Biopharmaceutics & Drug Disposition最新文献

{"title":"Irinotecan-induced gastrointestinal damage alters the expression of peptide transporter 1 and absorption of cephalexin in rats","authors":"Ayuko Imaoka,&nbsp;Tomoki Hattori,&nbsp;Takeshi Akiyoshi,&nbsp;Hisakazu Ohtani","doi":"10.1002/bdd.2372","DOIUrl":"10.1002/bdd.2372","url":null,"abstract":"<p>Irinotecan causes severe gastrointestinal damage, which may affect the expression of intestinal transporters. However, neither the expression of peptide transporter 1 (Pept1) nor the pharmacokinetics of Pept1 substrate drugs has been investigated under irinotecan-induced gastrointestinal damage. Therefore, the present study quantitatively investigated the effects of irinotecan-induced gastrointestinal damage on the intestinal expression of Pept1 and absorption of cephalexin (CEX), a typical Pept1 substrate, in rats. Irinotecan was administered intravenously to rats for 4 days to induce gastrointestinal damage. The expression of <i>Pept1</i> mRNA and the Pept1 protein in the upper, middle, and lower segments of the small intestine of irinotecan-treated rats was assessed by quantitative real-time polymerase chain reaction (PCR) and western blotting, respectively. The pharmacokinetic profile of CEX was examined after its oral or intravenous administration (10 mg/kg). In irinotecan-treated rats, ∼2-fold increases in Pept1 protein levels were observed in all three segments, whereas mRNA levels remained unchanged. The oral bioavailability of CEX significantly decreased to 76% of that in control rats. The decrease in passive diffusion caused by intestinal damage may have overcome the increase in Pept1-mediated uptake. In conclusion, irinotecan may decrease the intestinal absorption of Pept1 substrate drugs; however, it increased the expression of intestinal Pept1.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 5","pages":"372-379"},"PeriodicalIF":2.1,"publicationDate":"2023-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdd.2372","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9890940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective inhibitory effects of suberosin on CYP1A2 in human liver microsomes","authors":"Sanjita Paudel,&nbsp;Hyoje Jo,&nbsp;Taeho Lee,&nbsp;Sangkyu Lee","doi":"10.1002/bdd.2370","DOIUrl":"10.1002/bdd.2370","url":null,"abstract":"<p>Suberosin is a natural phytoconstituent isolated from <i>Citropsis articulata,</i> especially employed for its anticoagulant properties. Although metabolic studies assessing suberosin have been conducted, it is possible interactions with drugs and food have not yet been investigated. In the present study, we analyzed the selective inhibitory effects of suberosin on cytochrome P450 (CYP) enzymes using a cocktail probe assay. Various concentrations of suberosin (0–50 μM) were incubated with isoform-specific CYP probes in human liver microsomes (HLMs). We found that suberosin significantly inhibited CYP1A2-catalyzed phenacetin <i>O</i>-deethylation, exhibiting IC₅₀ values of 9.39 ± 2.05 and 3.07 ± 0.45 μM with and without preincubation in the presence of β-NADPH, respectively. Moreover, suberosin showed concentration-dependent, but not time-dependent, CYP1A2 inhibition in HLMs, indicating that suberosin acts as a substrate and reversible CYP1A2 inhibitor. Using a Lineweaver-Burk plot, we found that suberosin competitively inhibited CYP1A2-catalyzed phenacetin <i>O</i>-deethylation. Furthermore, suberosin showed similar inhibitory effects on recombinant human CYP1A1 and 1A2. In conclusion, suberosin may elicit herb–drug interactions by selectively inhibiting CYP1A2 during the concurrent administration of drugs that act as CYP1A2 substrates.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 5","pages":"365-371"},"PeriodicalIF":2.1,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9779521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Coming full circle: The potential utility of real-world evidence to discern predictions from a physiologically based pharmacokinetic model","authors":"Joseph A. Grillo,&nbsp;Douglas McNair,&nbsp;Ping Zhao","doi":"10.1002/bdd.2369","DOIUrl":"10.1002/bdd.2369","url":null,"abstract":"<p>Today real word data (RWD) are playing a greater role in informing health care decisions. A physiologically based pharmacokinetic model (PBPK) and observed exposure–risk relationship predicted an increased bleeding risk induced by rivaroxaban (RXB) in patients with mild to moderate chronic kidney disease (CKD) taking concomitant medications that are combined Pgp-CYP3A inhibitors. In this commentary, we explore the potential use of RWD to assess the clinical consequence of this complex drug–drug interaction predicted from PBPK. This is a retrospective, case control, pilot study using a RWD dataset of 896,728 patients with mild to moderate chronic kidney disease and rivaroxaban use that was refined based upon combined Pgp-CYP3A inhibitor exposure and report of drug-induced bleeding (DIB). The odds ratio of patients with mild to moderate chronic kidney disease taking rivaroxaban with or without concurrent Pgp-CYP3A inhibitor use having a DIB was calculated. The odds ratio for DIB was 2.04 (CI₉₅ 1.82, 2.3; <i>p</i> &lt; 0.001) suggesting an approximate doubling of bleeding risk which is consistent with the rivaroxaban exposure changes predicted by the published PBPK model and observed exposure–risk relationship. This exploratory analysis demonstrated the potential utility of RWD to assess model-based predictions as part of a drugs life cycle management.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 4","pages":"344-347"},"PeriodicalIF":2.1,"publicationDate":"2023-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10537760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Model-informed drug development: The mechanistic HSK3486 physiologically based pharmacokinetic model informing dose decisions in clinical trials of specific populations","authors":"Miao Zhang,&nbsp;Zhiheng Yu,&nbsp;Huan Liu,&nbsp;Xu Wang,&nbsp;Haiyan Li,&nbsp;Xueting Yao,&nbsp;Dongyang Liu","doi":"10.1002/bdd.2368","DOIUrl":"10.1002/bdd.2368","url":null,"abstract":"<p>HSK3486, a central nervous system inhibitor, has demonstrated superior anesthetic properties in comparison with propofol. Owing to the high liver extraction ratio of HSK3486 and the limited susceptibility to the multi-enzyme inducer, rifampicin, the indicated population of HSK3486 is substantial. Nevertheless, in order to expand the population with indications, it is crucial to assess the systemic exposure of HSK3486 in specific populations. Moreover, the main metabolic enzyme of HSK3486 is UGT1A9, which shows a gene polymorphism in the population. Thus, to scientifically design the dose regimen for clinical trials in specific populations, a HSK3486 physiologically based pharmacokinetic model was developed in 2019 to support model-informed drug development (MIDD). Several untested scenarios of HSK3486 administration in specific populations, and the effect of the UGT1A9 gene polymorphism on HSK3486 exposure were estimated as well. The predicted systemic exposure was increased slightly in patients with hepatic impairment and in the elderly, consistent with later clinical trial data. Meanwhile, there was no change in the systemic exposure of patients with severe renal impairment and in neonates. However, under the same dose, the predicted exposure of pediatric patients aged 1 month to 17 years was decreased significantly (about 21%–39%). Although these predicted results in children have not been validated by clinical data, they are comparable to clinical findings for propofol in children. The dose of HSK3486 in pediatrics may need to be increased and can be adjusted according to the predicted results. Moreover, the predicted HSK3486 systemic exposure in the obese population was increased by 28%, and in poor metabolizers of UGT1A9 might increase by about 16%–31% compared with UGT1A9 extensive metabolizers. Combined with the relatively flat exposure–response relationship for efficacy and safety (unpublished), obesity and genetic polymorphisms are unlikely to result in clinically significant changes in the anesthetic effect at the 0.4 mg/kg dose in adults. Therefore, MIDD can indeed provide supportive information for dosing decisions and facilitate the efficient and effective development of HSK3486.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 3","pages":"259-273"},"PeriodicalIF":2.1,"publicationDate":"2023-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10094942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between α-defensin 5 and the expression and function of P-glycoprotein in differentiated intestinal Caco-2 cells","authors":"Genki Yasuda,&nbsp;Atsuhito Kubota,&nbsp;Keisuke Okamoto,&nbsp;Katsuya Narumi,&nbsp;Ayako Furugen,&nbsp;Izumi Kato,&nbsp;Ayako Mori,&nbsp;Yoshitaka Saito,&nbsp;Takashi Satoh,&nbsp;Natsuko Takahashi-Suzuki,&nbsp;Ken Iseki,&nbsp;Masaki Kobayashi","doi":"10.1002/bdd.2367","DOIUrl":"10.1002/bdd.2367","url":null,"abstract":"<p>α-Defensin 5 is known to be secreted by Paneth cells in the small intestine and plays an important role in eliminating pathogenic microorganisms. It has been reported that a decrease in α-defensin 5 level in the human small intestine is a risk of inflammatory bowel disease (IBD). Furthermore, P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter superfamily, encoded by the ABCB1/MDR1 gene, plays an important role in the front line of host defense by protecting the gastrointestinal barrier from xenobiotic accumulation and may contribute to the development and persistence of IBD. Therefore, we examined the relationship between α-defensin 5 and the expression and function of P-gp using a human gastrointestinal model cell line (Caco-2). We found that <i>MDR1</i> mRNA and P-gp protein level were increased in Caco-2 cells as well as α-defensin 5 secretion corresponded with the duration of cell culture. Exposure to α-defensin 5 peptide and recombinant tumor necrosis factor-α (TNF-α) significantly increased the expression and function P-gp. The mRNA levels of interleukin (<i>IL</i>)<i>-</i><i>8</i>, <i>IL-6</i>, <i>TNF-α</i>, <i>IL-1β</i>, and <i>IL-2</i> were also increased following exposure to TNF-α, similar to α-defensin 5 treatment. These results suggest that α-defensin 5 regulates P-gp expression and function by increasing TNF-α expression in Caco-2 cells.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 5","pages":"358-364"},"PeriodicalIF":2.1,"publicationDate":"2023-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9951422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shared learning from a physiologically based pharmacokinetic modeling strategy for human pharmacokinetics prediction through retrospective analysis of Genentech compounds","authors":"Jialin Mao,&nbsp;Fang Ma,&nbsp;Jesse Yu,&nbsp;Tom De Bruyn,&nbsp;Miaoran Ning,&nbsp;Christine Bowman,&nbsp;Yuan Chen","doi":"10.1002/bdd.2359","DOIUrl":"10.1002/bdd.2359","url":null,"abstract":"<p>The quantitative prediction of human pharmacokinetics (PK) including the PK profile and key PK parameters are critical for early drug development decisions, successful phase I clinical trials, and the establishment of a range of doses to enable phase II clinical dose selection. Here, we describe an approach employing physiologically based pharmacokinetic (PBPK) modeling (Simcyp) to predict human PK and to validate its performance through retrospective analysis of 18 Genentech compounds for which clinical data are available. In short, physicochemical parameters and <i>in vitro</i> data for preclinical species were integrated using PBPK modeling to predict the <i>in vivo</i> PK observed in mouse, rat, dog, and cynomolgus monkey. Through this process, the <i>in vitro</i> to <i>in vivo</i> extrapolation (IVIVE) was determined and then incorporated into PBPK modeling in order to predict human PK. Overall, the prediction obtained using this PBPK-IVIVE approach captured the observed human PK profiles of the compounds from the dataset well. The predicted C_max was within 2-fold of the observed C_max for 94% of the compounds while the predicted area under the curve (AUC) was within 2-fold of the observed AUC for 72% of the compounds. Additionally, important IVIVE trends were revealed through this investigation, including application of scaling factors determined from preclinical IVIVE to human PK prediction for each molecule. Based upon the analysis, this PBPK-based approach now serves as a practical strategy for human PK prediction at the candidate selection stage at Genentech.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 4","pages":"315-334"},"PeriodicalIF":2.1,"publicationDate":"2023-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10221322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiologically-based pharmacokinetic/pharmacodynamic modeling to predict tumor growth inhibition and the efficacious dose of selective estrogen receptor degraders in humans","authors":"Anjani Ganti,&nbsp;Sijia Yu,&nbsp;Danielle Sharpnack,&nbsp;Ellen Ingalla,&nbsp;Tom De Bruyn","doi":"10.1002/bdd.2358","DOIUrl":"10.1002/bdd.2358","url":null,"abstract":"<p>GDC-9545 (giredestrant) is a highly potent, nonsteroidal, oral selective estrogen receptor antagonist and degrader that is being developed as a best-in-class drug candidate for early-stage and advanced drug-resistant breast cancer. GDC-9545 was designed to improve the poor absorption and metabolism of its predecessor GDC-0927, for which development was halted due to a high pill burden. This study aimed to develop physiologically-based pharmacokinetic/pharmacodynamic (PBPK-PD) models to characterize the relationships between oral exposure of GDC-9545 and GDC-0927 and tumor regression in HCI-013 tumor-bearing mice, and to translate these PK-PD relationships to a projected human efficacious dose by integrating clinical PK data. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the animal and human Simcyp V20 Simulator (Certara) and adequately described each compound's systemic drug concentrations and antitumor activity in the dose-ranging xenograft experiments in mice. The established PK-PD relationship was translated to a human efficacious dose by substituting mouse PK for human PK. PBPK input values for human clearance were predicted using allometry and in vitro in vivo extrapolation approaches and human volume of distribution was predicted from simple allometry or tissue composition equations. The integrated human PBPK-PD model was used to simulate TGI at clinically relevant doses. Translating the murine PBPK-PD relationship to a human efficacious dose projected a much lower efficacious dose for GDC-9545 than GDC-0927. Additional sensitivity analysis of key parameters in the PK-PD model demonstrated that the lower efficacious dose of GDC-9545 is a result of improvements in clearance and absorption. The presented PBPK-PD methodology can be applied to support lead optimization and clinical development of many drug candidates in discovery or early development programs.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 4","pages":"301-314"},"PeriodicalIF":2.1,"publicationDate":"2023-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10537252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-depth analysis of patterns in selection of different physiologically-based pharmacokinetic modeling tools: Part II — Assessment of model reusability and comparison between open and non-open source-code software","authors":"Hamza Khaled Abdelmajed Aldibani,&nbsp;Arham Jamaal Rajput,&nbsp;Amin Rostami-Hodjegan","doi":"10.1002/bdd.2360","DOIUrl":"10.1002/bdd.2360","url":null,"abstract":"Whilst the reproducibility of models in the area of systems biology and quantitative systems pharmacology has been the focus of attention lately, the concept of ‘reusability’ is not addressed. With the advent of the ‘Model Master File’ dominating some regulatory discussions on pharmaceutical applications of physiologically‐based pharmacokinetic (PBPK) models, reusability becomes a vital aspect of confidence in their use. Herein, we define ‘reusability’ specifically in the context of PBPK models and investigate the influence of open versus non‐open source‐code (NOSC) nature of the software on the extent of ‘reusability’. Original articles (n = 145) that were associated with the development of novel PBPK models were identified as source models and citations to these reports, which involved further PBPK model development, were explored (n > 1800) for reuse cases of the source PBPK model whether in full or partial form. The nature of source‐code was a major determinant of external reusability for PBPK models (>50% of the NOSC models as opposed <25% of open source‐code [OSC]). Full reusability of the models was not common and mostly involved internal reuse of the OSC model (by the group who had previously developed the original model). The results were stratified by the software utilised (various), organisations involved (academia, industry, regulatory), and type of reusability (full vs. partial). The clear link between external reuse of models and NOSC PBPK software might stem from many elements related to quality and trust that require further investigation, and challenges the unfounded notion that OSC models are associated with higher uptake for reuse.","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 4","pages":"292-300"},"PeriodicalIF":2.1,"publicationDate":"2023-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdd.2360","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10167518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In-depth analysis of patterns in selection of different physiologically based pharmacokinetic modeling tools: Part I – Applications and rationale behind the use of open source-code software","authors":"Arham Jamaal Rajput,&nbsp;Hamza Khaled Abdelmajed Aldibani,&nbsp;Amin Rostami-Hodjegan","doi":"10.1002/bdd.2357","DOIUrl":"10.1002/bdd.2357","url":null,"abstract":"<p>PBPK applications published in the literature support a greater adoption of non-open source-code (NOSC) software as opposed to open source-code (OSC) alternatives. However, a significant number of PBPK modelers are still using OSC software, understanding the rationale for the use of this modality is important and may help those embarking on PBPK modeling. No previous analysis of PBPK modeling trends has included the rationale of the modeler. An in-depth analysis of PBPK applications of OSC software is warranted to determine the true impact of OSC software on the rise of PBPK. Publications focusing on PBPK modeling applications, which used OSC software, were identified by systematically searching the scientific literature for original articles. A total of 171 articles were extracted from the narrowed subset. The rise in the use of OSC software for PBPK applications was greater than the general discipline of pharmacokinetics (9 vs. 4), but less than the overall growth of the PBPK area (9 vs. 43). Our report demonstrates conclusively that the surge in PBPK usage is primarily attributable to the availability and implementations of NOSC software. Modelers preferred not to share the reasons for their selection of certain modeling software and no ‘explicit’ rationale was given to support the use of OSC analysed by this study. As the preference for NOSC versus OSC software tools in the PBPK area continues to be divided, initiatives to add the rationale in using one form over another to every future PBPK modeling report will be a welcomed and informative addition.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 3","pages":"274-285"},"PeriodicalIF":2.1,"publicationDate":"2023-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bdd.2357","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9731291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Develop adult extrapolation to pediatrics and pediatric dose optimization based on the physiological pharmacokinetic model of azithromycin","authors":"Luhua Liang,&nbsp;Wentao Li,&nbsp;Zhihao Zhang,&nbsp;Dingyuan Li,&nbsp;Sijing Pu,&nbsp;Rongwu Xiang,&nbsp;Fei Zhai","doi":"10.1002/bdd.2352","DOIUrl":"10.1002/bdd.2352","url":null,"abstract":"<p>Physiologically-based pharmacokinetic (PBPK) models are more frequently used for supporting pediatric dose selection in small-molecule drugs. Through literature research, drug parameters of azithromycin and clinical data from different studies were obtained. Through parameter optimization of the absorption and dissolution process, the adult intravenous model was extended to the adult oral model. The adult intravenous and oral PBPK models are precise to meet the AAFE&lt;2 standard, and the pharmacokinetic parameters of the predicted values of the model are all within the mean standard deviation of the clinical observations. The values of plasma protein unbound fraction, renal clearance, and gastric juice pH between adults and pediatrics were changed by using the age-dependent pediatric organ maturity formula, and the adult model was extrapolated to the pediatric model. The final developed pediatric PBPK model was used to evaluate optimal dosing for children of different developmental ages. The relationship between the frist dose and age was as follows: 8.8 mg/kg/day from 0.5 to 2 years old, 9.2 mg/kg/day from 3 to 6 years old, 9.4 mg/kg/day from 7 to 12 years old, and 8.2 mg/kg/day from 13 to 18 years old, taken in half for 2–5 days. Simultaneously, the simulated exposures achieved with the dosing regimen proposed were comparable to adult plasma exposures for treatment of community-acquired pneumonia. A reasonable azithromycin pharmacokinetic–pharmacodynamic model for adults and pediatrics has been established, which can be demonstrated by the use of literature pediatric data to develop pediatric PBPK models, expanding the scope of this powerful modeling tool.</p>","PeriodicalId":8865,"journal":{"name":"Biopharmaceutics & Drug Disposition","volume":"44 3","pages":"245-258"},"PeriodicalIF":2.1,"publicationDate":"2023-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9737177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}