المؤلفون: Shun Hayashi, Hiroko Kawaguchi, Takao Watanabe, Izuru Miyawaki, Tatsuki Fukami, Miki Nakajima

مصطلحات موضوعية: Biochemistry, Medicine, Cell Biology, Genetics, Physiology, Pharmacology, Biotechnology, Cancer, Biological Sciences not elsewhere classified, Information Systems not elsewhere classified, Tipepidine, drug repositioning, CYP2D6, drug interaction, physiologically based pharmacokinetic modelling

الوصف: Tipepidine, an antitussive drug, has been reported to have central pharmacological effects and can be expected to be safely repositioned as treatment for psychiatric disorders. Since tipepidine requires three doses per day, development of a once-daily medication would be highly beneficial. Previously, we reported that combination use with quinidine, a CYP2D6 inhibitor, prolongs the half-life of tipepidine in chimeric mice with humanised liver. In this study, to predict this combination effect in humans, a physiologically based pharmacokinetic (PBPK) model was developed, and quantitative simulation was conducted. The simulation results indicated that concomitant administration of tipepidine with quinidine increased the predicted C max , AUC , and t 1/2 of tipepidine in the Japanese population by 3.4-, 6.6-, and 2.4-fold, respectively. Furthermore, to compare with another approach that aims to prolong the half-life, the PK profile of tipepidine administered in hypothetical extended-release form was simulated. Extended-release form was predicted to be more influenced by CYP2D6 genotype than combination with quinidine, and the predicted plasma exposure was markedly increased in poor metabolizers, potentially leading to adverse effects. In conclusion, quantitative simulation using the PBPK model suggests the feasibility of the safe repositioning of tipepidine as a once-daily medication in combination with quinidine. Tipepidine, an antitussive drug, has been reported to have central pharmacological effects and can be expected to be safely repositioned as treatment for psychiatric disorders. Since tipepidine requires three doses per day, development of a once-daily medication would be highly beneficial. Previously, we reported that combination use with quinidine, a CYP2D6 inhibitor, prolongs the half-life of tipepidine in chimeric mice with humanised liver. In this study, to predict this combination effect in humans, a physiologically based pharmacokinetic (PBPK) model was developed, and quantitative simulation was ...

العلاقة: https://figshare.com/articles/journal_contribution/Prediction_of_combination_effect_of_quinidine_on_the_pharmacokinetics_of_tipepidine_using_a_physiologically_based_pharmacokinetic_model/25018370Test

الإتاحة: https://doi.org/10.6084/m9.figshare.25018370.v1Test
https://figshare.com/articles/journal_contribution/Prediction_of_combination_effect_of_quinidine_on_the_pharmacokinetics_of_tipepidine_using_a_physiologically_based_pharmacokinetic_model/25018370Test

المؤلفون: Musther, Helen

المساهمون: Hallifax, David, Rostami-Hochaghan, Amin

مصطلحات موضوعية: 615.1, Drug distribution, Physiologically Based Pharmacokinetic modelling, Volume of distribution

الوصف: Descriptions of drug distribution are critical in the drug discovery and development process, with models available to describe and predict relevant parameters (Kp values) for use in physiologicallybased pharmacokinetic (PBPK) models. However, current prediction models have been observed to have limitations that could compromise their continued use. Parameters relating to drug-plasma binding and drug-lipid binding or partitioning are key features in predictions of Kp, however, these are subject to a number of assumptions that cannot easily be challenged due to the lack of supporting in vitro data. Initial comparisons of volume of distribution (Vss) predictions to available in vivo data, indicated that drugs for which distribution is poorly predicted display a range of physicochemical and blood-binding properties, suggesting a number of potential reasons for erroneous predictions. The hypothesis that lipid contributions are not accounted for in equilibrium dialysis measures of drug binding in plasma was challenged by development and validation of a novel assay utilising delipidated serum. Fraction unbound determinations in normal serum and delipidated serum showed a statistically significant 2.88-fold difference for imipramine (strongly basic, logPO:W 4.8), indicating that lipid binding is included when using this technique, and that correction models need not be developed for this contribution. However, for the weakly basic midazolam (logPO:W 3.15), no difference was observed, potentially suggesting mechanisms for lipid binding are related to factors other than just the lipophilicity. Collation of a literature database for plasma binding values for 4 drugs indicated high uncertainty in measured in vitro data, with this uncertainty reflected in subsequent Vss predictions, and care in assessing data incorporated into these models is advised. Explorations of the binding of drugs to individual phospholipid and unique combination cell mimic liposomes was undertaken by development of surface plasmon resonance (SPR) methods, and application of different models for data fitting. The acidic binding phospholipid affinity constant (Ka,AP) was determined with phosphatidylserine for 15 drugs, with the resultant values showing a poor correlation with the values derived from the commonly used blood cell binding calculation. Use of the SPR derived Ka,AP values in predictions of Vss led to an increase in precision with an observed AAFE of 3.14 compared to 3.37 using the blood cell binding calculated values. Binding of 14 drugs to phosphatidylcholine liposomes indicated that basic drugs bind more strongly to the acidic phospholipids, however, zwitterions can behave differently. A case study comparing terfenadine and fexofenadine highlighted the impact of drug structure differences on the lipid-binding capability. Comparisons, conducted here for the first time, of SPR derived binding (Kd) and partitioning (Kp) parameters for phosphatidylcholine, to the 0.3P+0.7 term, used to describe neutral phospholipid binding in the current tissue distribution prediction models, did not indicate a strong correlation. The determination of capture corrected binding isotherms for individual phospholipids and combination liposomes for 3 drugs indicated differences in capacity and affinity between the lipids, including differences between acidic phospholipids, which are not accounted for in the current prediction models. Combinations of Kd and Bmax (binding capacity) indicated that the use of only phosphatidylserine and phosphatidylcholine would not allow the estimation of cell mimic binding although, in the binding isotherms, cell mimic liposomes without cholesterol appeared to behave similarly to neutral phospholipid liposomes. The addition of cholesterol in the cell mimic resulted in a decrease in the binding of drug. Expansion of the use of the cell mimic liposomes to 17, predominantly acidic, uptake transporter substrates gave a poor correlation to observed logD7.4, and in vitro derived passive diffusion and cell permeability parameters for hepatocyte assays. Comparisons of equilibrium dialysis liposome binding with SPR data for propranolol, midazolam and bosentan indicated a potential difference in lipid-binding and membrane association mechanisms for acidic lipophilic drugs, compared to basic lipophilic drugs. Finally, an extensive evaluation of the available literature data for human tissue lipid composition revealed serious limitations, with prioritisation of tissues for an in vitro determination of lipid components driven by the potential impact on the overall Vss prediction recommended. In conclusion, this study provides a comprehensive review of the lipid binding parameters used in current models for the predictions of drug tissue distribution, and assessment of the limitations of the current terms, with supporting in vitro data. The complexities of the mechanisms driving drug-lipid binding have been highlighted, and a deeper understanding of the interplay between physicochemical, structural and external contributions is shown necessary for the development of improved models.

الوصول الحر: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.825903Test

المؤلفون: Julia Macente, Nina Nauwelaerts, Francesca M. Russo, Jan Deprest, Karel Allegaert, Bart Lammens, Rodolfo Hernandes Bonan, Jessica M. Turner, Sailesh Kumar, Andrea Diniz, Frederico S. Martins, Pieter Annaert

مصطلحات موضوعية: Pharmacology, Basic Pharmacology, Clinical Pharmacology and Therapeutics, Clinical Pharmacy and Pharmacy Practice, Pharmaceutical Sciences, Pharmacogenomics, Toxicology (incl. Clinical Toxicology), Pharmacology and Pharmaceutical Sciences not elsewhere classified, physiologically-based pharmacokinetic modelling, PBPK, model informed drug development, MIDD, sildenafil, revatio, congenital diaphragmatic hernia, pregnant women

الوصف: Sildenafil is a potent vasodilator and phosphodiesterase type five inhibitor, commercially known as Revatio ® and approved for the treatment of pulmonary arterial hypertension. Maternal administration of sildenafil during pregnancy is being evaluated for antenatal treatment of several conditions, including the prevention of pulmonary hypertension in fetuses with congenital diaphragmatic hernia. However, determination of a safe and effective maternal dose to achieve adequate fetal exposure to sildenafil remains challenging, as pregnancy almost always is an exclusion criterion in clinical studies. Physiologically-based pharmacokinetic (PBPK) modelling offers an attractive approach for dose finding in this specific population. The aim of this study is to exploit physiologically-based pharmacokinetic modelling to predict the required maternal dose to achieve therapeutic fetal exposure for the treatment congenital diaphragmatic hernia. A full-PBPK model was developed for sildenafil and N-desmethyl-sildenafil using the Simcyp simulator V21 platform, and verified in adult reference individuals, as well as in pregnant women, taking into account maternal and fetal physiology, along with factors known to determine hepatic disposition of sildenafil. Clinical pharmacokinetic data in mother and fetus were previously obtained in the RIDSTRESS study and were used for model verification purposes. Subsequent simulations were performed relying either on measured values for fetal fraction unbound (fu = 0.108) or on values predicted by the simulator (fu = 0.044). Adequate doses were predicted according to the efficacy target of 15 ng/mL (or 38 ng/mL) and safety target of 166 ng/mL (or 409 ng/mL), assuming measured (or predicted) fu values, respectively. Considering simulated median profiles for average steady state sildenafil concentrations, dosing regimens of 130 mg/day or 150 mg/day (administered as t.i.d.), were within the therapeutic window, assuming either measured or predicted fu values, respectively. For safety reasons, ...

العلاقة: https://figshare.com/articles/presentation/Presentation1_PBPK-based_dose_finding_for_sildenafil_in_pregnant_women_for_antenatal_treatment_of_congenital_diaphragmatic_hernia_pdf/22267321Test

الإتاحة: https://doi.org/10.3389/fphar.2023.1068153.s001Test
https://figshare.com/articles/presentation/Presentation1_PBPK-based_dose_finding_for_sildenafil_in_pregnant_women_for_antenatal_treatment_of_congenital_diaphragmatic_hernia_pdf/22267321Test

المؤلفون: Leyanis Rodriguez-Vera, Xuefen Yin, Mohammed Almoslem, Karolin Romahn, Brian Cicali, Viera Lukacova, Rodrigo Cristofoletti, Stephan Schmidt

المصدر: Pharmaceutics, Vol 15, Iss 10, p 2486 (2023)

مصطلحات موضوعية: physiologically based pharmacokinetic modelling (PBPK), drug–drug interactions (DDIs), phenytoin, cytochrome P450 2C9 (CYP2C9), cytochrome P450 2C19 (CYP2C19), Pharmacy and materia medica, RS1-441

الوصف: Regulatory agencies worldwide expect that clinical pharmacokinetic drug–drug interactions (DDIs) between an investigational new drug and other drugs should be conducted during drug development as part of an adequate assessment of the drug’s safety and efficacy. However, it is neither time nor cost efficient to test all possible DDI scenarios clinically. Phenytoin is classified by the Food and Drug Administration as a strong clinical index inducer of CYP3A4, and a moderate sensitive substrate of CYP2C9. A physiologically based pharmacokinetic (PBPK) platform model was developed using GastroPlus® to assess DDIs with phenytoin acting as the victim (CYP2C9, CYP2C19) or perpetrator (CYP3A4). Pharmacokinetic data were obtained from 15 different studies in healthy subjects. The PBPK model of phenytoin explains the contribution of CYP2C9 and CYP2C19 to the formation of 5-(4′-hydroxyphenyl)-5-phenylhydantoin. Furthermore, it accurately recapitulated phenytoin exposure after single and multiple intravenous and oral doses/formulations ranging from 248 to 900 mg, the dose-dependent nonlinearity and the magnitude of the effect of food on phenytoin pharmacokinetics. Once developed and verified, the model was used to characterize and predict phenytoin DDIs with fluconazole, omeprazole and itraconazole, i.e., simulated/observed DDI AUC ratio ranging from 0.89 to 1.25. This study supports the utility of the PBPK approach in informing drug development.

وصف الملف: electronic resource

العلاقة: https://www.mdpi.com/1999-4923/15/10/2486Test; https://doaj.org/toc/1999-4923Test

الوصول الحر: https://doaj.org/article/a264f6e2b35344d99f434b3337e22602Test

المؤلفون: Tan, Shawn pei feng, Willemin, Marie‐emilie, Snoeys, Jan, Shen, Hong, Rostami‐hodjegan, Amin, Scotcher, Daniel, Galetin, Aleksandra

المصدر: Tan , S P F , Willemin , M , Snoeys , J , Shen , H , Rostami‐hodjegan , A , Scotcher , D & Galetin , A 2023 , ' Development of 4-Pyridoxic Acid PBPK Model to Support Biomarker- Informed Evaluation of OAT1/3 Inhibition and Effect of Chronic Kidney Disease ' , Clinical Pharmacology & Therapeutics . https://doi.org/10.1002/cpt.3029Test

مصطلحات موضوعية: Drug-drug interaction, Endogenous Biomarker, Chronic Kidney Disease, Physiologically-based Pharmacokinetic Modelling, Organic Anion Transporters

الوصف: Monitoring endogenous biomarkers is increasingly used to evaluate transporter-mediated drug-drug interactions (DDIs) in early drug development and may be applied to elucidate changes in transporter activity in disease. 4-pyridoxic acid (PDA) has been identified as the most sensitive plasma endogenous biomarker of renal organic anion transporters (OAT1/3). Increase in PDA baseline concentrations was observed after administration of probenecid, a strong clinical inhibitor of OAT1/3 and also in chronic kidney disease (CKD) patients. The aim of this study was to develop and verify a physiologically-based pharmacokinetic (PBPK) model of PDA, to predict the magnitude of probenecid DDI and predict the CKD-related changes in PDA baseline. PBPK model for PDA was first developed in healthy population, building on from previous population pharmacokinetic modelling, and incorporating a mechanistic kidney model to consider OAT1/3-mediated renal secretion. Probenecid PBPK model was adapted from the Simcyp database and re-verified to capture its dose-dependent pharmacokinetics (n=9 studies). The PBPK model successfully predicted the PDA plasma concentrations, area under the curve and renal clearance in healthy subjects at baseline and after single/multiple probenecid doses. Prospective simulations in severe CKD predicted successfully the increase in PDA plasma concentration relative to healthy (within two-fold of observed data) after accounting for 60% increase to fraction unbound in plasma and additional 50% decline in OAT1/3 activity beyond the decrease in glomerular filtration rate. The verified PDA PBPK model supports future robust evaluation of OAT1/3 DDI in drug development and increases our confidence in predicting exposure and renal secretion in CKD patients.

وصف الملف: application/pdf

العلاقة: https://research.manchester.ac.uk/en/publications/4f90ccdb-4dc2-4283-933c-90846d41ae99Test

الإتاحة: https://doi.org/10.1002/cpt.3029Test
https://research.manchester.ac.uk/en/publications/4f90ccdb-4dc2-4283-933c-90846d41ae99Test
https://pure.manchester.ac.uk/ws/files/274634385/Clin_Pharma_and_Therapeutics_2023_Tan.pdfTest

المؤلفون: Andrew Lim, Pradeep Sharma, Oleg Stepanov, Venkatesh Pilla Reddy

المصدر: Pharmaceutics; Volume 15; Issue 5; Pages: 1552

مصطلحات موضوعية: pharmacokinetic modelling, PBPK modelling, popPK modelling, pharmacokinetics, pediatrics, monoclonal antibodies, physiologically based pharmacokinetic modelling, population pharmacokinetics

الوصف: Ethical regulations and limited paediatric participants are key challenges that contribute to a median delay of 6 years in paediatric mAb approval. To overcome these barriers, modelling and simulation methodologies have been adopted to design optimized paediatric clinical studies and reduce patient burden. The classical modelling approach in paediatric pharmacokinetic studies for regulatory submissions is to apply body weight-based or body surface area-based allometric scaling to adult PK parameters derived from a popPK model to inform the paediatric dosing regimen. However, this approach is limited in its ability to account for the rapidly changing physiology in paediatrics, especially in younger infants. To overcome this limitation, PBPK modelling, which accounts for the ontogeny of key physiological processes in paediatrics, is emerging as an alternative modelling strategy. While only a few mAb PBPK models have been published, PBPK modelling shows great promise demonstrating a similar prediction accuracy to popPK modelling in an Infliximab paediatric case study. To facilitate future PBPK studies, this review consolidated comprehensive data on the ontogeny of key physiological processes in paediatric mAb disposition. To conclude, this review discussed different use-cases for pop-PK and PBPK modelling and how they can complement each other to increase confidence in pharmacokinetic predictions.

وصف الملف: application/pdf

العلاقة: Pharmacokinetics and Pharmacodynamics; https://dx.doi.org/10.3390/pharmaceutics15051552Test

الإتاحة: https://doi.org/10.3390/pharmaceutics15051552Test

المؤلفون: Tom G. Jacobs, Marika A. de Hoop-Sommen, Thomas Nieuwenstein, Joyce E. M. van der Heijden, Saskia N. de Wildt, David M. Burger, Angela Colbers, Jolien J. M. Freriksen

المصدر: Pharmaceutics; Volume 15; Issue 5; Pages: 1424

مصطلحات موضوعية: HIV, physiologically based pharmacokinetic modelling, chronic kidney disease, paediatrics, emtricitabine, lamivudine

الوصف: Dose recommendations for lamivudine or emtricitabine in children with HIV and chronic kidney disease (CKD) are absent or not supported by clinical data. Physiologically based pharmacokinetic (PBPK) models have the potential to facilitate dose selection for these drugs in this population. Existing lamivudine and emtricitabine compound models in Simcyp® (v21) were verified in adult populations with and without CKD and in non-CKD paediatric populations. We developed paediatric CKD population models reflecting subjects with a reduced glomerular filtration and tubular secretion, based on extrapolation from adult CKD population models. These models were verified using ganciclovir as a surrogate compound. Then, lamivudine and emtricitabine dosing strategies were simulated in virtual paediatric CKD populations. The compound and paediatric CKD population models were verified successfully (prediction error within 0.5- to 2-fold). The mean AUC ratios in children (GFR-adjusted dose in CKD population/standard dose in population with normal kidney function) were 1.15 and 1.23 for lamivudine, and 1.20 and 1.30 for emtricitabine, with grade-3- and -4-stage CKD, respectively. With the developed paediatric CKD population PBPK models, GFR-adjusted lamivudine and emtricitabine dosages in children with CKD resulted in adequate drug exposure, supporting paediatric GFR-adjusted dosing. Clinical studies are needed to confirm these findings.

وصف الملف: application/pdf

العلاقة: Pharmacokinetics and Pharmacodynamics; https://dx.doi.org/10.3390/pharmaceutics15051424Test

الإتاحة: https://doi.org/10.3390/pharmaceutics15051424Test

المؤلفون: 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, Kyeong-Ryoon Lee

المصدر: Pharmaceutics; Volume 15; Issue 3; Pages: 942

مصطلحات موضوعية: enavogliflozin, DWP16001, GCC5694A, sodium-glucose cotransporter 2 inhibitor, diabetes mellitus, physiologically based pharmacokinetic modelling, pharmacokinetics, mechanistic kidney model, in vitro–in vivo extrapolation

الوصف: 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.

وصف الملف: application/pdf

العلاقة: Pharmacokinetics and Pharmacodynamics; https://dx.doi.org/10.3390/pharmaceutics15030942Test

الإتاحة: https://doi.org/10.3390/pharmaceutics15030942Test

المؤلفون: Meslin, Matthieu, Beausoleil, Claire, Zeman, Florence, Antignac, Jean-Philippe, Kolossa-Gehring, Marike, Rousselle, Christophe, Apel, Petra

المساهمون: Direction de l'Evaluation des Risques (DER), Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES), Institut National de l'Environnement Industriel et des Risques (INERIS), Laboratoire d'étude des Résidus et Contaminants dans les Aliments (LABERCA), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), German Federal Environmental Agency / Umweltbundesamt (UBA), European Project: 733032,H2020,HBM4EU(2017)

المصدر: ISSN: 2305-6304 ; Toxics ; https://anses.hal.science/anses-03661044Test ; Toxics, 2022, 10 (5), pp.228. ⟨10.3390/toxics10050228⟩ ; https://www.mdpi.com/2305-6304/10/5/228Test.

مصطلحات موضوعية: human biomonitoring (HBM), HBM4EU, internal exposure, biomarkers, endocrine disruptors, bisphenol A (BPA), bisphenol S (BPS), bisphenols, human biomonitoring guidance value (HBM-GV), physiologically based pharmacokinetic modelling (PBPK), risk assessment, [SDV.TOX]Life Sciences [q-bio]/Toxicology, [SDV.EE.SANT]Life Sciences [q-bio]/Ecology, environment/Health, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie

الوصف: International audience ; Within the European Joint Programme HBM4EU, Human Biomonitoring Guidance Values (HBM-GVs) were derived for several prioritised substances. In this paper, the derivation of HBM-GVs for the general population (HBM-GVGenPop) and workers (HBM-GVworker) referring to bisphenol S (BPS) is presented. For the general population, this resulted in an estimation of the total urinary concentration of BPS of 1.0 µg/L assuming a 24 h continuous exposure to BPS. For workers, the modelling was refined in order to reflect continuous exposure during the working day, leading to a total urinary concentration of BPS of 3.0 µg/L. The usefulness for risk assessment of the HBM-GVs derived for BPS and bisphenol A (BPA) is illustrated. Risk Characterisation Ratios (RCRs) were calculated leading to a clear difference between risk assessments performed for both bisphenols, with a very low RCR regarding exposure to BPA., contrary to that obtained for BPS. This may be due to the endocrine mediated endpoints selected to derive the HBM-GVs for BPS, whereas the values calculated for BPA are based on the temporary Tolerable Daily Intake (t-TDI) from EFSA set in 2015. A comparison with the revised TDI recently opened for comments by EFSA is also discussed. Regarding the occupational field, results indicate that the risk from occupational exposure to both bisphenols cannot be disregarded.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/35622642; info:eu-repo/grantAgreement//733032/EU/European Human Biomonitoring Initiative/HBM4EU; anses-03661044; https://anses.hal.science/anses-03661044Test; https://anses.hal.science/anses-03661044/documentTest; https://anses.hal.science/anses-03661044/file/Meslin_Toxics_2022.pdfTest; PUBMED: 35622642; WOS: 000803380300001

الإتاحة: https://doi.org/10.3390/toxics10050228Test
https://anses.hal.science/anses-03661044Test
https://anses.hal.science/anses-03661044/documentTest
https://anses.hal.science/anses-03661044/file/Meslin_Toxics_2022.pdfTest

المؤلفون: Karel Allegaert, Mohammad Yaseen Abbasi, Robin Michelet, Olusola Olafuyi

المصدر: Pharmaceutics; Volume 14; Issue 9; Pages: 1957

مصطلحات موضوعية: physiologically based pharmacokinetic modelling, propofol, low cardiac output, pharmacokinetics, neonate, developmental pharmacology, asphyxia, hypothermia, pediatrics

الوصف: Background: pathophysiological changes such as low cardiac output (LCO) impact pharmacokinetics, but its extent may be different throughout pediatrics compared to adults. Physiologically based pharmacokinetic (PBPK) modelling enables further exploration. Methods: A validated propofol model was used to simulate the impact of LCO on propofol clearance across age groups using the PBPK platform, Simcyp® (version 19). The hepatic and renal extraction ratio of propofol was then determined in all age groups. Subsequently, manual infusion dose explorations were conducted under LCO conditions, targeting a 3 µg/mL (80–125%) propofol concentration range. Results: Both hepatic and renal extraction ratios increased from neonates, infants, children to adolescents and adults. The relative change in clearance following CO reductions increased with age, with the least impact of LCO in neonates. The predicted concentration remained within the 3 µg/mL (80–125%) range under normal CO and LCO (up to 30%) conditions in all age groups. When CO was reduced by 40–50%, a dose reduction of 15% is warranted in neonates, infants and children, and 25% in adolescents and adults. Conclusions: PBPK-driven, the impact of reduced CO on propofol clearance is predicted to be age-dependent, and proportionally greater in adults. Consequently, age group-specific dose reductions for propofol are required in LCO conditions.

وصف الملف: application/pdf

العلاقة: Pharmacokinetics and Pharmacodynamics; https://dx.doi.org/10.3390/pharmaceutics14091957Test

الإتاحة: https://doi.org/10.3390/pharmaceutics14091957Test