Journal of Clinical Pharmacology最新文献

{"title":"Pharmacokinetic Interactions of Rolapitant With Cytochrome P450 3A Substrates in Healthy Subjects.","authors":"Xiaodong Wang,&nbsp;Jing Wang,&nbsp;Sujata Arora,&nbsp;Lorraine Hughes,&nbsp;Jennifer Christensen,&nbsp;Sharon Lu,&nbsp;Zhi-Yi Zhang","doi":"10.1002/jcph.1339","DOIUrl":"https://doi.org/10.1002/jcph.1339","url":null,"abstract":"<p><p>Rolapitant (Varubi) is a neurokinin-1 receptor antagonist approved for the prevention of chemotherapy-induced nausea and vomiting. Rolapitant is primarily metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme. Unlike other neurokinin-1 receptor antagonists, rolapitant is neither an inhibitor nor an inducer of CYP3A4 in vitro. The objective of this analysis was to examine the pharmacokinetics of rolapitant in healthy subjects and assess drug-drug interactions between rolapitant and midazolam (a CYP3A substrate), ketoconazole (a CYP3A inhibitor), or rifampin (a CYP3A4 inducer). Three phase 1, open-label, drug-drug interaction studies were conducted to examine the pharmacokinetic interactions of orally administered rolapitant with midazolam, rolapitant with ketoconazole, and rolapitant with rifampin. The pharmacokinetic profiles of midazolam and 1-hydroxy midazolam metabolites were essentially unchanged when coadministered with rolapitant, indicating the lack of a clinically relevant inhibition or induction of CYP3A by rolapitant. Coadministration of ketoconazole with rolapitant had no effects on rolapitant maximum concentration and resulted in an approximately 20% increase in the area under the concentration-time curve of rolapitant, suggesting that strong CYP3A inhibitors have minimal inhibitory effects on rolapitant exposure. Repeated administrations of rifampin appeared to reduce rolapitant exposure, resulting in a 33% decrease in maximum concentration and 87% decrease in area under the concentration-time curve from time zero to infinity. Coadministration of rolapitant did not affect the exposure of midazolam. Rifampin coadministration resulted in lower concentrations of rolapitant, and ketoconazole coadministration had no or minimal effects on rolapitant exposure. Rolapitant was safe and well tolerated when coadministered with ketoconazole, rifampin, or midazolam. No new safety signals were reported compared with previous studies of rolapitant.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"488-499"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1339","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36718343","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":"Complementary Pharmacokinetic Profiles of Netupitant and Palonosetron Support the Rationale for Their Oral Fixed Combination for the Prevention of Chemotherapy-Induced Nausea and Vomiting.","authors":"James Gilmore,&nbsp;Alberto Bernareggi","doi":"10.1002/jcph.1338","DOIUrl":"https://doi.org/10.1002/jcph.1338","url":null,"abstract":"<p><p>NEPA is the first fixed-combination antiemetic composed of the neurokinin-1 receptor antagonist netupitant (netupitant; 300 mg) and the 5-hydroxytryptamine-3 receptor antagonist palonosetron (palonosetron; 0.50 mg). This study evaluated the pharmacokinetic profiles of netupitant and palonosetron. The pharmacokinetic profiles of both drugs were summarized using data from phase 1-3 clinical trials. netupitant and palonosetron have high absolute bioavailability (63%-87% and 97%, respectively). Their overall systemic exposures and maximum plasma concentrations are similar under fed and fasting conditions. netupitant binds to plasma proteins in a high degree (>99%), whereas palonosetron binds to a low extent (62%). Both drugs have large volumes of distribution (cancer patients: 1656-2257 L and 483-679 L, respectively). netupitant is metabolized by cytochrome P450 3A4 to 3 major pharmacologically active metabolites (M1, M2, and M3). palonosetron is metabolized by cytochrome P450 2D6 to 2 major substantially inactive metabolites (M4 and M9). Both drugs have similar intermediate-to-low systemic clearances and long half-lives (cancer patients: netupitant, 19.5-20.8 L/h and 56.0-93.8 hours; palonosetron: 7.0-11.3 L/h and 43.8-65.7 hours, respectively). netupitant and its metabolites are eliminated via the hepatic/biliary route (87% of the administered dose), whereas palonosetron and its metabolites are mainly eliminated via the kidneys (85%-93%). Altogether, these data explain the lack of pharmacokinetic interactions between netupitant and palonosetron at absorption, binding, metabolic, or excretory level, thus highlighting their compatibility as the oral fixed combination NEPA, with administration convenience that may reduce dosing mistakes and increase treatment compliance.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"472-487"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1338","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36651265","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":"Population Pharmacokinetic Study and Individual Dose Adjustments of High-Dose Methotrexate in Chinese Pediatric Patients With Acute Lymphoblastic Leukemia or Osteosarcoma.","authors":"Ka Ho Hui,&nbsp;Ho Man Chu,&nbsp;Pui Shan Fong,&nbsp;Wai Tsoi Frankie Cheng,&nbsp;Tai Ning Lam","doi":"10.1002/jcph.1349","DOIUrl":"https://doi.org/10.1002/jcph.1349","url":null,"abstract":"<p><p>High-dose methotrexate (>0.5 g/m² ) is among the first-line chemotherapeutic agents used in treating acute lymphoblastic leukemia (ALL) and osteosarcoma in children. Despite rapid hydration, leucovorin rescue, and routine therapeutic drug monitoring, severe toxicity is not uncommon. This study aimed at developing population pharmacokinetic (popPK) models of high-dose methotrexate for ALL and osteosarcoma and demonstrating the possibility and convenience of popPK model-based individual dose optimization using R and shiny, which is more accessible, efficient, and clinician-friendly than NONMEM. The final data set consists of 36 ALL (354 observations) and 16 osteosarcoma (585 observations) patients. Covariate model building and parameter estimations were done using NONMEM and Perl-speaks-NONMEM. Diagnostic Plots and bootstrapping validated the models' performance and stability. The dose optimizer developed based on the validated models can obtain identical individual parameter estimates as NONMEM. Compared to calling a NONMEM execution and reading its output, estimating individual parameters within R reduces the execution time from 8.7-12.8 seconds to 0.4-1.0 second. For each subject, the dose optimizer can recommend (1) an individualized optimal dose and (2) an individualized range of doses. For osteosarcoma, recommended optimal doses by the optimizer resemble the final doses at which the subjects were eventually stabilized. The dose optimizers developed demonstrated the potential to inform dose adjustments using a model-based, convenient, and efficient tool for high-dose methotrexate. Although the dose optimizer is not meant to replace clinical judgment, it provides the clinician with the individual pharmacokinetics perspective by recommending the (range of) optimal dose.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"566-577"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1349","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36790260","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":"Quantitative Modeling Analysis Demonstrates the Impact of CYP2C19 and CYP2D6 Genetic Polymorphisms on the Pharmacokinetics of Amitriptyline and Its Metabolite, Nortriptyline.","authors":"Ara Koh,&nbsp;Kwan Cheol Pak,&nbsp;Hee Youn Choi,&nbsp;Sunae Ryu,&nbsp;Seung-Eun Choi,&nbsp;Ki Soon Kim,&nbsp;Kyun-Seop Bae,&nbsp;Hyeong-Seok Lim","doi":"10.1002/jcph.1344","DOIUrl":"https://doi.org/10.1002/jcph.1344","url":null,"abstract":"<p><p>Amitriptyline is a tricyclic antidepressant that is metabolized mainly by CYP2C19 and CYP2D6 enzymes. Higher plasma levels of amitriptyline and its active metabolite, nortriptyline, are associated with an increased risk of adverse events including anticholinergic effects. The aim of this study was to evaluate the effects of CYP2C19 and CYP2D6 genetic polymorphisms on amitriptyline and nortriptyline pharmacokinetics. Twenty-four Korean healthy adult male volunteers were enrolled in the study after stratification by their CYP2C19 and CYP2D6 genotypes. Serial blood draws for pharmacokinetic analysis were made after a single oral 25-mg dose of amitriptyline was administered. Plasma amitriptyline and nortriptyline concentrations were measured by a validated liquid chromatography with tandem mass spectrometry. Population pharmacokinetic modeling analysis was conducted using NONMEM, which evaluated the effects of CYP2C19 and CYP2D6 genotypes on amitriptyline and nortriptyline pharmacokinetics. The biotransformation of amitriptyline into nortriptyline was significantly different between subjects with the CYP2C19*2/*2, *2/*3, and *3/*3 genotypes and those with the other genotypes, with an estimated metabolic clearance of 17 and 61.5 L/h, respectively. Clearance of amitriptyline through pathways other than biotransformation into nortriptyline was estimated as 18.8 and 30.6 L/h for subjects with the CYP2D6*10/*10 and *10/*5 genotypes and those with the other genotypes, respectively. This study demonstrated a quantitative effect of the CYP2C19 and CYP2D6 genotypes on amitriptyline and nortriptyline pharmacokinetics. Production of nortriptyline from amitriptyline was associated with CYP2C19 genotypes, and clearance of amitriptyline through pathways other than biotransformation into nortriptyline was associated with CYP2D6 genotypes. These observations may be useful in developing individualized, optimal therapy with amitriptyline.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"532-540"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1344","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36685773","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":"Safety Exposure-Response Analysis for Daclatasvir, Asunaprevir, and Beclabuvir Combinations in HCV-Infected Subjects.","authors":"Mayu Osawa,&nbsp;Takayo Ueno,&nbsp;Tomomi Shiozaki,&nbsp;Hanbin Li,&nbsp;Tushar Garimella","doi":"10.1002/jcph.1347","DOIUrl":"https://doi.org/10.1002/jcph.1347","url":null,"abstract":"<p><p>The combination regimen of daclatasvir, asunaprevir, and beclabuvir has been developed for the treatment of hepatitis C virus infection. The objectives of this analysis were to characterize the relationship between the exposures of the daclatasvir, asunaprevir, and beclabuvir regimen and liver-related laboratory elevations (Grade 3 or 4 alanine aminotransferase [ALT] and total bilirubin [Tbili]), and to evaluate the impact of selected covariates on the exposure-response relationships. The exposure-response analysis was performed with data from 1 phase 2 and 3 phase 3 studies in hepatitis C virus-infected subjects. The probability of liver-related laboratory elevations were modeled using linear logistic regression. Selected covariates were tested using a forward-addition and backward-elimination approach. The final model for ALT elevation included Asian race, body weight in non-Asian subjects, and asunaprevir exposure. The final model for Tbili elevation included Asian race, fibrosis score (F0-F3 or F4) and asupanprevir exposure. Asian subjects had greater the Grade 3 or 4 ALT and Tbili elevation rates than non-Asians. The Grade 3 or 4 ALT elevation rate increased with decreasing body weight in non-Asian subjects. Subjects with F4 fibrosis score had a higher rate of Grade 3 or 4 Tbili elevation compared to subjects with F0 to F3 fibrosis score. Higher asunaprevir exposure was associated with increases in Grade 3 or 4 ALT and Tbili elevation rates; however, the impact on the ALT elevation was not clinically relevant and the effect on Tbili elevation was smaller than the other significant covariates.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"557-565"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1347","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36797847","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":"Factors Associated With Cysticidal Treatment Response in Extraparenchymal Neurocysticercosis.","authors":"Rocio Osorio,&nbsp;Roger Carrillo-Mezo,&nbsp;Matthew L Romo,&nbsp;Andrea Toledo,&nbsp;Carlos Matus,&nbsp;Iliana González-Hernández,&nbsp;Helgi Jung,&nbsp;Agnès Fleury","doi":"10.1002/jcph.1346","DOIUrl":"https://doi.org/10.1002/jcph.1346","url":null,"abstract":"<p><p>Extraparenchymal neurocysticercosis is the most severe form of cysticercosis, and response to treatment is suboptimal. We sought to determine how demographic and clinical characteristics and albendazole sulfoxide concentrations were related to cysticidal treatment response. We conducted a longitudinal study of 31 participants with extraparenchymal vesicular parasites who received the same treatment, albendazole 30 mg/kg/day for 10 days with dexamethasone 0.4 mg/kg/day for 13 days, followed by a prednisone taper. Response to treatment was determined by parasite volumes before and 6 months after treatment. Eight participants (25.8%) had a complete treatment response, 16 (51.6%) had a treatment response > 50% but < 100%, and 7 (22.6%) had a treatment response < 50%. Complete treatment response was significantly associated with higher concentrations of albendazole sulfoxide (P = .032), younger age (P = .032), fewer cysts (P = .049) and lower pretreatment parasite volume (P = .037). Higher number of previous cysticidal treatment courses was associated with a noncomplete treatment response (P = .023). Although the large proportion of participants with less than a complete response emphasizes the need to develop more efficacious pharmacologic regimens, the association of albendazole sulfoxide concentrations with treatment response highlights the importance of optimizing existing therapeutic regimens. In addition, the association of treatment response with parasite volume emphasizes the importance of early diagnosis.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"548-556"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1346","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36706465","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":"Population Pharmacokinetics and Bayesian Estimation of Mycophenolic Acid Exposure in Chinese Renal Allograft Recipients After Administration of EC-MPS.","authors":"Bing Chen,&nbsp;Kun Shao,&nbsp;Hui-Min An,&nbsp;Hao-Qiang Shi,&nbsp;Jia-Qian Lu,&nbsp;Xiao-Hui Zhai,&nbsp;Xiao-Xue Liu,&nbsp;Xiang-Hui Wang,&nbsp;Da Xu,&nbsp;Pei-Jun Zhou","doi":"10.1002/jcph.1352","DOIUrl":"https://doi.org/10.1002/jcph.1352","url":null,"abstract":"<p><p>The aim of the present study is to establish a population pharmacokinetic (PPK) model of mycophenolic acid (MPA) and limited sampling strategy models for the estimation of MPA exposure in Chinese adult renal allograft recipients following oral administration of enteric coated mycophenolate sodium (EC-MPS). A total of 74 sets of full pharmacokinetic profiles and 47 sets of MPA-sparing samples were collected from 102 renal transplant recipients who received oral EC-MPS. The MPA concentration was determined by an enzyme-multiplied immunoassay technique, and the pathophysiologic data were recorded. The PPK model was constructed using nonlinear mixed-effects modeling, and the limited sampling strategy models for MPA were established by using multiple regression analysis and the maximum a posteriori Bayesian assay based on 2 to 4 sampling time points following EC-MPS administration. The pharmacokinetics of MPA were best described by a 2-compartment model with a first-order absorption process and a lag time of absorption. The clearance of MPA was 12.3 ± 1.14 L/h. Comedicating with cyclosporine A was found to have a significant impact on the clearance/bioavailability of MPA (P < .01). Sampling strategies consisted of plasma concentration at 1.5, 2, 4 (C1.5-C2-C4) hours and 1.5, 2, 4, 6 (C1.5-C2-C4-C6) hours after EC-MPS administration were shown to be suitable for the estimation of the MPA area under the concentration-time curve in these patients. The PPK model was acceptable and can describe the pharmacokinetics of MPA in Chinese renal transplant recipients administered EC-MPS. The area under the concentration-time curve of MPA in Chinese renal transplant recipients could be estimated through a limited sampling strategy method, based on which individualized immunosuppressive regimens could be designed.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"578-589"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1352","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36771525","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":"The JAK1 Inhibitor Upadacitinib Has No Effect on the Pharmacokinetics of Levonorgestrel and Ethinylestradiol: A Study in Healthy Female Subjects.","authors":"Mohamed-Eslam F Mohamed,&nbsp;Sheryl Trueman,&nbsp;Tian Feng,&nbsp;Alan Friedman,&nbsp;Ahmed A Othman","doi":"10.1002/jcph.1350","DOIUrl":"https://doi.org/10.1002/jcph.1350","url":null,"abstract":"<p><p>Upadacitinib is a novel selective oral Janus kinase 1 (JAK) inhibitor being developed for treatment of several inflammatory diseases. Oral contraceptives are anticipated to be a common concomitant medication in the target patient populations. This study was designed to evaluate the effect of multiple doses of upadacitinib on the pharmacokinetics of ethinylestradiol and levonorgestrel in healthy female subjects. This phase I, single-center, open-label, 2-period crossover study evaluated the effect of multiple doses of 30 mg once daily extended-release upadacitinib on the pharmacokinetics of a single oral dose of ethinylestradiol/levonorgestrel (0.03/0.15 mg; administered alone in period 1 and on day 12 of a 14-day regimen of upadacitinib in period 2) in 22 healthy female subjects. The ratios (90% confidence intervals) for maximum plasma concentration and area under the plasma drug concentration-time curve from time zero to infinity following administration of ethinylestradiol/levonorgestrel with upadacitinib compared with administration of ethinylestradiol/ levonorgestrel alone were 0.96 (0.89-1.02) and 1.1 (1.04-1.19), respectively, for ethinylestradiol, and 0.96 (0.87-1.06) and 0.96 (0.85-1.07), respectively, for levonorgestrel. The harmonic mean terminal half-life for ethinylestradiol (7.7 vs 7.0 hours) and levonorgestrel (37.1 vs 33.1 hours) was similar in the presence and absence of upadacitinib. Ethinylestradiol and levonorgestrel were bioequivalent in the presence and absence of upadacitinib. Therefore, upadacitinib can be administered concomitantly with oral contraceptives containing ethinylestradiol or levonorgestrel.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"510-516"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1350","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36737317","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":"Meta-analysis of hepatic cytochrome P450 ontogeny to underwrite the prediction of pediatric pharmacokinetics using physiologically based pharmacokinetic modeling.","authors":"Vijay V Upreti,&nbsp;Jan L Wahlstrom","doi":"10.1002/jcph.585","DOIUrl":"https://doi.org/10.1002/jcph.585","url":null,"abstract":"<p><p>The accurate prediction of pharmacokinetics (PK) is fundamental to underwriting safety and efficacy in pediatric clinical trials; age-dependent PK may be observed with pediatrics because of the growth and maturation processes that occur during development. Understanding the ontogeny of drug-metabolizing enzymes is a critical enabler for pediatric PK prediction, as enzyme expression or activity may change with age. Although ontogeny functions for the cytochrome P450s (CYPs) have been developed, disconnects between ontogeny functions for the same CYP may exist, depending on whether the functions were derived from in vitro or in vivo data. This report describes the development of ontogeny functions for all the major hepatic CYPs based on in vitro or in vivo data; these ontogeny functions were subsequently incorporated into a physiologically based pharmacokinetic model and evaluated. Pediatric PK predictions based on in vivo-derived ontogeny functions performed markedly better than those developed from in vitro data for intravenous (100% versus 51% within 2-fold, respectively) and oral (98% versus 67%, respectively) dosing. The verified models were then applied to complex pediatric scenarios involving active metabolites, CYP polymorphisms and physiological changes because of critical illness; the models reasonably explained the observed age-dependent changes in pediatric PK. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"266-83"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.585","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33875440","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":"Semimechanistic model describing gastric emptying and glucose absorption in healthy subjects and patients with type 2 diabetes.","authors":"Oskar Alskär,&nbsp;Jonatan I Bagger,&nbsp;Rikke M Røge,&nbsp;Filip K Knop,&nbsp;Mats O Karlsson,&nbsp;Tina Vilsbøll,&nbsp;Maria C Kjellsson","doi":"10.1002/jcph.602","DOIUrl":"https://doi.org/10.1002/jcph.602","url":null,"abstract":"<p><p>The integrated glucose-insulin (IGI) model is a previously published semimechanistic model that describes plasma glucose and insulin concentrations after glucose challenges. The aim of this work was to use knowledge of physiology to improve the IGI model's description of glucose absorption and gastric emptying after tests with varying glucose doses. The developed model's performance was compared to empirical models. To develop our model, data from oral and intravenous glucose challenges in patients with type 2 diabetes and healthy control subjects were used together with present knowledge of small intestinal transit time, glucose inhibition of gastric emptying, and saturable absorption of glucose over the epithelium to improve the description of gastric emptying and glucose absorption in the IGI model. Duodenal glucose was found to inhibit gastric emptying. The performance of the saturable glucose absorption was superior to linear absorption regardless of the gastric emptying model applied. The semiphysiological model developed performed better than previously published empirical models and allows better understanding of the mechanisms underlying glucose absorption. In conclusion, our new model provides a better description and improves the understanding of dynamic glucose tests involving oral glucose. </p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"56 3","pages":"340-8"},"PeriodicalIF":2.9,"publicationDate":"2016-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.602","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33880495","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}