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Clinical Pharmacology in Drug... Jun 2023Ibuprofen is a nonsteroidal anti-inflammatory agent. In this study, we compared the pharmacokinetic properties, bioequivalence, and safety of a newly developed generic... (Randomized Controlled Trial)
Randomized Controlled Trial
Ibuprofen is a nonsteroidal anti-inflammatory agent. In this study, we compared the pharmacokinetic properties, bioequivalence, and safety of a newly developed generic formulation (test) and a branded formulation (reference) of 0.2 g ibuprofen granules in healthy Chinese participants in fasting and fed arms. The randomized, single-dose, open-label, two-preparation, two-sequence, two-period crossover study had a washout period of 7 days between each period. It was conducted in 72 participants, 24 in the fasting arm and 48 in the fed arm. The concentration of ibuprofen in the plasma was determined using high-performance liquid chromatography-tandem mass spectroscopy. The primary pharmacokinetic parameters were calculated using a noncompartmental model. Safety assessments were performed throughout the study. The mean values of C , AUC , and AUC for the test and reference preparations of ibuprofen were 19 295 and 21 101 ng/mL, 70 795 and 70 558 ng * h/mL, and 72 023 and 71 647 ng * h/mL, respectively, in the fasting arm and 11 299 and 11 605 ng/mL, 70 983 and 69 157 ng * h/mL, and 73 279 and 71 267 ng * h/mL, respectively, in the fed arm. For all parameters, bioequivalence was within acceptable limits. No serious adverse reactions were reported in this study. This study demonstrated that the 2 formulations of ibuprofen granules were bioequivalent in healthy Chinese volunteers under fasting and fed conditions.
Topics: Humans; Therapeutic Equivalency; Ibuprofen; Cross-Over Studies; Area Under Curve; Biological Availability
PubMed: 36575962
DOI: 10.1002/cpdd.1211 -
Journal of Veterinary Internal Medicine Jul 2022Isavuconazole is a triazole antifungal drug that has shown good efficacy in human patients. Absorption and pharmacokinetics have not been evaluated in cats.
BACKGROUND
Isavuconazole is a triazole antifungal drug that has shown good efficacy in human patients. Absorption and pharmacokinetics have not been evaluated in cats.
OBJECTIVES
To determine the pharmacokinetics of isavuconazole in cats given a single IV or PO dose.
ANIMALS
Eight healthy, adult research cats.
METHODS
Four cats received 100 mg capsules of isavuconazole PO. Four cats received 5 mg/kg isavuconazole solution IV. Serum was collected at predetermined intervals for analysis using ultra-high performance liquid chromatography-tandem mass spectrometry. Data were analyzed using a 2-compartment uniform weighting pharmacokinetic analysis with lag time for PO administration and a 2 compartment, 1/y weighting for IV administration. Predicted 24 and 48-hour dosing intervals of 100 mg isavuconazole administered PO were modeled and in vitro plasma protein binding was assessed.
RESULTS
Both PO and IV drug administration resulted in high serum concentrations. Intravenous and PO formulations of isavuconazole appear to be able to be used interchangeably. Peak serum isavuconazole concentrations occurred 5 ± 3.8 hours after PO administration with an elimination rate half-life of 66.2 ± 55.3 hours. Intersubject variability was apparent in both the PO and IV groups. Two cats vomited 6 to 8 hours after PO administration. No adverse effects were observed in the IV group. Oral bioavailability was estimated to be approximately 88%. Serum protein binding was calculated to be approximately 99.0% ± 0.03%.
CONCLUSIONS AND CLINICAL IMPORTANCE
Isavuconazole might prove to be useful in cats with fungal disease given its favorable pharmacokinetics. Additional studies on safety, efficacy, and tolerability of long-term isavuconazole use are needed.
Topics: Administration, Intravenous; Administration, Oral; Animals; Area Under Curve; Biological Availability; Cats; Half-Life; Humans; Nitriles; Pyridines; Triazoles
PubMed: 35616184
DOI: 10.1111/jvim.16452 -
The Journal of Pharmacology and... Feb 2021A semimechanistic physiologically based pharmacokinetic (PBPK) model for chloroquine (CQ), a highly lysosomotropic weak base, was applied to digitized rat and human...
A semimechanistic physiologically based pharmacokinetic (PBPK) model for chloroquine (CQ), a highly lysosomotropic weak base, was applied to digitized rat and human concentration versus time data. The PBPK model in rat featured plasma and red blood cell (RBC) concentrations, extensive and apparent nonlinear tissue distribution, fitted hepatic and renal intrinsic clearances, and a plasma half-life of about 1 day. Tissue-to-plasma CQ ratios at 50 hours after dosing were highest in lung, kidney, liver, and spleen (182-318) and lower in heart, muscle, brain, eye, and skin (11-66). The RBC-to-plasma ratio of 11.6 was assumed to reflect cell lipid partitioning. A lysosome-based extended model was used to calculate subcellular CQ concentrations based on tissue mass balances, fitted plasma, interstitial and free cytosol concentrations, and literature-based pH and pKa values. The CQ tissue component concentrations ranked as follows: lysosome > > acidic phospholipid > plasma = interstitial = cytosol ≥ neutral lipids. The extensive lysosome sequestration appeared to change over time and was attributed to lowering pH values caused by proton pump influx of hydrogen ions. The human-to-rat volume of distribution () ratio of 7 used to scale rat tissue partitioning to human along with estimation of hepatic clearance allowed excellent fitting of oral-dose PK (150-600 mg) of CQ with a 50-day half-life in humans. The prolonged PK of chloroquine was well characterized for rat and human with this PBPK model. The calculated intratissue concentrations and lysosomal effects have therapeutic relevance for CQ and other cationic drugs. SIGNIFICANCE STATEMENT: Sequestration in lysosomes is a major factor controlling the pharmacokinetics and pharmacology of chloroquine and other cationic drugs. This report provides comprehensive physiologic modeling of chloroquine distribution in tissues and overall disposition in rat and human that reveals expected complexities and inferences related to its subcellular association with various tissue components.
Topics: Animals; Antimalarials; Brain; Chloroquine; Erythrocytes; Hepatobiliary Elimination; Humans; Lysosomes; Models, Theoretical; Muscles; Myocardium; Rats; Renal Elimination; Species Specificity; Tissue Distribution
PubMed: 33277347
DOI: 10.1124/jpet.120.000385 -
Clinical Pharmacology in Drug... Sep 2022This study aimed to evaluate the bioequivalence of two pazopanib tablet formulations in healthy Chinese subjects. A randomized, open-label, single-dose, two-period,... (Randomized Controlled Trial)
Randomized Controlled Trial
This study aimed to evaluate the bioequivalence of two pazopanib tablet formulations in healthy Chinese subjects. A randomized, open-label, single-dose, two-period, two-sequence, crossover study was conducted under fasting conditions. A total of 32 eligible subjects were randomly administered a single dose of a 200-mg generic or branded pazopanib tablet with a 16-day washout period. Blood samples were collected before and up to 72 hours after dosing. Pharmacokinetic parameters were analyzed with noncompartmental analysis. Safety assessments included physical examinations, laboratory tests, and adverse events reporting. Maximum plasma concentration (C ), area under the plasma concentration-time curve (AUC) from zero to the last quantifiable concentration (AUC ), and AUC from zero to infinity (AUC ) were similar between the generic and branded products (all P > .05). The 90% confidence intervals of the geometric mean ratio of the test/reference products for C , AUC , and AUC were 89.1%-117.1%, 81.9%-108.5%, and 82.4%-109.6%, respectively. There were no serious adverse events during the study. The newly developed generic pazopanib tablet was bioequivalent to the reference product under fasting conditions. Both formulations were well tolerated in healthy Chinese volunteers.
Topics: Area Under Curve; Biological Availability; China; Cross-Over Studies; Drugs, Generic; Humans; Indazoles; Pyrimidines; Sulfonamides; Tablets; Therapeutic Equivalency
PubMed: 35384398
DOI: 10.1002/cpdd.1096 -
Expert Opinion on Investigational Drugs May 2023CT-P47 is a candidate tocilizumab biosimilar. This study assessed the pharmacokinetic (PK) equivalence of CT-P47 and European Union-approved reference tocilizumab... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
CT-P47 is a candidate tocilizumab biosimilar. This study assessed the pharmacokinetic (PK) equivalence of CT-P47 and European Union-approved reference tocilizumab (EU-tocilizumab) in healthy Asian adults.
RESEARCH DESIGN AND METHODS
This double-blind, multicenter, parallel-group trial randomized healthy adults (1:1) to receive a single (162 mg/0.9 mL) subcutaneous dose of CT-P47 or EU-tocilizumab. The primary endpoint (Part 2) was PK equivalence by area under the concentration - time curve (AUC) from time zero to last quantifiable concentration (AUC), AUC from time zero to infinity (AUC), and maximum serum concentration (C). PK equivalence was concluded if 90% confidence intervals (CIs) for the ratios of geometric least-squares means (gLSMs) were within the 80-125% equivalence margin. Additional PK endpoints, immunogenicity, and safety were evaluated.
RESULTS
In Part 2, 289 participants were randomized (146 CT-P47; 143 EU-tocilizumab); 284 received study drug. AUC, AUC, and C were equivalent between CT-P47 and EU-tocilizumab: 90% CIs for the ratios of gLSMs were within the 80-125% equivalence margin. Secondary PK endpoints, immunogenicity, and safety were comparable between groups.
CONCLUSIONS
CT-P47 demonstrated PK equivalence with EU-tocilizumab and was well tolerated, following a single dose in healthy adults.
CLINICAL TRIAL REGISTRATION
www.clinicaltrials.gov identifier is NCT05188378.
Topics: Adult; Humans; Biosimilar Pharmaceuticals; Therapeutic Equivalency; Healthy Volunteers; Area Under Curve; Double-Blind Method; Tomography, X-Ray Computed
PubMed: 37231670
DOI: 10.1080/13543784.2023.2212155 -
Molecules (Basel, Switzerland) Dec 2022Natural medicine has been widely used for clinical treatment and health care in many countries and regions. Additionally, extracting active ingredients from traditional... (Review)
Review
Natural medicine has been widely used for clinical treatment and health care in many countries and regions. Additionally, extracting active ingredients from traditional Chinese medicine and other natural plants, defining their chemical structure and pharmacological effects, and screening potential druggable candidates are also uprising directions in new drug research and development. Physiologically based pharmacokinetic (PBPK) modeling is a mathematical modeling technique that simulates the absorption, distribution, metabolism, and elimination of drugs in various tissues and organs in vivo based on physiological and anatomical characteristics and physicochemical properties. PBPK modeling in drug research and development has gradually been recognized by regulatory authorities in recent years, including the U.S. Food and Drug Administration. This review summarizes the general situation and shortcomings of the current research on the pharmacokinetics of natural medicine and introduces the concept and the advantages of the PBPK model in the study of pharmacokinetics of natural medicine. Finally, the pharmacokinetic studies of natural medicine using the PBPK models are summed up, followed by discussions on the applications of PBPK modeling to the enzyme-mediated pharmacokinetic changes, special populations, new drug research and development, and new indication adding for natural medicine. This paper aims to provide a novel strategy for the preclinical research and clinical use of natural medicine.
Topics: Pharmaceutical Preparations; Medicine; Models, Biological; Pharmacokinetics
PubMed: 36557804
DOI: 10.3390/molecules27248670 -
Toxicology and Applied Pharmacology Apr 2021By extending our Paraquat (PQ) work to include primates we have implemented a modelling and simulation strategy that has enabled PQ pharmacokinetic data to be integrated...
By extending our Paraquat (PQ) work to include primates we have implemented a modelling and simulation strategy that has enabled PQ pharmacokinetic data to be integrated into a single physiologically based pharmacokinetic (PBPK) model that enables more confident extrapolation to humans. Because available data suggested there might be differences in PQ kinetics between primates and non-primates, a radiolabelled study was conducted to characterize pharmacokinetics and excretion in Cynomolgus monkeys. Following single intravenous doses of 0.01 or 0.1 mg paraquat dichloride/kg bw, plasma PQ concentration-time profiles were dose-proportional. Excretion up to 48 h (predominantly urinary) was 82.9%, with ca. 10% remaining unexcreted. In vitro blood binding was similar across Cynomolgus monkeys, humans and rat. Our PBPK model for the rat, mouse and dog, employing a single set of PQ-specific parameters, was scaled to Cynomolgus monkeys and well represented the measured plasma concentration-time profiles over 14 days. Addition of a cartilage compartment to the model better captured the percent remaining in the monkeys at 48 h, whilst having negligible effect on model predictions for the other species. The PBPK model performed well for all four species, demonstrating there is little difference in PQ kinetics between non-primates and primates enabling a more confident extrapolation to humans. Scaling of the PBPK model to humans, with addition of a human-specific dermal submodel based on in vitro human dermal absorption data, provides a valuable tool that could be employed in defining internal dosimetry to complement human health risk assessments.
Topics: Animals; Computer Simulation; Herbicides; Humans; Infusions, Intravenous; Intestinal Elimination; Macaca fascicularis; Models, Biological; Paraquat; Rats; Renal Elimination; Risk Assessment; Skin Absorption; Species Specificity; Tissue Distribution; Toxicokinetics
PubMed: 33631232
DOI: 10.1016/j.taap.2021.115463 -
Nutrients Nov 2022Succinic acid is widely used as a food additive, and its effects on sepsis, cancer, ataxia, and obesity were recently reported. Dietary drug exposure studies have been...
Succinic acid is widely used as a food additive, and its effects on sepsis, cancer, ataxia, and obesity were recently reported. Dietary drug exposure studies have been conducted to evaluate the in vivo efficacy of succinic acid, but limited pharmacokinetic information is available. Therefore, this study evaluated the pharmacokinetic profiles and tissue distribution of succinic acid following a single intravenous or oral dose. A surrogate analyte, succinic acid-C (CSA), was administrated to distinguish endogenous and exogenous succinic acid. The concentration of CSA was determined by a validated analytical method using mass spectrometry. After a 10 mg/kg intravenous dose, non-compartmental pharmacokinetic analysis in plasma illustrated that the clearance, volume of distribution, and terminal half-life of CSA were 4574.5 mL/h/kg, 520.8 mL/kg, and 0.56 h, respectively. Oral CSA was absorbed and distributed quickly (bioavailability, 1.5%) at a dose of 100 mg/kg. In addition, CSA exposure was the highest in the liver, followed by brown adipose tissue, white adipose tissue, and the kidneys. This is the first report on the pharmacokinetics of succinic acid after a single dose in mice, and these results could provide a foundation for selecting dosing regimens for efficacy studies.
Topics: Mice; Animals; Tissue Distribution; Succinic Acid; Administration, Oral; Biological Availability; Administration, Intravenous
PubMed: 36432443
DOI: 10.3390/nu14224757 -
Journal of Veterinary Pharmacology and... Jul 2022The study was designed to determine the pharmacokinetic profile and bioavailability of a novel pregabalin 50 mg/ml oral solution formulation (Bonqat , Orion...
The study was designed to determine the pharmacokinetic profile and bioavailability of a novel pregabalin 50 mg/ml oral solution formulation (Bonqat , Orion Corporation Orion Pharma) in 6 healthy laboratory cats. The cats received pregabalin as single oral doses of 2.5, 5, and 7.5 mg/kg, dose 5 mg/kg on two consecutive days, and a single intravenous dose of 2.5 mg/kg. The washout period between each administration was four weeks. The cats were monitored for clinical signs and level of sedation, and blood samples were taken before pregabalin dosing and at pre-defined time points up to 168 h after dosing. Plasma concentrations of pregabalin were determined using a validated liquid chromatography-tandem mass spectrometry method. The mean maximum plasma concentration of 10.1 μg/ml was reached between 0.5 and 1 h after oral administration of the clinical dose 5 mg/kg. The mean half-life after oral administration of dose 5 mg/kg was 14.7 h and the mean systemic bioavailability was 94%. Pregabalin showed linear pharmacokinetics from 2.5 to 7.5 mg/kg. Exposures after a single dose and re-dosing of 5 mg/kg at 24 h were comparable. Pregabalin was well tolerated with mild sedation and mildly uncoordinated movements observed in few cats at dose 7.5 mg/kg. As a conclusion, study results show rapid absorption, linear pharmacokinetics, and high oral bioavailability of pregabalin without safety concerns after administration of oral solution in cats.
Topics: Administration, Intravenous; Administration, Oral; Animals; Area Under Curve; Biological Availability; Cats; Half-Life; Pregabalin
PubMed: 35466408
DOI: 10.1111/jvp.13061 -
Expert Review of Clinical Immunology May 2022Tocilizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody against the interleukin-6 receptor (IL-6 R). MSB11456 is a proposed tocilizumab biosimilar. (Randomized Controlled Trial)
Randomized Controlled Trial
Pharmacokinetics and pharmacodynamics of a proposed tocilizumab biosimilar MSB11456 versus both the US-licensed and EU-approved products: a randomized, double-blind trial.
BACKGROUND
Tocilizumab is a recombinant humanized monoclonal immunoglobulin G1 antibody against the interleukin-6 receptor (IL-6 R). MSB11456 is a proposed tocilizumab biosimilar.
OBJECTIVES
To assess the pharmacokinetic and pharmacodynamic similarity of MSB11456 to both US-licensed and EU-approved tocilizumab.
METHODS
Healthy adult volunteers (N = 685) received a single 162 mg subcutaneous injection of MSB11456, US-licensed tocilizumab, or EU-approved tocilizumab in this randomized, double-blind, parallel-group study. Blood samples were taken pre-dose and for up to 48 days post-dose. Primary endpoint pharmacokinetic parameters were analyzed using analysis of covariance. Secondary pharmacodynamic measures included serum-soluble IL-6 R and serum C-reactive protein. Safety data were analyzed descriptively.
RESULTS
Pharmacokinetic equivalence (with all corresponding 90% confidence intervals for the geometric least squares mean ratios within the predefined 80.00% to 125.00% equivalence margin) was demonstrated between MSB11456 and both US-licensed and EU-approved tocilizumab, as well as between the reference products. Pharmacodynamic analyses demonstrated similarity of MSB11456 and both US-licensed and EU-approved tocilizumab, as well as between the reference products. Safety, tolerability, and immunogenicity were comparable between treatments.
CONCLUSION
Pharmacokinetic and pharmacodynamic similarity of MSB11456, US-licensed tocilizumab, and EU-approved tocilizumab were demonstrated, and the three products had comparable immunogenicity and safety, supporting MSB11456 as a biosimilar to tocilizumab.
Topics: Adult; Antibodies, Monoclonal, Humanized; Area Under Curve; Biosimilar Pharmaceuticals; Double-Blind Method; Healthy Volunteers; Humans; Interleukin-6; Therapeutic Equivalency
PubMed: 35354411
DOI: 10.1080/1744666X.2022.2060204