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Antimicrobial Agents and Chemotherapy Sep 2018Eravacycline (7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline or TP-434) is a novel, fully synthetic broad-spectrum fluorocycline with potent activity...
Eravacycline (7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline or TP-434) is a novel, fully synthetic broad-spectrum fluorocycline with potent activity against Gram-positive bacteria, anaerobes, and multidrug-resistant We characterized the plasma pharmacokinetics of eravacycline and conducted a comprehensive analysis of the eravacycline tissue distribution in rabbits after multiple-day dosing. For single-dose pharmacokinetic analysis, eravacycline was administered to New Zealand White (NZW) rabbits at 1, 2, 4, 8, and 10 mg/kg of body weight intravenously (i.v.) once a day (QD) ( = 20). For multidose pharmacokinetic analysis, eravacycline was administered at 0.5, 1, 2, and 4 mg/kg i.v. QD ( = 20) for 6 days. Eravacycline concentrations in plasma and tissues were analyzed by a liquid chromatography-tandem mass spectrometry assay. Mean areas under the concentration-time curves (AUCs) following a single eravacycline dose ranged from 5.39 μg · h/ml to 183.53 μg · h/ml. Within the multidose study, mean AUCs ranged from 2.53 μg · h/ml to 29.89 μg · h/ml. AUCs correlated linearly within the dosage range ( = 0.97; = 0.0001). In the cardiopulmonary system, the concentrations were the highest in the lung, followed by the heart > pulmonary alveolar macrophages > bronchoalveolar lavage fluid; for the intra-abdominal system, the concentrations were the highest in bile, followed by the liver > gallbladder > spleen > pancreas; for the renal system, the concentrations were the highest in urine, followed by those in the renal cortex > renal medulla; for the musculoskeletal tissues, the concentrations were the highest in muscle psoas, followed by those in the bone marrow > adipose tissue; for the central nervous system, the concentrations were the highest in cerebrum, followed by those in the aqueous humor > cerebrospinal fluid > choroid > vitreous. The prostate and seminal vesicles demonstrated relatively high mean concentrations. The plasma pharmacokinetic profile of 0.5 to 4 mg/kg in NZW rabbits yields an exposure comparable to that in humans (1 or 2 mg/kg every 12 h) and demonstrates target tissue concentrations in most sites.
Topics: Animals; Anti-Bacterial Agents; Area Under Curve; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae; Female; Gram-Positive Bacteria; Male; Microbial Sensitivity Tests; Rabbits; Tetracyclines; Tissue Distribution
PubMed: 29941646
DOI: 10.1128/AAC.00275-18 -
International Journal of Environmental... May 2011Simultaneous or sequential exposure to multiple chemicals may cause interactions in the pharmacokinetics (PK) and/or pharmacodynamics (PD) of the individual chemicals.... (Review)
Review
Simultaneous or sequential exposure to multiple chemicals may cause interactions in the pharmacokinetics (PK) and/or pharmacodynamics (PD) of the individual chemicals. Such interactions can cause modification of the internal or target dose/response of one chemical in the mixture by other chemical(s), resulting in a change in the toxicity from that predicted from the summation of the effects of the single chemicals using dose additivity. In such cases, conducting quantitative cumulative risk assessment for chemicals present as a mixture is difficult. The uncertainties that arise from PK interactions can be addressed by developing physiologically based pharmacokinetic (PBPK) models to describe the disposition of chemical mixtures. Further, PK models can be developed to describe mechanisms of action and tissue responses. In this article, PBPK/PD modeling efforts conducted to investigate chemical interactions at the PK and PD levels are reviewed to demonstrate the use of this predictive modeling framework in assessing health risks associated with exposures to complex chemical mixtures.
Topics: Animals; Drug Interactions; Humans; Models, Chemical; Pharmacokinetics; Risk Assessment
PubMed: 21655141
DOI: 10.3390/ijerph8051613 -
Clinical Therapeutics Jun 2021Celecoxib-tramadol co-crystal (CTC) is a first-in-class co-crystal of celecoxib and racemic tramadol. This Phase 1 bioavailability study compared single-dose... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Celecoxib-tramadol co-crystal (CTC) is a first-in-class co-crystal of celecoxib and racemic tramadol. This Phase 1 bioavailability study compared single-dose pharmacokinetic (PK) parameters of CTC with those of the individual reference products from the United States, immediate-release celecoxib and tramadol, taken alone and simultaneously to determine their systemic exposure.
METHODS
This was a single-center, randomized, single-dose, open-label, 4-period, 4-sequence, crossover study conducted in healthy subjects between October and December 2016. Study treatments included 200-mg CTC (equivalent to 112-mg celecoxib and 88-mg tramadol; Treatment-1); 100-mg tramadol (Treatment-2); 100-mg celecoxib (Treatment-3); and 100-mg celecoxib plus 100-mg tramadol (Treatment-4). The PK parameters of interest were C, AUC, and AUC which were also calculated normalized to the dose. T was only considered as supportive. The statistical analysis was based on a parametric analysis of variance model of the PK parameters; the two-sided 90% CI of the ratio of geometric mean values for the C, AUC, and AUC was based on ln-transformed data, and T was rank-transformed.
FINDINGS
Thirty-six subjects aged 18 to 55 years (21 male subjects, 15 female subjects; mean age, 35 years) participated in the study. Celecoxib from CTC presented a lower C, reduced AUCs, and a faster T. The interference in celecoxib absorption when celecoxib and tramadol are administered together was minimized with the CTC. For Treatment-1, -3, and -4, celecoxib PK parameters were 259, 318, and 165 ng/mL (C), respectively; 1930, 2348, and 1929 ng • h/mL (AUC); and 1.5, 3.0, and 2.5 hours (T). Tramadol and its active metabolite O-desmethyl tramadol from CTC presented lower C and AUCs as well as a longer T. Tramadol/O-desmethyl tramadol PK parameters for Treatment-1, -2, and -4 were 214/55, 305/78, and 312/78 ng/mL for C; 2507/846, 2709/965, and 2888/1010 ng • h/mL for AUC; and 3.0/4.0, 2.0/2.5, and 1.9/2.5 hours for T Reported adverse events (none unexpected) occurred more frequently with Treatment-2 and Treatment-4.
IMPLICATIONS
The aim of this study was to compare the PK profile of the US-marketed tramadol and celecoxib products with CTC to determine their systemic exposure and to validate the dosing regimen for a subsequent pivotal factorial Phase 3study. PK parameters of each active component in CTC were favorably modified by co-crystallization and did not result in higher systemic exposure compared with US-marketed celecoxib, tramadol, and their concomitant administration. © 2021 Elsevier HS Journals, Inc.
Topics: Adult; Area Under Curve; Biological Availability; Celecoxib; Cross-Over Studies; Female; Humans; Male; Therapeutic Equivalency; Tramadol
PubMed: 34167827
DOI: 10.1016/j.clinthera.2021.04.002 -
Clinical Pharmacokinetics Nov 2022The dispersible tablet formulation (DTF) of pretomanid has been developed to facilitate future use in children. This work aimed to assess the pharmacokinetics (PK) and... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND AND INTRODUCTION
The dispersible tablet formulation (DTF) of pretomanid has been developed to facilitate future use in children. This work aimed to assess the pharmacokinetics (PK) and relative bioavailability of the DTF compared to the marketed formulation (MF) and the potential influence of dose.
METHODS
Pretomanid DTF was investigated in a single-dose, randomized, four-period, cross-over study, with 7 days of washout between doses. Forty-eight healthy volunteers were enrolled and randomized into one of two panels to receive doses either in the fasted state or after a high-fat meal. Each volunteer received doses of 10, 50, and 200 mg DTF, and 200 mg MF pretomanid. Blood samples for pharmacokinetic assessment were drawn following a rich schedule up to 96 h after each single dose. The study data from the panel receiving the high-fat meal were analyzed using a nonlinear mixed-effects modeling approach, and all data were characterized with noncompartmental methods.
RESULTS
A one-compartment model with first-order elimination and absorption through a transit compartment captured the mean and variability of the observed pretomanid concentrations with acceptable precision. No significant difference in bioavailability was found between formulations. The mean absorption time for the DTF was typically 137% (86-171%) of that for the MF. The bioavailability was found to be dose dependent with a small positive and larger negative correlation under fed and fasted conditions, respectively.
CONCLUSION
Using data from a relative bioavailability study in healthy adult volunteers, a mathematical model has been developed to inform dose selection for the investigation of pretomanid in children using the new dispersible tablet formulation. Under fed conditions and at the currently marketed adult dose of 200 mg, the formulation type was found to influence the absorption rate, but not the bioavailability. The bioavailability of the DTF was slightly positively correlated with doses when administered with food.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04309656, first posted on 16 March 2020.
Topics: Adult; Child; Humans; Cross-Over Studies; Area Under Curve; Tablets; Biological Availability; Fasting; Administration, Oral; Therapeutic Equivalency
PubMed: 36180816
DOI: 10.1007/s40262-022-01163-w -
Antimicrobial Agents and Chemotherapy Oct 2020The purpose of this study was to assess the safety, tolerability, pharmacokinetics (PK), and biodistribution of novel oral amphotericin B (AmpB) formulations following...
Assessing the Safety, Tolerability, Pharmacokinetics, and Biodistribution of Novel Oral Formulations of Amphotericin B following Single- and Multiple-Dose Administration to Beagle Dogs.
The purpose of this study was to assess the safety, tolerability, pharmacokinetics (PK), and biodistribution of novel oral amphotericin B (AmpB) formulations following single- and multiple-oral-dose administration to healthy beagle dogs. The liquid formulation of AmpB was administered to three male dogs, and the capsule formulations of AmpB were administered to each of two groups of six male dogs. Blood was collected for pharmacokinetic evaluation on days 1, 2, and 3 (up to 72 h postdosing). Dogs receiving the capsule formulations further received a single oral dose of 100 mg once daily for three more days, and on the 4th day, blood samples were taken at 24 h postdosing and the dogs were humanely sacrificed with the removal of organs, from which tissue samples were taken for analysis of the AmpB content. Multiple-dose studies were completed for 7 or 14 days with daily doses of up to 1,000 mg/day with the capsule formulations. All oral formulations of AmpB following both single- and multiple-dose administration were well tolerated in the dogs, and there were no relevant adverse signs observed, such as changes in hematologic, coagulation, or biochemistry parameters; loss of weight; changes in food or water intake; or signs of gastrointestinal distress. The oral absorption of AmpB from the liquid formulation and the capsule formulations were similar, with no significant differences. The tissue distributions of AmpB were similar following repeated doses of the two capsule formulations to dogs. Following 14 days of treatment with the iCo-010 liquid formulation and the iCo-019 and iCo-022 capsule formulations, the range of values of the maximum observed plasma concentration () was 53.2 to 62.3, 24.9 to 66.4, and 36.7 to 85.2 ng/ml, respectively; the range of values of the time to was 4 to 12, 4 to 24, and 2 to 24 h, respectively; and the range of values of the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration was 2,635 to 3,071, 1,053 to 2,517, and 1,443 to 3,713 ng · h/ml, respectively. We have developed a safe novel oral AmpB formulation suitable for future efficacy studies.
Topics: Administration, Oral; Amphotericin B; Animals; Area Under Curve; Dogs; Male; Tissue Distribution
PubMed: 32816728
DOI: 10.1128/AAC.01111-20 -
Gut Microbes May 2020Increasing evidence suggests a role of the gut microbiota in patients' response to medicinal drugs. In our recent study, we combined genomics of human gut commensals and...
Increasing evidence suggests a role of the gut microbiota in patients' response to medicinal drugs. In our recent study, we combined genomics of human gut commensals and gnotobiotic animal experiments to quantify microbiota and host contributions to drug metabolism. Informed by experimental data, we built a physiology-based pharmacokinetic model of drug metabolism that includes intestinal compartments with microbiome drug-metabolizing activity. This model successfully predicted serum levels of metabolites of three different drugs, quantified microbial contribution to systemic drug metabolite exposure, and simulated the effect of different parameters on host and microbiota drug metabolism. In this addendum, we expand these simulations to assess the effect of microbiota on the systemic drug and metabolite levels under conditions of altered host physiology, microbiota drug-metabolizing activity or physico-chemical properties of drugs. This work illustrates how and under which circumstances the gut microbiome may influence drug pharmacokinetics, and discusses broader implications of expanded pharmacokinetic models.
Topics: Animals; Enterohepatic Circulation; Gastrointestinal Microbiome; Gastrointestinal Tract; Germ-Free Life; Humans; Intestinal Absorption; Mice; Models, Animal; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 31564204
DOI: 10.1080/19490976.2019.1667724 -
Journal of Veterinary Pharmacology and... Nov 2021The pharmacokinetics of enflicoxib were evaluated in both a bioavailability study and a multi-dose safety study in Beagle dogs. When administered at 8 mg/kg, the oral...
The pharmacokinetics of enflicoxib were evaluated in both a bioavailability study and a multi-dose safety study in Beagle dogs. When administered at 8 mg/kg, the oral bioavailability (F) of enflicoxib was 44.1% in fasted dogs, but F increased to 63.4% under post prandial conditions. Enflicoxib is rapidly metabolised. After the first 48 h, the plasma levels of its pyrazol metabolite were much higher and persistent than those of the parent compound. Following intravenous administration, the total body plasma clearance of enflicoxib was of 140 ml/h/kg and the volume of distribution based on the terminal phase was 4 L/kg. Plasma protein binding for both compounds was approximately 99%. The blood to plasma ratio for the pyrazol metabolite showed saturable kinetics with higher blood cell affinity at lower total blood concentrations which ranged from 2.49 to 0.95 for concentrations from 1 to 15 µg/ml. Enflicoxib and its pyrazol metabolite exhibited dose-proportional pharmacokinetics for single oral doses of 8-40 mg⁄kg and for multiple oral doses of 4-20 mg⁄kg. After 7 months of repeated weekly administrations, pre-dose plasma concentrations (C ) remained constant throughout the study, with no trend to any significant over-accumulation. The mean terminal elimination half-life (t ) was 20 h for enflicoxib and 17 days for the pyrazol metabolite. The pharmacokinetic profile of enflicoxib and its pyrazol metabolite in dogs supports the proposed dosing regimen in which doses are separated by 1 week.
Topics: Administration, Intravenous; Animals; Area Under Curve; Biological Availability; Dogs; Half-Life; Protein Binding
PubMed: 34160092
DOI: 10.1111/jvp.12995 -
Critical Care Clinics Apr 2008For appropriate antibiotic therapy and selection, the clinician must be familiar with pharmacodynamic concepts that integrate an antibiotic's microbiologic activity,... (Review)
Review
For appropriate antibiotic therapy and selection, the clinician must be familiar with pharmacodynamic concepts that integrate an antibiotic's microbiologic activity, pharmacokinetic properties, and mode of bacterial killing. Much of the traditional dosing methods that continue to this day are based more on habit rather than science. This article addresses these issues and explains the basis for the new scientific ways to administer antibiotics to optimize patient outcomes.
Topics: Anti-Bacterial Agents; Area Under Curve; Bacterial Infections; Biological Availability; Critical Care; Half-Life; Humans; Tissue Distribution
PubMed: 18361949
DOI: 10.1016/j.ccc.2007.12.008 -
Clinical Pharmacokinetics Sep 2020There appears to be a mismatch between the assumed therapeutic equivalence of generic drugs, their interchangeability, and reported clinical discomfort following generic...
There appears to be a mismatch between the assumed therapeutic equivalence of generic drugs, their interchangeability, and reported clinical discomfort following generic drug use and drug switches. In this article, we describe why we are of the opinion that the current regulatory approach to the evaluation of generic drugs based on average bioequivalence is sufficient to expect therapeutic equivalence in the clinical setting. This has often been debated, specifically as adverse drug reactions related to generic drug switches are regularly reported. We agree that clinical discomfort during a bioequivalent drug switch may indeed be caused by different exposures to the active substance. However, this difference in exposure is not a result of the characteristics or quality of generic drugs; it is caused by the pharmacokinetic within-subject variability of the active substance, i.e., the variability on the bioavailability of the active substance, when comparing two occasions of administration of the same drug product, to the same patient. Therefore, reported clinical discomfort following generic drug use and drug switches does not warrant a change in the regulatory approach to the evaluation of the bioequivalence of generic drugs. Switching from a brand-name drug to currently approved generic drugs, or between different generic drugs, will in principle result in comparable exposure, within boundaries determined by the within-subject variability of the pharmacokinetics of the active substance involved.
Topics: Area Under Curve; Biological Availability; Drug Substitution; Drugs, Generic; Government Regulation; Humans; Therapeutic Equivalency
PubMed: 32557345
DOI: 10.1007/s40262-020-00909-8 -
Journal of Veterinary Pharmacology and... Jan 2023Telmisartan is an angiotensin II receptor blocker that has great potential to improve the treatment of hypertension, proteinuria, and cardiovascular disease in dogs. A...
Telmisartan is an angiotensin II receptor blocker that has great potential to improve the treatment of hypertension, proteinuria, and cardiovascular disease in dogs. A feline-approved telmisartan oral solution (TOS) is available, but this formulation has not been evaluated in dogs. The aims of this study were to establish the pharmacokinetics of telmisartan administered as TOS and determine the effect of feeding on drug absorption in dogs. In a cross-over design, seven healthy dogs received 1 mg/kg telmisartan orally as TOS with or without food and underwent serial measurement of plasma telmisartan concentrations over 24 h. Bioequivalence of TOS administered with vs. without food was assessed by the 90% confidence interval method for maximum concentration (C ), and the observed and extrapolated areas under the curve (AUC and AUC ). The mean ratios of these parameters were 0.97 (CI 0.74-1.27), 0.92 (0.81-1.03), and 0.90 (0.82-1.00), respectively. Feeding methods were not bioequivalent based on C due to interindividual variation. These results suggest that TOS can be given to dogs with or without food but should be administered in the same way consistently. Additional pharmacokinetic and pharmacodynamic studies are warranted to confirm this recommendation and establish the therapeutic targets for telmisartan in dogs.
Topics: Animals; Dogs; Cats; Telmisartan; Therapeutic Equivalency; Cross-Over Studies; Administration, Oral; Area Under Curve
PubMed: 36355449
DOI: 10.1111/jvp.13104