Journal of Clinical Pharmacology最新文献

{"title":"Contemporary Use of Oral Inotropes in the Outpatient Treatment of Heart Failure: Analysis of a Japanese Nationwide Database.","authors":"Michikazu Nakai, Yoshitaka Iwanaga, Koshiro Kanaoka, Yoko Sumita, Yuichi Nishioka, Tomoya Myojin, Katsuki Okada, Tatsuya Noda, Tomoaki Imamura, Yoshihiro Miyamoto","doi":"10.1002/jcph.70015","DOIUrl":"https://doi.org/10.1002/jcph.70015","url":null,"abstract":"<p><p>Clinical evidence of oral inotrope use for advanced heart failure (HF) is limited. This study investigated the contemporary use and association of oral inotropes with prognosis in the outpatient treatment of advanced HF using a nationwide administrative claims database in Japan. Patients hospitalized with acute HF between 2014 and 2021 were identified from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. Associations of the drug use after discharge with the 2-year prognosis were examined in a propensity-matching cohort, and hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Of the 428,650 patients discharged with HF in 4433 hospitals, 14,374 (3.4%) had taken oral inotropes, most of whom (95.0%) took pimobendan. Patients taking oral inotropes were younger and more likely to receive HF drugs. Cardiomyopathy as the etiology and the use of intravenous inotropes during hospitalization were more frequently observed. In the 2-year prognosis, oral inotrope use was associated with higher all-cause mortality and HF rehospitalization rates (HR [95% CI]: 1.59 [1.51, 1.66] and 1.54 [1.48, 1.61], respectively). Concomitant use of pimobendan and β-blockers was associated with lower mortality and HF rehospitalization (0.81 [0.74, 0.88] and 0.85 [0.79, 0.92], respectively) compared with pimobendan without β-blockers. Although no association was found between oral inotrope use and favorable prognosis, concomitant use of β-blockers may be a better strategy for oral inotrope use in advanced HF.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544166","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":"A Physiologically Based Pharmacokinetic Model of an Oral Tyrosine Kinase 2 Inhibitor Deucravacitinib in Healthy Adults.","authors":"Xinyue Chen, Zhoumeng Lin","doi":"10.1002/jcph.70014","DOIUrl":"https://doi.org/10.1002/jcph.70014","url":null,"abstract":"<p><p>This study presents the first physiologically based pharmacokinetic (PBPK) model for deucravacitinib, a novel oral selective tyrosine kinase 2 (TYK2) inhibitor approved for treating moderate-to-severe plaque psoriasis. Using GastroPlus, we developed and validated a comprehensive PBPK model incorporating multiple elimination pathways and enterohepatic circulation. The model was calibrated using single-dose pharmacokinetic data (3-40 mg) from healthy adults and validated against external datasets from multiple clinical studies across different populations. Model predictions demonstrated strong agreement with observed data, with simulated/observed ratios for the area under the curve (AUC) and maximum plasma concentration (C_max) consistently falling within 0.5-2.0 across all dosing regimens. Linear regression analysis showed a robust correlation between simulated and observed plasma concentrations for both single (R² ≈ 0.78) and multiple (R² ≈ 0.77) dosing scenarios. While the model accurately predicted early-phase pharmacokinetics and exposure metrics, slight underestimation was observed during the terminal elimination phase. The successful validation across Western and Chinese populations demonstrates the capability of the model to account for population-specific physiological differences. This validated PBPK model provides a mechanistic framework for investigating deucravacitinib pharmacokinetics in various clinical scenarios and could support future investigations in special populations, particularly those with renal or hepatic impairment where significant exposure changes have been observed clinically.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544160","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":"Comparing the Efficacy of Various Insulin Types: Pharmacokinetic and Pharmacodynamic Modeling of Glucose Clamp Effects in Healthy Volunteers.","authors":"Yi Chien Chang, William J Jusko","doi":"10.1002/jcph.70010","DOIUrl":"https://doi.org/10.1002/jcph.70010","url":null,"abstract":"<p><p>This study compares the pharmacokinetics and efficacy of various subcutaneously (SC) dosed insulin analogs, including rapid-acting, intermediate-acting, long-acting, and regular human insulin, using mechanistic pharmacokinetic (PK) and pharmacodynamic (PD) models. These models were applied to data from euglycemic clamp studies in healthy volunteers, where insulin pharmacokinetics and its effects on glucose utilization were monitored. Data from published studies were digitized and modeled using MONOLIX (Version 2024). The PK model described insulin absorption via sequential first-order processes and linear elimination. The PD effects were captured using a model combination of biophase, indirect, and receptor down-regulation components. While PK parameters-especially absorption rates-varied between insulin types, a common set of nonlinear PD parameters was sought to account for dose-related differences in glucose utilization. The maximum glucose stimulation ( <math> <semantics><msub><mi>S</mi> <mi>max</mi></msub> <annotation>${{{mathrm{S}}}_{{mathrm{max}}}}$</annotation></semantics> </math> ) was 163, and the insulin concentration for a half-maximal effect ( <math> <semantics><mrow><mi>S</mi> <msub><mi>C</mi> <mn>50</mn></msub> </mrow> <annotation>${mathrm{S}}{{{mathrm{C}}}_{50}}$</annotation></semantics> </math> ) were 1156 pmol/L for insulin lispro, regular human insulin, neutral protamine hagedorn (NPH) insulin, and insulin glargine; 674 pmol/L for insulin aspart; and 5335 pmol/L for insulin detemir. Insulin detemir showed similar overt effects as the other insulin types but with smaller clearances and lower potency. This mechanism-based glucose-insulin model demonstrated that most insulin analogs exhibit similar receptor- and transporter-related parameters. The model, with specific PK but unified PD parameters, may enable clinical optimization of insulin therapy by highlighting differences in pharmacokinetics and operating common intrinsic glucose utilization parameters.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143469738","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":"Ertapenem in the Context of Hypoalbuminemia: Implications for Critically Ill Patients.","authors":"Micaela Elene Seazzu, M Gabriela Cabanilla","doi":"10.1002/jcph.70011","DOIUrl":"https://doi.org/10.1002/jcph.70011","url":null,"abstract":"<p><p>The global rise in extended-spectrum β-lactamase-producing Enterobacterales (ESBL-E) has created significant challenges in the management of severe infections, including bacteremia. Ertapenem, a once-daily carbapenem with high protein-binding affinity (85%-95%), is an ideal option for ESBL-E because of its spectrum and dosing convenience. However, hypoalbuminemia, a common condition in critically ill patients that is independently associated with poor outcomes, raises concerns about altered pharmacokinetics, specifically increased free drug fractions, enhanced clearance, and shortened half-life. These pharmacokinetic changes have been hypothesized to lead to suboptimal drug levels and treatment failure, although clinical evidence remains inconsistent. This narrative review examines ertapenem's pharmacokinetic and pharmacodynamic changes in patients with hypoalbuminemia, focusing on its clinical implications. While some studies have reported suboptimal outcomes in critically ill patients, others have demonstrated comparable efficacy to broader spectrum carbapenems when minimum inhibitory concentration values are favorable, and source control is achieved. These findings challenge the concerns raised in the 2024 Infectious Diseases Society of America Gram-negative resistance guidance, which cautions against ertapenem use in patients with hypoalbuminemia. Rather than universally avoiding ertapenem, clinicians should prioritize individualized decision making based on patient-specific factors. Further research is warranted to optimize dosing strategies. However, current data suggest that ertapenem remains a viable and effective option in this high-risk population when used judiciously.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143460188","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 Effects of the Early and Late Phases of Septic Shock on the Population Pharmacokinetics of Vancomycin.","authors":"Tanisa Lexnoi, Apinya Boonpeng, Wichai Santimaleeworagun, Kessarin Chaisiri, Jutamas Dechsanga, Veerapong Vattanavanit, Chutchawan Ungthammakhun, Sirima Sitaruno","doi":"10.1002/jcph.70009","DOIUrl":"https://doi.org/10.1002/jcph.70009","url":null,"abstract":"<p><p>Pathophysiologic changes in the early and late phases of septic shock affect the pharmacokinetic (PK) parameters, varying dose adjustments may be necessary. This study aimed to create the PK models of vancomycin in the early and late phases of septic shock and to describe the association between the area under the curve from 0 to 24 h (AUC_0-24) and acute kidney injury (AKI). The data from patients with septic shock receiving vancomycin was collected either prospectively or retrospectively. A nonlinear mixed-effects modeling approach was used to develop the PK models. A total of 208 septic shock patients were enrolled and classified into the early (n = 96) and the late phase (n = 112). A two-compartment PK model is the best base model for both phases of septic shock. The model that best predicted the clearance (CL) of both phases was the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation, which was not indexed to body surface area (BSA). Albumin (ALB) was a covariate associated with vancomycin CL only in the late phase. The typical values of CL and volume of distribution (V_d) in the early phase were 1.71 L/h and 68.94 L. In the late phase, CL was 1.65 L/h, and V_d was 66.36 L. The AKI was observed in patients with a high simulated AUC_0-24. The population PK model of vancomycin in the early and late phases of septic shock has been established. The CKD-EPI not indexed to BSA predicts vancomycin CL in both phases. ALB was associated with CL in the late phase.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450621","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":"FCGR2A/FCGR3A Gene Polymorphisms and Clinical Variables as Predictors of Response to Tocilizumab and Rituximab in Patients With Rheumatoid Arthritis.","authors":"Alberto Jiménez Morales,&nbsp;Mar Maldonado-Montoro,&nbsp;Juan Enrique Martínez de la Plata,&nbsp;Cristina Pérez Ramírez,&nbsp;Abdelali Daddaoua,&nbsp;Carolina Alarcón Payer,&nbsp;Manuela Expósito Ruiz,&nbsp;Carlos García Collado","doi":"10.1002/jcph.1341","DOIUrl":"https://doi.org/10.1002/jcph.1341","url":null,"abstract":"<p><p>We evaluated the influence of clinical, biochemical, and genetic factors on response in 142 patients diagnosed with rheumatoid arthritis, of whom 87 patients were treated with tocilizumab (61.26%) and 55 patients were treated with rituximab (38.7%;) according to the variables European League Against Rheumatism (EULAR) response, remission, low disease activity, and improvement in Disease Activity Score, 28 joints (DAS28) at 6, 12, and 18 months. A retrospective prospective cohort study was conducted. Patients carrying the FCGR3A rs396991-TT genotype treated with tocilizumab showed higher EULAR response (OR, 5.075; 95%CI, 1.20-21.33; P = .027) at 12 months, those who were naive for biological disease-modifying antirheumatic drugs (bDMARDs) at the beginning of treatment showed satisfactory EULAR response, higher remission, and greater improvement in DAS28 at 6 months. Younger age at start of tocilizumab treatment was associated with satisfactory EULAR response at 18 months and greater remission at 6 and 18 months. Subcutaneous tocilizumab administration was associated with higher remission at 6 months and improved low disease activity rate at 12 months. In patients treated with rituximab, carriers of the FCGR2A rs1801274-TT genotype had higher EULAR response at 6 months (OR, 4.861; 95%CI, 1.11-21.12; P = .035), 12 months (OR, 4.667; p = 0.066, 95%CI, 0.90-24.12; P = .066), and 18 months (OR, 2.487; 95%CI, 0.35-17.31; P = .357), higher remission (OR: 10.625; p = 0.044, CI_95% : 1.07, 105.47) at 6 months, and greater improvement in DAS28 at 12 months (B = 0.782; 95%CI, -0.15 to 1.71; P = .098) and 18 months (B = 1.414; 95%CI, 0.19-2.63; P = .025). The FCGR3A rs396991-G allele was associated with improved low disease activity rate (OR, 4.904; 95%CI, 0.84-28.48; P = .077) and greater improvement in DAS28 (B = -1.083; 95%CI, -1.98 to -0.18; P = .021) at 18 months. Patients with a lower number of previous biological therapies had higher remission at 12 months. We suggest that the FCGR3A rs396991-TT genotype, higher baseline value of DAS28, subcutaneous tocilizumab administration, younger age at the beginning of treatment, and being bDMARD naive are associated with better response to tocilizumab. In patients treated with rituximab, we found better response in those patients with the FCGR2A rs1801274-TT genotype, the FCGR3A rs396991-G allele, and lower number of previous biological therapies.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"517-531"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1341","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36749159","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":"Food Effect Study Design With Oral Drugs: Lessons Learned From Recently Approved Drugs in Oncology.","authors":"Mark Farha,&nbsp;Eric Masson,&nbsp;Helen Tomkinson,&nbsp;Ganesh Mugundu","doi":"10.1002/jcph.1351","DOIUrl":"https://doi.org/10.1002/jcph.1351","url":null,"abstract":"<p><p>Evaluation of the effect of food on the pharmacokinetics of oral oncology drugs is critical to drug development, as food can mitigate or exacerbate toxicities and alter systemic exposure. Our aim is to expand on current US Food and Drug Administration (FDA) guidance and provide data-driven food-effect study design recommendations specific to the oncology therapeutic area. Data for recently approved small-molecule oncology drugs was extracted from the clinical pharmacology review in the sponsor's FDA submission package. Information on subject selection, meal types, timing of the study relative to the pivotal trial, and study outcomes was analyzed. The number of subjects enrolled ranged from 12 to 60, and the majority of studies (19 of 29) were conducted in healthy volunteers. Using AstraZeneca cost data, healthy volunteer studies were estimated to cost 10-fold less than cancer patient studies. Nine of 29 (31%) studies included meals with multiple levels of fat content. Analysis of a subset of 16 drugs revealed that final results for the food-effect study were available before the start of the pivotal trial for only 2 drugs. Conducting small food-effect studies powered to estimate effect, rather than confirm no effect, with only a standardized high-fat meal according to FDA guidance may eliminate unnecessary studies, reduce cost, and improve efficiency in oncology drug development. Starting food-effect studies as early as possible is key to inform dosing in pivotal trials.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"463-471"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1351","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36769125","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 of Adjunctive Lacosamide in Pediatric Patients With Epilepsy.","authors":"Julia Winkler,&nbsp;Rik Schoemaker,&nbsp;Armel Stockis","doi":"10.1002/jcph.1340","DOIUrl":"https://doi.org/10.1002/jcph.1340","url":null,"abstract":"<p><p>A pediatric population pharmacokinetic model including covariate effects was developed using data from 2 clinical trials in pediatric patients with epilepsy (SP0847 and SP1047). Lacosamide plasma concentration-time data (n = 402) were available from 79 children with body weights ranging from 6 to 76 kg, and a balanced age distribution (6 months to <2 years: n = 14; 2 to <6 years: n = 22; 6 to <12 years: n = 25; 12 to <18 years: n = 18). A single-compartment population pharmacokinetic model with first-order absorption and elimination described the data adequately. Plasma clearance was modeled using allometric scaling on body weight with a freely estimated allometric exponent, while volume of distribution used a fixed theoretical allometric exponent. Covariate search identified a significant effect of enzyme-inducing antiepileptic drugs resulting in a 35% decrease in lacosamide average plasma concentration. No additional effects on clearance could be attributed to race, sex, age, or renal function. Different dosing adaptation schemes by body weight bands were simulated to approximate, in pediatric patients aged 4 to 17 years, the same average plasma concentration as in adult patients receiving the maximum recommended lacosamide daily dose.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"541-547"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1340","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36677841","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 Exposure-Response Modeling Analyses of Golimumab in Children With Moderately to Severely Active Ulcerative Colitis.","authors":"Yan Xu,&nbsp;Omoniyi J Adedokun,&nbsp;Daphne Chan,&nbsp;Chuanpu Hu,&nbsp;Zhenhua Xu,&nbsp;Richard S Strauss,&nbsp;Jeffrey S Hyams,&nbsp;Dan Turner,&nbsp;Honghui Zhou","doi":"10.1002/jcph.1353","DOIUrl":"https://doi.org/10.1002/jcph.1353","url":null,"abstract":"<p><p>Population pharmacokinetics (PK) and exposure-response (E-R) analyses were conducted to compare the PK and E-R relationships of golimumab between children and adults with ulcerative colitis. PK data following subcutaneous golimumab administration to children with ulcerative colitis (6-17 years) in the PURSUIT-PEDS-PK study, adults with ulcerative colitis in the PURSUIT study, and children with pediatric polyarticular juvenile idiopathic arthritis (2-17 years) in the GO-KIDS study, were included in the population PK analysis. E-R analysis was conducted using logistic regression to link serum golimumab concentration and Mayo score-based efficacy outcomes in pediatric and adult ulcerative colitis. Golimumab PK was adequately described by a 1-compartment model with first-order absorption and elimination. Golimumab apparent clearance and volume of distribution increased with body weight. Golimumab apparent clearance was higher in patients with lower serum albumin, no methotrexate use, and positive antibodies to golimumab; age was not an influential factor after accounting for body weight. Model-estimated terminal half-life (9.2 days in children; 9.5 days in adults) and other PK parameters suggest that golimumab PK properties are generally comparable between children and adults with ulcerative colitis. Simulations suggest that a higher induction dose than that tested in PURSUIT-PEDS-PK may be needed for children ≤45 kg to achieve exposures comparable to adults. Comparable E-R relationships between children and adults with ulcerative colitis were observed, although children appeared to be more responsive for the more stringent remission end point. The overall comparable PK and E-R relationships between children and adults support the extrapolation of golimumab efficacy from the adult to the pediatric ulcerative colitis population.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"590-604"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1353","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36769091","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":"Dosing Recommendations for Quetiapine When Coadministered With HIV Protease Inhibitors.","authors":"Mario R Sampson,&nbsp;Kelly Y Cao,&nbsp;Paula L Gish,&nbsp;Kyong Hyon,&nbsp;Poonam Mishra,&nbsp;William Tauber,&nbsp;Ping Zhao,&nbsp;Esther H Zhou,&nbsp;Islam R Younis","doi":"10.1002/jcph.1345","DOIUrl":"https://doi.org/10.1002/jcph.1345","url":null,"abstract":"<p><p>Although current quetiapine labeling recommends that its dosage should be lowered 6-fold when coadministered with strong cytochrome P450 (CYP)3A inhibitors, a reported case of coma in a patient receiving quetiapine with lopinavir and ritonavir prompted the reevaluation of labeling recommendations for the dosing of quetiapine when coadministered with human immunodeficiency virus (HIV) protease inhibitors. Literature and database (FDA Adverse Event Reporting System and United States Symphony Health Solutions' Integrated Dataverse Database) searches allowed us to identify cases of coma and related adverse events involving the coadministration of quetiapine and HIV protease inhibitors and to estimate the frequency of concomitant use. Literature review and physiologically based pharmacokinetic modeling allowed us to estimate the potential for CYP3A inhibition to contribute to adverse events related to HIV protease inhibitor-quetiapine coadministration. We identified excess sedation following coadministration of quetiapine and an HIV protease inhibitor in 3 reports without obvious confounders. In prescription claims data, 0.4% of quetiapine patients were dispensed a concurrent ritonavir prescription. The quetiapine dose was not reduced on ritonavir initiation in 90% of therapy episodes. Available data indicate to us that all HIV protease inhibitors combined with ritonavir are likely to be strong CYP3A inhibitors. We predicted that ritonavir would increase quetiapine exposure comparable to the strong CYP3A inhibitor ketoconazole. The current dosing recommendations for use of quetiapine with strong CYP3A inhibitors (ie, 6-fold lower quetiapine dose) are appropriate and should be followed when quetiapine is coadministered with HIV protease inhibitors.</p>","PeriodicalId":48908,"journal":{"name":"Journal of Clinical Pharmacology","volume":"59 4","pages":"500-509"},"PeriodicalIF":2.9,"publicationDate":"2019-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jcph.1345","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36685774","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}