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 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 Development and Application of a Life-Stage Physiologically Based Pharmacokinetic (PBPK) Model to the Assessment of Internal Dose of Pyrethroids in Humans

2019 ◽  
Vol 173 (1) ◽  
pp. 86-99 ◽  
Author(s):  
Pankajini Mallick ◽  
Marjory Moreau ◽  
Gina Song ◽  
Alina Y Efremenko ◽  
Salil N Pendse ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pbpk Model ◽  
Life Stage ◽  
Internal Exposure ◽  
Target Tissue ◽  
Physiologically Based Pharmacokinetic ◽  
Age Related ◽  
Physiologically Based

Abstract To address concerns around age-related sensitivity to pyrethroids, a life-stage physiologically based pharmacokinetic (PBPK) model, supported by in vitro to in vivo extrapolation (IVIVE) was developed. The model was used to predict age-dependent changes in target tissue exposure of 8 pyrethroids; deltamethrin (DLM), cis-permethrin (CPM), trans-permethrin, esfenvalerate, cyphenothrin, cyhalothrin, cyfluthrin, and bifenthrin. A single model structure was used based on previous work in the rat. Intrinsic clearance (CLint) of each individual cytochrome P450 or carboxylesterase (CES) enzyme that are active for a given pyrethroid were measured in vitro, then biologically scaled to obtain in vivo age-specific total hepatic CLint. These IVIVE results indicate that, except for bifenthrin, CES enzymes are largely responsible for human hepatic metabolism (>50% contribution). Given the high efficiency and rapid maturation of CESs, clearance of the pyrethroids is very efficient across ages, leading to a blood flow-limited metabolism. Together with age-specific physiological parameters, in particular liver blood flow, the efficient metabolic clearance of pyrethroids across ages results in comparable to or even lower internal exposure in the target tissue (brain) in children than that in adults in response to the same level of exposure to a given pyrethroid (Cmax ratio in brain between 1- and 25-year old = 0.69, 0.93, and 0.94 for DLM, bifenthrin, and CPM, respectively). Our study demonstrated that a life-stage PBPK modeling approach, coupled with IVIVE, provides a robust framework for evaluating age-related differences in pharmacokinetics and internal target tissue exposure in humans for the pyrethroid class of chemicals.

scholarly journals Physiologically-based pharmacokinetic modelling of infant exposure to efavirenz through breastfeeding

2018 ◽  
Vol 1 ◽  
pp. 16 ◽  
Author(s):  
Adeniyi Olagunju ◽  
Rajith K. R. Rajoli ◽  
Shakir A. Atoyebi ◽  
Saye Khoo ◽  
Andrew Owen ◽  
...  
Keyword(s):  
Breast Milk ◽  
Clinical Data ◽  
Pbpk Model ◽  
Whole Body ◽  
Published Data ◽  
Exposure Index ◽  
Infant Exposure ◽  
Reduced Dose ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Background: Very little is known about the level of infant exposure to many drugs commonly used during breastfeeding. The aim of this study was to develop a physiologically-based pharmacokinetic (PBPK) model for predicting infant exposure to maternal efavirenz through breastmilk. Methods: A breastfeeding PBPK model combining whole-body maternal and infant sub-models was constructed from drug-specific and system parameters affecting drug disposition using mathematical descriptions. The model was validated against published data on the pharmacokinetics of efavirenz in nursing mother-infant pairs. Further simulations were conducted to assess exposure in the context of the 400 mg reduced dose of efavirenz as well as best- and worse-case scenarios. Results: The model adequately described efavirenz pharmacokinetics, with over 80% of observed data points (203 matched breast milk and plasma pairs) within the predictive interval. All parameters were within 2-fold difference of clinical data. Median (range) predicted versus observed breast milk AUC0-24, Cmax and Cmin at the standard 600 mg dose were 75.0 (18.5-324) versus 68.5 (26.3-257) µg.hr/mL, 4.56 (1.17-16.0) versus 5.39 (1.43-18.4) µg/mL, and 2.11 (0.38-12.3) versus 1.68 (0.316-9.57) µg/mL, respectively. Predicted plasma AUC0-24, Cmax and Cmin at 400 mg reduced dose were similar to clinical data from non-breastfeeding adults. Model-predicted infant plasma concentrations were similar to clinical data, 0.15 (0.026–0.78) μg/mL at the 400 mg maternal dose in pooled analysis, approximately 25% lower than simulated exposure at 600 mg. The maximum exposure index was observed in the youngest infants, 5.9% (2.2-20) at 400 mg and 8.7% (3.2-29) at 600 mg. Thirteen and 36% of 10 days-1 month old infants were predicted to have exposure index above the 10% recommended threshold at 400 mg and 600 mg maternal dose, respectively. Conclusions: This application of PBPK modelling opens up opportunities for expanding our understanding of infant exposure to maternal drugs through breastfeeding.

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.

scholarly journals Physiologically based pharmacokinetic modelling to predict the clinical effect of CYP3A inhibitors/inducers on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment

2021 ◽  
Author(s):  
Akiko Watanabe ◽  
Tomoko Ishizuka ◽  
Makiko Yamada ◽  
Yoshiyuki Igawa ◽  
Takako Shimizu ◽  
...  
Keyword(s):  
Hepatic Impairment ◽  
Healthy Subjects ◽  
Pbpk Model ◽  
Plasma Exposure ◽  
Pbpk Modelling ◽  
Oral Dosing ◽  
Physiologically Based Pharmacokinetic ◽  
Concurrent Use ◽  
Study Results ◽  
Physiologically Based

Abstract Purpose Esaxerenone is a novel, oral, nonsteroidal treatment for hypertension. Physiologically based pharmacokinetic (PBPK) modelling was performed to predict the drug–drug interaction (DDI) effect of cytochrome P450 (CYP)3A modulators on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment. Methods In our PBPK model, the fraction of esaxerenone metabolised by CYP3A was estimated from mass-balance data and verified and optimised by clinical DDI study results with strong CYP3A modulators. The model was also verified by the observed pharmacokinetics after multiple oral dosing and by the effect of hepatic impairment on esaxerenone pharmacokinetics. The model was applied to predict the DDI effects on esaxerenone pharmacokinetics with untested CYP3A modulators in healthy subjects and with strong CYP3A modulators in subjects with hepatic impairment. Results The PBPK model well described esaxerenone pharmacokinetics after multiple oral dosing. The predicted fold changes in esaxerenone plasma exposure after coadministration with strong CYP3A modulators were comparable with the observed data (1.53-fold with itraconazole and 0.31-fold with rifampicin). Predicted DDIs with untested moderate CYP3A modulators were less than the observed DDI with strong CYP3A modulators. The PBPK model also described the effect of hepatic impairment on esaxerenone plasma exposure. The predicted DDI results with strong CYP3A modulators in subjects with hepatic impairment indicate that, for concomitant use of CYP3A modulators, caution is advised for subjects with hepatic impairment, as is for healthy subjects. Conclusion The PBPK model developed predicted esaxerenone pharmacokinetics and DDIs and informed concurrent use of esaxerenone with CYP3A modulators.

scholarly journals Physiologically-Based Pharmacokinetic (PBPK) Modeling Providing Insights into Fentanyl Pharmacokinetics in Adults and Pediatric Patients

Pharmaceutics ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 908
Author(s):  
Lukas Kovar ◽  
Andreas Weber ◽  
Michael Zemlin ◽  
Yvonne Kohl ◽  
Robert Bals ◽  
...  
Keyword(s):  
Pbpk Model ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Pbpk Modeling ◽  
Pharmacokinetic Studies ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Age Related ◽  
Physiologically Based ◽  
Pediatric Populations

Fentanyl is widely used for analgesia, sedation, and anesthesia both in adult and pediatric populations. Yet, only few pharmacokinetic studies of fentanyl in pediatrics exist as conducting clinical trials in this population is especially challenging. Physiologically-based pharmacokinetic (PBPK) modeling is a mechanistic approach to explore drug pharmacokinetics and allows extrapolation from adult to pediatric populations based on age-related physiological differences. The aim of this study was to develop a PBPK model of fentanyl and norfentanyl for both adult and pediatric populations. The adult PBPK model was established in PK-Sim® using data from 16 clinical studies and was scaled to several pediatric subpopulations. ~93% of the predicted AUClast values in adults and ~88% in pediatrics were within 2-fold of the corresponding value observed. The adult PBPK model predicted a fraction of fentanyl dose metabolized to norfentanyl of ~33% and a fraction excreted in urine of ~7%. In addition, the pediatric PBPK model was used to simulate differences in peak plasma concentrations after bolus injections and short infusions. The novel PBPK models could be helpful to further investigate fentanyl pharmacokinetics in both adult and pediatric populations.

scholarly journals The Use of a Physiologically Based Pharmacokinetic Modelling in a “Full-Chain” Exposure Assessment Framework: A Case Study on Urban and Industrial Pollution in Northern Italy

Atmosphere ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1228
Author(s):  
Lorenzo Vaccari ◽  
Andrea Ranzi ◽  
Annamaria Colacci ◽  
Grazia Ghermandi ◽  
Sergio Teggi
Keyword(s):  
Pbpk Model ◽  
Human Health Risk ◽  
Human Biomonitoring ◽  
Waste Incinerator ◽  
Case Scenario ◽  
Pbpk Modelling ◽  
Worst Case ◽  
Pilot Studies ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Background and goals: The estimate of the internal dose provided by physiologically based pharmacokinetic (PBPK) modelling is a big step forward in the frame of human health risk assessment (HRA) from contaminating sources. The PBPK model included in the MERLIN-Expo platform was here tested with data collected in a human biomonitoring (HBM) pilot study to check model efficacy in predicting concentrations in human blood and urine of people exposed to a modern solid waste incinerator (SWI). The aim of the study was to investigate if the use of a PBPK model integrated in a computational platform could replace more expensive and invasive pilot studies. Twenty eight subjects living and working within 4 km of the incinerator (exposed) and 21 subjects living and working outside this area (unexposed) were selected among the population recruited in the HBM study. The group of exposed (E) subjects and the group of non-exposed (NE) subjects were comparable for all relevant anthropometric characteristics and exposure parameters except for the exposure to SWI emissions. Three different scenarios were created: an “only diet-scenario” (DS), a “worst case scenario” (WCS) and a “most likely scenario” (MLS). The platform was tested for blood-lead (B-Pb), urinary-lead (U-Pb), urinary-anthracene (U-Ant) and urinary-fluoranthene (U-Flt). Average estimated U-Pb was statistically equal to the measured one (est. 0.411~0.278; meas. 0.398~0.455 µg/L) and estimated vs. measured U-Ant differ by one order of magnitude only (est. 0.018~0.010; meas. 0.537~0.444 ng/L) while for U-Flt and B-Pb, the error was respectively of two and four orders of magnitude. It is likely that the extremely high accuracy in the Pb concentration input values referring to diet led to the very accurate estimate for this chemical in urine, but the higher error in the B-Pb computed value suggests that PBPK model equations cannot entirely capture the dynamics for blood compartments. MERLIN-Expo seems a very promising tool in saving time, energy and money in the screening step of the HRA framework; however, many software validations are still required.

scholarly journals Predicting Pharmacokinetics of a Tenofovir Alafenamide Subcutaneous Implant Using Physiologically Based Pharmacokinetic Modelling

2020 ◽  
Vol 64 (8) ◽  
Author(s):  
Rajith K. R. Rajoli ◽  
Zach R. Demkovich ◽  
Charles Flexner ◽  
Andrew Owen ◽  
Marco Siccardi
Keyword(s):  
Peripheral Blood ◽  
Pbpk Model ◽  
Mononuclear Cells ◽  
Plasma Concentrations ◽  
Antiretroviral Drugs ◽  
Release Rates ◽  
Peripheral Blood Mononuclear ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based ◽  
Tenofovir Alafenamide

ABSTRACT Long-acting (LA) administration using a subcutaneous (s.c.) implant presents opportunities to simplify administration of antiretroviral drugs, improve pharmacological profiles, and overcome suboptimal adherence associated with daily oral formulations. Tenofovir alafenamide (TAF) is a highly potent nucleoside reverse transcriptase inhibitor (NRTI) and an attractive agent for LA delivery, with a high potency and long intracellular half-life. The aim of this study was to predict minimum TAF doses required to achieve concentrations effective for HIV preexposure prophylaxis (PrEP). Daily drug release requirements were then ascertained by averaging across the dosing interval. A TAF physiologically based pharmacokinetic (PBPK) model was developed and partially qualified against available oral single- and multiple-dose pharmacokinetics. The models were assumed to be qualified when simulated values were within 2-fold of the observed mean. TAF s.c. implants were simulated in five hundred individuals, reporting predicted TAF plasma and tenofovir (TFV) plasma concentrations for various release rates. Intracellular TFV diphosphate (TFV-DP) concentrations were also simulated in peripheral blood cells and cervical and rectal tissues. The minimum dose predicted to achieve intracellular TFV-DP levels above a target concentration of 48 fmol/106 cells for a month was identified. TAF, TFV, and TFV-DP concentrations for release rates between 1.0 and 1.6 mg/day were simulated. The PBPK model indicated that a minimum release of 1.4 mg/day TAF is necessary to achieve TFV-DP concentrations above the identified target in peripheral blood mononuclear cells (PBMCs). TFV-DP cervical and rectal tissue concentrations were predicted to be between 1.5 and 2.0 fmol/106 cells and 0.9 and 1.1 fmol/106 cells, respectively, for release rates between 1.3 and 1.6 mg/day. These simulations provide target minimum doses for LA TAF PrEP in humans. Based on the generated results, multiple implants delivering a total of 1.4 mg/day of TAF subcutaneously could provide protection levels for approximately 6 months to 1 year. This modeling may inform future design of s.c. implants to mitigate adherence issues for effective PrEP applications.

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.

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