Research

11 pages, 1103 KiB

Open AccessArticle

Pharmacokinetic and Pharmacodynamic Rationale for Extending VEGF Inhibition Increasing Intravitreal Aflibercept Dose

by Daniele Veritti, Valentina Sarao, Francesco Di Bin and Paolo Lanzetta

Pharmaceutics 2023, 15(5), 1416; https://doi.org/10.3390/pharmaceutics15051416 - 06 May 2023

Cited by 2 | Viewed by 1747

Background: The effects of various dosages and treatment regimens on intravitreal aflibercept concentrations and the proportion of free vascular endothelial growth factor (VEGF) to total VEGF were evaluated using a drug and disease assessment model. The 8 mg dosage received specific attention. Methods: [...] Read more.

Background: The effects of various dosages and treatment regimens on intravitreal aflibercept concentrations and the proportion of free vascular endothelial growth factor (VEGF) to total VEGF were evaluated using a drug and disease assessment model. The 8 mg dosage received specific attention. Methods: A time-dependent mathematical model was developed and implemented using Wolfram Mathematica software v12.0. This model was used to obtain drug concentrations after multiple doses of different aflibercept dosages (0.5 mg, 2 mg, and 8 mg) and to estimate the time-dependent intravitreal free VEGF percentage levels. A series of fixed treatment regimens were modeled and evaluated as potential clinical applications. Results: The simulation results indicate that 8 mg aflibercept administered at a range of treatment intervals (between 12 and 15 weeks) would allow for the proportion of free VEGF to remain below threshold levels. Our analysis indicates that these protocols maintain the ratio of free VEGF below 0.001%. Conclusions: Fixed q12–q15 (every 12–15 weeks) 8 mg aflibercept regimens can produce adequate intravitreal VEGF inhibition. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)

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26 pages, 4408 KiB

Open AccessArticle

In Silico Analyses of a Promising Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis Targeting Superoxide Dismutase I Protein

by Gabriel Rodrigues Coutinho Pereira, Bárbara de Azevedo Abrahim-Vieira and Joelma Freire de Mesquita

Pharmaceutics 2023, 15(4), 1095; https://doi.org/10.3390/pharmaceutics15041095 - 29 Mar 2023

Cited by 2 | Viewed by 1712

Abstract

Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disorder in adults, which is associated with a highly disabling condition. To date, ALS remains incurable, and the only drugs approved by the FDA for its treatment confer a limited survival benefit. Recently, [...] Read more.

Amyotrophic lateral sclerosis (ALS) is the most prevalent motor neuron disorder in adults, which is associated with a highly disabling condition. To date, ALS remains incurable, and the only drugs approved by the FDA for its treatment confer a limited survival benefit. Recently, SOD1 binding ligand 1 (SBL-1) was shown to inhibit in vitro the oxidation of a critical residue for SOD1 aggregation, which is a central event in ALS-related neurodegeneration. In this work, we investigated the interactions between SOD1 wild-type and its most frequent variants, i.e., A4V (NP_000445.1:p.Ala5Val) and D90A (NP_000445.1:p.Asp91Val), with SBL-1 using molecular dynamics (MD) simulations. The pharmacokinetics and toxicological profile of SBL-1 were also characterized in silico. The MD results suggest that the complex SOD1-SBL-1 remains relatively stable and interacts within a close distance during the simulations. This analysis also suggests that the mechanism of action proposed by SBL-1 and its binding affinity to SOD1 may be preserved upon mutations A4V and D90A. The pharmacokinetics and toxicological assessments suggest that SBL-1 has drug-likeness characteristics with low toxicity. Our findings, therefore, suggested that SBL-1 may be a promising strategy to treat ALS based on an unprecedented mechanism, including for patients with these frequent mutations. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)

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23 pages, 3364 KiB

Open AccessArticle

Physiologically Based Pharmacokinetic Modelling to Predict Pharmacokinetics of Enavogliflozin, a Sodium-Dependent Glucose Transporter 2 Inhibitor, in Humans

by Min-Soo Kim, Yoo-Kyung Song, Ji-Soo Choi, Hye Young Ji, Eunsuk Yang, Joon Seok Park, Hyung Sik Kim, Min-Joo Kim, In-Kyung Cho, Suk-Jae Chung, Yoon-Jee Chae and Kyeong-Ryoon Lee

Pharmaceutics 2023, 15(3), 942; https://doi.org/10.3390/pharmaceutics15030942 - 14 Mar 2023

Cited by 4 | Viewed by 2142

Abstract

Enavogliflozin is a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor approved for clinical use in South Korea. As SGLT2 inhibitors are a treatment option for patients with diabetes, enavogliflozin is expected to be prescribed in various populations. Physiologically based pharmacokinetic (PBPK) modelling can rationally [...] Read more.

Enavogliflozin is a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor approved for clinical use in South Korea. As SGLT2 inhibitors are a treatment option for patients with diabetes, enavogliflozin is expected to be prescribed in various populations. Physiologically based pharmacokinetic (PBPK) modelling can rationally predict the concentration–time profiles under altered physiological conditions. In previous studies, one of the metabolites (M1) appeared to have a metabolic ratio between 0.20 and 0.25. In this study, PBPK models for enavogliflozin and M1 were developed using published clinical trial data. The PBPK model for enavogliflozin incorporated a non-linear urinary excretion in a mechanistically arranged kidney model and a non-linear formation of M1 in the liver. The PBPK model was evaluated, and the simulated pharmacokinetic characteristics were in a two-fold range from those of the observations. The pharmacokinetic parameters of enavogliflozin were predicted using the PBPK model under pathophysiological conditions. PBPK models for enavogliflozin and M1 were developed and validated, and they seemed useful for logical prediction. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)

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17 pages, 1384 KiB

Open AccessArticle

Building a Human Physiologically Based Pharmacokinetic Model for Aflatoxin B1 to Simulate Interactions with Drugs

by Orphélie Lootens, Marthe De Boevre, Jia Ning, Elke Gasthuys, Jan Van Bocxlaer, Sarah De Saeger and An Vermeulen

Pharmaceutics 2023, 15(3), 894; https://doi.org/10.3390/pharmaceutics15030894 - 09 Mar 2023

Cited by 1 | Viewed by 2073

Abstract

Mycotoxins such as aflatoxin B1 (AFB1) are secondary fungal metabolites present in food commodities and part of one’s daily exposure, especially in certain regions, e.g., sub-Saharan Africa. AFB1 is mostly metabolised by cytochrome P450 (CYP) enzymes, namely, CYP1A2 and CYP3A4. As a consequence [...] Read more.

Mycotoxins such as aflatoxin B1 (AFB1) are secondary fungal metabolites present in food commodities and part of one’s daily exposure, especially in certain regions, e.g., sub-Saharan Africa. AFB1 is mostly metabolised by cytochrome P450 (CYP) enzymes, namely, CYP1A2 and CYP3A4. As a consequence of chronic exposure, it is interesting to check for interactions with drugs taken concomitantly. A physiologically based pharmacokinetic (PBPK) model was developed based on the literature and in-house-generated in vitro data to characterise the pharmacokinetics (PK) of AFB1. The substrate file was used in different populations (Chinese, North European Caucasian and Black South African), provided by SimCYP^® software (v21), to evaluate the impact of populations on AFB1 PK. The model’s performance was verified against published human in vivo PK parameters, with AUC ratios and C_max ratios being within the 0.5–2.0-fold range. Effects on AFB1 PK were observed with commonly prescribed drugs in South Africa, leading to clearance ratios of 0.54 to 4.13. The simulations revealed that CYP3A4/CYP1A2 inducer/inhibitor drugs might have an impact on AFB1 metabolism, altering exposure to carcinogenic metabolites. AFB1 did not have effects on the PK of drugs at representative exposure concentrations. Therefore, chronic AFB1 exposure is unlikely to impact the PK of drugs taken concomitantly. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)

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23 pages, 45314 KiB

Open AccessArticle

Melatonin Mitigates Cisplatin-Induced Ovarian Dysfunction via Altering Steroidogenesis, Inflammation, Apoptosis, Oxidative Stress, and PTEN/PI3K/Akt/mTOR/AMPK Signaling Pathway in Female Rats

by Amal Al-Shahat, Mohey A. E. Hulail, Nada M. M. Soliman, Tarek Khamis, Liana Mihaela Fericean, Ahmed Hamed Arisha and Rania S. Moawad

Pharmaceutics 2022, 14(12), 2769; https://doi.org/10.3390/pharmaceutics14122769 - 10 Dec 2022

Cited by 11 | Viewed by 3837

Abstract

Ovarian damage and fertility impairment are major side effects of chemotherapy in pre-menopausal cancer patients. Cisplatin is a widely used chemotherapeutic drug. The present study was designed to assess the ameliorative effects of melatonin as an adjuvant for fertility preservation. Thirty-two adult female [...] Read more.

Ovarian damage and fertility impairment are major side effects of chemotherapy in pre-menopausal cancer patients. Cisplatin is a widely used chemotherapeutic drug. The present study was designed to assess the ameliorative effects of melatonin as an adjuvant for fertility preservation. Thirty-two adult female Wistar rats were divided randomly into four equal groups: Control, Melatonin, Cisplatin (CP) treated, and CP + Melatonin treated. The cisplatin-treated group showed decreased body and ovarian weights, decreased serum E2 and AMH, increased serum LH and FSH, reduced ovarian levels of SOD, CAT, GSH, and TAC, and increased ovarian MDA. The histopathological examination of the cisplatin-treated group showed deleterious changes within ovarian tissue in the form of damaged follicles and corpus luteum, hemorrhage, and inflammatory infiltrates with faint PAS reaction in zona pellucida, increased ovarian collagen deposition, and marked expression of caspase-3 immune reaction in granulosa and theca cells, stroma, and oocytes. Alongside, there was a significant downregulation in the mRNA expression of steroidogenic enzymes, IL10, AMPK, PI3K, AKT, mTOR, and PTEN, while TGF-β1, IL1β, IL6, TNF-α, NF-Kβ, P53, p38-MAPK, JNK, and FOXO3 mRNA expressions were upregulated in cisplatin-treated rats’ ovarian tissue. Coadministration of cisplatin-treated rats with melatonin reversed these changes significantly. In conclusion, melatonin’s antioxidant, anti-inflammatory, and anti-apoptotic activities could modulate ovarian disturbances induced by cisplatin and preserve fertility. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)

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22 pages, 6377 KiB

Open AccessArticle

Changes in Disposition of Ezetimibe and Its Active Metabolites Induced by Impaired Hepatic Function: The Influence of Enzyme and Transporter Activities

by Ningjie Xie, Hong Wang, Hua Qin, Zitao Guo, Hao Xue, Jiafeng Hu and Xiaoyan Chen

Pharmaceutics 2022, 14(12), 2743; https://doi.org/10.3390/pharmaceutics14122743 - 08 Dec 2022

Cited by 2 | Viewed by 1576

Abstract

Ezetimibe (EZE) is a selective cholesterol absorption inhibitor. Hepatic impairment significantly increases the systemic exposure of EZE and its main active phenolic glucuronide, EZE-Ph. Although changes in efflux transporter activity partly explain the changes in EZE-Ph pharmacokinetics, the causes of the changes to [...] Read more.

Ezetimibe (EZE) is a selective cholesterol absorption inhibitor. Hepatic impairment significantly increases the systemic exposure of EZE and its main active phenolic glucuronide, EZE-Ph. Although changes in efflux transporter activity partly explain the changes in EZE-Ph pharmacokinetics, the causes of the changes to EZE and the effects of the administration route on EZE-Ph remain unclear. A carbon tetrachloride (CCl₄)-induced hepatic failure rat model was combined with in vitro experiments to explore altered EZE and EZE-Ph disposition caused by hepatic impairment. The plasma exposure of EZE and EZE-Ph increased by 11.1- and 4.4-fold in CCl₄-induced rats following an oral administration of 10 mg/kg EZE, and by 2.1- and 16.4-fold after an intravenous injection. The conversion of EZE to EZE-Ph decreased concentration-dependently in CCl₄-induced rat liver S9 fractions, but no change was observed in the intestinal metabolism. EZE-Ph was a substrate for multiple efflux and uptake transporters, unlike EZE. In contrast to efflux transporters, no difference was seen in the hepatic uptake of EZE-Ph between control and CCl₄-induced rats. However, bile acids that accumulated due to liver injury inhibited the uptake of EZE-Ph by organic anion transporting polypeptides (OATPs) (glycochenodeoxycholic acid and taurochenodeoxycholic acid had IC₅₀ values of 15.1 and 7.94 μM in OATP1B3-overexpressed cells). In conclusion, the increased plasma exposure of the parent drug EZE during hepatic dysfunction was attributed to decreased hepatic glucuronide conjugation, whereas the increased exposure of the metabolite EZE-Ph was mainly related to transporter activity, particularly the inhibitory effects of bile acids on OATPs after oral administration. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)

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20 pages, 2028 KiB

Open AccessArticle

Prediction of Drug–Drug–Gene Interaction Scenarios of (E)-Clomiphene and Its Metabolites Using Physiologically Based Pharmacokinetic Modeling

by Christina Kovar, Lukas Kovar, Simeon Rüdesheim, Dominik Selzer, Boian Ganchev, Patrick Kröner, Svitlana Igel, Reinhold Kerb, Elke Schaeffeler, Thomas E. Mürdter, Matthias Schwab and Thorsten Lehr

Pharmaceutics 2022, 14(12), 2604; https://doi.org/10.3390/pharmaceutics14122604 - 25 Nov 2022

Cited by 1 | Viewed by 1605

Abstract

Clomiphene, a selective estrogen receptor modulator (SERM), has been used for the treatment of anovulation for more than 50 years. However, since (E)-clomiphene ((E)-Clom) and its metabolites are eliminated primarily via Cytochrome P450 (CYP) 2D6 and CYP3A4, exposure can [...] Read more.

Clomiphene, a selective estrogen receptor modulator (SERM), has been used for the treatment of anovulation for more than 50 years. However, since (E)-clomiphene ((E)-Clom) and its metabolites are eliminated primarily via Cytochrome P450 (CYP) 2D6 and CYP3A4, exposure can be affected by CYP2D6 polymorphisms and concomitant use with CYP inhibitors. Thus, clomiphene therapy may be susceptible to drug–gene interactions (DGIs), drug–drug interactions (DDIs) and drug–drug–gene interactions (DDGIs). Physiologically based pharmacokinetic (PBPK) modeling is a tool to quantify such DGI and DD(G)I scenarios. This study aimed to develop a whole-body PBPK model of (E)-Clom including three important metabolites to describe and predict DGI and DD(G)I effects. Model performance was evaluated both graphically and by calculating quantitative measures. Here, 90% of predicted C_max and 80% of AUC_last values were within two-fold of the corresponding observed value for DGIs and DD(G)Is with clarithromycin and paroxetine. The model also revealed quantitative contributions of different CYP enzymes to the involved metabolic pathways of (E)-Clom and its metabolites. The developed PBPK model can be employed to assess the exposure of (E)-Clom and its active metabolites in as-yet unexplored DD(G)I scenarios in future studies. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)

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16 pages, 3403 KiB

Open AccessArticle

AdipoRon Inhibits Neuroinflammation Induced by Deep Hypothermic Circulatory Arrest Involving the AMPK/NF-κB Pathway in Rats

by Weidong Yan, Sizhe Gao, Qiaoni Zhang, Jiachen Qi, Gang Liu, Yuan Teng, Jian Wang, Shujie Yan and Bingyang Ji

Pharmaceutics 2022, 14(11), 2467; https://doi.org/10.3390/pharmaceutics14112467 - 15 Nov 2022

Cited by 4 | Viewed by 1959

Abstract

Deep hypothermic circulatory arrest (DHCA) can induce systemic inflammatory response syndrome, including neuroinflammation. Finding suitable compounds is necessary for attenuating neuroinflammation and avoiding cerebral complications following DHCA. In the present study, we established DHCA rat models and monitored the vital signs during the [...] Read more.

Deep hypothermic circulatory arrest (DHCA) can induce systemic inflammatory response syndrome, including neuroinflammation. Finding suitable compounds is necessary for attenuating neuroinflammation and avoiding cerebral complications following DHCA. In the present study, we established DHCA rat models and monitored the vital signs during the surgical process. After surgery, we found significantly increased proinflammatory cytokines (IL-6, IL-1β, and TNF-α) in DHCA rats. Quantitative proteomics analysis was performed for exploring the differentially expressed proteins in hippocampus of DHCA rats and the data showed the adiponectin receptor 1 protein was upregulated. More importantly, administration of AdipoRon, a small-molecule adiponectin receptor agonist, could improve the basic vital signs and attenuate the increased IL-6, IL-1β, and TNF-α in DHCA rats. Furthermore, AdipoRon inhibits the activation of microglia (M1 state) and promotes their transition to an anti-inflammatory state, via promoting the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), and downregulating nuclear factor kappa B (NF-κB) in DHCA rats. Consistently, we used LPS-treated BV2 cells to mimic the neuroinflammatory condition and found that AdipoRon dose-dependently decreased cytokines, along with increased phosphorylation of AMPK and downregulated NF-κB. In conclusion, our present data supported that AdipoRon inhibited DHCA-induced neuroinflammation via activating the hippocampal AMPK/NF-κB pathway. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)

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14 pages, 2560 KiB

Open AccessArticle

Development and Evaluation of a Physiologically Based Pharmacokinetic Model of Labetalol in Healthy and Diseased Populations

by Hafsa Hafsa, Ammara Zamir, Muhammad Fawad Rasool, Imran Imran, Hamid Saeed, Tanveer Ahmad, Sary Alsanea, Ali A. Alshamrani, Abdullah H. Alruwaili and Faleh Alqahtani

Pharmaceutics 2022, 14(11), 2362; https://doi.org/10.3390/pharmaceutics14112362 - 02 Nov 2022

Cited by 8 | Viewed by 2813

Abstract

Labetalol is a drug that exhibits both alpha and beta-adrenergic receptor-blocking properties. The American Heart Association/American Stroke Association (AHA/ASA) has recommended labetalol as an initial treatment option for the management of severe hypertension. The physiologically based pharmacokinetic (PBPK) model is an in silico [...] Read more.

Labetalol is a drug that exhibits both alpha and beta-adrenergic receptor-blocking properties. The American Heart Association/American Stroke Association (AHA/ASA) has recommended labetalol as an initial treatment option for the management of severe hypertension. The physiologically based pharmacokinetic (PBPK) model is an in silico approach to determining the pharmacokinetics (PK) of a drug by incorporating blood flow and tissue composition of the organs. This study was conducted to evaluate the primary reasons for the difference in PK after intravenous (IV) and oral administration in healthy and diseased (renal and hepatic) populations. A comprehensive literature search was done using two databases, PubMed and Google Scholar. Various PK parameters were screened for the development of the PBPK model utilizing a population-based PK-Sim simulator. Simulations were performed after creating building blocks firstly in healthy individuals and then in diseased patients after IV and oral administration. The disposition of labetalol after IV and oral administration occurring in patients with the hepatic and renal disease was predicted. The model was evaluated by calculating the R_obs/_pred ratio and average fold error (AFE), which was in the two-fold error range. Moreover, Box-whisker plots were made to compare the overall concentration of the drug in the body at various stages of disease severity. The presented model provides useful quantitative estimates of drug dosing in patients fighting against severe chronic diseases. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)

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14 pages, 3685 KiB

Open AccessArticle

Findings on In Vitro Transporter-Mediated Drug Interactions and Their Follow-Up Actions for Labeling: Analysis of Drugs Approved by US FDA between 2017 and 2021

by Kyeong-Ryoon Lee, Ji-Eun Chang, Jongmin Yoon, Hyojeong Jin and Yoon-Jee Chae

Pharmaceutics 2022, 14(10), 2078; https://doi.org/10.3390/pharmaceutics14102078 - 29 Sep 2022

Cited by 1 | Viewed by 1173

Abstract

Understanding possible follow-up actions on in vitro findings helps determine the necessity of labeling for drug interactions. We analyzed information for in vitro findings on transporter-mediated interactions of drugs approved by the U.S. Food and Drug Administration’s Center for Drug Evaluation and Research [...] Read more.

Understanding possible follow-up actions on in vitro findings helps determine the necessity of labeling for drug interactions. We analyzed information for in vitro findings on transporter-mediated interactions of drugs approved by the U.S. Food and Drug Administration’s Center for Drug Evaluation and Research for the last five years (i.e., 2017–2021) and their follow-up actions for labeling. Higher R values than the pre-defined cut-off were observed with 3.7–39.1% inhibitor drugs in a simple prediction. Among these drugs, 16–41.7% were labeled with their potential drug interactions, while results of supporting studies or scientific rationales were submitted for the other drugs leading to no interaction labeling. In vitro transporter substrates were reported with 1.7–67.6% of drugs. The interaction labels for these substrate drugs were observed in up to 40% of drugs, while the other drugs were not labeled on the drug interactions with claims for their low interaction potential, evidenced by clinical studies or scientific rationales. The systematic and comprehensive analysis in this study will provide insight into the management of in vitro findings for transporter substrate or inhibitor drugs. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)

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11 pages, 613 KiB

Open AccessArticle

Simulation-Based Gastrointestinal Endoscopy Sedations: A Novel Validation to Multidrug Pharmacodynamic Modeling

by Jing-Yang Liou, Hsin-Yi Wang, I-Ting Kuo, Wen-Kuei Chang and Chien-Kun Ting

Pharmaceutics 2022, 14(10), 2056; https://doi.org/10.3390/pharmaceutics14102056 - 27 Sep 2022

Viewed by 1057

Abstract

Pharmacodynamic models have described the interactions between anesthetics. Applying the models to clinical practice is still problematic due to inherent limitations: 1. modeling conditions are different from practice. 2. One model can only describe one endpoint. To tackle these, we propose a new [...] Read more.

Pharmacodynamic models have described the interactions between anesthetics. Applying the models to clinical practice is still problematic due to inherent limitations: 1. modeling conditions are different from practice. 2. One model can only describe one endpoint. To tackle these, we propose a new method of model validation for recovery and intraprocedural sedation adequacy with a three-drug pharmacodynamic model using six published clinical studies that contain midazolam, opioid, and propofol. Mean drug dose, intraprocedural sedation level, procedure, and recovery time are extracted from each study. Simulated drug regimens are designed to best approximate study conditions. A published deep sedation model is used for simulation. Model-predicted recovery time and intraprocedural sedation scores are compared with the original clinical study outcomes. The model successfully predicted recovery times in eight out of nine regimens. Lower doses of midazolam are associated with faster recovery. Model prediction of intraprocedural sedation level was compatible with the clinical studies in five out of seven regimens. The three-drug pharmacodynamic model describes the course of gastrointestinal endoscopy sedations from clinical studies well. Model predictions are consistent with the results from clinical studies. The approach implies that large scale validation can be performed repeatedly. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)

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23 pages, 5758 KiB

Open AccessArticle

Development and Evaluation of a Physiologically Based Pharmacokinetic Model for Predicting Haloperidol Exposure in Healthy and Disease Populations

by Mohammed S. Alasmari, Fawaz Alasmari, Abdullah F. Alasmari, Aws Alshamsan, Sary Alsanea, Muhammad F. Rasool and Faleh Alqahtani

Pharmaceutics 2022, 14(9), 1795; https://doi.org/10.3390/pharmaceutics14091795 - 26 Aug 2022

Cited by 2 | Viewed by 2462

Abstract

The physiologically based pharmacokinetic (PBPK) approach can be used to develop mathematical models for predicting the absorption, distribution, metabolism, and elimination (ADME) of administered drugs in virtual human populations. Haloperidol is a typical antipsychotic drug with a narrow therapeutic index and is commonly [...] Read more.

The physiologically based pharmacokinetic (PBPK) approach can be used to develop mathematical models for predicting the absorption, distribution, metabolism, and elimination (ADME) of administered drugs in virtual human populations. Haloperidol is a typical antipsychotic drug with a narrow therapeutic index and is commonly used in the management of several medical conditions, including psychotic disorders. Due to the large interindividual variability among patients taking haloperidol, it is very likely for them to experience either toxic or subtherapeutic effects. We intend to develop a haloperidol PBPK model for identifying the potential sources of pharmacokinetic (PK) variability after intravenous and oral administration by using the population-based simulator, PK-Sim. The model was initially developed and evaluated to predict the PK of haloperidol and its reduced metabolite in adult healthy population after intravenous and oral administration. After evaluating the developed PBPK model in healthy adults, it was used to predict haloperidol–rifampicin drug–drug interaction and was extended to tuberculosis patients. The model evaluation was performed using visual assessments, prediction error, and mean fold error of the ratio of the observed-to-predicted values of the PK parameters. The predicted PK values were in good agreement with the corresponding reported values. The effects of the pathophysiological changes and enzyme induction associated with tuberculosis and its treatment, respectively, on haloperidol PK, have been predicted precisely. For all clinical scenarios that were evaluated, the predicted values were within the acceptable two-fold error range. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)

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19 pages, 1875 KiB

Open AccessArticle

Daily Intraperitoneal Administration of Rosiglitazone Does Not Improve Lung Function or Alveolarization in Preterm Rabbits Exposed to Hyperoxia

by Giorgio Aquila, Yannick Regin, Xabier Murgia, Fabrizio Salomone, Costanza Casiraghi, Chiara Catozzi, Enrica Scalera, Matteo Storti, Francesca Stretti, Giancarlo Aquino, Giorgia Cavatorta, Roberta Volta, Carmelina Di Pasquale, Caterina Amato, Fabio Bignami, Davide Amidani, Barbara Pioselli, Elisa Sgarbi, Paolo Ronchi, Giuseppe Mazzola, Ignacio Valenzuela and Jaan Toelen Show full author list Hide full author list

Pharmaceutics 2022, 14(7), 1507; https://doi.org/10.3390/pharmaceutics14071507 - 20 Jul 2022

Cited by 1 | Viewed by 2520

Abstract

Thiazolidinediones (TZDs) are potent PPARγ agonists that have been shown to attenuate alveolar simplification after prolonged hyperoxia in term rodent models of bronchopulmonary dysplasia. However, the pulmonary outcomes of postnatal TZDs have not been investigated in preterm animal models. Here, we first investigated [...] Read more.

Thiazolidinediones (TZDs) are potent PPARγ agonists that have been shown to attenuate alveolar simplification after prolonged hyperoxia in term rodent models of bronchopulmonary dysplasia. However, the pulmonary outcomes of postnatal TZDs have not been investigated in preterm animal models. Here, we first investigated the PPARγ selectivity, epithelial permeability, and lung tissue binding of three types of TZDs in vitro (rosiglitazone (RGZ), pioglitazone, and DRF-2546), followed by an in vivo study in preterm rabbits exposed to hyperoxia (95% oxygen) to investigate the pharmacokinetics and the pulmonary outcomes of daily RGZ administration. In addition, blood lipids and a comparative lung proteomics analysis were also performed on Day 7. All TZDs showed high epithelial permeability through Caco-2 monolayers and high plasma and lung tissue binding; however, RGZ showed the highest affinity for PPARγ. The pharmacokinetic profiling of RGZ (1 mg/kg) revealed an equivalent biodistribution after either intratracheal or intraperitoneal administration, with detectable levels in lungs and plasma after 24 h. However, daily RGZ doses of 1 mg/kg did not improve lung function in preterm rabbits exposed to hyperoxia, and daily 10 mg/kg doses were even associated with a significant lung function worsening, which could be partially explained by the upregulation of lung inflammation and lipid metabolism pathways revealed by the proteomic analysis. Notably, daily postnatal RGZ produced an aberrant modulation of serum lipids, particularly in rabbit pups treated with the 10 mg/kg dose. In conclusion, daily postnatal RGZ did not improve lung function and caused dyslipidemia in preterm rabbits exposed to hyperoxia. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)

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21 pages, 1558 KiB

Open AccessArticle

Prediction of Pharmacokinetics of IDP-73152 in Humans Using Physiologically-Based Pharmacokinetics

by Myongjae Lee, Yoo-Seong Jeong, Min-Soo Kim, Kyung-Mi An and Suk-Jae Chung

Pharmaceutics 2022, 14(6), 1157; https://doi.org/10.3390/pharmaceutics14061157 - 28 May 2022

Viewed by 1980

Abstract

IDP-73152, a novel peptide deformylase inhibitor with an antibacterial effect against Gram-positive bacteria, is in phase I development. The objective of this study was to develop a physiologically-based pharmacokinetic model (PBPK) for IDP-73152 in animals, and to extend the model to humans. Biopharmaceutical [...] Read more.

IDP-73152, a novel peptide deformylase inhibitor with an antibacterial effect against Gram-positive bacteria, is in phase I development. The objective of this study was to develop a physiologically-based pharmacokinetic model (PBPK) for IDP-73152 in animals, and to extend the model to humans. Biopharmaceutical properties of IDP-73152 are determined using in vitro/in vivo experimentations for the PBPK model. A transit model consisting of gastrointestinal segments is applied for an estimation of the intestinal absorption kinetics. The PBPK model of IDP-73152 in rats is able to appropriately predict the plasma concentration–time profiles after the administration of IDP-73152 at different doses and by different routes (combined absolute average fold error (cAAFE), 1.77). The model is also found to be adequate in predicting the plasma concentration–time profiles of IDP-73152 in mice (cAAFE 1.59) and dogs (cAAFE 1.42). Assuming the oral administration of IDP-73152 to humans at doses of 640 and 1280 mg, the model is able to reproduce the concentration–time profiles obtained in humans (cAAFE 1.38); therefore, these observations indicate that the PBPK model used for IDP-73152 is applicable to animal species and humans. This model may be useful in predicting efficacious doses of IDP-73152 for the management of infectious disease in humans. Full article

(This article belongs to the Special Issue Advances in Pharmacokinetics, Pharmacodynamics and Drug Interactions)

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