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

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.

Download Full-text

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

Alcohol and Alcoholism ◽

10.1093/alcalc/agaa129 ◽

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.

Download Full-text

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

Toxicology Research ◽

10.1039/c8tx00309b ◽

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.

Download Full-text

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

Frontiers in Pharmacology ◽

10.3389/fphar.2021.692741 ◽

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.

Download Full-text

Simulating Intestinal Transporter and Enzyme Activity in a Physiologically Based Pharmacokinetic Model for Tenofovir Disoproxil Fumarate

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00105-17 ◽

2017 ◽

Vol 61 (7) ◽

Cited By ~ 3

Author(s):

Darren M. Moss ◽

Paul Domanico ◽

Melynda Watkins ◽

Seonghee Park ◽

Ryan Randolph ◽

...

Keyword(s):

Enzyme Activity ◽

Tenofovir Disoproxil Fumarate ◽

Drug Exposure ◽

Pbpk Model ◽

Intestinal Transport ◽

Pbpk Modeling ◽

Time Curve ◽

Physiologically Based Pharmacokinetic ◽

Physiologically Based

ABSTRACT Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, has oral bioavailability (25%) limited by intestinal transport (P-glycoprotein), and intestinal degradation (carboxylesterase). However, the influence of luminal pancreatic enzymes is not fully understood. Physiologically based pharmacokinetic (PBPK) modeling has utility for estimating drug exposure from in vitro data. This study aimed to develop a PBPK model that included luminal enzyme activity to inform dose reduction strategies. TDF and tenofovir stability in porcine pancrelipase concentrations was assessed (0, 0.48, 4.8, 48, and 480 U/ml of lipase; 1 mM TDF; 37°C; 0 to 30 min). Samples were analyzed using mass spectrometry. TDF stability and permeation data allowed calculation of absorption rates within a human PBPK model to predict plasma exposure following 6 days of once-daily dosing with 300 mg of TDF. Regional absorption of drug was simulated across gut segments. TDF was degraded by pancrelipase (half-lives of 0.07 and 0.62 h using 480 and 48 U/ml, respectively). Previously reported maximum concentration (C max; 335 ng/ml), time to C max (T max; 2.4 h), area under the concentration-time curve from 0 to 24 h (AUC0–24; 3,045 ng · h/ml), and concentration at 24 h (C 24; 48.3 ng/ml) were all within a 0.5-fold difference from the simulated C max (238 ng/ml), T max (3 h), AUC0–24 (3,036 ng · h/ml), and C 24 (42.7 ng/ml). Simulated TDF absorption was higher in duodenum and jejunum than in ileum (p<0.05). These data support that TDF absorption is limited by the action of intestinal lipases. Our results suggest that bioavailability may be improved by protection of drug from intestinal transporters and enzymes, for example, by coadministration of enzyme-inhibiting agents or nanoformulation strategies.

Download Full-text

An Open-Label Study of the Impact of Hepatic Impairment on the Pharmacokinetics and Safety of Single Oral and Intravenous Doses of Omadacycline

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01650-20 ◽

2020 ◽

Vol 64 (11) ◽

Cited By ~ 1

Author(s):

Steven J. Kovacs ◽

Lillian Ting ◽

Jens Praestgaard ◽

Gangadhar Sunkara ◽

Haiying Sun ◽

...

Keyword(s):

Hepatic Impairment ◽

Healthy Subjects ◽

Geometric Mean ◽

The United States ◽

Moderate Hepatic Impairment ◽

Severe Hepatic Impairment ◽

Open Label ◽

Time Curve ◽

The Impact ◽

Mild Hepatic Impairment

ABSTRACT Omadacycline is a once-daily oral or intravenous (i.v.) aminomethylcycline antibiotic approved in the United States for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) in adults. Omadacycline pharmacokinetics were characterized in 18 patients with hepatic impairment and 12 matched healthy subjects. Patients with hepatic impairment received i.v. omadacycline at 100 mg (mild hepatic impairment) or 50 mg (moderate and severe hepatic impairment) and oral omadacycline at 300 mg (mild hepatic impairment) or 150 mg (moderate hepatic impairment); oral omadacycline was not evaluated in those with severe hepatic impairment. Safety monitoring included the collection of adverse events (AEs), performance of laboratory tests, determination of vital signs, and performance of electrocardiograms. Omadacycline exposures were similar in patients with hepatic impairment and healthy subjects following i.v. or oral administration, with the geometric mean ratios for the area under the concentration-time curve and the maximum drug concentration ranging from 0.79 to 1.42. Omadacycline was safe and well tolerated. Overall, 13/30 (43.3%) participants experienced an AE; those occurring in more than 1 participant included headache (13.3%), nausea (6.7%), infusion-site pain (6.7%), contusion (6.7%), and dizziness (6.7%), with no differences based on the degree of hepatic impairment or the route of administration. Asymptomatic increases in heart rate were observed; none was considered an AE. These findings suggest that no omadacycline dose adjustment is warranted in patients with hepatic impairment.

Download Full-text

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

European Journal of Clinical Pharmacology ◽

10.1007/s00228-021-03194-x ◽

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.

Download Full-text

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

Pharmaceutics ◽

10.3390/pharmaceutics13060813 ◽

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.

Download Full-text

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

Pharmaceutics ◽

10.3390/pharmaceutics13060778 ◽

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.

Download Full-text