British journal of clinical pharmacology最新文献_第9页

Pharmacokinetic modelling to enable early attrition of repurposed antiviral drug combination candidates with a high likelihood of failure in COVID-19 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2024-10-10 DOI: 10.1111/bcp.16312

{"title":"Pharmacokinetic modelling to enable early attrition of repurposed antiviral drug combination candidates with a high likelihood of failure in COVID-19","authors":"","doi":"10.1111/bcp.16312","DOIUrl":"10.1111/bcp.16312","url":null,"abstract":"33Pharmacokinetic modelling to enable early attrition of repurposed antiviral drug combination candidates with a high likelihood of failure in COVID-19Lorraine Ralph1, Olivier Touzelet2, Ahlam Ali2, Joanne Sharp1, Richard Walker2, James Stewart3, Miles Carroll4, Ultan Power2 and Andrew Owen11Centre of Excellence for Long-acting Therapeutics, University of Liverpool; 2School of Medicine, Dentistry and Biomedical Sciences, Queens University Belfast; 3Infection Biology & Microbiomes, University of Liverpool; 4Pandemic Sciences Institute, Medical Sciences Division, University of OxfordIntroduction: COVID-19 remains a concern in some patient population groups such as those who are immunosuppressed. While antiviral monotherapy is available, development of combination therapy could offer improved efficacy while reducing the risk of developing resistance. Repurposing drugs already approved or at late stage development can speed up the time to market, reduce risk of failure and decrease costs relative to more traditional development programmes. To avoid unnecessary waste of resources when selecting drugs for potential repurposing, it is essential to rule out compounds that are unlikely to achieve efficacious concentrations at safe doses in patients.Aim: To conduct pharmacokinetic modelling and simulations to predict drug concentrations in patients for drug combinations identified as having activity against SARS-CoV-2 in vitro.Methods: Literature searches were performed using PubMed to identify clinical concentration–time profiles for drug combinations determined as having synergistic activity against SARS-CoV-2 in Calu-3 and AAT cells. Published data were digitalised using WebPlotDigitizer and formatted for pharmacokinetic analysis. One-, two- and three- compartment models were fitted to the data as appropriate using R. Selected models were used to simulate plasma concentration-time profiles in a patient population (n = 1000) at dose regimens considered to have an acceptable safety profile. Simulated plasma concentrations were compared with the in vitro calculated EC90 values for SARS-CoV-2.Results: In vitro studies identified 37 drug combinations with synergistic efficacy against SARS-CoV-2. Five drugs could not undergo PK modelling due to unavailability of clinical concentration data in the literature. Two drugs had been withdrawn from the market due to adverse events so did not undergo any further PK evaluation. Three drugs were eliminated from further evaluation due to other reasons (formulation challenges, prior clinical testing, etc.). Of the remaining combinations, PK simulations identified 18 combinations where at least one drug would not achieve efficacious systemic concentra","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"22-23"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16312","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399444","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}

引用次数: 0

Comprehensive population pharmacokinetic modelling of sugemalimab, an anti-programmed death-ligand 1 (PD-L1) human monoclonal antibody, in patients with solid tumours or lymphomas across multiple Phase I-III studies. 针对实体瘤或淋巴瘤患者的多项 I-III 期研究，建立抗程序性死亡配体 1 (PD-L1) 人类单克隆抗体 sugemalimab 的全面群体药代动力学模型。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2024-10-10 DOI: 10.1111/bcp.16276

Kun Wang, Chaohsuan Pan, Fengyan Xu, Archie N Tse, Yucheng Sheng

{"title":"Comprehensive population pharmacokinetic modelling of sugemalimab, an anti-programmed death-ligand 1 (PD-L1) human monoclonal antibody, in patients with solid tumours or lymphomas across multiple Phase I-III studies.","authors":"Kun Wang, Chaohsuan Pan, Fengyan Xu, Archie N Tse, Yucheng Sheng","doi":"10.1111/bcp.16276","DOIUrl":"https://doi.org/10.1111/bcp.16276","url":null,"abstract":"Aims: The aim of this study was to develop a population pharmacokinetics model for sugemalimab, a monoclonal antibody that targets programmed death-ligand 1 (PD-L1), using data from Phase I-III trials and to assess clinical factors affecting sugemalimab exposure.Methods: A nonlinear mixed-effect modelling approach was employed to analyse pooled data from nine studies involving 1628 subjects to characterize the PopPK of sugemalimab. This investigation examined the influence of various covariates on sugemalimab pharmacokinetics (PK), encompassing demographics, baseline hepatic and renal function-related covariates, and others (including anti-drug antibody [ADA], combination treatment, Eastern Cooperative Oncology Group [ECOG] performance score, tumour burden and tumour type). Estimation accuracy and predictive ability of the final model were evaluated using various methods. The influence of covariates on sugemalimab exposure was assessed by simulation from the final model.Results: A two-compartment model with first-order elimination and time-varying clearance effectively described the PK of sugemalimab. Covariate analyses revealed significant relationships between sugemalimab clearance and body weight, albumin, gender, ADA, tumour burden and tumour type. The statistically significant covariates on central volume were body weight, albumin, gender and tumour type. No significant relationships were found in the final model for age, race, alanine aminotransferase, aspartate aminotransferase, creatinine, total bilirubin, alkaline phosphatase, combination treatment, creatinine clearance, ECOG, renal function or hepatic function. All significant covariates demonstrated less than a 20% effect on sugemalimab exposure.Conclusions: The PopPK model adequately described the pharmacokinetic profile of sugemalimab with no clinically meaningful impact observed on its exposure across all covariates. Dose adjustment does not appear to be necessary.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399377","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}

引用次数: 0

Pharmacokinetics of molnupiravir and favipiravir in plasma separation cards from patients with COVID-19: Agile CST-2 and CST-6 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2024-10-10 DOI: 10.1111/bcp.16295

{"title":"Pharmacokinetics of molnupiravir and favipiravir in plasma separation cards from patients with COVID-19: Agile CST-2 and CST-6","authors":"","doi":"10.1111/bcp.16295","DOIUrl":"10.1111/bcp.16295","url":null,"abstract":"16Pharmacokinetics of molnupiravir and favipiravir in plasma separation cards from patients with COVID-19: Agile CST-2 and CST-6Beth Thompson1, Laura Else1, Elizabeth Challenger1, Richard Fitzgerald1,2, Helen Reynolds1,2, Laura Dickinson1, Colin Hale2, Tom Fletcher2,3, Tim Rowland2,3 and Saye Khoo1,21University of Liverpool; 2Royal Liverpool University Hospital; 3Liverpool School of Tropical MedicineBackground: Molnupiravir (MPV) and favipiravir (FVP) are broadly active antiviral ribonucleoside analogues. Both have demonstrated efficacy in treatment of COVID-19 and have been investigated for use against other high-consequence infections. Collection of liquid plasma (L-PL) in remote settings, where diseases like haemorrhagic fevers are endemic, can be challenging. HemaSep dried blood spots (HS-DBS) offer a useful alternative to L-PL, separating plasma upon contact as a distinct outer ring (HS-PL) and shipped at ambient temperatures. HS-DBS were collected alongside L-PL in the AGILE CST-2/CST-6 clinical trials to evaluate the pharmacokinetics of single and repeat doses of these agents in patients with confirmed COVID-19 disease.Materials and methods: AGILE-CST-2 and CST-6 were open-label 2:1 randomized controlled phase I trials comparing MPV and FVP, respectively, with standard of care, designed to determine the optimal dose for treatment of symptomatic COVID-19 patients (CST-2; n = 12, CST-6; n = 16). MPV was orally delivered twice daily (BD) for 10 doses, with dose escalations (300/600/800 mg BD) across three cohorts, whereas FVP was intravenously administered BD for 14 doses, with dose escalations across four cohorts (600/1200/1800/2400 mg). Paired L-PL and HS-DBS were collected over 0–4 h post-dose (CST-2) and 0–12 h post-dose (CST-6) following administration of single (day 1) and multiple doses (day 5–CST-2; day 3–CST-6). HS-PL were excised and extracted with 50:50 acetonitrile:1 mM ammonium acetate (CST-2) and acetonitrile (CST-6). Concentrations of MPV active metabolite ß-d-N4-hydroxycytidine (NHC) and FVP were quantified using LC-MS (NHC-HS-PL: 2.5–250 ng/sample, L-PL: 2.5-5000 ng/mL; FVP-HS-PL: 50-5000 ng/sample, L-PL: 1000-100 000 ng/mL). HS-PL values were normalized to ng/mL and pharmacokinetic parameters (Cmax, AUClast) derived using non-compartmental analysis. Linear regression and Bland–Altman plots were used to compare methods.Results: NHC L-PL geometric mean Cmax increased with each dosing cohort (n = 4/cohort) 300/600/800 mg [day 1: 1197/2440/3447 ng/mL; day 5: 1065/1865/3546 ng/mL]. The mean difference between all HS-PL and L-PL NHC was 27% (−69%–143%). HS-PL Cmax were: day 1, 1749/2441/4986 ng/mL; day 5, 1559/1992/4618 ng/mL. Intersubjec","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"13"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16295","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399427","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}

引用次数: 0

Model based comparison of cabotegravir pharmacokinetics following thigh and gluteal injections 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2024-10-10 DOI: 10.1111/bcp.16296

{"title":"Model based comparison of cabotegravir pharmacokinetics following thigh and gluteal injections","authors":"","doi":"10.1111/bcp.16296","DOIUrl":"10.1111/bcp.16296","url":null,"abstract":"17Model based comparison of cabotegravir pharmacokinetics following thigh and gluteal injectionsSusan Ford1, Kelong Han1, Ronald D'Amico2 and William Spreen21GSK; 2ViiV HealthcareBackground: Cabotegravir (CAB) long-acting (LA) intramuscular (IM) gluteal injections are approved for HIV-1 pre-exposure prophylaxis (PrEP) and combination treatment with rilpivirine. The [i]vastus lateralis[/i] (lateral) thigh muscle is a potential alternative site of administration in cases of gluteal injection fatigue or physical obstruction. We aimed to characterize CAB pharmacokinetics (PK) and its association with demographics following thigh administration in comparison to gluteal administration using population PK (PPK) analysis.Material and methods: Fourteen participants (pts) who were HIV negative and received a 600 mg single thigh injection in phase 1 study 208832 and 118 pts who were HIV-positive and received thigh injections [400 mg monthly (QM) × 4 or 600 mg every-2-months (Q2M) × 2] after >3 years of gluteal injections in phase 3b study 207966 (ATLAS-2M) provided CAB concentrations for the analysis. An established gluteal PPK model was fit to PK data following both gluteal and thigh injections, enabling within-person comparison in ATLAS-2M pts. Gluteal parameters were fixed. Thigh parameters including absorption rate constant (KA-thigh) and bioavailability (F-thigh) were estimated. CAB PK profiles following chronic or intermittent thigh injections administered QM and Q2M were simulated and compared to gluteal injections. PK target was that 95% of pts maintain concentrations >0.45 μg/mL, the 5th percentile of observed CAB trough concentration following the gluteal initiation injection in phase 3 Studies.Results: 1254 concentrations from 366 thigh injections and 2022 concentrations from 1631 gluteal injections were analysed. Similar to gluteal administration, KA-thigh was associated with sex and BMI. KA-thigh was correlated with and was generally faster than KA-gluteal, described by the additive linear relationship: KA-thigh = KA-gluteal + 0.000253 h[sup] − 1[/sup]. Terminal half-life of thigh administration was 26% (male) and 39% (female) shorter than for gluteal administration. F-thigh was 90% of gluteal injection. PK target was maintained following chronic QM thigh injections or alternating thigh-gluteal injections for either QM or Q2M regimens but not following chronic Q2M thigh injections.Conclusions: PPK modelling and simulation support chronic thigh administration of CAB LA QM and intermittent thigh injections for both QM and Q2M regimens. However, simulated chronic Q2M thigh administration did not maintain PK target established in pivotal trials and therefore is not recommended.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"14"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16296","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399428","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}

引用次数: 0

Predicting drug–drug interactions between ainuovirine and rifampicin plus isoniazid using PBPK modelling 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2024-10-10 DOI: 10.1111/bcp.16302

{"title":"Predicting drug–drug interactions between ainuovirine and rifampicin plus isoniazid using PBPK modelling","authors":"","doi":"10.1111/bcp.16302","DOIUrl":"10.1111/bcp.16302","url":null,"abstract":"23Predicting drug–drug interactions between ainuovirine and rifampicin plus isoniazid using PBPK modellingLu Hongzhou1, Meng Xianmin1 and Qin Hong21The Third People's Hospital of Shenzhen, The Second Affiliated Hospital of Southern University of Science and Technology; 2Jiangsu Aidea Pharmaceutical Co., LtdObjectives: Ainuovirine (ANV) is a newly developed next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) metabolized by CYP2C19. The primary objective of this study was to simulate and predict drug–drug interaction (DDI) between ainuovirine and rifampicin (RIF) combined with isoniazid (INH) using physiologically based pharmacokinetic (PBPK) modelling. Additionally, we aimed to recommend suitable dose adjustments for ANV for the treatment of people living with HIV (PLWH) coinfected with tuberculosis.Methods: A comprehensive whole-body PBPK model for DDI was developed using PK-SIM® (version 11.2, Open Systems Pharmacology, USA). This model was validated against phase 1 DDI study of ANV with RIF and reported clinical data for all drugs administered alone and ANV-RIF/ANV-INH dual- and triple-drug concomitantly. The model contained the potent induction and concentration-dependent inhibition mechanisms of RIF and INH on CYP2C19. The model was considered verified if the predicted pharmacokinetic values vs. observed were within 0.5–2-fold. Alternative dosing regimens for ANV were simulated to ensure that the Ctrough exceeded the clinical reference interval's lower limit of 153.04 ± 59.22 ng/mL, while the Cmax remained below the upper limit of 526.45 ± 143.52 ng/mL.Results: The PBPK model was successfully verified according to the criteria. Simulation of different dose adjustments predicted that a change in regimen to 225 mg ANV (75 + 150 mg, while 75 mg co-administered with RIF plus INH, 150 mg after 12 h) may alleviate the inhibition effect of INH on ANV Cmax and induction effect of RIF on ANV Ctrough at steady state, which were within the clinical reference intervals.Conclusions: The developed PBPK model characterized the opposite effect-mediated DDI between RIF and INH on ANV, accurately predicting a narrowed therapeutic window when 150 mg daily of ANV co-administered with RIF plus INH. A change in the ANV dosing regimen from 150 to 225 mg was predicted to mitigate the effect of the DDI on the Cmax and Ctrough of ANV, maintaining plasma concentration levels above the therapeutic threshold while not too high.Keywords: ainuovirine, drug–drug interactions, isoniazid, pharmacokinetics, rifampicin","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"17-18"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16302","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399434","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}

引用次数: 0

The case of dolutegravir plus darunavir antiretroviral regimens: Is it always useful to double the drug doses? 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2024-10-10 DOI: 10.1111/bcp.16306

{"title":"The case of dolutegravir plus darunavir antiretroviral regimens: Is it always useful to double the drug doses?","authors":"","doi":"10.1111/bcp.16306","DOIUrl":"10.1111/bcp.16306","url":null,"abstract":"27The case of dolutegravir plus darunavir antiretroviral regimens: Is it always useful to double the drug doses?Dario Cattaneo1, Anna Ridolfo1, Andrea Giacomelli1, Antonella Castagna2, Spinello Antinori1 and Cristina Gervasoni11Luigi Sacco University Hospital; 2IRCSS San Raffaele Scientific InstituteBackground: It has recently been shown that dolutegravir trough concentrations are differently affected by antiretroviral drug combinations [doi: 10.1097/QAD.0000000000003843]. Here, we focused on dolutegravir plus darunavir-based combinations, with the aim to investigate the effect of the booster and/or the timing of administration on drug plasma trough concentrations.Materials and methods: This retrospective, observational study included consecutive PWH receiving dolutegravir plus darunavir antiretroviral regimens for at least 3 months, with at least one assessment of dolutegravir plasma concentrations. We considered true trough drug concentrations (i.e. blood samples taken 12 or 24 h after the last drug intake) or trough concentrations back-estimated by pharmacokinetic modelling taking into account the time interval between the last dose intake and the blood sample and the drug terminal half-life. Samples without clear information on the timing of the last drug dose and/or blood draw were excluded from the study. PWH concomitantly treated with strong drug inducers (i.e. rifampicin, carbamazepine, NNRTIs) were not included.Results: Two hundred TDMs of dolutegravir from 116 PWH were included in the statistical analyses. Dolutegravir and darunavir trough concentrations ranged, respectively, from 70 to 3648 ng/mL (inter-individual variability of 60%) and from 102 to 11 876 ng/mL (inter-individual variability of 72%). As shown in Table 2, the antiretroviral drug combination associated with the highest dolutegravir trough concentration was dolutegravir plus darunavir/cobicistat, both given once daily (1410 ± 788 ng/mL), whereas dolutegravir once daily plus darunavir/ritonavir twice daily had the lowest trough concentrations (686 ± 481 ng/mL). Doubling the dose of dolutegravir did not result in a significant increase of drug trough concentrations compared to once daily regimens. Among the once daily regimens, the highest darunavir trough concentrations were measured with ritonavir (2850 ± 1456 ng/mL, p < .05 vs. cobicistat-based regimens). Doubling the drug dose resulted in a significant increase of darunavir trough concentrations (4445 ± 2926 ng/mL, p < .05).Conclusions: Dolutegravir trough concentrations were significantly reduced in PWH receiving darunavir/ritonavir twice daily. This is likely related to the inductive effect of ritonavir (but not of cobicistat) on the enzymes (glucuronosyltransferase) and/or drug transporters involve","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"19-20"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16306","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399438","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}

引用次数: 0

Cellular pharmacology of NRTI anabolites in PBMCS and platelets among persons with HIV receiving ABC/3TC- or TAF/FTC-based art 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2024-10-10 DOI: 10.1111/bcp.16286

{"title":"Cellular pharmacology of NRTI anabolites in PBMCS and platelets among persons with HIV receiving ABC/3TC- or TAF/FTC-based art","authors":"","doi":"10.1111/bcp.16286","DOIUrl":"10.1111/bcp.16286","url":null,"abstract":"7Cellular pharmacology of NRTI anabolites in PBMCS and platelets among persons with HIV receiving ABC/3TC- or TAF/FTC-based artStefanie Schwab1, Travis Nemkov1, David Nerguizian1, Brian Branchford2, Seth Hosford1, Vincent Mainella1, Ryan Coyle1, Nicholas Barker1, Bethany Johnson1, Laura Roon1, Erin Garst1, Martin Williams1, Jia-Hua Zheng1, Lucas Ellison1, Lane Bushman1, Peter Anderson1 and Kristina Brooks11University Of Colorado Anschutz Medical Campus; 2Medical Sciences Institute VersitiBackground: Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) undergo phosphorylation within a variety of cell types due to structural similarities with endogenous nucleotides. Characterizing the intracellular pharmacology of NRTI anabolites in less commonly studied cell types, such as platelets, may provide insight into associations with cardiometabolic side effects. The objectives of these analyses were to compare (1) relative cellular concentrations of NRTIs in peripheral blood mononuclear cells (PBMCs) and platelets and (2) profiles of platelet metabolomics among persons with HIV (PWH) taking either tenofovir (TFV) alafenamide (TAF)/emtricitabine (FTC) or abacavir (ABC; converted to carbovir [CBV])/lamivudine (3TC).Materials and methods: PWH receiving ABC/3TC 600/300 mg or TAF/FTC 25/200 mg as part of their antiretroviral therapy (ART) with HIV VL < 200 copies/mL for ≥6 months were enrolled (NCT04301661). Adherence was confirmed using video directly observed therapy (vDOT) for 28 ± 3 days prior to pharmacokinetic sample collection (2 ± 1 h post-dose). Whole blood was processed into PBMCs and platelets. LC-MS/MS methods were used to quantify anabolites (TFV-DP, CBV-TP, FTC-TP, 3TC-TP) in both cell types, in addition to the monophosphate (MP) and diphosphate (DP) fractions in platelets. Drug concentrations (per 106 cells) were normalized to cell volume to determine relative intracellular concentrations in PBMCs and platelets, reported as geometric mean (GM) and GM ratio (GMR). Extracts of resting platelets were analysed using a previously established targeted metabolomics MS assay. Differences between arms were screened using fold changes and Wilcoxon rank-sum tests between median metabolite peak intensities.Results: Data were available in 25 PWH receiving ART containing either ABC/3TC (n = 12) or TAF/FTC (n = 13); 88% were male, 52% White, 20% Black, and 24% Hispanic/Latino. Median (IQR) age was 46 (38, 54) years and BMI 26.0 (22.1, 31.3). Baseline demographics were comparable between treatment arms. Participants on ABC/3TC were on dolutegravir (n = 12); darunavir/cobicistat (n = 1) or darunavir/ritonavir (n = 1). Partic","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"7"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16286","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399418","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}

引用次数: 0

Estimation of ganciclovir exposure by machine learning 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2024-10-10 DOI: 10.1111/bcp.16290

{"title":"Estimation of ganciclovir exposure by machine learning","authors":"","doi":"10.1111/bcp.16290","DOIUrl":"10.1111/bcp.16290","url":null,"abstract":"11Estimation of ganciclovir exposure by machine learningJean Woillard, Hamza Sayadi, Yeleen Fromage and Selim Arraki ZavaInserm U1248, Univ Limoges, Chu LimogesBackground: Valganciclovir, an oral prodrug of ganciclovir (GCV), is prescribed to prevent cytomegalovirus infection following transplantation. Dosing adjustments are often based solely on creatinine clearance to achieve a target GCV AUC0–24 h of 40–50 mg.h/L. However, this approach can result in significant overexposure or underexposure to the drug, potentially compromising efficacy or increasing toxicity. This study aimed to develop and validate machine learning (ML) algorithms capable of accurately estimating GCV AUC, thereby improving dosing precision.Methods: We simulated 5000 patients for each dosing regimen using two published population pharmacokinetic models (Lalagkas et al., Veniza et al.). These simulated patients were split into training (75%) and testing (25%) datasets. To further evaluate generalizability, an additional validation dataset of 200 patients per regimen was created using two distinct models (Caldés et al., Chen et al.). We developed three ML algorithm configurations using creatinine clearance in combination with either two or three drug concentrations sampled between T0 and T12h and three concentrations restricted between T0 and T6h. The performance of these ML configurations was assessed in both the testing and validation datasets and compared to maximum a posteriori Bayesian estimation (MAP-BE) applied to the Lalagkas et al. and Veniza et al. models within the validation datasets.Results: Among the ML algorithms evaluated, XGBoost consistently demonstrated the lowest root mean square error (RMSE) during a 10-fold cross-validation, indicating superior predictive accuracy. Models incorporating three blood samples yielded the most precise GCV AUC predictions. In the testing dataset, these models exhibited a relative bias ranging from −0.02% to 1.5% and a relative RMSE between 2.6% and 8.5%. In the validation dataset, the models achieved a relative bias of 1.5% to 5.8% and 8.9% to 16.5%, with a relative RMSE of 8.5% to 9.6% and 10.7% to 19.7% for the Caldés et al. and Chen et al. models, respectively. Notably, the ML algorithm predictions of AUC were significantly more accurate compared to those obtained through the MAP-BE method.Conclusions: The XGBoost machine learning models provided highly accurate estimates of GCV AUC from as few as two or three blood samples in combination with creatinine clearance. This approach represents a robust limited sampling strategy that can optimize therapeutic drug monitoring, potentially enhancing the clinical management of patients undergoing valganciclovir therapy by reducing the risks associated with drug overexposure and underexposure.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"10"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16290","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399422","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}

引用次数: 0

Pharmacokinetic data of lopinavir/ritonavir in second-line treatment of African children living with HIV 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2024-10-10 DOI: 10.1111/bcp.16294

{"title":"Pharmacokinetic data of lopinavir/ritonavir in second-line treatment of African children living with HIV","authors":"","doi":"10.1111/bcp.16294","DOIUrl":"10.1111/bcp.16294","url":null,"abstract":"15Pharmacokinetic data of lopinavir/ritonavir in second-line treatment of African children living with HIVAnne Kamphuis1, Hylke Waalewijn1,2, Alexander Szucbert3, Chishala Chabala4, Mutsa Bwakura-Dangarembizi5, Shafic Makumbi6, Joan Nangiya6, Vivian Mumbiro5, Veronica Mulenga4, Victor Mussiime6, David Burger1, Diana Gibb3 and Angela Colbers11Radboud Research Institute for Medical Innovation (RIMI), Radboudumc; 2Division of Clinical Pharmacology, Department of Medicine, University of Cape Town; 3Medical Research Council Clinical Trials Unit at University College London; 4University Teaching Hospital; 5University of Zimbabwe Clinical Research Centre; 6Joint Clinical Research CentreBackground: Children living with HIV require specific strengths and formulations of antiretrovirals. Lopinavir/ritonavir (LPV/r) is recommended by the WHO for children as preferred bPI for second-line. As paediatric 100/25 mg tablets have inconsistent availability in some countries, using adult 200/50 mg tablets for children could simplify procurement. For children weighing 25–34.9 kg, the daily recommended dose of 600/150 mg could be achieved by dosing two 200/50 mg tablets in the morning and one in the evening, instead of three 100/25 mg tablets twice daily (current WHO-recommendation). In CHAPAS-4 (#ISRCTN22964075), second-line treatment options for children with HIV were investigated. We performed a nested PK substudy to evaluate LPV/r exposure in children with different NRTI backbones.Methods: Children with HIV aged 3–15 years failing NNRTI-based first-line treatment were randomized to four anchor drugs with emtricitabine/tenofovir alafenamide or standard-of-care NRTIs (abacavir or zidovudine with lamivudine). Children weighing 14–24.9 kg received 200/50 mg LPV/r twice daily; children weighing 25–34.9 kg received 400/100 mg LPV/r in the morning and 200/50 mg in the evening; and children weighing ≥35 kg received 400/100 mg LPV/r twice daily. At steady state, PK blood samples were taken at pre-dose, 1, 2, 4, 6, 8 and 12 h after LPV/r intake with food. LPV concentrations were measured using a validated HPLC method. Lopinavir AUC0–12 h, Cmax and Ctrough were calculated using non-compartmental analysis. PK data of children receiving similar dosages were used for comparison. The individual target Ctrough was defined as 1.0 mg/L. Statistical analysis was performed using ANOVA on log-transformed values with Tukey post hoc analysis to detect differences in LPV PK parameters between weight bands and NRTI backbones.Results: Fifty-one children were included in this substudy. Eleven children were excluded for va","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"12-13"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16294","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399426","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}

引用次数: 0

In vitro characterization and physiologically based pharmacokinetic modelling for molnupiravir and its active metabolite 艾滋病、肝炎和其他抗病毒药物临床药理学国际研讨会摘要。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2024-10-10 DOI: 10.1111/bcp.16303

{"title":"In vitro characterization and physiologically based pharmacokinetic modelling for molnupiravir and its active metabolite","authors":"","doi":"10.1111/bcp.16303","DOIUrl":"10.1111/bcp.16303","url":null,"abstract":"24In vitro characterization and physiologically based pharmacokinetic modelling for molnupiravir and its active metaboliteMary Aladwani, Usman Arshad, Helen Cox, Paul Curley, Anthony Valentijn, Lee Tatham, Rajith Rajoli, Henry Pertinez and Andrew OwenUniversity of LiverpoolIntroduction: Molnupiravir (MOL) is recommended by the WHO for treatment of COVID-19 patients with mild to moderate symptoms but may also have application as a broad spectrum antiviral. MOL is converted to its active metabolite NHC after absorption, which induces error catastrophe, stopping viral replication. This work aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model for better prediction of MOL drug disposition, requiring assessments of apparent permeability (Papp), intrinsic clearance (Clint) and blood/plasma ratio for MOL and NHC. Validation of an LC-MS/MS method for quantifying MOL and NHC in various matrices was also undertaken.Methods: An LC-MS/MS method was developed and validated for simultaneous quantification of MOL and NHC in transporter buffer, human plasma and human liver microsomes. Papp of MOL in Caco-2 cell monolayers was determined at 50 μM. Papp determination for NHC was unnecessary since it is formed subsequent to absorption. Clint of MOL and NHC were investigated in human liver microsomes. Blood-to-plasma ratio of NHC was determined via standard methodology. Clinical data from a published study (Khoo et al., 2021) were utilized to develop and validate a PBPK model, with simulations carried out in Teoreler (www.liverpool.ac.uk/centre-of-excellence-for-long-acting-therapeutics/teoreler), a web-based pharmacokinetic platform. A dose of 800 mg was simulated, utilizing the in vitro generated parameters and apparent clearance from clinical PK studies.Results: The LC-MS/MS method had a runtime of 3.5 min and an analytical measuring range of 7.81–2000 ng/mL (linear regression 1/X, R2 = .99) for MOL in all matrices and NHC in human plasma, and human liver microsomes. For MOL and NHC the LOD and LOQ were 1.95 ng/mL and 7.81 ng/mL. Intra- and inter-day precision and accuracy metrics were within acceptable limits and recovery rates of MOL and NHC from matrices were consistently above 70%.MOL demonstrated a Papp of 1.46 × 10−6 cm/s. In human microsomes MOL exhibits an elimination, potentially attributable to hepatic carboxylase enzymes, whereas NHC exhibited no intrinsic clearance with a Κel values of 0. Both MOL and NHC showed a blood-to-plasma ratio of ~1.PBPK model simulations for NHC in plasma incorporating these in vitro parameter values, combined with the necessary observed apparent clearance from an empirical fitting to the clinical data, and Kps predicted using Poulin and Theil method showed acceptable agreement with observed clinical PK exposure, with an AFE of 1.02 ± 0.24. Mean simulated vs. o","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"18"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16303","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399435","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}

引用次数: 0