scholarly journals Physiologically Based Pharmacokinetic Modeling of Cefadroxil in Mouse, Rat, and Human to Predict Concentration–Time Profile at Infected Tissue

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhongxia Tan ◽  
Youxi Zhang ◽  
Chao Wang ◽  
Le Sun
Keyword(s):  
Plasma Concentration ◽  
Pbpk Model ◽  
Oral Absorption ◽  
Time Profile ◽  
Infected Tissue ◽  
Dose Selection ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Physiologically Based

The aim of this study was to develop physiologically based pharmacokinetic (PBPK) models capable of simulating cefadroxil concentrations in plasma and tissues in mouse, rat, and human. PBPK models in this study consisted of 14 tissues and 2 blood compartments. They were established using measured tissue to plasma partition coefficient (Kp) in mouse and rat, absolute expression levels of hPEPT1 along the entire length of the human intestine, and the transporter kinetic parameters. The PBPK models also assumed that all the tissues were well-stirred compartments with perfusion rate limitations, and the ratio of the concentration in tissue to the unbound concentration in plasma is identical across species. These PBPK models were validated strictly by a series of observed plasma concentration–time profile data. The average fold error (AFE) and absolute average fold error (AAFE) values were all less than 2. The models’ rationality and accuracy were further demonstrated by the almost consistent Vss calculated by the PBPK model and noncompartmental method, as well as the good allometric scaling relationship of Vss and CL. The model suggests that hPEPT1 is the major transporter responsible for the oral absorption of cefadroxil in human, and the plasma concentration–time profiles of cefadroxil were not sensitive to dissolution rate faster than T85% = 2 h. The cefadroxil PBPK model in human is reliable and can be used to predict concentration–time profile at infected tissue. It may be useful for dose selection and informative decision-making during clinical trials and dosage form design of cefadroxil and provide a reference for the PBPK model establishment of hPEPT1 substrate.

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 Development of a Physiologically Based Pharmacokinetic Model for Prediction of Ethanol Concentration-Time Profile in Different Organs

2020 ◽  
Author(s):  
Armin Sadighi ◽  
Lorenzo Leggio ◽  
Fatemeh Akhlaghi
Keyword(s):  
Pbpk Model ◽  
Organ Damage ◽  
Time Profile ◽  
Sensitivity Analyses ◽  
Pbpk Modeling ◽  
Time Curve ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Physiologically Based

Abstract Aims A physiologically based pharmacokinetic (PBPK) modeling approach was used to simulate the concentration-time profile of ethanol (EtOH) in stomach, duodenum, plasma and other tissues upon consumption of beer and whiskey under fasted and fed conditions. Methods A full PBPK model was developed for EtOH using the advanced dissolution, absorption and metabolism (ADAM) model fully integrated into the Simcyp Simulator® 15 (Simcyp Ltd., Sheffield, UK). The prediction performance of the developed model was verified and the EtOH concentration-time profile in different organs was predicted. Results Simcyp simulation showed ≤ 2-fold difference in values of EtOH area under the concentration-time curve (AUC) in stomach and duodenum as compared to the observed values. Moreover, the simulated EtOH maximum concentration (Cmax), time to reach Cmax (Tmax) and AUC in plasma were comparable to the observed values. We showed that liver is exposed to the highest EtOH concentration, faster than other organs (Cmax = 839.50 mg/L and Tmax = 0.53 h), while brain exposure of EtOH (AUC = 1139.43 mg·h/L) is the highest among all other organs. Sensitivity analyses (SAs) showed direct proportion of EtOH rate and extent of absorption with administered EtOH dose and inverse relationship with gastric emptying time (GE) and steady-state volume of distribution (Vss). Conclusions The current PBPK model approach might help with designing in vitro experiments in the area of alcohol organ damage or alcohol-drug interaction studies.

scholarly journals Physiologically Based Pharmacokinetic Model for Terbinafine in Rats and Humans

2002 ◽  
Vol 46 (7) ◽  
pp. 2219-2228 ◽  
Author(s):  
Mahboubeh Hosseini-Yeganeh ◽  
Andrew J. McLachlan
Keyword(s):  
Human Plasma ◽  
Oral Absorption ◽  
Volume Of Distribution ◽  
Time Profile ◽  
Bolus Administration ◽  
Time Data ◽  
Concentration Data ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Physiologically Based

ABSTRACT The aim of this study was to develop a physiologically based pharmacokinetic (PB-PK) model capable of describing and predicting terbinafine concentrations in plasma and tissues in rats and humans. A PB-PK model consisting of 12 tissue and 2 blood compartments was developed using concentration-time data for tissues from rats (n = 33) after intravenous bolus administration of terbinafine (6 mg/kg of body weight). It was assumed that all tissues except skin and testis tissues were well-stirred compartments with perfusion rate limitations. The uptake of terbinafine into skin and testis tissues was described by a PB-PK model which incorporates a membrane permeability rate limitation. The concentration-time data for terbinafine in human plasma and tissues were predicted by use of a scaled-up PB-PK model, which took oral absorption into consideration. The predictions obtained from the global PB-PK model for the concentration-time profile of terbinafine in human plasma and tissues were in close agreement with the observed concentration data for rats. The scaled-up PB-PK model provided an excellent prediction of published terbinafine concentration-time data obtained after the administration of single and multiple oral doses in humans. The estimated volume of distribution at steady state (V ss) obtained from the PB-PK model agreed with the reported value of 11 liters/kg. The apparent volume of distribution of terbinafine in skin and adipose tissues accounted for 41 and 52%, respectively, of the V ss for humans, indicating that uptake into and redistribution from these tissues dominate the pharmacokinetic profile of terbinafine. The PB-PK model developed in this study was capable of accurately predicting the plasma and tissue terbinafine concentrations in both rats and humans and provides insight into the physiological factors that determine terbinafine disposition.

scholarly journals Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 813
Author(s):  
Yoo-Seong Jeong ◽  
Min-Soo Kim ◽  
Nora Lee ◽  
Areum Lee ◽  
Yoon-Jee Chae ◽  
...  
Keyword(s):  
Gastric Acid ◽  
Pbpk Model ◽  
Pbpk Modeling ◽  
Drug Candidate ◽  
Metabolite Formation ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models predict drug interactions as pharmacokinetic profiles in biological matrices can be mechanistically simulated. Here, we propose an optimized and validated PBPK model for fexuprazan by integrating in vitro, in vivo, and in silico data. The extent of fexuprazan tissue distribution in humans was predicted using tissue-to-plasma partition coefficients in rats and the allometric relationships of fexuprazan distribution volumes (VSS) among preclinical species. Urinary fexuprazan excretion was minimal (0.29–2.02%), and this drug was eliminated primarily by the liver and metabolite formation. The fraction absorbed (Fa) of 0.761, estimated from the PBPK modeling, was consistent with the physicochemical properties of fexuprazan, including its in vitro solubility and permeability. The predicted oral bioavailability of fexuprazan (38.4–38.6%) was within the range of the preclinical datasets. The Cmax, AUClast, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets.

Plasma concentration profiles for hepatotoxic pyrrolizidine alkaloid senkirkine in humans extrapolated from rat data sets using a simplified physiologically based pharmacokinetic model

2021 ◽  
Vol 15 ◽  
Author(s):  
Yusuke Kamiya ◽  
Tomonori Miura ◽  
Airi Kato ◽  
Norie Murayama ◽  
Makiko Shimizu ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Human Plasma ◽  
In Silico ◽  
Pbpk Model ◽  
Pyrrolizidine Alkaloid ◽  
Water Soluble ◽  
Food Plants ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Aim: The main aim of the current study was to obtain forward dosimetry assessments of pyrrolizidine alkaloid senkirkine plasma and liver concentrations by setting up a human physiologically based pharmacokinetic (PBPK) model based on the limited information available. Background: The risks associated with plant-derived pyrrolizidine alkaloids as natural toxins have been assessed. Objective: The pyrrolizidine alkaloid senkirkine was investigated because it was analyzed in a European transcriptomics study of natural hepatotoxins and in a study of the alkaloidal constituents of traditional Japanese food plants Petasites japonicus. The in silico human plasma and liver concentrations of senkirkine were modeled using doses reported for acute-term toxicity in humans. Methods: Using a simplified PBPK model established using rat pharmacokinetic data, forward dosimetry was conducted. Since in vitro rat and human intrinsic hepatic clearances were similar; an allometric scaling approach was applied to rat parameters to create a human PBPK model. Results: After oral administration of 1.0 mg/kg in rats in vivo, water-soluble senkirkine was absorbed and cleared from plasma to two orders of magnitude below the maximum concentration in 8 h. Human in silico senkirkine plasma concentration curves were generated after virtual daily oral administrations of 3.0 mg/kg senkirkine (the dose involved in an acute fatal hepatotoxicity case). A high concentration of senkirkine in the culture medium caused in vitro hepatotoxicity as evidenced by lactate dehydrogenase leakage from human hepatocyte-like HepaRG cells. Conclusion: Higher virtual concentrations of senkirkine in human liver and plasma than those in rat plasma were estimated using the current rat and human PBPK models. Current simulations suggest that if P. japonicus (a water-soluble pyrrolizidine alkaloid-producing plant) is ingested daily as food, hepatotoxic senkirkine could be continuously present in human plasma and liver.

scholarly journals Physiologically Based Pharmacokinetic Modelling for Nicotine and Cotinine Clearance in Pregnant Women

2021 ◽  
Vol 12 ◽  
Author(s):  
Basile Amice ◽  
Harvey Ho ◽  
En Zhang ◽  
Chris Bullen
Keyword(s):  
Pregnant Women ◽  
Pbpk Model ◽  
Research Report ◽  
Pharmacokinetic Parameters ◽  
Nicotine Concentration ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Fetal Organs ◽  
Temporal Profiles

Introduction: Physiologically based pharmacokinetic (PBPK) models for the absorption, disposition, metabolism and excretion (ADME) of nicotine and its major metabolite cotinine in pregnant women (p-PBPK) are rare. The aim of this short research report is to present a p-PBPK model and its simulations for nicotine and cotinine clearance.Methods: The maternal-placental-fetal compartments of the p-PBPK model contain a total of 16 compartments representing major maternal and fetal organs and tissue groups. Qualitative and quantitative data of nicotine and cotinine disposition and clearance have been incorporated into pharmacokinetic parameters.Results: The p-PBPK model reproduced the higher clearance rates of nicotine and cotinine in pregnant women than non-pregnant women. Temporal profiles for their disposition in organs such as the brain were also simulated. Nicotine concentration reaches its maximum value within 2 min after an intravenous injection.Conclusion: The proposed p-PBPK model produces results consistent with available data sources. Further pharmacokinetic experiments are required to calibrate clearance parameters for individual organs, and for the fetus.

scholarly journals Food Effects on Oral Drug Absorption: Application of Physiologically-Based Pharmacokinetic Modeling as a Predictive Tool

Pharmaceutics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 672
Author(s):  
Lisa Cheng ◽  
Harvey Wong
Keyword(s):  
Oral Absorption ◽  
Current Knowledge ◽  
Pediatric Population ◽  
Physicochemical Characteristics ◽  
Oral Drug ◽  
Food Effects ◽  
Predictive Tool ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

The bioavailability of an orally administered small molecule is often dictated by drug-specific physicochemical characteristics and is influenced by many biological processes. For example, in fed or fasted conditions, the transit time within the gastrointestinal tract can vary, confounding the ability to predict the oral absorption. As such, the effects of food on the pharmacokinetics of compounds in the various biopharmaceutics classification system (BCS) classes need to be assessed. The consumption of food leads to physiological changes, including fluctuations in the gastric and intestinal pH, a delay in gastric emptying, an increased bile secretion, and an increased splanchnic and hepatic blood flow. Despite the significant impact of a drug’s absorption and dissolution, food effects have not been fully studied and are often overlooked. Physiologically-based pharmacokinetic (PBPK) models can be used to mechanistically simulate a compound’s pharmacokinetics under fed or fasted conditions, while integrating drug properties such as solubility and permeability. This review discusses the PBPK models published in the literature predicting the food effects, the models’ strengths and shortcomings, as well as future steps to mitigate the current knowledge gap. We observed gaps in knowledge which limits the ability of PBPK models to predict the negative food effects and food effects in the pediatric population. Overall, the further development of PBPK models to predict food effects will provide a mechanistic basis to understand a drug’s behavior in fed and fasted conditions, and will help enable the drug development process.

scholarly journals Revisiting a physiologically based pharmacokinetic model for cocaine with a forensic scope

2019 ◽  
Vol 8 (3) ◽  
pp. 432-446
Author(s):  
María Elena Bravo-Gómez ◽  
Laura Nayeli Camacho-García ◽  
Luz Alejandra Castillo-Alanís ◽  
Miguel Ángel Mendoza-Meléndez ◽  
Alejandra Quijano-Mateos
Keyword(s):  
Pharmacokinetic Model ◽  
Pbpk Model ◽  
Whole Body ◽  
Physiologically Based Pharmacokinetic Model ◽  
Time Profiles ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Physiologically Based ◽  
Permeability Rate ◽  
Different Tissues

A whole-body permeability-rate-limited physiologically based pharmacokinetic (PBPK) model for cocaine was developed with the aim to predict the concentration–time profiles of the drug in blood and different tissues in humans.

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