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Clinical Pharmacology in Drug... May 2023Voriconazole is a first-line medicine for treating invasive aspergillosis. We aimed to evaluate the bioequivalence (BE) of voriconazole injection in Chinese healthy...
Voriconazole is a first-line medicine for treating invasive aspergillosis. We aimed to evaluate the bioequivalence (BE) of voriconazole injection in Chinese healthy volunteers (HVs). In this single-center, randomized, single-dose, 2-cycle, fasting-dose BE study, HVs (n = 24) were 1:1 divided into 2 groups (test [T]-reference [R] and R-T) and received 6 mg/kg of voriconazole intravenously with a 7-day washout. The plasma was collected for up to 72 hours at the time point after dosing on day 1/day 8. The plasma concentration of voriconazole was measured by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were ascertained on the basis of a noncompartmental model. In the BE study, the geometric mean ratios of the maximum concentration, area under the concentration-time curve from time 0 to the last measurable plasma concentration, and area under the concentration-time curve from time 0 to infinity were 101.1%, 105.6%, and 105.5%, respectively, and the 90%CI fell within 80%-125%. Adverse events were observed in 26.1% of subjects in the T formulation stage and 17.4% in the R formulation stage. Under the BE study, voriconazole values from T and R formulations were bioequivalent.
Topics: Humans; Area Under Curve; Biological Availability; East Asian People; Therapeutic Equivalency; Voriconazole
PubMed: 36785899
DOI: 10.1002/cpdd.1218 -
Advanced Drug Delivery Reviews Sep 2007The concept of correlating pharmacokinetic parameters with body weight (termed as pharmacokinetic interspecies scaling) from different animal species has become a useful... (Review)
Review
The concept of correlating pharmacokinetic parameters with body weight (termed as pharmacokinetic interspecies scaling) from different animal species has become a useful tool in drug development. Interspecies scaling is based on the power function, where the body weight of the species is plotted against the pharmacokinetic parameter of interest. Clearance, volume of distribution, and elimination half-life are the three most frequently extrapolated pharmacokinetic parameters. The predicted pharmacokinetic parameter clearance can be used for estimating a first-in-human dose. Over the years, many approaches have been suggested to improve the prediction of aforementioned pharmacokinetic parameters in humans from animal data. A literature review indicates that there are different degrees of success with different methods for different drugs. Interspecies scaling is also a very useful tool in veterinary medicine. The knowledge of pharmacokinetics in veterinary medicine is important for dosage selection, particularly in the treatment of large animals such as horses, camels, elephants, or other large zoo animals. Despite the potential for extrapolation error, the reality is that interspecies scaling is needed across many veterinary practice situations, and therefore will be used. For this reason, it is important to consider mechanisms for reducing the risk of extrapolation errors that can seriously affect animal safety and therapeutic response. Overall, although interspecies scaling requires continuous refinement and better understanding, the rationale approach of interspecies scaling has a lot of potential during the drug development process.
Topics: Animals; Body Weight; Chemistry, Pharmaceutical; Drug Design; Half-Life; Humans; Liver Circulation; Metabolic Clearance Rate; Pharmacokinetics; Protein Binding; Species Specificity; Veterinary Drugs
PubMed: 17826864
DOI: 10.1016/j.addr.2007.05.015 -
Scientific Reports Mar 2021Enteric reabsorption occurs when a drug is secreted into the intestinal lumen and reabsorbed into the systemic circulation. This distribution process is evidenced by...
Enteric reabsorption occurs when a drug is secreted into the intestinal lumen and reabsorbed into the systemic circulation. This distribution process is evidenced by multiple peaks in pharmacokinetic profiles. Commonly, hepatobiliary drug secretion is assumed to be the underlying mechanism (enterohepatic reabsorption, EHR), neglecting other possible mechanisms such as gastric secretion (enterogastric reabsorption, EGR). In addition, the impact of drug reabsorption on systemic clearance, volume of distribution and bioavailability has been a subject of long-standing discussions. In this work, we propose semi-mechanistic pharmacokinetic models to reflect EHR and EGR and compare their respective impact on primary pharmacokinetic parameters. A simulation-based analysis was carried out considering three drug types with the potential for reabsorption, classified according to their primary route of elimination and their hepatic extraction: (A) hepatic metabolism-low extraction; (B) hepatic metabolism-intermediate/high extraction; (C) renal excretion. Results show that an increase in EHR can significantly reduce the clearance of drugs A and B, increase bioavailability of B drugs, and increase the volume of distribution for all drugs. Conversely, EGR had negligible impact in all pharmacokinetic parameters. Findings provide background to explain and forecast the role that this process can play in pharmacokinetic variability, including drug-drug interactions and disease states.
Topics: Administration, Intravenous; Biological Availability; Computer Simulation; Intestinal Absorption; Kinetics; Models, Biological; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 33707635
DOI: 10.1038/s41598-021-85174-w -
Naunyn-Schmiedeberg's Archives of... Aug 2020A new highly specific high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method coupled to microdialysis sampling was developed and...
A new highly specific high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method coupled to microdialysis sampling was developed and validated for simultaneous determination of L-ephedrine, D-pseudoephedrine, L-methyl-ephedrine, cinnamic acid, liquiritin, amygdalin, and glycyrrhizic acid both in rat blood and brain after oral administration of Mahuang decoction in this paper. An Agilent Zorbax SB-C using the 0.1% formic acid water solution and acetonitrile as mobile phase with a gradient elution was applied to the chromatographic separation. The ion transitions were quantified in positive mode for D-pseudoephedrine, L-ephedrine, L-methylephedrine, and diphenhydramine (internal standard), while negative mode for liquiritin, glycyrrhizic acid, amygdalin, cinnamic acid, and prednisolone (internal standard). Several parameters of the method including linearity, accuracy, precision, stability, and matrix effect were within acceptable ranges. The results showed the LC-MS/MS method coupled to microdialysis sampling can be utilized for the pharmacokinetic studies of these seven ingredients in vivo. According to the pharmacokinetic results, the pharmacokinetic parameters of L-ephedrine, D-pseudoephedrine, L-methylephedrine, glycyrrhizic acid, cinnamic acid, liquiritin, and amygdalin were totally different in rat blood and brain, the bioavailability of ephedrine and amygdalin in the blood and brain was higher, while the MRT of ephedrine was the shortest. In the rat brain, the elimination rate of three Ephedra alkaloids was lower than that of the remaining four components. This research offered more basic pharmacokinetic information on the safety mechanisms of Mahuang decoction.
Topics: Administration, Oral; Animals; Biological Availability; Brain; Chromatography, High Pressure Liquid; Drugs, Chinese Herbal; Male; Metabolic Clearance Rate; Microdialysis; Rats, Sprague-Dawley; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Tissue Distribution
PubMed: 31900519
DOI: 10.1007/s00210-019-01786-0 -
Clinical Pharmacokinetics Aug 1989With the ever-increasing population of cigarette smokers, the potential for cigarette smoke to affect drug therapy both pharmacokinetically and pharmacodynamically is... (Review)
Review
With the ever-increasing population of cigarette smokers, the potential for cigarette smoke to affect drug therapy both pharmacokinetically and pharmacodynamically is significant. The overriding pharmacokinetic effect is increased drug metabolism through the induction of liver enzymes. The constituents of tobacco smoke, primarily nicotine, have their own pharmacological effects which may potentiate or antagonise the desired pharmacological effect of a particular drug, thereby affecting its efficacy. Furthermore, end-organ responsiveness may also be altered by tobacco. These latter 2 aspects constitute altered clinical pharmacodynamics. Approximately 30 drugs have been evaluated in terms of cigarette smoking. Induction of liver enzymes has been shown to increase the metabolism of imipramine, meprobamate, oestrogens, pentazocine, phenylbutazone, theophylline and warfarin. Nicotine has been shown to inhibit diuresis, alter ulcer healing, impair subcutaneous absorption, affect protein binding and stimulate catecholamine release; these effects have been evaluated in terms of therapy with frusemide (furosemide), histamine H2-antagonists, insulin, lignocaine (lidocaine) and beta-blockers, respectively. The interactions have not been correlated with clinical significance in all cases. Diminished end-organ responsiveness may account for reduced drowsiness in smokers receiving chlorpromazine and benzodiazepines, compared with non-smokers. Smoking has been associated with diminished pain tolerance, requiring increased dosages of morphine, pethidine (meperidine) and propoxyphene. Enzyme-inducers such as carbamazepine, phenytoin and phenobarbitone appear to be minimally affected by cigarette smoke, perhaps because hepatic enzymes are already maximally stimulated. Codeine, corticosteroids and nortriptyline do not appear to be affected by cigarette smoke. The bioavailability of glutethimide is higher in smokers, but this has not been associated with greater efficacy. The effect of smoking on paracetamol (acetaminophen) has been variable, depending on the extent of smoking, and does not appear to be of clinical significance.
Topics: Animals; Drug Therapy; Humans; Pharmacokinetics; Smoking
PubMed: 2673608
DOI: 10.2165/00003088-198917020-00003 -
The Veterinary Clinics of North... Sep 2013This article describes clinical examples in which pharmacokinetic parameters can be used to optimize veterinary patient care. Specific applications include extrapolating...
This article describes clinical examples in which pharmacokinetic parameters can be used to optimize veterinary patient care. Specific applications include extrapolating drug dosages, optimizing therapy with therapeutic drug monitoring, interpreting pharmacokinetic information provided by drug labels and pharmaceutical companies, and adjusting drug dosages in patients with hepatic or renal failure.
Topics: Animals; Area Under Curve; Biological Availability; Dose-Response Relationship, Drug; Half-Life; Humans; Microbial Sensitivity Tests; Off-Label Use; Veterinary Drugs; Veterinary Medicine
PubMed: 23890235
DOI: 10.1016/j.cvsm.2013.04.002 -
Journal of Ethnopharmacology Oct 2014Escin, a natural mixture of triterpene saponins, is commonly utilized for the treatment of chronic venous insufficiency, hemorrhoids, inflammation and edema. Escin Ia is...
ETHNOPHARMACOLOGICAL RELEVANCE
Escin, a natural mixture of triterpene saponins, is commonly utilized for the treatment of chronic venous insufficiency, hemorrhoids, inflammation and edema. Escin Ia is the chief active ingredient in escin and plays key role in mediating its pharmacological effects. Adequate pharmacokinetic data are essential for proper application of escin agent in clinical practice. However, pharmacokinetic properties of escin Ia are still poorly understood and this conflicts with the growing use of escin agent over the years. The goal of this study is to investigate the pharmacokinetic behavior of escin Ia in rats after low, medium and high-dose intravenous administration.
MATERIALS AND METHODS
Wistar rats were divided into 3 groups (n=6 per group) and escin Ia was administered via the caudal vein at doses of 0.5, 1.0 and 2.0 mg/kg, respectively. Subsequently, the concentrations of escin Ia and its metabolite isoescin Ia, a positional isomer of escin Ia, in rats׳ plasma were measured by an established liquid chromatography tandem mass spectrometry (LC-MS/MS) method at various time points following the administration of the drug. Main pharmacokinetic parameters were calculated by non-compartmental analysis using the TopFit 2.0 software package (Thomae GmbH, Germany).
RESULTS
After intravenous administration, the Cmax and AUC of escin Ia increased in a dose-proportional manner at the dose of 0.5 mg/kg and 1.0 mg/kg, while increased in a more than dose-proportional manner at the doses of 1.0 mg/kg and 2.0 mg/kg. The t₁/₂ was significantly longer with increased intravenous doses, while other parameters such as CL and Vd also exhibit disagreement among three doses. Taken together, our data showed dose-dependent pharmacokinetic profile of escin Ia in rats after intravenous administration at the doses of 0.5-2.0 mg/kg. After intravenous administration, escin Ia was rapidly and extensively converted to isoescin Ia.
CONCLUSIONS
The results suggested dose-dependent pharmacokinetics of escin Ia at the doses of 0.5-2.0 mg/kg after intravenous administration. Escin Ia is isomerized to isoescin Ia rapidly and extensively regardless of the doses.
Topics: Animals; Area Under Curve; Chromatography, Liquid; Dose-Response Relationship, Drug; Escin; Female; Half-Life; Male; Metabolic Clearance Rate; Rats; Rats, Wistar; Tandem Mass Spectrometry
PubMed: 25193683
DOI: 10.1016/j.jep.2014.08.032 -
Seminars in Perinatology Apr 2020The effects of the many biochemical and physiologic changes of pregnancy on the dose-response relationship of drugs administered to pregnant women are poorly understood.... (Review)
Review
The effects of the many biochemical and physiologic changes of pregnancy on the dose-response relationship of drugs administered to pregnant women are poorly understood. The dose-response relationship is affected by pharmacokinetics, or what the body does to a drug, and pharmacodynamics, or what a drug does to the body. Insights into the potential effects of the changes of pregnancy on one aspect of the dose-response relationship of a drug can be obtained by studying the pharmacokinetics of the drug in the various stages of pregnancy and the postpartum period. There are several available approaches to studying pharmacokinetic changes in pregnancy. Single trough screening studies can provide qualitative estimates of elimination clearance, which with the dosing rate determines the steady-state drug concentration, throughout pregnancy and into the postpartum period. Population pharmacokinetic studies such as two stage pharmacokinetic studies and studies using a nonlinear mixed effects pharmacokinetic modeling approach can characterize pharmacokinetic changes more rigorously.
Topics: Absorption, Physiological; Dose-Response Relationship, Drug; Drug Elimination Routes; Female; Humans; Pharmaceutical Preparations; Pharmacokinetics; Pharmacological Phenomena; Pregnancy; Tissue Distribution
PubMed: 32093881
DOI: 10.1016/j.semperi.2020.151227 -
International Journal of Clinical... Mar 2024Tofacitinib is an oral Janus kinase (JAK) inhibitor marketed as an immunomodulator that can effectively treat rheumatoid arthritis. This study aimed to compare the... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Tofacitinib is an oral Janus kinase (JAK) inhibitor marketed as an immunomodulator that can effectively treat rheumatoid arthritis. This study aimed to compare the pharmacokinetics and evaluate the bioequivalence of tofacitinib free base (CKD-374) with those of tofacitinib citrate (Xeljanz).
MATERIALS AND METHODS
A randomized, open-label, single-dose, 2-sequence, 2-period crossover study was conducted in healthy Korean male subjects. A total of 36 subjects were randomized into two sequence groups. At each period, subjects were administered the test formulation (tofacitinib free base, 5 mg) or the reference formulation (tofacitinib citrate, 8.078 mg; as tofacitinib, 5 mg). The plasma samples were collected up to 12 hours post dose and analyzed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration (C) and area under the plasma concentration vs. time curve from dosing to the last measurable concentration (AUC), were determined by non-compartmental analysis. The 90% confidence intervals (CIs) of the geometric mean ratios for C and AUC were calculated to evaluate pharmacokinetic equivalence.
RESULTS
The 90% CIs of the geometric mean ratios of C and AUC for tofacitinib free base to tofacitinib citrate were 0.9144 - 1.1230 and 1.0245 - 1.0932, respectively. All reported adverse events were of mild intensity, and there were no serious adverse events.
CONCLUSION
In healthy Korean male adult subjects, the pharmacokinetic parameters of tofacitinib free base and tofacitinib citrate were evaluated and met the pharmacokinetic bioequivalent criteria. Both formulations were safe and well-tolerated.
Topics: Adult; Humans; Male; Therapeutic Equivalency; Biological Availability; Cross-Over Studies; Area Under Curve; Chemistry, Pharmaceutical; Republic of Korea; Tablets; Healthy Volunteers; Piperidines; Pyrimidines
PubMed: 38174885
DOI: 10.5414/CP204480 -
The American Journal of Medicine Mar 1993The pharmacokinetic properties of fleroxacin in relation to other quinolones are presented. Fleroxacin, like all quinolones, is well absorbed, reaching peak... (Review)
Review
The pharmacokinetic properties of fleroxacin in relation to other quinolones are presented. Fleroxacin, like all quinolones, is well absorbed, reaching peak concentrations within 2 hours. Interactions with Ca2+ and Al3+ are minimal and possibly of little clinical importance. The drug is eliminated via filtration in the kidney. It is therefore sensitive to changes in renal function. Accumulation of drug in the body is minimal, and change from intravenous to oral dosing results in nearly identical serum concentrations. Aside from the modest effect of metals on its absorption, fleroxacin does not interact/compete with substances oxidized in the liver, such as theophylline, and drug interactions are minimal. Its long serum half-life (8-12 hours) allows once-a-day dosing. This feature, along with its modest drug interactions, makes fleroxacin an attractive quinolone, at least with respect to its pharmacokinetics.
Topics: Absorption; Anti-Infective Agents; Biological Availability; Fleroxacin; Half-Life; Humans
PubMed: 8452184
DOI: No ID Found