scholarly journals Pharmacokinetics of caffeine self-administered in overdose in a Japanese patient admitted to hospital

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Koichiro Adachi ◽  
Satoru Beppu ◽  
Mariko Terashima ◽  
Toshiaki Fukuda ◽  
Jun Tomizawa ◽  
...  
Keyword(s):  
Suicide Attempts ◽  
Medical Center ◽  
Dose Range ◽  
Lethal Dose ◽  
Plasma Concentrations ◽  
Current Case ◽  
Primary Metabolite ◽  
Physiologically Based Pharmacokinetic ◽  
Elimination Half ◽  
Caffeine Overdose

Abstract Background Caffeine (0.1 g) is used as a central nervous system stimulant and as a nontoxic phenotyping probe for cytochrome P450 1A2. However, an increasing number of suicide attempts by caffeine overdose have been recently reported. Case presentation A 25-year-old woman (body weight, 43 kg) who intentionally took an overdose of 5.9 g caffeine as a suicide attempt was emergently admitted to Kyoto Medical Center. The plasma concentrations of caffeine and its primary metabolite, N-demethylated paraxanthine, in the current case were 100 and 7.3 μg/mL, 81 and 9.9 μg/mL, 63 and 12 μg/mL, and 21 and 14 μg/mL, at 12, 20, 30, and 56 h after oral overdose, respectively. The observed apparent terminal elimination half-life of caffeine during days 1 and 2 of hospitalization was 27 h, which is several times longer than the reported normal value. This finding implied nonlinearity of caffeine pharmacokinetics over such a wide dose range, which could affect the accuracy of values simulated by a simplified physiologically based pharmacokinetic model founded on a normal dose of 100 mg. Low serum potassium levels (2.9 and 3.5 mM) on days 1 and 2 may have been caused by the caffeine overdose in the current case. Conclusions The patient underwent infusion with bicarbonate Ringer’s solution and potassium chloride and was discharged on the third day of hospitalization despite taking a potentially lethal dose of caffeine. The virtual plasma exposures of caffeine estimated using the current simplified PBPK model were higher than the measured values. The present results based on drug monitoring data and additional pharmacokinetic predictions could serve as a useful guide in cases of caffeine overdose.

scholarly journals Pharmacokinetics of loxoprofen in a self-administered overdose in a Japanese patient admitted to hospital

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Koichiro Adachi ◽  
Yuki Sugitani ◽  
Ryo Unita ◽  
Kosuke Yoshida ◽  
Satoru Beppu ◽  
...  
Keyword(s):  
Pbpk Model ◽  
Medical Center ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Case Presentation ◽  
Physiologically Based Pharmacokinetic ◽  
Elimination Half ◽  
Level Of Consciousness ◽  
Hospital Days ◽  
Propionic Acid Derivative

Abstract Background Loxoprofen is a propionic acid derivative and is the most widely prescribed non-steroidal anti-inflammatory drug in Japan. Loxoprofen is generally considered to be relatively nontoxic. Case presentation A 33-year-old man (body weight, 55 kg) who intentionally took an overdose of 100 tablets of loxoprofen (6000 mg) as a suicide attempt was emergently admitted to Kyoto Medical Center. On arrival, the patient was suffering disorders of consciousness. His plasma concentrations of loxoprofen and its reduced trans-alcohol metabolite were 52 and 24 μg/mL, 3.7 and 2.3 μg/mL, 0.81 and 0.54 μg/mL, and 0.015 and 0.011 μg/mL, respectively, at 4, 26, 50, and 121 h after the oral overdose. The observed apparent terminal elimination half-life of loxoprofen during days 1 and 2 of hospitalization was in the range 6–12 h, which is several times longer than the reported normal value. This finding implied nonlinearity of loxoprofen pharmacokinetics over the current 100-fold dose range, which could affect the accuracy of values simulated by a simplified physiologically based pharmacokinetic (PBPK) model founded on data from a normal dose of 60 mg. The reasons for the delayed eliminations from plasma of loxoprofen and its trans-alcohol metabolite in this case are uncertain, but slight renal impairment (low eGFR values) developed on the second and third hospital days and could be a causal factor. Conclusions Because the patient’s level of consciousness had gradually improved, he was discharged on the fourth day of hospitalization. The virtual plasma exposures of loxoprofen and its reduced trans-alcohol metabolite estimated using the current simplified PBPK model were lower than the measured values in the overdose case. The present results based on drug monitoring data and pharmacokinetic predictions could serve as a useful guide in cases of loxoprofen overdose.

scholarly journals Pharmacokinetics of anticoagulant edoxaban in overdose in a Japanese patient transported to hospital

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Koichiro Adachi ◽  
Jumpei Tuchiya ◽  
Satoru Beppu ◽  
Kei Nishiyama ◽  
Makiko Shimizu ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Pharmacokinetic Model ◽  
Medical Center ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Physiologically Based Pharmacokinetic Model ◽  
Current Case ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Abstract Background The anticoagulant edoxaban is used clinically at doses of 30–60 mg/day; however, we experienced a patient who had taken an overdose of edoxaban of 750 mg. We investigated the pharmacokinetics of edoxaban in this patient by using liquid chromatography–tandem spectrometry to estimate the follow-up period in emergency clinical practice with this medicine. Case presentation The patient was a 57-year-old woman (body weight, 69 kg) who had taken a single oral dose of 750 mg of edoxaban in a suicide attempt. She was emergently admitted to Kyoto Medical Center. The patient’s edoxaban plasma concentrations during ambulance transport (8 h after oral administration) were ~ 4900 ng/ml, and the concentration gradually decreased to ~ 10 ng/mL and to detectable but unmeasurable levels of ~ 1.0 ng/mL at 60 h and 100 h, respectively. The linear range of the relationship between the dose and plasma concentration was assumed to have been exceeded during the first 8 h; however, the measured elimination rate of edoxaban was similar to that visualized curves predicted by a simplified physiologically based pharmacokinetic model previously established. Conclusion Simplified physiologically based pharmacokinetic models for creating visualized curves have proven to be useful not only during drug discovery or chemical risk assessment but also in cases of medical poisoning. We used a physiologically based pharmacokinetic model previously established for edoxaban to predict the pharmacokinetics in the current case. It is hoped that the results of this study, which encompass drug monitoring data in the patient and visualized pharmacokinetic prediction, will serve as an index when setting the treatment and follow-up period in cases of drug overdose for medicines such as edoxaban in emergency clinical practice.

The clinical pharmacokinetics of zolmitriptan

Cephalalgia ◽  
1997 ◽  
Vol 17 (18_suppl) ◽  
pp. 15-20 ◽  
Author(s):  
R Dixon ◽  
A Warrander
Keyword(s):  
Indoleacetic Acid ◽  
Oral Treatment ◽  
Dose Range ◽  
Parent Compound ◽  
Plasma Concentrations ◽  
Time Profile ◽  
Multiple Dosing ◽  
Clinical Pharmacokinetics ◽  
Concentration Time ◽  
Elimination Half

Zolmitriptan (Zomig™, formerly 311C90) is a novel, oral, acute treatment for migraine. In healthy volunteers it is rapidly and extensively absorbed and has favorable oral bioavailability (approximately 40%) which is not affected by concomitant food intake. On average, 75% of its eventual Cmax is achieved within 1 h of dosing. Plasma concentrations are sustained for 4 to 6 h after dosing with single or multiple peaks in the plasma concentration-time profile, reflecting continued absorption down the gastrointestinal tract. The pharmacokinetics of zolmitriptan indicate dose proportionality over the dose range of 2.5 to 50 mg and there are no significant changes on multiple dosing. Zolmitriptan is cleared by metabolism followed by urinary excretion of the metabolites. There are three major metabolites, one of which, the N-desmethyl metabolite, is active as a 5HT1D agonist and has mean plasma concentrations approximately two thirds those of the parent compound. The other two metabolites, the N-oxide and indoleacetic acid, are inactive. The elimination half lives of zolmitriptan and its metabolites are similar, approximately 3 h. Zolmitriptan and its active metabolite are minimally protein bound in the plasma (approximately 25%). In migraine patients, plasma concentrations of zolmitriptan and its metabolites are lower during a migraine attack than outside an attack. In summary, the pharmacokinetics of zolmitriptan are simple, predictable and appropriate to an acute oral treatment for migraine.

The Measurement of Heparin and Other Therapeutic Sufphated Polysaccharides in Plasma, Serum and Urine

1985 ◽  
Vol 54 (03) ◽  
pp. 630-634 ◽  
Author(s):  
J Dawes ◽  
C V Prowse ◽  
D D Pepper
Keyword(s):  
Biological Fluids ◽  
Anticoagulant Activity ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Heparin Therapy ◽  
Competitive Binding Assay ◽  
First Order Kinetics ◽  
Activity Measurements ◽  
Heparin Activity ◽  
Dose Dependent

SummaryThe competitive binding assay described will specifically and accurately measure concentrations of administered heparin in biological fluids with a sensitivity of 60 ng ml-1. Neither endogenous glycosaminoglycans, nor plasma proteins such as ATIII and PF4 interfere in the assay. Semi-synthetic highly sulphated heparinoids and LMW heparin can also be measured. Using this assay heparin clearance followed simple first-order kinetics over the dose range 100-5,000 units, but the half-life was strongly dose-dependent. There was good correlation with heparin activity measurements by APTT and anti-Xa clotting assays. Plasma concentrations were measurable for at least 5 h following subcutaneous injection of 10,000 units of heparin. Excretion in the urine could be followed after all but the lowest intravenous dose. This assay, used in conjunction with measurements of heparin anticoagulant activity, will be valuable in the elucidation of mechanisms of action of heparin and the heparinoids, and in the assessment and management of problems related to heparin therapy.

scholarly journals Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug–Drug Interaction with Rifampin and Liver Impairment

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 778
Author(s):  
Bettina Gerner ◽  
Oliver Scherf-Clavel
Keyword(s):  
Hepatic Impairment ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Enterohepatic Recirculation ◽  
Maximum Plasma ◽  
Good Precision ◽  
Physiologically Based Pharmacokinetic ◽  
Starting Point ◽  
Physiologically Based

Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug–drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (Cmax) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9–1.2 for AUC and 0.8–1.1 for Cmax). DDI with Rifampin led to a reduction in predicted AUC by 77%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations.

scholarly journals Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Interactions

2020 ◽  
Vol 37 (12) ◽  
Author(s):  
Hannah Britz ◽  
Nina Hanke ◽  
Mitchell E. Taub ◽  
Ting Wang ◽  
Bhagwat Prasad ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Organic Anion ◽  
Plasma Concentrations ◽  
Whole Body ◽  
Time Profiles ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Anion Transporter ◽  
Physiologically Based

Abstract Purpose To provide whole-body physiologically based pharmacokinetic (PBPK) models of the potent clinical organic anion transporter (OAT) inhibitor probenecid and the clinical OAT victim drug furosemide for their application in transporter-based drug-drug interaction (DDI) modeling. Methods PBPK models of probenecid and furosemide were developed in PK-Sim®. Drug-dependent parameters and plasma concentration-time profiles following intravenous and oral probenecid and furosemide administration were gathered from literature and used for model development. For model evaluation, plasma concentration-time profiles, areas under the plasma concentration–time curve (AUC) and peak plasma concentrations (Cmax) were predicted and compared to observed data. In addition, the models were applied to predict the outcome of clinical DDI studies. Results The developed models accurately describe the reported plasma concentrations of 27 clinical probenecid studies and of 42 studies using furosemide. Furthermore, application of these models to predict the probenecid-furosemide and probenecid-rifampicin DDIs demonstrates their good performance, with 6/7 of the predicted DDI AUC ratios and 4/5 of the predicted DDI Cmax ratios within 1.25-fold of the observed values, and all predicted DDI AUC and Cmax ratios within 2.0-fold. Conclusions Whole-body PBPK models of probenecid and furosemide were built and evaluated, providing useful tools to support the investigation of transporter mediated DDIs.

scholarly journals Physiologically Based Pharmacokinetic Model of Rifapentine and 25-Desacetyl Rifapentine Disposition in Humans

2016 ◽  
Vol 60 (8) ◽  
pp. 4860-4868
Author(s):  
Todd J. Zurlinden ◽  
Garrett J. Eppers ◽  
Brad Reisfeld
Keyword(s):  
Time Course ◽  
Pbpk Model ◽  
Plasma Concentrations ◽  
Optimal Dose ◽  
Tissue Level ◽  
Pharmacokinetic Data ◽  
Rat Tissues ◽  
Content Type ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

ABSTRACTRifapentine (RPT) is a rifamycin antimycobacterial and, as part of a combination therapy, is indicated for the treatment of pulmonary tuberculosis (TB) caused byMycobacterium tuberculosis. Although the results from a number of studies indicate that rifapentine has the potential to shorten treatment duration and enhance completion rates compared to other rifamycin agents utilized in antituberculosis drug regimens (i.e., regimens 1 to 4), its optimal dose and exposure in humans are unknown. To help inform such an optimization, a physiologically based pharmacokinetic (PBPK) model was developed to predict time course, tissue-specific concentrations of RPT and its active metabolite, 25-desacetyl rifapentine (dRPT), in humans after specified administration schedules for RPT. Starting with the development and verification of a PBPK model for rats, the model was extrapolated and then tested using human pharmacokinetic data. Testing and verification of the models included comparisons of predictions to experimental data in several rat tissues and time course RPT and dRPT plasma concentrations in humans from several single- and repeated-dosing studies. Finally, the model was used to predict RPT concentrations in the lung during the intensive and continuation phases of a current recommended TB treatment regimen. Based on these results, it is anticipated that the PBPK model developed in this study will be useful in evaluating dosing regimens for RPT and for characterizing tissue-level doses that could be predictors of problems related to efficacy or safety.

scholarly journals Toxicity and Pharmacokinetic Studies of Lidocaine and Its Active Metabolite, Monoethylglycinexylidide, in Goat Kids

Animals ◽  
2018 ◽  
Vol 8 (8) ◽  
pp. 142
Author(s):  
Dinakaran Venkatachalam ◽  
Paul Chambers ◽  
Kavitha Kongara ◽  
Preet Singh
Keyword(s):  
Total Dose ◽  
Plasma Concentrations ◽  
Subcutaneous Administration ◽  
Lidocaine Hydrochloride ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Liquid Chromatography Mass Spectrometry ◽  
Elimination Half ◽  
The Mean ◽  
Safe Dose

This study determined the convulsant plasma concentrations and pharmacokinetic parameters following cornual nerve block and compared the results to recommend a safe dose of lidocaine hydrochloride for goat kids. The plasma concentrations of lidocaine and monoethylglycinexylidide (MGX) were quantified using liquid chromatography-mass spectrometry. A total dose of 7 mg/kg body weight (BW) was tolerated and should therefore be safe for local and regional anesthesia in goat kids. The mean plasma concentration and mean total dose that produced convulsions in goat kids were 13.59 ± 2.34 µg/mL and 12.31 ± 1.42 mg/kg BW (mean ± S.D.), respectively. The absorption of lidocaine following subcutaneous administration was rapid with Cmax and Tmax of 2.12 ± 0.81 µg/mL and 0.33 ± 0.11 h, respectively. The elimination half-lives (t½λz) of lidocaine hydrochloride and MGX were 1.71 ± 0.51 h and 3.19 ± 1.21 h, respectively. Injection of 1% lidocaine hydrochloride (0.5 mL/site) was safe and effective in blocking the nerves supplying horn buds in goat kids.

scholarly journals Clinical Characteristics of Non-Suicidal Self-Injury and Suicide Attempts among Psychiatric Patients in Korea: A Retrospective Chart Review

2020 ◽  
Vol 17 (4) ◽  
pp. 320-330
Author(s):  
Yubeen Bae ◽  
Yoanna Seong ◽  
Seok Hyeon Kim ◽  
Sojung Kim
Keyword(s):  
Clinical Characteristics ◽  
Chart Review ◽  
Suicide Attempts ◽  
Medical Center ◽  
Psychiatric Patients ◽  
Retrospective Chart Review ◽  
The Other ◽  
Novelty Seeking ◽  
Medical Chart Review ◽  
Self Injury

Objective Limited data exist on non-suicidal self-injury (NSSI) and suicide attempts among psychiatric patients in Korea. In this study, we investigated the clinical characteristics of patients who engaged in NSSI and/or suicide attempts.Methods We performed a retrospective medical chart review of patients with NSSI and/or suicide attempts at the psychiatric department of a university medical center in Seoul between 2017 and 2019. According to their history, patients were allocated to one of three groups: NSSI only, suicide attempts only and NSSI and suicide attempts group. Groups were compared based on sociodemographic characteristics and psychological assessments.Results Overall, 80 patients with NSSI and/or suicide attempts were evaluated. Patients with NSSI and suicide attempts were more likely to be female than the other two groups. Patients with NSSI and suicide attempts were more likely to suffer from Cluster B personality disorder than the other groups. And patients with NSSI and suicide attempts scored significantly higher on novelty-seeking in TCI and RC8, RC9 in MMPI-2.Conclusion Patients with NSSI and/or suicide attempts were more likely to be female, younger, and showed higher levels of psychological disturbances. These findings highlight the importance of early detection and intervention for patients with NSSI.

scholarly journals Pharmacokinetics of Doxycycline in Adults with Cystic Fibrosis

2011 ◽  
Vol 56 (1) ◽  
pp. 70-74 ◽  
Author(s):  
Paul M. Beringer ◽  
Heather Owens ◽  
Albert Nguyen ◽  
Debbie Benitez ◽  
Adupa Rao ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Oral Administration ◽  
Maximum Concentration ◽  
Airway Remodeling ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Time Curve ◽  
Elimination Half ◽  
Dose Oral

ABSTRACTCystic fibrosis (CF) is characterized by a chronic neutrophilic inflammatory response resulting in airway remodeling and progressive loss of lung function. Doxycycline is a tetracycline antibiotic that inhibits matrix metalloproteinase 9, a protease known to be associated with the severity of lung disease in CF. The pharmacokinetics of doxycycline was investigated during the course of a clinical trial to evaluate the short-term efficacy and safety in adults with CF. Plasma samples were obtained from 14 patients following a single intravenous dose and after 2 and 4 weeks of oral administration of doses ranging from 40 to 200 mg daily. The data were analyzed using noncompartmental and compartmental pharmacokinetics. The maximum concentration of drug in serum (Cmax) and area under the concentration-time curve from 0 h to infinity (AUC0-∞) values ranged from 1.0 to 3.16 mg/liter and 15.2 to 47.8 mg/liter × h, respectively, following single intravenous doses of 40 to 200 mg.Cmaxand time to maximum concentration of drug in serum (Tmax) values following multiple-dose oral administration ranged from 1.15 to 3.04 mg/liter and 1.50 to 2.33 h, respectively, on day 14 and 1.48 to 3.57 mg/liter and 1.00 to 2.17 on day 28. Predose sputum/plasma concentration ratios on days 14 and 28 ranged from 0.33 to 1.1 (mean, 0.71 ± 0.33), indicating moderate pulmonary penetration. A 2-compartment model best described the combined intravenous and oral data. Absorption was slow and delayed (absorption rate constant [Ka], 0.414 h−1; lag time, 0.484 h) but complete (bioavailability [F], 1.16). The distribution and elimination half-lives were 0.557 and 18.1 h, respectively. Based on these data, the plasma concentrations at the highest dose, 200 mg/day, are in the range reported to produce anti-inflammatory effectsin vivoand should be evaluated in clinical trials.

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