PBPK modelling of dexamethasone in patients with COVID-19 and liver disease

The aim of the study was to apply Physiologically-Based Pharmacokinetic (PBPK) modelling to predict the effect of liver disease (LD) on the pharmacokinetics (PK) of dexamethasone (DEX) in the treatment of COVID-19. A whole-body PBPK model was created to simulate 100 adult individuals aged 18-60 years. Physiological changes (e.g., plasma protein concentration, liver size, CP450 expression, hepatic blood flow) and portal vein shunt were incorporated into the LD model. The changes were implemented by using the Child-Pugh (CP) classification system. DEX was qualified using clinical data in healthy adults for both oral (PO) and intravenous (IV) administrations and similarly propranolol (PRO) and midazolam (MDZ) were qualified with PO and IV clinical data in healthy and LD adults. The qualified model was subsequently used to simulate a 6 mg PO and 20 mg IV dose of DEX in patients with varying degrees of LD, with and without shunting. The PBPK model was successfully qualified across DEX, MDZ and PRO. In contrast to healthy adults, the simulated systemic clearance of DEX decreased (35% - 60%) and the plasma concentrations increased (170% - 400%) in patients with LD. Moreover, at higher doses of DEX, the AUC ratio between healthy/LD individuals remained comparable to lower doses. The exposure of DEX in different stages of LD was predicted through PBPK modelling, providing a rational framework to predict PK in complex clinical scenarios related to COVID-19. Model simulations suggest dose adjustments of DEX in LD patients are not necessary considering the low dose administered in the COVID-19 protocol.

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

AAS Open Research ◽

10.12688/aasopenres.12860.1 ◽

2018 ◽

Vol 1 ◽

pp. 16 ◽

Cited By ~ 4

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.

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

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz506 ◽

2019 ◽

Vol 75 (3) ◽

pp. 640-647 ◽

Cited By ~ 2

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.

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Parallel Reduction of Plasma Levels of High and Low Molecular Weight Kininogen in Patients with Cirrhosis

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614849 ◽

1999 ◽

Vol 82 (11) ◽

pp. 1428-1432 ◽

Cited By ~ 9

Author(s):

Cheryl Scott ◽

Francesco Salerno ◽

Elettra Lorenzano ◽

Werner Müller-Esterl ◽

Angelo Agostoni ◽

...

Keyword(s):

Molecular Weight ◽

Liver Disease ◽

Liver Function ◽

Plasma Levels ◽

Plasma Concentrations ◽

Normal Subjects ◽

Low Molecular Weight ◽

Major Band ◽

Sds Page ◽

Normal Controls

SummaryLittle is known about the regulation of high-molecular-weight-kininogen (HK) and low-molecular-weight-kininogen (LK) or the relationship of each to the degree of liver function impairment in patients with cirrhosis. In this study, we evaluated HK and LK quantitatively by a recently described particle concentration fluorescence immunoassay (PCFIA) and qualitatively by SDS PAGE and immunoblotting analyses in plasma from 33 patients with cirrhosis presenting various degrees of impairment of liver function. Thirty-three healthy subjects served as normal controls. Patients with cirrhosis had significantly lower plasma levels of HK (median 49 μg/ml [range 22-99 μg/ml]) and LK (58 μg/ml [15-100 μg/ml]) than normal subjects (HK 83 μg/ml [65-115 μg/ml]; LK 80 μg/ml [45-120 μg/ml]) (p < 0.0001). The plasma concentrations of HK and LK were directly related to plasma levels of cholinesterase (P < 0.0001) and albumin (P < 0.0001 and P < 0.001) and inversely to the Child-Pugh score (P < 0.0001) and to prothrombin time ratio (P < 0.0001) (reflecting the clinical and laboratory abnormalities in liver disease). Similar to normal individuals, in patients with cirrhosis, plasma HK and LK levels paralleled one another, suggesting that a coordinate regulation of those proteins persists in liver disease. SDS PAGE and immunoblotting analyses of kininogens in cirrhotic plasma showed a pattern similar to that observed in normal controls for LK (a single band at 66 kDa) with some lower molecular weight forms noted in cirrhotic plasma. A slight increase of cleavage of HK (a major band at 130 kDa and a faint but increased band at 107 kDa) was evident. The increased cleavage of HK was confirmed by the lower cleaved kininogen index (CKI), as compared to normal controls. These data suggest a defect in hepatic synthesis as well as increased destructive cleavage of both kininogens in plasma from patients with cirrhosis. The decrease of important regulatory proteins like kininogens may contribute to the imbalance in coagulation and fibrinolytic systems, which frequently occurs in cirrhotic patients.

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Association between hand muscle thickness and whole-body skeletal muscle mass in healthy adults: a pilot study

Journal of Physical Therapy Science ◽

10.1589/jpts.29.1644 ◽

2017 ◽

Vol 29 (9) ◽

pp. 1644-1648 ◽

Cited By ~ 6

Author(s):

Akio Morimoto ◽

Tadashi Suga ◽

Nobuaki Tottori ◽

Michio Wachi ◽

Jun Misaki ◽

...

Keyword(s):

Skeletal Muscle ◽

Pilot Study ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Muscle Thickness ◽

Healthy Adults ◽

Whole Body ◽

Hand Muscle

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The Impact of Nordic Walking on Bone Properties in Postmenopausal Women with Pre-Diabetes and Non-Alcohol Fatty Liver Disease

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18147570 ◽

2021 ◽

Vol 18 (14) ◽

pp. 7570

Author(s):

Xiaming Du ◽

Chao Zhang ◽

Xiangqi Zhang ◽

Zhen Qi ◽

Sulin Cheng ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Postmenopausal Women ◽

Fatty Liver Disease ◽

Whole Body ◽

Nordic Walking ◽

Significant Group ◽

Time Interaction ◽

Bone Properties ◽

The Impact

This study investigated the impact of Nordic walking on bone properties in postmenopausal women with pre-diabetes and non-alcohol fatty liver disease (NAFLD). A total of 63 eligible women randomly participated in the Nordic walking training (AEx, n = 33), or maintained their daily lifestyle (Con, n = 30) during intervention. Bone mineral content (BMC) and density (BMD) of whole body (WB), total femur (TF), femoral neck (FN), and lumbar spine (L2-4) were assessed by dual-energy X-ray absorptiometry. Serum osteocalcin, pentosidine, receptor activator of nuclear factor kappa-B ligand (RANKL) levels were analyzed by ELISA assay. After an 8.6-month intervention, the AEx group maintained their BMCTF, BMDTF, BMCL2−4, and BMDL2−4, and increased their BMCFN (p = 0.016), while the Con group decreased their BMCTF (p = 0.008), BMDTF (p = 0.001), and BMDL2−4 (p = 0.002). However, no significant group × time interaction was observed, except for BMDL2−4 (p = 0.013). Decreased pentosidine was correlated with increased BMCWB(r = −0.352, p = 0.019). The intervention has no significant effect on osteocalcin and RANKL. Changing of bone mass was associated with changing of pentosidine, but not with osteocalcin and RANKL. Our results suggest that Nordic walking is effective in preventing bone loss among postmenopausal women with pre-diabetes and NAFLD.

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The Effect of Different Turn Speeds on Whole-Body Coordination in Younger and Older Healthy Adults

Sensors ◽

10.3390/s21082827 ◽

2021 ◽

Vol 21 (8) ◽

pp. 2827

Author(s):

Fuengfa Khobkhun ◽

Mark Hollands ◽

Jim Richards

Keyword(s):

Older Adults ◽

Repeated Measures ◽

Mixed Model ◽

Healthy Adults ◽

Whole Body ◽

Onset Latency ◽

Step Frequency ◽

Step Size ◽

Younger Adults ◽

Mixed Model Analysis

Difficulty in turning is prevalent in older adults and results in postural instability and risk of falling. Despite this, the mechanisms of turning problems have yet to be fully determined, and it is unclear if different speeds directly result in altered posture and turning characteristics. The aim of this study was to identify the effects of turning speeds on whole-body coordination and to explore if these can be used to help inform fall prevention programs in older adults. Forty-two participants (21 healthy older adults and 21 younger adults) completed standing turns on level ground. Inertial Measurement Units (XSENS) were used to measure turning kinematics and stepping characteristics. Participants were randomly tasked to turn 180° at one of three speeds; fast, moderate, or slow to the left and right. Two factors mixed model analysis of variance (MM ANOVA) with post hoc pairwise comparisons were performed to assess the two groups and three turning speeds. Significant interaction effects (p < 0.05) were seen in; reorientation onset latency of head, pelvis, and feet, peak segmental angular separation, and stepping characteristics (step frequency and step size), which all changed with increasing turn speed. Repeated measures ANOVA revealed the main effects of speeds within the older adults group on those variables as well as the younger adults group. Our results suggest that turning speeds result in altered whole-body coordination and stepping behavior in older adults, which use the same temporospatial sequence as younger adults. However, some characteristics differ significantly, e.g., onset latency of segments, peak head velocity, step frequency, and step size. Therefore, the assessment of turning speeds elucidates the exact temporospatial differences between older and younger healthy adults and may help to determine some of the issues that the older population face during turning, and ultimately the altered whole-body coordination, which lead to falls.

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Physiologically Based Pharmacokinetic Models of Probenecid and Furosemide to Predict Transporter Mediated Drug-Drug Interactions

Pharmaceutical Research ◽

10.1007/s11095-020-02964-z ◽

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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Conservation of whole body nitric oxide metabolism in human alcoholic liver disease: Implications for nitric oxide production

Scandinavian Journal of Gastroenterology ◽

10.1080/00365520500442724 ◽

2006 ◽

Vol 41 (7) ◽

pp. 820-825 ◽

Cited By ~ 3

Author(s):

Eric A. G. Demoncheaux ◽

David A. Elphick ◽

Marc B. Dürner ◽

Gail E. Higgins ◽

David Crowther ◽

...

Keyword(s):

Nitric Oxide ◽

Liver Disease ◽

Alcoholic Liver Disease ◽

Whole Body ◽

Nitric Oxide Production ◽

Oxide Production ◽

Nitric Oxide Metabolism ◽

Human Alcoholic

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Physiologically Based Pharmacokinetic Model of Rifapentine and 25-Desacetyl Rifapentine Disposition in Humans

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00031-16 ◽

2016 ◽

Vol 60 (8) ◽

pp. 4860-4868

Author(s):

Todd J. Zurlinden ◽

Garrett J. Eppers ◽

Brad Reisfeld

Keyword(s):

Time Course ◽

Pbpk Model ◽

Plasma Concentrations ◽

Optimal Dose ◽

Tissue Level ◽

Pharmacokinetic Data ◽

Rat Tissues ◽

Content Type ◽

Physiologically Based Pharmacokinetic ◽

Physiologically Based

ABSTRACTRifapentine (RPT) is a rifamycin antimycobacterial and, as part of a combination therapy, is indicated for the treatment of pulmonary tuberculosis (TB) caused byMycobacterium tuberculosis. Although the results from a number of studies indicate that rifapentine has the potential to shorten treatment duration and enhance completion rates compared to other rifamycin agents utilized in antituberculosis drug regimens (i.e., regimens 1 to 4), its optimal dose and exposure in humans are unknown. To help inform such an optimization, a physiologically based pharmacokinetic (PBPK) model was developed to predict time course, tissue-specific concentrations of RPT and its active metabolite, 25-desacetyl rifapentine (dRPT), in humans after specified administration schedules for RPT. Starting with the development and verification of a PBPK model for rats, the model was extrapolated and then tested using human pharmacokinetic data. Testing and verification of the models included comparisons of predictions to experimental data in several rat tissues and time course RPT and dRPT plasma concentrations in humans from several single- and repeated-dosing studies. Finally, the model was used to predict RPT concentrations in the lung during the intensive and continuation phases of a current recommended TB treatment regimen. Based on these results, it is anticipated that the PBPK model developed in this study will be useful in evaluating dosing regimens for RPT and for characterizing tissue-level doses that could be predictors of problems related to efficacy or safety.

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Comparison of the diagnostic performance and impact on management of 18F-FDG PET/CT and whole-body MRI in multiple myeloma

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-020-05182-2 ◽

2021 ◽

Author(s):

Olwen Westerland ◽

◽

Ashik Amlani ◽

Christian Kelly-Morland ◽

Michal Fraczek ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Data ◽

Bone Disease ◽

Fdg Pet ◽

Diagnostic Performance ◽

Whole Body ◽

Bone Lesions ◽

Pet Ct ◽

18F Fdg ◽

Fdg Pet Ct

Abstract Purpose Comparative data on the impact of imaging on management is lacking for multiple myeloma. This study compared the diagnostic performance and impact on management of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and whole-body magnetic resonance imaging (WBMRI) in treatment-naive myeloma. Methods Forty-six patients undergoing 18F-FDG PET/CT and WBMRI were reviewed by a nuclear medicine physician and radiologist, respectively, for the presence of myeloma bone disease. Blinded clinical and imaging data were reviewed by two haematologists in consensus and management recorded following clinical data ± 18F-FDG PET/CT or WBMRI. Bone disease was defined using International Myeloma Working Group (IMWG) criteria and a clinical reference standard. Per-patient sensitivity for lesion detection was established. McNemar test compared management based on clinical assessment ± 18F-FDG PET/CT or WBMRI. Results Sensitivity for bone lesions was 69.6% (32/46) for 18F-FDG PET/CT (54.3% (25/46) for PET component alone) and 91.3% (42/46) for WBMRI. 27/46 (58.7%) of cases were concordant. In 19/46 patients (41.3%) WBMRI detected more focal bone lesions than 18F-FDG PET/CT. Based on clinical data alone, 32/46 (69.6%) patients would have been treated. Addition of 18F-FDG PET/CT to clinical data increased this to 40/46 (87.0%) patients (p = 0.02); and WBMRI to clinical data to 43/46 (93.5%) patients (p = 0.002). The difference in treatment decisions was not statistically significant between 18F-FDG PET/CT and WBMRI (p = 0.08). Conclusion Compared to 18F-FDG PET/CT, WBMRI had a higher per patient sensitivity for bone disease. However, treatment decisions were not statistically different and either modality would be appropriate in initial staging, depending on local availability and expertise.

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