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 A Physiologically Based Pharmacokinetic Analysis To Predict the Pharmacokinetics of Intravenous Isavuconazole in Patients with or without Hepatic Impairment

2021 ◽  
Vol 65 (5) ◽  
Author(s):  
Huiping Huang ◽  
Helin Xie ◽  
Nupur Chaphekar ◽  
Ruichao Xu ◽  
Raman Venkataramanan ◽  
...  
Keyword(s):  
Hepatic Impairment ◽  
Pbpk Model ◽  
Pharmacokinetic Analysis ◽  
Moderate Hepatic Impairment ◽  
Healthy Population ◽  
Severe Hepatic Impairment ◽  
Time Curve ◽  
Physiologically Based Pharmacokinetic ◽  
Concentration Time ◽  
Physiologically Based

ABSTRACT Isavuconazole (ISA) is an azole antifungal used in the treatment of invasive aspergillosis and mucormycosis. Patients with mild or moderate hepatic impairment have lower clearance (CL) than the healthy population. Currently, there are no data on ISA in patients with severe hepatic impairment (Child-Pugh class C). The purposes of this study were to build a physiologically based pharmacokinetic (PBPK) model to describe the pharmacokinetics (PK) of intravenous ISA and to predict changes in ISA disposition in different patient populations and in patients with hepatic impairment so as to guide personalized dosing. By incorporating the systemic and drug-specific parameters of ISA, the model was initially developed in a healthy population and was validated with 10 independent PK profiles obtained from healthy subjects and from patients with normal liver function. The results showed satisfactory predictive capacity; most of the relative predictive errors were within ±30% for the area under the concentration-time curve (AUC) and the maximum concentration of the drug in serum (Cmax). The observed concentration-time profiles of ISA in plasma were well described by the model-predicted profiles. The model adequately predicted the reduced CL of ISA in patients with mild or moderate hepatic impairment. Furthermore, the model predicted a decrease in CL of about 60% in patients with severe hepatic impairment. Therefore, we recommend reducing the dose by 50% in patients with severe hepatic impairment. The model also predicted differences in the PK of ISA between Caucasian and Asian populations, with a Chinese/Caucasian CL ratio of 0.67. The PBPK model of ISA that was developed provides a reasonable approach for optimizing the dosage regimen in different ethnic populations and in patients with severe hepatic impairment.

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 Characterization of Plasma Protein Alterations in Pregnant and Postpartum Individuals Living With HIV to Support Physiologically-Based Pharmacokinetic Model Development

2021 ◽  
Vol 9 ◽  
Author(s):  
Sherry Zhao ◽  
Mary Gockenbach ◽  
Manuela Grimstein ◽  
Hari Cheryl Sachs ◽  
Mark Mirochnick ◽  
...  
Keyword(s):  
Plasma Protein ◽  
Pbpk Model ◽  
Model Development ◽  
Postpartum Women ◽  
Drug Dosing ◽  
Women Living With Hiv ◽  
Physiologically Based Pharmacokinetic ◽  
Study Results ◽  
Physiologically Based ◽  
Living With Hiv

Background: Alterations in plasma protein concentrations in pregnant and postpartum individuals can influence antiretroviral (ARV) pharmacokinetics. Physiologically-based pharmacokinetic (PBPK) models can serve to inform drug dosing decisions in understudied populations. However, development of such models requires quantitative physiological information (e.g., changes in plasma protein concentration) from the population of interest.Objective: To quantitatively describe the time-course of albumin and α1-acid glycoprotein (AAG) concentrations in pregnant and postpartum women living with HIV.Methods: Serum and plasma protein concentrations procured from the International Maternal Pediatric Adolescent AIDS Clinical Trial Protocol 1026s (P1026s) were analyzed using a generalized additive modeling approach. Separate non-parametric smoothing splines were fit to albumin and AAG concentrations as functions of gestational age or postpartum duration.Results: The analysis included 871 and 757 serum albumin concentrations collected from 380 pregnant (~20 to 42 wks gestation) and 354 postpartum (0 to 46 wks postpartum) women, respectively. Thirty-six and 32 plasma AAG concentrations from 31 pregnant (~24 to 38 wks gestation) and 30 postpartum women (~2–13 wks postpartum), respectively, were available for analysis. Estimated mean albumin concentrations remained stable from 20 wks gestation to term (33.4 to 34.3 g/L); whereas, concentrations rapidly increased postpartum until stabilizing at ~42.3 g/L 15 wk after delivery. Estimated AAG concentrations slightly decreased from 24 wks gestation to term (53.6 and 44.9 mg/dL) while postpartum levels were elevated at two wks after delivery (126.1 mg/dL) and subsequently declined thereafter. Computational functions were developed to quantitatively communicate study results in a form that can be readily utilized for PBPK model development.Conclusion: By characterizing the trajectory of plasma protein concentrations in pregnant and postpartum women living with HIV, our analysis can increase confidence in PBPK model predictions for HIV antiretrovirals and better inform drug dosing decisions in this understudied population.

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 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 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.

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