British journal of clinical pharmacology最新文献_第8页

Long-acting cabotegravir and rilpivirine plasma exposures in the clinical setting: The role of pharmacogenetics 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.16292

{"title":"Long-acting cabotegravir and rilpivirine plasma exposures in the clinical setting: The role of pharmacogenetics","authors":"","doi":"10.1111/bcp.16292","DOIUrl":"10.1111/bcp.16292","url":null,"abstract":"13Long-acting cabotegravir and rilpivirine plasma exposures in the clinical setting: The role of pharmacogeneticsJessica Cusato1, Micol Ferrara2, Miriam Antonucci2, Razvan Goldan1, Sara Soloperto1, Giovanni Di Perri3, Antonio D'avolio1, Andrea Calcagno3 and Stefano Bonora31Department of Medical Sciences, Laboratory of Clinical Pharmacology and Pharmacogenetics, University of Turin; 2ASL Città di Torino; 3Unit of Infectious Diseases, Department of Medical Sciences, University of TurinBackground: Wide inter-individual variability in the pharmacokinetics of rilpivirine (RPV) and cabotegravir (CABO) has been reported in the first weeks after starting long acting injectable drugs (LAI) treatment. Furthermore, reduced RPV and/or CABO plasma trough concentrations combined with other risk factors (i.e. resistance-associated mutations, BMI ≥ 30 kg/m2) have been related with increased risk of virologic failure. However, data on the potential role of pharmacogenetics in affecting LAI pharmacokinetics and, possibly, the clinical outcome are lacking. Consequently, we aimed at evaluating the impact of genetic polymorphisms in affecting LAI drug exposure in PWH.Material and methods: RPV and CABO concentrations were quantified by chromatography, both in plasma and in peripheral blood mononuclear cells (PBMCs), before starting therapy (oral administration, baseline, only for RPV) and at 1, 3, 5, 7, 9 and 11 months (M) of therapy with LAI administration. The 4 × PA-IC90 were considered as the efficacy cut-off values, set at 50 and 664 ng/mL for RPV and CABO, respectively. Regression analysis was performed in order to evaluate which factors are able to predict the efficacy-related values of 50 ng/mL for RPV and 664 ng/mL for CABO respectively at 3 months of therapy.Polymorphisms in genes encoding enzymes and transporters involved in drug metabolism and elimination (CYP2C19, CYP3A4, CYP3A5, UGT1A1, ABCB1, ABCG2) were analysed through real-time PCR.Results: One hundred and seventy-seven PWH were enrolled: 85.3% males with median age of 50.7 years (IQR 43.3; 59.1). Median plasma and PBMC antiretroviral drug levels at different timings are reported in Table 1. Following associations were found: baseline plasma RPV and ABCB1 3435 CT/TT (p = .039) and UGT1A1 023 TT (p = .028), 1 M CABO intracellular levels and ABCB1 1236 CT/TT (p = .047), M3 ratio CABO and CYP2C19 AA (p = .025) and UGT1A1 023 CT/TT (p = .009), M3 RPV plasma and CYP3A4*22 (p = .035), M5 ratio CABO and ABCG2 421 CA/AA (p = .020), M5 plasma CABO and UGT1A1 023 TT (p = .010), M9 plasma RPV and CYP3A4*22 (p = .046), M11 plasma RPV and ABCB1 1236 CT/TT (p = .042), M11 intracellular RPV and ABC","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"11"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16292","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399424","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

Pharmacometrics analyses and modelling of concentration-corrected QT interval and concentration-creatine kinase MB in healthy adults and treatment-naïve people with HIV-1 on ainuovirine monotherapy, and combined with lamivudine and tenofovir DF: The pooled analyses of early clinical pharmacology studies 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.16301

{"title":"Pharmacometrics analyses and modelling of concentration-corrected QT interval and concentration-creatine kinase MB in healthy adults and treatment-naïve people with HIV-1 on ainuovirine monotherapy, and combined with lamivudine and tenofovir DF: The pooled analyses of early clinical pharmacology studies","authors":"","doi":"10.1111/bcp.16301","DOIUrl":"10.1111/bcp.16301","url":null,"abstract":"22Pharmacometrics analyses and modelling of concentration-corrected QT interval and concentration-creatine kinase MB in healthy adults and treatment-naïve people with HIV-1 on ainuovirine monotherapy, and combined with lamivudine and tenofovir DF: The pooled analyses of early clinical pharmacology studiesSu Bin1, Wu Hao1, Wang Meixia1, Hao Xiaohua2, Hong Qin3 and Wu Yuechan31Beijing Youan Hospital Affiliated to Capital Medical University; 2Beijing Ditan Hospital Affiliated to Capital Medical University; 3Jiangsu Aidea Pharmaceutical Co., LtdBackground: People with HIV-1 (PWH) are susceptible to corrected QT (QTc) interval prolongation, especially when on some specific antiretroviral regimens. Ainuovirine (ANV) is a new-generation NNRTI developed for HIV-1 treatment. The pooled analyses aimed to investigate effects of ainuovirine monotherapy and combined with lamivudine (3TC) and tenofovir DF (TDF) on electrocardiography and myocardial biomarker of healthy people and treatment-naïve PWH.Methods: Sixty-eight (n = 68) healthy adults were enrolled and exposed to ANV in single ascending dose (SAD), food effect (FE) and drug–drug interaction (DDI) with 3TC/TDF studies; 28 PWH were enrolled into multiple ascending dose (MAD) study and received ANV monotherapy for 10 successive days. ANV, 75–300 mg, was given to all participants under the fasting condition. A basic structure model (c-QTc) was established between observed plasma ANV concentration and change in corrected QT interval (ΔQTcF) with the linear mixed effect method. All model parameters were estimated using the first-order conditional estimation with interaction (FOCEI), with the linear model prioritized. An additional statistical random effect model was used to depict inter- and intra-individual variations without covariate adjusted. A simple linear regression model was also used to evaluate the correlation between ΔQTcF and plasma concentration, regardless of inter-individual variability. A 95% confidence interval containing 0 for the slope indicates negative QT prolongation. Changes in concentration-creatine kinase MB (c-CKMB) were also analysed using a similar methodology for evaluation of ANV myocardial safety.Results: A total of 492 post-dose ECG sampling points from 85 participants were included in the analysis. A linear population c-QTc model was established, which demonstrated the 95% CI of [−0.018, 0.0064] for the slope (containing 0), with favourable goodness of fit, precision and reliability. The simple linear regression model showed a slope of −0.003 [−0.010, 0.004], with no statistically significant difference from 0 (p = .409). CKMB levels did not change significantly with ACC007 monotherapy and remained well below the upper limit of normal (ULN, 3.6 ng/mL); CKMB levels ","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"17"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16301","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399433","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

TFV-DP adherence interpretations from TDF using an updated 50% methanol and 50% water extraction method for DBS 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.16313

{"title":"TFV-DP adherence interpretations from TDF using an updated 50% methanol and 50% water extraction method for DBS","authors":"","doi":"10.1111/bcp.16313","DOIUrl":"10.1111/bcp.16313","url":null,"abstract":"34TFV-DP adherence interpretations from TDF using an updated 50% methanol and 50% water extraction method for DBSCorwin Coppinger1, Mary Morrow1, Samantha MaWhinney1, Martin Williams1, Lane Bushman1, Kristina Brooks1, Kenneth Mugwanya1,2 and Peter Anderson11University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences; 2Department of Global Health, University of WashingtonBackground: Intraerythrocytic tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in dried blood spots (DBS) have been used in many clinical trials to better understand cumulative and recent adherence, respectively. The original validated extraction utilized 70% methanol and 30% water (70:30), which required controlled extraction conditions for reproducible results. We recently validated a 50% methanol and 50% water extraction (50:50), which yields better and more reproducible drug recoveries with fewer limitations on the control of extraction conditions. The aim of this study was to compare the extraction performances (70:30 vs. 50:50) and to adjust the original TFV-DP interpretations, which was based on 70:30, using the 50:50 extraction process.Methods: DBS from the Benchmark study were used for this analysis. The benchmark study included 53 African cisgender women without HIV randomized to two, four or seven doses per week, directly observed, for 8 weeks. An additional 17 pregnant women received 7 doses/week for 8 weeks. DBS samples were collected weekly; each sample included five 50uL spots. Three hundred ninety-six samples were available for this analysis. Both extraction methods were run in parallel to assess the relative efficiency of extracting TFV-DP and FTC-TP: Two 3-mm punches were removed from the same 50 μL spot from each card, and one punch was extracted with 70:30 and the other with 50:50. TFV-DP and FTC-TP concentrations were quantified using validated LC-MS/MS. A linear regression on the logarithmic scale was used to compare the results from the two extraction methods. The fold difference between extraction methods was applied to the original 70:30 TFV-DP adherence interpretations, which were <350 (<2 dose/week), 350–699 (2–3 doses/week), 700–1249 (4–6 doses/week) and ≥1250 fmol/punch (7 doses/week). These were generated from the DOT-DBS study conducted in the United States.Results: Data from the 70:30 extraction were within 10% of the original 70:30 TFV-DP adherence table estimates based on DOT-DBS, validating these interpretations for African cisgender women. The 50:50 extraction resulted in 1.27 (95% CI 1.25, 1.28) higher TFV-DP concentrations compared with the 70:30 extraction. The conversion factor of 1.27 was applied to the previous 70:30 TFV-DP benchmarks to produce the following interpretations for 50:50 ext","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"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.16313","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399445","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

Bictegravir exposures in adults with HIV and tuberculosis on a rifampicin-based tuberculosis treatment regimen 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.16284

{"title":"Bictegravir exposures in adults with HIV and tuberculosis on a rifampicin-based tuberculosis treatment regimen","authors":"","doi":"10.1111/bcp.16284","DOIUrl":"10.1111/bcp.16284","url":null,"abstract":"5Bictegravir exposures in adults with HIV and tuberculosis on a rifampicin-based tuberculosis treatment regimenAnushka Naidoo1,2, Hylke Waalewijn3, Kogieleum Naidoo1,2, Marothi Letsoalo1, Gillian Dorse1, Rubeshan Perumal1,2, Emmanuella Osuala1, Nonpumelelo Zungu1, Phindile Msomi1, Paolo Denti3 and Kelly Dooley41Center for the AIDS Program of Research in South Africa (CAPRISA), Nelson R Mandela School of Medicine, University of KwaZulu-Natal; 2Centre for the AIDS Programme of Research in South Africa (CAPRISA), South African Medical Research Council (SAMRC)-CAPRISA-TB-HIV Pathogenesis and Treatment Research Unit, University of KwaZulu-Natal Nelson R Mandela School of Medicine; 3Division of Clinical Pharmacology, Department of Medicine, University of Cape Town; 4Vanderbilt University Medical CenterBackground: Bictegravir (BIC) has not been evaluated in people with HIV (PWH) and tuberculosis (TB) taking rifampicin-based TB treatment. Healthy volunteer data showed that rifampicin reduced BIC exposure by about 80%; however, trough concentrations remained threefold above the inhibitory quotient (IQ1) of 0.162 mg/L. Potential exposures below IQ1 in few individuals or breakthrough viremia may be mitigated by a long dissociation half-life of BIC from the HIV-1 integrase enzyme.Methods: INSIGHT (NCT04734652) is an open-label, non-comparative phase 2b randomized controlled trial in ART-naïve or non-naïve adults with HIV and TB, initiated on a rifampicin-based TB regimen (<8 weeks). Participants were randomized in a 2:1 ratio to either the BIC arm (bictegravir/emtricitabine/tenofovir alafenamide) or a standard of care dolutegravir arm (TLD), dosed twice daily until 2 weeks' post-TB treatment and once daily thereafter, until 48 weeks. Forty-three participants in the BIC arm were enrolled in a semi-intensive pharmacokinetic (PK) sub-study. Semi-intensive PK sampling was done at pre-dose, 1, 2, 4, 6 and 8–12 h post-dose during TB treatment and pre-dose, 1, 2, 4, 6–8 and 24–25 h post-dose after TB treatment. BIC concentrations were assayed using a validated LC-MS/MS method. Non-compartmental PK analyses for BIC were conducted in R using the PKNCA package (version 10.2). Participants underwent regular clinical and safety visits, including HIV viral load measurements at baseline, weeks 4, 8, 12, 24, 40 and 48. We report the preliminary PK data and primary endpoint results for the proportion of participants with plasma HIV-1-RNA < 50 copies/mL at the end of TB treatment (week 24).Results: We enrolled 122 participants: 80 in the BIC and 42 in the DTG arm. Forty-three (35%) were female, with median (IQR) baseline viral load (copies/mL) and CD4 + (cells/μL) of 75 649 (22 784–391 299) and 172 (1","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"6"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16284","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399416","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

Development of a USP-4 IVIVC methodology for LAI antivirals: Case studies with cabotegravir and rilpivirine 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.16297

{"title":"Development of a USP-4 IVIVC methodology for LAI antivirals: Case studies with cabotegravir and rilpivirine","authors":"","doi":"10.1111/bcp.16297","DOIUrl":"10.1111/bcp.16297","url":null,"abstract":"18Development of a USP-4 IVIVC methodology for LAI antivirals: Case studies with cabotegravir and rilpivirineEmad Anaam, Henry Pertinez, Lee Tatham, Paul Curley, Paul Valentijn, Eduardo Gallardo Toledo, Joanne Sharp and Andrew OwenUniversity of LiverpoolBackground: Long-acting injectables (LAI) offer a promising approach to improving adherence and efficacy in the treatment of HIV. Establishing a reliable in vitro-in vivo correlation (IVIVC) is critical for predicting the in vivo performance of these formulations. This study aimed to develop a USP apparatus 4 (USP-4) IVIVC methodology specifically for LAI antivirals using cabotegravir (CAB) and rilpivirine (RPV) as model compounds.Material and methods: CAB and RPV formulations were subjected to in vitro release testing using the USP-4 apparatus with dose release from a float-a-lyzer dialysis device. Method optimization investigated adjustment of parameters such as temperature, dialysis membrane MWCO and flow rate, Tween 20 excipient concentration and pH of the circulating buffer. Cumulative release profiles were sampled and analysed over a period of 30 days and fitted with a bi-exponential mathematical model to allow extrapolation to estimate longer release durations. For in vivo analysis, clinical LAI pharmacokinetic (PK) data for CAB and RPV were obtained from literature, and in vivo release profiles derived through deconvolution using intravenous (IV) bolus disposition impulse responses estimated for both drugs via PBPK scaling due to lack of clinical IV data. IVIVC predictions and comparisons were made both by convolution of the in vitro release with IV disposition for direct comparison with the in vivo PK exposure profile and by Levy-plot correlations of in vitro and in vivo cumulative release.Results: Results obtained show sustained in vitro cumulative release for CAB and RPV over 30 days in the USP-4 system. However, in vitro cumulative release extrapolated for the duration of in vivo PK profiles was lower than cumulative release derived from in vivo data. Concordantly, convolution of the in vitro release profiles with estimated IV bolus disposition response underpredicted observed LAI PK exposure profiles. However, inclusion of a linear multiple scaling factor revealed the shape of the in vivo PK exposure profile was predicted by the in vitro release profile. This is illustrated in the Levy correlation plots showing partial correlation between in vitro and in vivo release but with deviation away from the line of unity.Conclusions: Initial results from developing a USP-4 methodology for application to LAI formulations and IVIVC to clinical LAI PK exposures indicate potential for prediction of in vivo PK exposure or utility as a means of ranking/comparing formulations by in vitro release. Work is ongoing to further investigate optimization of experimental parameters and to expand the library ","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"14-15"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16297","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399429","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

Dose proportionality and half-life of tenofovir in hair samples from those with differing adherence to TDF or TAF-based regimens monitored by directly observed therapy 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.16299

{"title":"Dose proportionality and half-life of tenofovir in hair samples from those with differing adherence to TDF or TAF-based regimens monitored by directly observed therapy","authors":"","doi":"10.1111/bcp.16299","DOIUrl":"10.1111/bcp.16299","url":null,"abstract":"20Dose proportionality and half-life of tenofovir in hair samples from those with differing adherence to TDF or TAF-based regimens monitored by directly observed therapyDavid Nerguizian1, Mary Morrow1, Samantha MaWhinney1, Monica Gandhi2, Hideaki Okochi2 and Peter Anderson11University of Colorado; 2University of CaliforniaBackground: Objective adherence metrics to antiretroviral therapy have been proven useful in interpreting clinical trial results. Hair tenofovir (TFV) concentrations are indicative of average adherence over approximately 1 month. The pharmacokinetics of TFV in hair have not been fully elucidated for TDF and TAF therapy following directly observed therapy (DOT) in people without HIV infection. The DOT-DBS and TAF-DBS studies, which used DOT to determine TFV-DP concentration benchmarks associated with variable adherence regimens, collected hair at regular intervals. This analysis aimed to assess concentrations, dose proportionality, comparability and the apparent half-life of TFV in hair from TDF and TAF.Methods: Hair samples were collected from adults without HIV in the DOT-DBS and TAF-DBS studies receiving either TDF 300 mg/FTC 200 mg or TAF 25 mg/FTC 200 mg, respectively, at 33%, 67% or 100% of daily doses. Participants were randomized to one adherence group for 12 weeks followed by a 12-week washout and then randomized to a different adherence group and followed for 12 additional weeks (36 weeks total). Approximately 100–200 hair strands were cut from the occipital portion of the scalp every 3 weeks. TFV concentrations were determined by a previously validated LC-MS/MS assay—reported as ng TFV/mg hair—and week 12 and 36 concentrations were summarized by treatment (TDF or TAF) and adherence group (33%, 67% or 100%). Dose proportionality was assessed using the power model. Ln TFV, concentrations were modelled linearly vs. Ln dose. Proportionality was assumed if the slope's 90% confidence interval (CI) was within 0.80 and 1.25. The apparent half-lives from TAF and TDF were determined assuming exponential decay during the 12-week washout phase.Results: Seventy samples were collected from 38 DOT-DBS participants (50% male; 7% Black, 55% White, 26% Hispanic) and 68 samples were collected from 35 TAF-DBS participants (51% male; 14% Black, 69% White, 17% Hispanic). Mean (%CV) TFV concentrations from TDF treatment were 0.0165 ng/mg (40.9%), 0.0454 (182%) and 0.0395 ng/mg (36.5%), while from TAF treatment they were 0.0142 ng/mg (30.9%), 0.0275 (28.5%) and 0.0409 ng/mg (42.1%) in the 33%, 67% and 100% adherence groups, respectively. Concentrations of TFV from TDF were less than dose proportional (slope 90% CI: 0.62, 0.96), and proportionality was still not achieved after removing one 67% dosing outlier (90% CI: 0.62, 0.94). TFV from TAF was dose propor","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"15-16"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16299","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399431","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 HIV Pharmacology Data Repository (PDR): Setting a new standard for clinical and preclinical pharmacokinetic data sharing 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.16300

{"title":"The HIV Pharmacology Data Repository (PDR): Setting a new standard for clinical and preclinical pharmacokinetic data sharing","authors":"","doi":"10.1111/bcp.16300","DOIUrl":"10.1111/bcp.16300","url":null,"abstract":"21The HIV Pharmacology Data Repository (PDR): Setting a new standard for clinical and preclinical pharmacokinetic data sharingMackenzie Cottrell1, Lauren Tompkins1, Adrian Khoei1, Alexander Tropsha1, Oleg Kapeljushnik2, Robert Hubal2, Julie Dumond1 and Angela Kashuba11UNC Eshelman School of Pharmacy; 2Renaissance Computing Institute at UNCBackground: Rapidly expanding clinical pharmacology modelling tools can be used to derive biological meaning through in silico study of archived pharmacokinetic (PK) data pools. Yet, a rate-limiting step to employing these approaches is the ability to access high-quality concentration vs. time (CvT) data, aggregated across disparate study designs in a way that is meaningful and usable for PK modelling. This is partly due to a lack of standardization for PK data description. To this end, we defined and applied a minimum information standard (MIS) for PK data description in the development of a web-based database—the HIV Pharmacology Data Repository (HIV PDR)—and demonstrate scientific utility through population PK modelling.Materials/methods: We defined the MIS with key reportable variables divided into three categories: intervention (drug, route, time and quantify), system (species dosed and anatomical compartment sampled) and concentration (chemical entity and concentration units quantified, including pro-drugs, drugs and metabolites). We identified 610 archived CvT Excel datasets fulfilling this MIS and created data dictionaries to harmonize terminology. The resulting database is stored in an SQL server with the front-end developed using an ASP.NET core with Angular and the back-end on an SQL Server 2017. We extracted CvT values for tenofovir (TFV) and its active metabolite (tenofovir diphosphate; TFVdp) within human plasma and peripheral blood mononuclear cells (PBMC) from study participants dosed with tenofovir disoproxil fumarate (TDF) and fit a population PK model using NONMEMv7.4.Results: Our data dictionaries collapsed 924 bioanalytical synonyms (analyte name and units) into 145 unique variables with units parsed in a separate column. Additionally, 246 descriptors of species and anatomical compartment were collapsed into 15 and 80 unique variables, respectively, with taxonomical and anatomical hierarchies. The final database aggregates 80 043 CvT datapoints of 77 chemically distinct compounds. Our extracted TDF dataset contained 913 plasma and 708 PBMC observations from 88 human study participants across three dosing levels (150, 300 and 600 mg) under first-dose and steady-state conditions. The final model fit first-order absorption (Ka) and elimination (CL) from the central compartment (Vc); a peripheral compartment (Vp and Q); one gut transit compartment (Ktr) to capture absorption delay; and a ","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"16"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16300","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399432","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

Single-ascending dose and food effect studies to assess safety and pharmacokinetics of ainuovirine, a novel non-nucleoside reverse transcriptase inhibitor, for treatment of HIV-1 infection 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.16307

{"title":"Single-ascending dose and food effect studies to assess safety and pharmacokinetics of ainuovirine, a novel non-nucleoside reverse transcriptase inhibitor, for treatment of HIV-1 infection","authors":"","doi":"10.1111/bcp.16307","DOIUrl":"10.1111/bcp.16307","url":null,"abstract":"28Single-ascending dose and food effect studies to assess safety and pharmacokinetics of ainuovirine, a novel non-nucleoside reverse transcriptase inhibitor, for treatment of HIV-1 infectionSu Bin1, Wu Hao1, Wang Meixia1, Yang Juan2, Yun Xinming2 and Qin Hong21Beijing Youan Hospital Affiliated to Capital Medical University; 2Jiangsu Aidea Pharmaceutical Co., LtdBackground: Ainuovirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of HIV-1 infection. This first-in-human study was conducted to characterize the tolerability, pharmacokinetics and food effect of single-ascending oral doses of ainuovirine in healthy adults.Methods: In the single-dose escalation study, three cohorts of each 10 participants, aged from 18 to 45 years, were randomly allocated to receive a single-dose ainuovirine 75, 150 or 300 mg, respectively. Inhibitory quotient (IQ) was defined as the ratio of the clinical trough concentration (C24h) to the 50% effective concentration (EC50). In the food effect study, 16 participants were equally assigned to a randomized, open-label, two-period crossover study and received a single oral dose of ainuovirine 150 mg in the fasting state or after a high-fat meal, with a 14-day washout period between periods.Results: Ainuovirine was well tolerated. Across all dosage groups, most adverse events were rated as mild in severity. Ainuovirine was readily absorbed, with a median Tmax of approximately 3 h. Ainuovirine exposure (Cmax and AUC) increased to a lesser extent than the dose proportionality. Median apparent terminal half-life (T1/2z) remained similar across three dose cohorts, slightly longer than 24 h. The IQs for wild type (EC50 = 2.2 ng/mL) were 36.4-, 51.7- and 61.0-fold, respectively; 5.2-, 7.4- and 8.8-fold for K103N mutant (EC50 = 15.3 ng/mL), respectively; and 3.6, 5.1 and 6.1 folds for Y181C mutant (EC50 = 22.1 ng/mL), respectively. The geometric mean ratios of Cmax, AUC0–t and AUC0–∞ in fed/fasting state were 190.07%, 136.73% and 141.71% respectively, with 90% CI of 169.52%–213.12%, 128.32%–145.69% and 131.59%–152.61%. The food effect of ainuovirine was evaluated clinically not significant.Conclusion: Ainuovirine was well tolerated and showed a dose-dependent, non-linear pharmacokinetics, eliciting no dose-limiting toxicity in healthy volunteers. Clinically insignificant food effect required no restriction in dosing without meal.Keywords: ainuovirine, food effect, pharmacokinetics","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"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.16307","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399439","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

Viral dynamic modelling of nirmatrelvir against in vitro SARS-COV-2 infection with different treatment initiation times 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.16308

{"title":"Viral dynamic modelling of nirmatrelvir against in vitro SARS-COV-2 infection with different treatment initiation times","authors":"","doi":"10.1111/bcp.16308","DOIUrl":"10.1111/bcp.16308","url":null,"abstract":"29Viral dynamic modelling of nirmatrelvir against in vitro SARS-COV-2 infection with different treatment initiation timesXualin Liu1, Kaley Hanrahan2, Sean Avedissian3, Evelyn Franco2,4, Coen van Hasselt1, Ashley Brown2,4 and Anne-Grete Märtson11Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University; 2Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida; 3Department of Pharmacy Practice and Science, University of Nebraska Medical Center; 4Department of Pharmaceutics, College of Pharmacy, University of FloridaBackground: The timing of antiviral treatment initiation plays an important role in drug efficacy. In vitro experiments have shown that delayed therapy initiation significantly decreased the antiviral efficacy of nirmatrelvir against SARS-CoV-2 infection. Further investigation is needed to gain understanding of the relationship between viral dynamics and the timing of treatment initiation to achieve better treatment response and to utilize existing SARS-CoV-2 data for emerging viral pathogens.Aims: The aim of this study is to investigate the SARS-CoV-2 viral dynamics using a systems pharmacology modelling, which incorporates viral load profile and the effect of therapy delay.Methods: In vitro data were obtained from antiviral experiments with five drug concentrations (0.004, 0.0156, 0.0625, 0.25 and 1 μg/mL) alongside a non-treatment control. The viral dynamic modelling was performed using the R package nlmixr2.A target cell-limited (TCL) model and TCL model with eclipse phase (TCLE) in combination with different drug effect models were tested. Viral kinetic parameters such as viral infection rate (β), death rate of infected cells (δ) and viral production rate (ρ) were first estimated using control group data. A direct effect model was then incorporated to describe the antiviral effect when there was no treatment delay. An indirect response model was adapted to modify the drug effect when the treatment was delayed. An additive residual error model was applied in all the tested models. The estimation was performed using the first-order conditional estimation with interaction (FOCEi) method. Models were evaluated and selected based on objective function value (OFV) and goodness of fit (GOF).Results: The in vitro data were well captured by a TCL model with sigmoid Emax drug effect. A direct effect model could best describe the concentration–effect relationship when the treatment started from day 0, while an adapted indirect response model had better performance when the therapy initiated from day 1 onwards, by adding a response controlling factor (k).The final estimates (RSE%) of ","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"20-21"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16308","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399440","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

A single once daily ABC/DTG/3TC tablet predicts safe and effective exposures in children 3 to <6 kg 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.16310

{"title":"A single once daily ABC/DTG/3TC tablet predicts safe and effective exposures in children 3 to <6 kg","authors":"","doi":"10.1111/bcp.16310","DOIUrl":"10.1111/bcp.16310","url":null,"abstract":"31A single once daily ABC/DTG/3TC tablet predicts safe and effective exposures in children 3 to <6 kgHardik Chandasana1, Kristina Brooks2, Ann Buchanan3, Lionel Tan4, Hilda Mujuru4, Angela Colbers5, Judy Hopking1, Marika Ciuffa1, Michael McKenna1, Andrew Wiznia6, Sean Brummel7, Adrie Bekker8, Tim Cressey9 and Helena Rabie81GSK; 2Anschutz Medical Campus, University of Colorado; 3ViiV Healthcare; 4University of Zimbabwe; 5Radboud University Medical Center; 6Jacobi Medical Center, Albert Einstein College of Medicine; 7Harvard T.H. Chan School of Public Health; 8Stellenbosch University; 9AMS-PHPT, Chiang Mai UniversityBackground: Abacavir (ABC)/dolutegravir (DTG)/lamivudine (3TC) is a fixed-dose combination (FDC) tablet approved for adults and children with HIV weighing ≥6 kg and aged ≥3 months. We evaluated whether ABC/DTG/3TC (60 mg/5 mg/30 mg) dispersible tablet (DT) once daily would achieve therapeutic targets in children weighing 3 to <6 kg (aged ≥4 weeks).Materials and methods: We used a population pharmacokinetic (PopPK) model-based approach leveraging existing data with single entities and FDC formulations from adults, infants and children with HIV. Drug-specific PopPK models incorporating expected enzyme and renal maturation functions were developed for ABC, DTG and 3TC and used to predict paediatric drug exposures. Simulations were performed with 1000 replicate trials of 200 participants. Exposure metrics (AUC0–24, Cmax and C24) were calculated for each drug and compared with pre-defined exposure target range (DTG C24 geometric mean [GM] 0.697–2.26 μg/mL, ABC AUC0–24 GM 6.3–50.4 μg*h/mL and 3TC AUC0–24 GM 6.3–26.5 μg*h/mL). We reviewed safety findings for ABC, DTG and 3TC in the lowest weight bands (WBs) of three paediatric trials (P1093, ODYSSEY and IMPAACT 2019), alongside available literature describing PK and safety of ABC and 3TC in neonates and infants under 3 months (including PETITE study).Results: Predicted GM steady-state plasma exposures of ABC, DTG and 3TC in children 3 to <6 kg receiving a single FDC of ABC/DTG/3TC DT were within the target ranges for each component. AUC0–24, Cmax and C24h of ABC, DTG and 3TC were also comparable to prior paediatric and adult studies. Review of paediatric safety data showed similar safety profiles across WBs and were consistent with the known safety profile of the individual drugs. Most children in these studies were on the higher WHO doses of 3TC 60 mg and ABC 120 mg for this WB.Conclusions: Predicted drug exposures support the ","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"21-22"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16310","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399442","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