stored solid gel system could undergo a “solid to liquid” transition after shaking. Once swallowed, the liquid gel could disperse well in the stomach as hydrogel beads. Then, the “liquid to solid” gelation occurred from the exterior to interior of each multiple-unit gel bead, triggered by the release of Zn2+ and Mg2+ from neutralization reactions. The formed gel demonstrated mild antacid effect that lasted for 3 hours and 66.3% pepsin inhibition in vivo. Moreover, the rats treated with the indobufen gel system showed a drug plasma concentration versus time curve with less fluctuation compared to the rats treated with the marketed preparation (YinDuo®) group. The gel system also exhibited an extended Tmax (6.50 hours) and reduced Cmax (52.87 μg/mL). Additionally, the gastric mucosal protection of the gel system was verified using three types of peptic gastric ulcer models. These findings suggested that this multiple-unit in situ gel could be a potential oral liquid sustained release delivery system for NSAIDs.

Preparation of chitosan-coated hollow tin dioxide nanoparticles and their application in improving the oral bioavailability of febuxostat

The aim of this study was to design a chitosan-coated hollow tin dioxide nanosphere (CS-HSn) for loading febuxostat (FEB) using an adsorption method to obtain a sustained-release system (CS-HSn-FEB) to improve the oral bioavailability of FEB. The morphological characteristics of hollow tin dioxide nanospheres (HSn) and CS-HSn were analyzed by transmission electron microscopy (TEM) and dynamic light scattering (DLS). The hemolysis test and CCK-8 test were used to assess the biosafety of HSn and CS-HSn. Powder X-ray diffraction (PXRD) and differential scanning thermal analysis (DSC) were performed on CS-HSn-FEB to analyze the drug presence status. The dissolution behavior and changes in plasma drug concentration of CS-HSn-FEB were evaluated in vitro and in vivo. Sections of intestinal tissues from SD rats were obtained to observe whether chitosan could increase the distribution of nanoparticles in the intestinal tissues. The results showed that FEB was present in CS-HSn in an amorphous state. Moreover, CS-HSn, with good biosafety, significantly improved the water solubility and oral absorption of FEB, indicating that CS-HSn has great potential to improve the intestinal absorption and oral bioavailability of insoluble drugs.

Pharmacokinetics and dialytic clearance of baricitinib during in vivo continuous venovenous haemodialysis in a patient with COVID-19

ObjectivesTo date, there are no published pharmacokinetic (PK) data for baricitinib in critically ill patients requiring continuous renal replacement therapy. This paper describes in detail the plasma PK and dialytic clearance of baricitinib in a patient infected with coronavirus disease 2019 (COVID-19) requiring continuous renal replacement therapy in order to suggest dosing strategies in this population. MethodsBaricitinib 2 mg daily was used for the treatment of COVID-19 in a critically ill patient on continuous venovenous haemodialysis (CVVHD). Prefiltration plasma drug concentrations of baricitinib were measured at hours 1, 2, 12, and 24 after drug administration. Postfiltration and ultrafiltrate concentrations were collected at hour 24. ResultsPlasma PK parameters of baricitinib in this patient were as follows: maximum plasma concentration (Cmax), 20.98 ng/mL; minimum plasma concentration (Cmin), 9.84 ng/mL; half-life (t1/2), 23.85 h; apparent volume of distribution at the steady state (Vss), 99.42 L; total clearance at the steady state (CLss), 2.89 L/h; and area under the concentration-time curve (AUC0–∞), 692.14 ng · h/mL. The saturation coefficient for baricitinib at 24 h after administration was 0.607. The transmembrane clearance of baricitinib by CVVHD running at a flow rate of 2 L/h was 1.21 L/h, representing 41.9% of the total clearance of baricitinib. ConclusionsIn a critically ill COVID-19 patient on CVVHD, a 2-mg dose of baricitinib achieves a Cmax comparable with healthy subjects, but total clearance was reduced to about 20%. Larger studies exploring multiple patients and dialysis modes are needed to determine the optimal dosing strategy for baricitinib in this patient population.

Biopolymer-Capped Pyrazinamide-Loaded Colloidosomes: In Vitro Characterization and Bioavailability Studies.

This study aimed to prepare colloidosome particles loaded with pyrazinamide (PZA). These drug-loaded colloidosomes were prepared using an in situ gelation technique using a central composite design with a shell made of calcium carbonate (CaCO3) particles. Optimal amounts of 150 mg of CaCO3, sodium alginate (2%), and 400 mg of poly(3-hydroxybutyrate-co-3-hydroxy valerate) (PHBV) concentration resulted in the maximum drug loading and efficient release profile. Field emission scanning electron microscopy results showed spherical porous particles with a good coating of the PHBV polymer. Additionally, Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), thermogravimetric and differential thermal analysis (TGA-DTA), and X-ray diffraction (XRD) analysis showed good compatibility between the drug and excipients. The pharmacokinetic studies demonstrated that the drug-loaded colloidosomes resulted in 4.26 times higher plasma drug concentrations with Cmax values of 32.386 ± 2.744 mcg/mL (PZA solution) and 115.868 ± 53.581 mcg/mL (PZA-loaded colloidosomes) and AUC0-t values of 61.24 mcg-h/mL (PZA solution) and 260.9 mcg-h/mL (PZA-loaded colloidosomes), indicating that colloidosomes have the potential to be effective drug carriers for delivering PZA to the target site.

Phase I study to assess the effect of adavosertib (AZD1775) on the pharmacokinetics of substrates of CYP1A2, CYP2C19, and CYP3A in patients with advanced solid tumors

PurposeAdavosertib may alter exposure to substrates of the cytochrome P450 (CYP) family of enzymes. This study assessed its effect on the pharmacokinetics of a cocktail of probe substrates for CYP3A (midazolam), CYP2C19 (omeprazole), and CYP1A2 (caffeine).MethodsPeriod 1: patients with locally advanced or metastatic solid tumors received ‘cocktail’: caffeine 200 mg, omeprazole 20 mg, and midazolam 2 mg (single dose); period 2: after 7- to 14-day washout, patients received adavosertib 225 mg twice daily on days 1–3 (five doses), with cocktail on day 3. After cocktail alone or in combination with adavosertib administration, 24-h pharmacokinetic sampling occurred for probe substrates and their respective metabolites paraxanthine, 5-hydroxyomeprazole (5-HO), and 1′-hydroxymidazolam (1′-HM). Safety was assessed throughout.ResultsOf 33 patients (median age 60.0 years, range 41–83) receiving cocktail, 30 received adavosertib. Adavosertib co-administration increased caffeine, omeprazole, and midazolam exposure by 49%, 80%, and 55% (AUC0–12), respectively; AUC0–t increased by 61%, 98%, and 55%. Maximum plasma drug concentration (Cmax) increased by 4%, 46%, and 39%. Adavosertib co-administration increased 5-HO and 1′-HM exposure by 43% and 54% (AUC0–12) and 49% and 58% (AUC0–t), respectively; paraxanthine exposure was unchanged. Adavosertib co-administration decreased Cmax for paraxanthine and 5–HO by 19% and 7%; Cmax increased by 33% for 1′-HM. After receiving adavosertib, 19 (63%) patients had treatment-related adverse events (six [20%] grade ≥ 3).ConclusionAdavosertib (225 mg bid) is a weak inhibitor of CYP1A2, CYP2C19, and CYP3A.ClinicalTrials.govNCT03333824