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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 -
Theranostics 2012Image guided technique is playing an increasingly important role in the investigation of the biodistribution and pharmacokinetics of drugs or drug delivery systems in... (Review)
Review
Image guided technique is playing an increasingly important role in the investigation of the biodistribution and pharmacokinetics of drugs or drug delivery systems in various diseases, especially cancers. Besides anatomical imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), molecular imaging strategy including optical imaging, positron emission tomography (PET) and single-photon emission computed tomography (SPECT) will facilitate the localization and quantization of radioisotope or optical probe labeled nanoparticle delivery systems in the category of theranostics. The quantitative measurement of the bio-distribution and pharmacokinetics of theranostics in the fields of new drug/probe development, diagnosis and treatment process monitoring as well as tracking the brain-blood-barrier (BBB) breaking through by high sensitive imaging method, and the applications of the representative imaging modalities are summarized in this review.
Topics: Animals; Blood-Brain Barrier; Diagnostic Imaging; Humans; Nanoparticles; Optical Imaging; Pharmacokinetics; Tissue Distribution
PubMed: 23227121
DOI: 10.7150/thno.4652 -
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 -
British Journal of Clinical Pharmacology Apr 2021Mycophenolic acid (MPA) is widely used in paediatric kidney transplant patients and sometimes prescribed for additional indications. Population pharmacokinetic or... (Review)
Review
Mycophenolic acid (MPA) is widely used in paediatric kidney transplant patients and sometimes prescribed for additional indications. Population pharmacokinetic or pharmacodynamic modelling has been frequently used to characterize the fixed, random and covariate effects of MPA in adult patients. However, MPA population pharmacokinetic data in the paediatric population have not been systematically summarized. The objective of this narrative review was to provide an up-to-date critique of currently available paediatric MPA population pharmacokinetic models, with emphases on modelling techniques, pharmacological findings and clinical relevance. PubMed and EMBASE were searched from inception of database to May 2020, where a total of 11 studies have been identified representing kidney transplant (n = 4), liver transplant (n = 1), haematopoietic stem cell transplant (n = 1), idiopathic nephrotic syndrome (n = 2), systemic lupus erythematosus (n = 2), and a combined population consisted of kidney, liver and haematopoietic stem cell transplant patients (n = 1). Critical analyses were provided in the context of MPA absorption, distribution, metabolism, excretion and bioavailability in this paediatric database. Comparisons to adult patients were also provided. With respect to clinical utility, Bayesian estimation models (n = 6) with acceptable accuracy and precision for MPA exposure determination have also been identified and systematically evaluated. Overall, our analyses have identified unique features of MPA clinical pharmacology in the paediatric population, while recognizing several gaps that still warrant further investigations. This review can be used by pharmacologists and clinicians for improving MPA pharmacokinetic-pharmacodynamic modelling and patient care.
Topics: Adult; Area Under Curve; Bayes Theorem; Biological Availability; Child; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid
PubMed: 33118201
DOI: 10.1111/bcp.14590 -
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 -
Pharmaceutical Research Dec 2019Intraperitoneal (IP) route of drug administration in laboratory animals is a common practice in many in vivo studies of disease models. While this route is an easy to... (Review)
Review
Intraperitoneal (IP) route of drug administration in laboratory animals is a common practice in many in vivo studies of disease models. While this route is an easy to master, quick, suitable for chronic treatments and with low impact of stress on laboratory rodents, there is a common concern that it may not be an acceptable route for drug administration in experimental studies. The latter is likely due to sparsity of information regarding pharmacokinetics of pharmacological agents and the mechanisms through which agents get systemic exposure after IP administration. In this review, we summarize the main mechanisms involved in bioavailability of IP administered drugs and provide examples of pharmacokinetic profiles for small and large molecules in comparison to other routes of administration. We conclude with a notion that IP administration of drugs in experimental studies involving rodents is a justifiable route for pharmacological and proof-of-concept studies where the goal is to evaluate the effect(s) of target engagement rather than properties of a drug formulation and/or its pharmacokinetics for clinical translation.
Topics: Animals; Biological Availability; Drug Administration Routes; Drug Compounding; Humans; Injections, Intraperitoneal; Injections, Subcutaneous; Models, Animal; Particle Size; Pharmaceutical Preparations; Pharmacokinetics; Signal Transduction
PubMed: 31873819
DOI: 10.1007/s11095-019-2745-x -
Leukemia Dec 2023Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel...
Dasatinib monohydrate indicated for the treatment of chronic myeloid leukemia displays pH-dependent solubility. The aim of reported development program of novel dasatinib anhydrate containing formulation was to demonstrate improved absorption and lower pharmacokinetic variability compared to dasatinib monohydrate. In a bioavailability study comparing formulations containing 110.6 mg and 140 mg of dasatinib as anhydrate and monohydrate, respectively, both C and AUC of dasatinib were within standard 80.00-125.00% range, while the intra- and inter-subject variability for AUC after the test product was approximately 3-fold and 1.5-fold less than after the reference, respectively.In a drug-drug interaction study, omeprazole 40 mg reduced the mean AUC of dasatinib by 19%, when the test was ingested 2 h before the 5th omeprazole dose. This decrease of exposure is clinically irrelevant and substantially less than after the reference. Co-prescription analysis supports the importance of pH-dependent solubility of dasatinib, as >21% of patients were treated concomitantly with a PPI and dasatinib despite warnings against this co-medication in the SmPC.The novel dasatinib anhydrate containing formulation demonstrated improved absorption and less pharmacokinetic variability compared to dasatinib monohydrate product, which may translate into improved clinical outcomes, although this needs to be proven by an appropriate trial.
Topics: Humans; Dasatinib; Biological Availability; Omeprazole; Cross-Over Studies; Area Under Curve; Administration, Oral
PubMed: 37789147
DOI: 10.1038/s41375-023-02045-1 -
Scientific Reports Aug 2020Troxipide is widely used to treat gastric ulcer (GU) in the clinic. However, a lack of systematic metabolic, pharmacokinetic and pharmacological studies limits its...
Troxipide is widely used to treat gastric ulcer (GU) in the clinic. However, a lack of systematic metabolic, pharmacokinetic and pharmacological studies limits its clinical use. This study aimed to firstly explore the metabolic, pharmacokinetic and pharmacological mechanisms of troxipide in rats with GU compared to normal control (NC) rats. First, metabolic study was perormed by a highly selective, high-resolution mass spectrometry method. A total of 45 metabolites, including 9 phase I metabolites and 36 phase II metabolites, were identified based on MS/MS spectra. Subsequently, the pharmacokinetics results suggested that the C, K, t, AUC and AUC of troxipide were significantly increased in rats with GU compared with NC rats. The V, K and absolute bioavailability of troxipide were obviously decreased in rats with GU compared with NC rats, and its tissue distribution (in the liver, lung and kidney) was significantly different between the two groups of rats. Additionally, the pharmacodynamic results suggested that the levels of biochemical factors (IL-17, IL-6, TNF-α, IFN-γ, AP-1, MTL, GAS, and PG-II) were significantly increased, the PG-Ӏ level was obviously decreased, and the protein expression levels of HSP-90, C-Cas-3 and C-PARP-1 were markedly increased in rats with GU compared with NC rats. The above results suggested that the therapeutic mechanisms underlying the metabolic, pharmacokinetic and pharmacological properties of troxipide in vivo in rats deserve further attention based on the importance of troxipide in the treatment of GU in this study, and these mechanisms could be targets for future studies.
Topics: Administration, Oral; Animals; Biological Availability; Biomarkers; Case-Control Studies; Disease Models, Animal; Male; Metabolomics; Piperidines; Rats; Stomach Ulcer; Tandem Mass Spectrometry; Tissue Distribution; Treatment Outcome
PubMed: 32788674
DOI: 10.1038/s41598-020-70312-7 -
Advanced Drug Delivery Reviews Jun 2015Although significant progress has been made in experimental high throughput screening (HTS) of ADME (absorption, distribution, metabolism, excretion) and pharmacokinetic... (Review)
Review
Although significant progress has been made in experimental high throughput screening (HTS) of ADME (absorption, distribution, metabolism, excretion) and pharmacokinetic properties, the ADME and Toxicity (ADME-Tox) in silico modeling is still indispensable in drug discovery as it can guide us to wisely select drug candidates prior to expensive ADME screenings and clinical trials. Compared to other ADME-Tox properties, human oral bioavailability (HOBA) is particularly important but extremely difficult to predict. In this paper, the advances in human oral bioavailability modeling will be reviewed. Moreover, our deep insight on how to construct more accurate and reliable HOBA QSAR and classification models will also discussed.
Topics: Administration, Oral; Animals; Biological Availability; Computer Simulation; Humans; Models, Biological; Pharmacokinetics
PubMed: 25582307
DOI: 10.1016/j.addr.2015.01.001 -
British Journal of Clinical Pharmacology Dec 19961. A high therapeutic ratio for the inhaled route of administration is achieved by delivering doses which achieve a high local concentration in the lung and relatively... (Review)
Review
1. A high therapeutic ratio for the inhaled route of administration is achieved by delivering doses which achieve a high local concentration in the lung and relatively low levels of systemic absorption. 2. Pharmacokinetic evaluation of drug absorption from the lungs provides an accurate and reproducible method for comparing different inhaler delivery systems, as well as for evaluating bioequivalence of generic drug formulations. 3. The measurement of drug absorption from the lungs may also be applied to assess the effects of inhalation technique on drug delivery in vivo. For example with salbutamol delivered via a large volume spacer, lung bioavailability has been shown to be altered by factors such as the number of actuated puffs, inhalation-actuation delay and washing procedure. 4. Differences in drug delivery to the lungs between dry powder reservoir and pressurised metered-dose aerosol devices translate directly into commensurate differences in clinical efficacy for delivery of both inhaled beta 2-adrenoceptor agonists and corticosteroids. 5. For inhaled corticosteroids, pharmacokinetic evaluation using oral charcoal to obviate alimentary absorption may be applied to quantify the relative gut and lung components of systemic bioavailability. In tandem with information on receptor potency and affinity, drug elimination and distribution, these data may help in part to explain observed differences between different inhaled corticosteroids in terms of their systemic bioactivity profiles. 6. Studies are required to evaluate whether pharmacokinetic evaluation of lung absorption is a suitable way of quantifying delivery of nebulised aminoglycoside antibiotics, as for example in patients with cystic fibrosis. 7. Pharmacokinetic evaluation appears to have an established role in the quantification of drug delivery to the lungs and provides important information which is complimentary to other techniques such as radiolabelled deposition. The next decade of research into pharmacokinetics of established and novel drugs and delivery systems is awaited with keen interest, and will hopefully provide a greater understanding into ways of optimising the benefit-risk ratio for inhaled drugs.
Topics: Administration, Inhalation; Biological Availability; Humans; Lung; Pharmacokinetics
PubMed: 8971424
DOI: 10.1046/j.1365-2125.1996.00493.x