British journal of clinical pharmacology最新文献

{"title":"Spotlight commentary: The role of therapeutic drug monitoring in optimizing treatment with antipsychotic medicines.","authors":"Jelcic Nina, Likic Robert, Tripkovic Mara","doi":"10.1111/bcp.16323","DOIUrl":"https://doi.org/10.1111/bcp.16323","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Incidence and trend of cardiac events among children and young adults exposed to psychopharmacological treatment (2006-2018): A nationwide register-based study.","authors":"Howaida Elmowafi, Jenny M Kindblom, Linda Halldner, David Gyllenberg, Estelle Naumburg","doi":"10.1111/bcp.16321","DOIUrl":"https://doi.org/10.1111/bcp.16321","url":null,"abstract":"<p><strong>Aims: </strong>The aim of this study was to assess cardiac event incidence and trends by sex and age in young patients on psychopharmacological treatment in Sweden.</p><p><strong>Methods: </strong>This nationwide incidence study encompassed data from Swedish registers (2006-2018). Patients aged 5-30 years were exposed to one or more psychotropic medications (attention deficit hyperactivity disorder medications, antihistamines, selective serotonin reuptake inhibitors, other antidepressants, anxiolytics, antipsychotics, hypnotics/sedatives). Annual incidences, trends and mean incidences of cardiac events (cardiac arrest, arrhythmias, fainting/collapse, sudden death) and recurrent events were calculated.</p><p><strong>Results: </strong>Among those exposed (n = 875 430, 2 647 957 patient-years, 55% female), 26 750 cardiac events were identified. The mean annual incidence of cardiac events and first-ever events were 0.99% and 0.80%, respectively, showing significant upward annual trends of 4.26% and 2.48%, respectively (P < .001). The highest incidences were among females aged 15-19 years (1.50%) and those exposed to polypharmacy (1.63%), anxiolytics (1.53%) or antihistamines (1.27%). The mean annual incidences of cardiac arrest and arrythmias, for both sexes, were 0.01% and 0.51%, respectively. Fainting/collapse accounted for about half of all events, occurring more often in females. The pattern of rising annual incidence remained after excluding fainting/collapse. In all, 21.1% of events were recurrent. Death, including sudden death, occurred in 13 patients.</p><p><strong>Conclusions: </strong>The mean annual incidence of cardiac events among young patients receiving psychopharmacological treatment was low, 0.99%, with an upward trend of 4.26% annually. Incidence was highest in adolescent females and patients exposed to polypharmacy. Our study highlights the need for more knowledge regarding the possible association between exposure to psychopharmacological treatment and cardiac events.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Importance of the UK Prescribing Safety Professor Assessment as a component of undergraduate medical assessment.","authors":"David Hepburn, Andrew William Hitchings, Kurt Wilson, Lynne Bollington, Emma Magavern, Mark J Caulfield, Simon Maxwell","doi":"10.1111/bcp.16324","DOIUrl":"https://doi.org/10.1111/bcp.16324","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142495480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Generating and translating evidence for safe and effective medication management in aged care homes.","authors":"Annie M L Ea, Amanda J Cross, Angelita Martini, Jacqueline Wesson, J Simon Bell","doi":"10.1111/bcp.16269","DOIUrl":"https://doi.org/10.1111/bcp.16269","url":null,"abstract":"<p><p>Generating and translating high-quality evidence is integral to providing safe and effective medication management for residents of aged care homes. Residents are often under-represented in trials of medication effectiveness and safety. This paper reviews opportunities and challenges for generating and translating evidence for safe and effective medication management in aged care homes. There are an increasing number of randomized controlled trials (RCTs) being conducted in aged care homes. Observational studies can also help address the evidence-practice gap arising from underrepresentation of residents in RCTs. Stepped-wedge and helix counterbalanced designs may help overcome limitations of traditional RCTs for evaluating medication management interventions in the aged care setting. Strategies for generating evidence include building effective partnerships with aged care homes and organizations, using novel trial designs, leveraging existing data and knowledge sharing through international platforms. Strategies for translating evidence include using quality indicators for audit and feedback, provision of education and training, engaging internal and external stakeholders, and development of local action plans and guideline implementation tools. There is an emerging interest in the role of knowledge brokers to facilitate knowledge translation. Future directions for generating and translating evidence include strengthening international research collaboration, industry partnerships, standardizing aged care home data to support national and international comparisons, and optimizing the use of technology. Initiatives may include improving access to routinely collected administrative health and medication data for conducting high-quality observational studies. Future studies should assess outcomes prioritized by residents to ensure that medication management strategies are tailored to their needs.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-dose and steady-state pharmacokinetics of clomipramine, yohimbine and clomipramine/yohimbine combination: A clinical drug-drug interaction study.","authors":"Amelie Leutzendorff, Valentin Al Jalali, Martin Bauer, Iris K Minichmayr, Birgit Reiter, Michael Wölfl- Duchek, Alina Nussbaumer-Pröll, Maria Weber, Sabine Eberl, Marie Spies, Maysa Sarhan, Johannes Geilen, Alexander Walther, Daniel Drai, Markus Zeitlinger","doi":"10.1111/bcp.16274","DOIUrl":"https://doi.org/10.1111/bcp.16274","url":null,"abstract":"<p><strong>Aims: </strong>Clomipramine (CLOMI) has shown effectiveness in treating premature ejaculation but is linked to erectile dysfunction and reduced libido. Yohimbine (YOH), by contrast, is effective in treating erectile dysfunction and may improve libido. Combining CLOMI and YOH could potentially leverage the benefits of both drugs. This study aimed to investigate the interactions between these drugs and to evaluate their safety profile.</p><p><strong>Methods: </strong>A prospective, open-labelled, single-centre, pharmacokinetic (PK) drug-drug interaction study was performed in 15 healthy male subjects. Single-dose and steady-state PK were investigated using noncompartmental analysis after mono- and combination therapy of the 2 orally applied drugs. Plasma sampling was performed at baseline, 0.5 (YOH), 1, 1.5 (YOH), 2, 3, 4, 5, 6, 8, 12 and 24 h (CLOMI). Differences in the area under the curve after multiple dosing (MD) were determined using an equivalence boundary of 80-125%.</p><p><strong>Results: </strong>The geometric mean ratio of the area under the curve up to 12 h for MD CLOMI (combination vs. monotherapy) was 112% (90% confidence interval: 104-120%), whereas for MD YOH this ratio was 137% (90% confidence interval: 112-168%). The study drugs were safe and well tolerated as mono- and combination therapy, with no major adverse events reported.</p><p><strong>Conclusion: </strong>A PK assessment of clomipramine and yohimbine indicated a clinically significant drug-drug interaction for MD YOH in combination with CLOMI. This might be explained by competitive, CLOMI-related inhibition of YOH metabolism, probably mediated by cytochrome P450 2D6. However, according to European Medicines Agency guidelines, the effect can be classified as interaction absent (<1,25 fold) or minor (>1.25-<2-fold). Given the complimentary mechanisms of action and the favourable safety profiles, the findings pave the way for future efficacy studies.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"\"Doctor, would it surprise you if there were prescribing errors in this patient's medication?\" Identifying eligible patients for in-hospital pharmacotherapeutic stewardship: A matched case-control study.","authors":"Rashudy F Mahomedradja, Birgit I Lissenberg-Witte, Kim C E Sigaloff, Jelle Tichelaar, Michiel A van Agtmael","doi":"10.1111/bcp.16253","DOIUrl":"https://doi.org/10.1111/bcp.16253","url":null,"abstract":"<p><strong>Background: </strong>Evaluating a patient's medication list is critical to reduce prescribing errors (PEs), but is a labour- and time-intensive process. Identification of patients at risk of PEs could improve the allocation of scarce time and resources, but currently available prediction tools are not effective.</p><p><strong>Objective: </strong>To investigate whether ward doctors can identify patients at risk of PEs.</p><p><strong>Methods: </strong>This prospective matched case-control study was conducted on three clinical wards in an academic hospital. Otolaryngology and oncology ward doctors used clinical intuition to select patients requiring a clinical medication review (CMR) (cases). These patients were then matched 1:1 on age (±10 years) and number (±1) of prescriptions with patients not selected for CMRs on the internal medicine and upper gastrointestinal surgery ward (controls). A multidisciplinary in-hospital pharmacotherapeutic stewardship team assessed the prevalence of PEs.</p><p><strong>Results: </strong>A total of 387 patients with 5191 prescriptions were included. Overall, 799 PEs affecting 279 patients (72.1%) were identified. Most PEs (58.8%) occurred during hospitalization. There were no significant differences in age, number of prescriptions, sex, renal function or documented allergies or intolerances between the cases and controls or between controls and other patients who did not receive a CMR. The incidence of PEs was higher in cases than in controls (97.5% vs 72.5%, odds ratio = 14.8, 95% confidence interval [CI] 1.8-121.1, P = .002)). The rate of PEs was three times higher in cases than in controls (incidence rate ratio = 3.0, 95% CI 2.3-4.0, P < .001).</p><p><strong>Conclusions: </strong>Ward doctors can effectively identify patients with PEs, and thus at risk of medication-related harm, using clinical intuition.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-induced liver injury associated with pretomanid, bedaquiline, and linezolid: Insights from FAERS database analysis.","authors":"Qingfeng He, Yang Li, Sifan Liu, Hao Xue, Xiaoqiang Xiang, Tao Wang, Zhen Feng","doi":"10.1111/bcp.16318","DOIUrl":"https://doi.org/10.1111/bcp.16318","url":null,"abstract":"<p><strong>Aims: </strong>The emergence of drug-resistant tuberculosis has necessitated novel treatments like the pretomanid, bedaquiline and linezolid (BPaL) regimen. This study investigated the association of drug-induced liver injury (DILI) with the BPaL regimen compared to first-line antituberculosis drugs (isoniazid, rifampin, pyrazinamide and ethambutol [HRZE]).</p><p><strong>Methods: </strong>A retrospective pharmacovigilance analysis was conducted using data from the US Food and Drug Administration Adverse Event Reporting System database from July 2019 to June 2023. Disproportionality analysis was employed to calculate the reporting odds ratio (ROR) of DILI for each component of the BPaL regimen. Onset time and mortality rates of DILI across different regimens were also compared.</p><p><strong>Results: </strong>We identified 1242 cases of BPaL-related DILI. Most cases occurred in individuals under 65 years of age (63.8%), with more male patients affected than females (51.4% vs 39.5%). The association between antituberculosis drugs and DILI was stronger for the HRZE regimen (ROR = 7.99, 95% confidence interval [CI] 7.74-8.25) than the BPaL regimen (ROR = 4.75, 95% CI 4.55-4.97). The median onset time for DILI was significantly shorter with the BPaL regimen (8 days, interquartile range [IQR] 3-28) compared to the HRZE regimen (20 days, IQR 6-48) (P < .001). Additionally, the BPaL regimen was associated with a higher risk of death due to DILI compared to the HRZE regimen (14.1% vs 10.4%, P = .003).</p><p><strong>Conclusions: </strong>Although the BPaL regimen had a lower overall risk of DILI compared to the HRZE regimen, it was significantly associated with DILI, indicating a need for careful monitoring during treatment.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experiences from the initial 3 years of introducing the British Pharmacological Society and UK Medical Schools Council Prescribing Safety Assessment for Danish junior doctors.","authors":"Kathrine Bendorff Moriat, Zandra Nymand Ennis, Thomas Øhlenschlæger, Troels Korshøj Bergmann","doi":"10.1111/bcp.16280","DOIUrl":"https://doi.org/10.1111/bcp.16280","url":null,"abstract":"<p><strong>Aims: </strong>The British Pharmacological Society and UK Medical Schools Council Prescription Safety Assessment (BPS/MSC PSA) is an electronic platform developed for assessing the prescription skills of medical students. Our aim was to investigate the feasibility of the BPS/MSC PSA in addressing prescribing competencies among junior doctors in a hospital setting.</p><p><strong>Methods: </strong>The Department of Clinical Pharmacology at Odense University Hospital established a Danish translated programme using the BPS/MSC PSA platform. We launched a formal 3-year programme in 2021, potentially assessing all first-year doctors at Odense University Hospital and Esbjerg Regional Hospital. Participation was followed by a survey.</p><p><strong>Results: </strong>During the period of 2021 to 2023 n = 364 doctors were invited, from which n = 246 participated. The compliance rate increased from 38% in 2021 to 88% in 2023. The mean assessment score (points normalized to percentage) across n = 246 participants was 71%, and 94% achieved a score of at least 50%. A subset of participants responded to the survey, with the majority of those completing the questionnaire indicating that the purpose of the assessment was clear. The items related to difficulty and number of questions received comparable evaluations, and most respondents found the questions clinically relevant.</p><p><strong>Conclusion: </strong>It is feasible to translate and implement the BPS/MSC PSA in a Danish hospital setting. The programme provides insight into the prescribing competencies of junior doctors and the participants are generally positive.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142458467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Once daily dosing of dolutegravir in combination with rifampicin in infants and children living with HIV: A population pharmacokinetic approach","authors":"","doi":"10.1111/bcp.16282","DOIUrl":"10.1111/bcp.16282","url":null,"abstract":"&lt;p&gt;&lt;b&gt;3&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Once daily dosing of dolutegravir in combination with rifampicin in infants and children living with HIV: A population pharmacokinetic approach&lt;/b&gt;&lt;/p&gt;&lt;p&gt;Lisanne Bevers&lt;sup&gt;1&lt;/sup&gt;, Angela Colbers&lt;sup&gt;1&lt;/sup&gt;, David Burger&lt;sup&gt;1&lt;/sup&gt;, Chishala Chabala&lt;sup&gt;2&lt;/sup&gt;, Alfeu Passanduca&lt;sup&gt;3&lt;/sup&gt;, Victor Musiime&lt;sup&gt;4&lt;/sup&gt;, Hilda Mujuru&lt;sup&gt;5&lt;/sup&gt;, Anna Turkova&lt;sup&gt;6&lt;/sup&gt;, Alasdair Bamford&lt;sup&gt;7&lt;/sup&gt; and Rob ter Heine&lt;sup&gt;1&lt;/sup&gt;&lt;/p&gt;&lt;p&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;i&gt;Department of Pharmacy, Radboud Institute for Medical Innovations (RIMI), Radboud University Medical Center;&lt;/i&gt; &lt;sup&gt;2&lt;/sup&gt;&lt;i&gt;Department of Paediatrics and Child Health, School of Medicine, University of Zambia;&lt;/i&gt; &lt;sup&gt;3&lt;/sup&gt;&lt;i&gt;Universidade Eduardo Mondlane Faculdade de Medicina;&lt;/i&gt; &lt;sup&gt;4&lt;/sup&gt;&lt;i&gt;Research Department, Joint Clinical Research Centre;&lt;/i&gt; &lt;sup&gt;5&lt;/sup&gt;&lt;i&gt;Clinical Research Centre, Faculty of Medicine and Health Sciences, University of Zimbabwe;&lt;/i&gt; &lt;sup&gt;6&lt;/sup&gt;&lt;i&gt;Medical Research Council Clinical Trials Unit at University College London;&lt;/i&gt; &lt;sup&gt;7&lt;/sup&gt;&lt;i&gt;Great Ormond Street Hospital for Children NHS Foundation Trust&lt;/i&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Dolutegravir clearance is increased in presence of rifampicin, due to induction of UGT1A1 and CYP3A4. This drug–drug interaction between rifampicin and dolutegravir can be overcome by twice-daily dolutegravir dosing with daily dose doubled. However, twice-daily dosing complicates treatment adherence, once-daily being preferred for children. Griesel et al. (2023) showed comparable virological suppression rates of once-daily dosing of dolutegravir &lt;i&gt;vs&lt;/i&gt;. twice-daily dosing in combination with rifampicin in adults. We therefore aimed to establish a potential once-daily dosing regimen for dolutegravir co-administered with rifampicin for use in the paediatric population.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; We developed a paediatric population pharmacokinetic model of dolutegravir in NONMEM based on intensive pharmacokinetic data from three large paediatric clinical trials, that is, ODYSSEY (NCT02259127), CHAPAS-4 (ISRCTN22964075) and EMPIRICAL (NCT03915366). The model was developed with 2522 dolutegravir plasma concentrations from 235 infants and children aged 3 months to 17 years, with concomitant rifampicin use in 36 subjects. To account for changes in pharmacokinetics as result of body size, all volume and flow parameters were allometrically scaled to a total body weight of 70 kg. Maturation of UGT1A1-mediated dolutegravir clearance in our population was also assessed. Physiologically plausible covariates were tested based on difference in the objective function value (dOFV) and the visual predictive checks (VPCs). A representative virtual population with 7000 children (3 to &lt;40 kg), equally distributed among different weight bands and formulations, was developed to perform the once-daily dosing simulations. Dosing of dolutegravir was based on the current World Health Organization (WHO) weight-band dosing recommendations. Our ","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16282","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399388","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiologically based pharmacokinetic modelling of the co-administration of ritonavir-boosted atazanavir and rifampicin in children co-treated for HIV and TB","authors":"","doi":"10.1111/bcp.16283","DOIUrl":"10.1111/bcp.16283","url":null,"abstract":"&lt;p&gt;&lt;b&gt;4&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Physiologically based pharmacokinetic modelling of the co-administration of ritonavir-boosted atazanavir and rifampicin in children co-treated for HIV and TB&lt;/b&gt;&lt;/p&gt;&lt;p&gt;Shakir Atoyebi&lt;sup&gt;1&lt;/sup&gt;, Maiara Montanha&lt;sup&gt;1&lt;/sup&gt;, Catherine Orrell&lt;sup&gt;2&lt;/sup&gt;, Henry Mugerwa&lt;sup&gt;3&lt;/sup&gt;, Marco Siccardi&lt;sup&gt;1,4&lt;/sup&gt;, Paolo Denti&lt;sup&gt;5&lt;/sup&gt; and Catriona Waitt&lt;sup&gt;1,6&lt;/sup&gt;&lt;/p&gt;&lt;p&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;i&gt;Department of Pharmacology &amp; Therapeutics, University of Liverpool;&lt;/i&gt; &lt;sup&gt;2&lt;/sup&gt;&lt;i&gt;Desmond Tutu Health Foundation, Institute of Infectious Disease and Molecular Medicine &amp; Department of Medicine, University of Cape Town;&lt;/i&gt; &lt;sup&gt;3&lt;/sup&gt;&lt;i&gt;Joint Clinical Research Centre;&lt;/i&gt; &lt;sup&gt;4&lt;/sup&gt;&lt;i&gt;ESQlabs GmbH;&lt;/i&gt; &lt;sup&gt;5&lt;/sup&gt;&lt;i&gt;Division of Pharmacology, Department of Medicine, University of Cape Town;&lt;/i&gt; &lt;sup&gt;6&lt;/sup&gt;&lt;i&gt;Infectious Diseases Institute, Makerere University College of Health Sciences&lt;/i&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Children living with HIV are disproportionately affected by tuberculosis. Limited options are available for adequate treatment of both diseases because rifampicin, a mainstay of several anti-TB regimens, reduces the exposure of multiple antiretrovirals like ritonavir-boosted atazanavir (ATV/r). Recent modelling and clinical studies (DERIVE [NCT04121195]) suggest doubling the dose of ATV/r 300/100 mg from once to twice daily would overcome the drug–drug interaction (DDI) effect with rifampicin in adults. In this study, physiologically based pharmacokinetic (PBPK) modelling was used to investigate if twice daily dosing of ATV/r could overcome the DDI effect of standard doses of rifampicin in children.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Material and methods&lt;/b&gt;: The published PBPK model used for studying DDI between ATV/r and rifampicin in adults was modified into its paediatric version. Equations describing key anatomical and physiological parameters (e.g. organ weights and blood flow) were modified to paediatric versions between ages 7 and 18 years. Adult levels of enzyme activity were maintained in the paediatric model. Rifampicin's drug absorption rate, apparent clearance and volume of distribution were also modified to paediatric values within the simple compartment used to model rifampicin PK. Model predictions were validated using observed clinical PK data of ATV/r alone and rifampicin alone in children with acceptability criteria maintained as absolute average fold error less than 2 between simulated and observed values. ATV/r 300/100 mg once daily and twice daily were each simulated with co-administered 300, 450 and 600 mg rifampicin in children distributed in three weight bands: 25–30 kg (7–11 years), 30–39 kg (8–14 years) and 50–70 kg (12–18 years), respectively. Simulated ATV Ctrough was compared against a clinical cut-off, ATV protein binding-adjusted 90% inhibitory concentration (PAIC90, 14 ng/mL).&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; The paediatric PBPK model was adequately validated with simulated PK of atazanavir and rifampicin having AAFEs &l","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16283","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}