scholarly journals Development of a physiologically based pharmacokinetic (PBPK) model of psilocybin and psilocin from magic mushroom in rats and humans

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 209
Author(s):  
Prinya Musikaphongsakul ◽  
Kimheang Ya ◽  
Pakpoom Subsoontorn ◽  
Manupat Lohitnavy
Keyword(s):  
Oral Administration ◽  
Pbpk Model ◽  
Simulated Data ◽  
The Body ◽  
Time Profiles ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Intravenous And Oral Administration ◽  
The Brain ◽  
Good Agreement

Background: Psilocybin (PB) is a psychoactive compound commonly found in magic mushroom (Psilocybe cubensis). PB is quickly converted by the body to psilocin (PI), which has a psychedelic effect through the activation of the 5-HT2A receptor in the brain. The objective of this study is to develop a physiologically based pharmacokinetic (PBPK) model of PB and PI in rats and humans for predicting concentrations of the psychoactive substance in the brain. Methods: Following a search in PubMed, three studies were retrieved and information concerning concentration-time profiles of PI were extracted from the selected studies. In the study in rats, PI was orally administered with a dose of 10.1 mg/kg. There were two studies in humans following a single intravenous dose of PB (1 mg) and oral dose of PB (0.224 mg/kg and 0.3 mg/kg). Berkeley Madonna software was used for computer coding and simulations. The developed PBPK model consisted of seven organ compartments (i.e. lung, heart, brain, fat, muscle, kidney, and liver). Results: The simulations show a good agreement between observed and simulated data, although results for oral administration in rats and humans showed under-predictions and results for intravenous administration in humans showed over-predictions. Conclusions: A PBPK model of PB and PI in rats and humans was developed and could predict concentration-time profiles of PI in plasma, particularly in the brain, following intravenous and oral administration of PB. This model may be useful for a safer dosage regimen of PB for patients with some disorders.

scholarly journals Understanding the Monoclonal Antibody Disposition after Subcutaneous Administration using a Minimal Physiologically based Pharmacokinetic Model

2018 ◽  
Vol 21 (1s) ◽  
pp. 130s-148s ◽  
Author(s):  
Ninad Varkhede ◽  
Laird Forrest
Keyword(s):  
Injection Site ◽  
Pbpk Model ◽  
Lymphatic System ◽  
Subcutaneous Administration ◽  
Physiological Parameters ◽  
The Body ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Minimal Pbpk ◽  
Minimal Pbpk Model

Purpose: Monoclonal antibodies (mAbs) are commonly administered by subcutaneous (SC) route. However, bioavailability is often reduced after SC administration. In addition, the sequential transfer of mAbs through the SC tissue and lymphatic system is not completely understood. Therefore, major objectives of this study were a) To understand absorption of mAbs via the lymphatic system after SC administration using physiologically based pharmacokinetic (PBPK) modeling, and b) to demonstrate application of the model for prediction of SC pharmacokinetics (PK) of mAbs. Methods: A minimal PBPK model was constructed using various physiological parameters related to the SC injection site and lymphatic system. The remainder of the body organs were represented using a 2-compartment model (central and peripheral compartments), with parameters derived from available intravenous (IV) PK data. The IV and SC clinical PK data of a total of 10 mAbs were obtained from literature. The SC PK data were used to estimate the lymphatic trunk-lymph node (LN) clearance. Results: The mean estimated lymphatic trunk-LN clearance obtained from 37 SC PK profiles of mAbs was 0.00213 L/h (0.001332 to 0.002928, 95% confidence intervals). The estimated lymphatic trunk-LN clearance was greater for the mAbs with higher isoelectric point (pI). In addition, the estimated clearance increased with decrease in the bioavailability. Conclusion: The minimal PBPK model identified SC injection site lymph flow, afferent and efferent lymph flows, and volumes associated with the SC injection site, lymphatic capillaries and lymphatic trunk-LN as important physiological parameters governing the absorption of mAbs after SC administration. The model may be used to predict PK of mAbs using the relationship of lymphatic trunk-LN clearance and the pI. In addition, the model can be used as a bottom platform to incorporate SC and lymphatic in vitro clearance data for mAb PK prediction in the future.

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.

scholarly journals A computational investigation of the ventilation structure and maximum rate of metabolism for a physiologically based pharmacokinetic (PBPK) model of inhaled xylene

BIOMATH ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 1901067
Author(s):  
Karen A Yokley ◽  
Jaclyn Ashcraft ◽  
Nicholas S Luke
Keyword(s):  
Inverse Problems ◽  
Blood Concentration ◽  
Maximum Rate ◽  
Pbpk Model ◽  
Simulated Data ◽  
Parameter Estimates ◽  
Computational Investigation ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Physiologically based pharmacokinetic (PBPK) models are systems of ordinary differential equations that estimate internal doses following exposure to toxicants. Most PBPK models use standard equations to describe inhalation and concentrations in blood. This study extends previous work investigating the effect of the structure of air and blood concentration equations on PBPK predictions. The current study uses an existing PBPK model of xylene to investigate if different values for the maximum rate of toxicant metabolism can result in similar compartmental predictions when used with different equations describing inhalation. Simulations are performed using values based on existing literature. Simulated data is also used to determine specific values that result in similar predictions from different ventilation structures. Differences in ventilation equation structure may affect parameter estimates found through inverse problems, although further investigation is needed with more complicated models.

Prediction of dolutegravir pharmacokinetics and dose optimization in neonates via physiologically based pharmacokinetic (PBPK) modelling

2019 ◽  
Vol 75 (3) ◽  
pp. 640-647 ◽  
Author(s):  
Fazila Bunglawala ◽  
Rajith K R Rajoli ◽  
Mark Mirochnick ◽  
Andrew Owen ◽  
Marco Siccardi
Keyword(s):  
Clinical Data ◽  
Pbpk Model ◽  
Simulated Data ◽  
Integrase Inhibitor ◽  
Antiretroviral Drugs ◽  
Pbpk Modelling ◽  
Physiologically Based Pharmacokinetic ◽  
Age Related ◽  
Optimal Dosing ◽  
Physiologically Based

Abstract Background Only a few antiretroviral drugs (ARVs) are recommended for use during the neonatal period and there is a need for more to be approved to increase treatment and prophylaxis strategies. Dolutegravir, a selective integrase inhibitor, has potential for treatment of HIV infection and prophylaxis of transmission in neonates. Objectives To model the pharmacokinetics of dolutegravir in neonates and to simulate a theoretical optimal dosing regimen. Methods The physiologically based pharmacokinetic (PBPK) model was built incorporating the age-related changes observed in neonates. Virtual neonates between 0 and 28 days were simulated. The model was validated against observed clinical data for raltegravir and midazolam in neonates, prior to the prediction of dolutegravir pharmacokinetics. Results Both raltegravir and midazolam passed the criteria for model qualification, with simulated data within 1.8-fold of clinical data. The qualified model predicted the pharmacokinetics for several multidose regimens of dolutegravir. Regimen 6 involved 5 mg doses with a 48 h interval from Day 1–20, increasing to 5 mg once daily on Week 3, yielding AUC and Ctrough values of 37.2 mg·h/L and 1.3 mg/L, respectively. These exposures are consistent with those observed in paediatric patients receiving dolutegravir. Conclusions Dolutegravir pharmacokinetics were successfully simulated in the neonatal PBPK model. The predictions suggest that during the first 3 weeks of life a 5 mg dose administered every 48 h may achieve plasma exposures needed for therapy and prophylaxis.

scholarly journals Pharmacokinetic Characterization of Supinoxin and Its Physiologically Based Pharmacokinetic Modeling in Rats

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 373
Author(s):  
Yoo-Kyung Song ◽  
Yun-Hwan Seol ◽  
Min Ju Kim ◽  
Jong-Woo Jeong ◽  
Hae-In Choi ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Oral Administration ◽  
Dose Range ◽  
Pbpk Modeling ◽  
Drug Candidate ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Intravenous And Oral Administration

Supinoxin is a novel anticancer drug candidate targeting the Y593 phospho-p68 RNA helicase, by exhibiting antiproliferative activity and/or suppression of tumor growth. This study aimed to characterize the in vitro and in vivo pharmacokinetics of supinoxin and attempt physiologically based pharmacokinetic (PBPK) modeling in rats. Supinoxin has good permeability, comparable to that of metoprolol (high permeability compound) in Caco-2 cells, with negligible net absorptive or secretory transport observed. After an intravenous injection at a dose range of 0.5–5 mg/kg, the terminal half-life (i.e., 2.54–2.80 h), systemic clearance (i.e., 691–865 mL/h/kg), and steady state volume of distribution (i.e., 2040–3500 mL/kg) of supinoxin remained unchanged, suggesting dose-independent (i.e., dose-proportional) pharmacokinetics for the dose ranges studied. After oral administration, supinoxin showed modest absorption with an absolute oral bioavailability of 56.9–57.4%. The fecal recovery following intravenous and oral administration was 16.5% and 46.8%, respectively, whereas the urinary recoveries in both administration routes were negligible. Supinoxin was mainly eliminated via NADPH-dependent phase I metabolism (i.e., 58.5% of total clearance), while UDPGA-dependent phase II metabolism appeared negligible in the rat liver microsome. Supinoxin was most abundantly distributed in the adipose tissue, gut, and liver among the nine major tissues studied (i.e., the brain, liver, kidneys, heart, lungs, spleen, gut, muscles, and adipose tissue), and the tissue exposure profiles of supinoxin were well predicted with physiologically based pharmacokinetics.

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.

scholarly journals 1315. No Dose Adjustment of Metformin with Fostemsavir Coadministration Based on Mechanistic Static and Physiologically Based Pharmacokinetic Models

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S669-S669
Author(s):  
Dung N Nguyen ◽  
Xiusheng Miao ◽  
Mindy Magee ◽  
Guoying Tai ◽  
Peter D Gorycki ◽  
...  
Keyword(s):  
Dose Adjustment ◽  
Pbpk Model ◽  
Systemic Exposure ◽  
Multidrug Resistant ◽  
Pbpk Modeling ◽  
Repeat Dose ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Abstract Background Fostemsavir (FTR) is an oral prodrug of the first-in-class attachment inhibitor temsavir (TMR) which is being evaluated in patients with multidrug resistant HIV-1 infection. In vitro studies indicated that TMR and its 2 major metabolites are inhibitors of organic cation transporters (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs). To assess the clinical relevance, of OCT and MATE inhibition, mechanistic static DDI prediction with calculated Imax,u/IC50 ratios was below the cut-off limits for a DDI flag based on FDA guidelines and above the cut-off limits for MATEs based on EMA guidelines. Methods Metformin is a commonly used probe substrate for OCT1, OCT2 and MATEs. To predict the potential for a drug interaction between TMR and metformin, a physiologically based pharmacokinetic (PBPK) model for TMR was developed based on its physicochemical properties, in vitro and in vivo data. The model was verified and validated through comparison with clinical data. The TMR PBPK model accurately described AUC and Cmax within 30% of the observed data for single and repeat dose studies with or without food. The SimCYP models for metformin and ritonavir were qualified using literature data before applications of DDI prediction for TMR Results TMR was simulated at steady state concentrations after repeated oral doses of FTR 600 mg twice daily which allowed assessment of the potential OCT1, OCT2, and MATEs inhibition by TMR and metabolites. No significant increase in metformin systemic exposure (AUC or Cmax) was predicted with FTR co-administration. In addition, a sensitivity analysis was conducted for either hepatic OCT1 Ki, or renal OCT2 and MATEs Ki values. The model output indicated that, a 10-fold more potent Ki value for TMR would be required to have a ~15% increase in metformin exposure Conclusion Based on mechanistic static models and PBPK modeling and simulation, the OCT1/2 and MATEs inhibition potential of TMR and its metabolites on metformin pharmacokinetics is not clinically significant. No dose adjustment of metformin is necessary when co-administered with FTR Disclosures Xiusheng Miao, PhD, GlaxoSmithKline (Employee) Mindy Magee, Doctor of Pharmacy, GlaxoSmithKline (Employee, Shareholder) Peter D. Gorycki, BEChe, MSc, PhD, GSK (Employee, Shareholder) Katy P. Moore, PharmD, RPh, ViiV Healthcare (Employee)

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.

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