British journal of clinical pharmacology最新文献_第10页

Pharmacokinetics, safety and efficacy study in pregnancy and existing cumulative data/evidence to support clinical use and labelling of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in pregnant women 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.16305

{"title":"Pharmacokinetics, safety and efficacy study in pregnancy and existing cumulative data/evidence to support clinical use and labelling of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in pregnant women with HIV","authors":"","doi":"10.1111/bcp.16305","DOIUrl":"10.1111/bcp.16305","url":null,"abstract":"26Pharmacokinetics, safety and efficacy study in pregnancy and existing cumulative data/evidence to support clinical use and labelling of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in pregnant women with HIVDhananjay Marathe, Priyanka Arora, Haeyoung Zhang, Jason Hindman, Hui Liu, Sandhya Girish, Casey Davis and Ramesh PalaparthyGilead Sciences, IncBackground: Safe, effective and convenient treatment options are needed for pregnant women with HIV. Bictegravir is metabolized by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and cytochrome P450 3A4 (CYP3A4). Pregnancy is associated with physiological changes, including increased CYP3A4 and UGT1A1 activities; however, limited data exist on the pharmacokinetics, safety and efficacy of B/F/TAF during pregnancy.Material and methods: An open-label study (NCT03960645) was conducted in virologically suppressed pregnant women with HIV-1 (n = 33). Steady-state plasma pharmacokinetic samples were collected over 24 h following once-daily oral B/F/TAF dosing during second/third trimesters of pregnancy and postpartum. Bictegravir exposure parameters during pregnancy and postpartum were compared and contextualized with prior pooled phase 3 data in non-pregnant participants. Plasma HIV-1 RNA/DNA was measured in mothers and their neonates. Efficacy response was calculated as the proportion of mothers with HIV-1 RNA < 50 copies/mL (missing = excluded) at delivery. Exposure-efficacy response (E-R) relationships were visualized and contextualized using pooled phase 3 data. Literature evidence from contemporary studies of B/F/TAF in different populations was collated for additional comparisons.Results: While plasma bictegravir AUCtau was lower (~59%) during pregnancy than postpartum, the difference was less pronounced when compared to non-pregnant adults with HIV (~40%). Bictegravir AUCtau was similar during second and third trimesters. Mean bictegravir Ctrough was >6 × inhibitory quotient (IQ)1 during pregnancy. All pregnant women maintained virologic suppression (VS), with HIV-1 RNA < 50 copies/mL at delivery (n = 32 [100%]) and no observed virologic failure or treatment-emergent resistance. B/F/TAF was well tolerated, with no adverse events (AEs) leading to premature discontinuation; AEs were consistent with those expected in this pregnant population. No cases of perinatal HIV transmission in neonates (n = 29) occurred. E-R relationship visualizations for once-daily B/F/TAF showed robustly high and plateaued responses over a large exposure range. Current literature is supportive of these data. In IMPAACT 2026 [1], similar efficacy/safety and bictegravir exposure changes during pregnancy were described in a different demographic population. In the INSIGHT trial [2], co-administration of twice-daily B/F/TAF with a rifampicin-based tuberculosis regimen in a","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"19"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16305","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399437","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

Favipiravir pharmacokinetics in saliva, tears and nasal secretions of hospitalized COVID-19 patients following intravenous favipiravir administration 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.16287

{"title":"Favipiravir pharmacokinetics in saliva, tears and nasal secretions of hospitalized COVID-19 patients following intravenous favipiravir administration","authors":"","doi":"10.1111/bcp.16287","DOIUrl":"10.1111/bcp.16287","url":null,"abstract":"8Favipiravir pharmacokinetics in saliva, tears and nasal secretions of hospitalized COVID-19 patients following intravenous favipiravir administrationElizabeth Challenger1, Tim Rowland2,3, Laura Else1, Laura Dickinson1, Colin Hale2, Rebecca Lyon2, Henry Pertinez4, Andrew Owen4, Helen Reynolds1, Justin Chiong1, Richard FitzGerald1, Saye Khoo1 and Tom Fletcher31Centre for Experimental Therapeutics, University Of Liverpool; 2Liverpool University Hospitals NHS Foundation Trust; 3Liverpool School of Tropical Medicine; 4Centre of Excellence for Long Acting Therapeutics (CELT), Department of Pharmacology and Therapeutics, Institute of Integrative, Systems and Molecular Biology, University of LiverpoolBackground: SARS-CoV-2 is transmitted between individuals when virions trapped in aerosols or large droplets are expelled through conversation, coughing or sneezing. Due to consistent emergence of new variants, evaluation of therapeutics for SARS-CoV-2 is crucial to maximize treatment options should more virulent or treatment resistant strains arise. Establishing the concentration of potential therapeutics in sites of SARS-CoV-2 transmission is essential to assess compartmentalization and prophylactic potential. Here we report favipiravir (FVP) concentrations in saliva, tears and nasal secretions in hospitalized COVID-19 patients enrolled on the AGILE CST-6 clinical trial.Materials and methods: AGILE CST-6 is a randomized, multicentre, seamless, adaptive, phase I/II platform study to evaluate safety and efficacy of intravenous (IV) FVP for the treatment of COVID-19. Patients with laboratory confirmed COVID-19 were enrolled 2:1 to receive IV FVP or standard of care (SoC); four cohorts of six patients (n = 4 FVP, n = 2 SoC) were enrolled, with escalating doses per cohort (600 mg, 1200 mg, 1800 mg, 2400 mg). Patients received IV FVP twice daily over 7 days, with paired plasma and non-plasma samples (saliva, nasal swabs, tear strips) collected between 6 and 12 h post-completion of IV infusion on days 1 and 3. FVP was quantified using validated LC-MS methods and FVP concentrations expressed as ng/mL. Descriptive statistics were computed (Phoenix 64, WinNonlin, v8.3) and FVP non-plasma:plasma ratios (NP:P) determined. Relationships between paired quantifiable non-plasma and plasma concentrations were evaluated by linear regression.Results: Sixteen individuals [seven females at birth; median (range) age, weight, number of days with COVID-19 symptoms were 76.5 years (52–93), 78.6 kg (52.1–125) and 5 days (2–11), respectively] received at least six doses of IV FVP. Analysis included 32 plasma/nasal, 31 saliva and 30 tear samples. FVP was quantifiable in 100%/91%/","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"8"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16287","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399419","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

Optimal dose and safety of intravenous favipiravir in hospitalized patients with SARS-COV-2: A phase I, open-label, dose-escalating, randomized controlled study 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.16288

{"title":"Optimal dose and safety of intravenous favipiravir in hospitalized patients with SARS-COV-2: A phase I, open-label, dose-escalating, randomized controlled study","authors":"","doi":"10.1111/bcp.16288","DOIUrl":"10.1111/bcp.16288","url":null,"abstract":"9Optimal dose and safety of intravenous favipiravir in hospitalized patients with SARS-COV-2: A phase I, open-label, dose-escalating, randomized controlled studyTim Rowland1,2, Richard FitzGerald2,3, Laura Else3, Elizabeth Challenger3, Laura Dickinson3, Lauren Walker2,3, Colin Hale2, Rebecca Lyon2, Karim Dhamani4, Margaret Irwin4, Yvanne Enever4, Michelle Tetlow3, Orod Osanlou5, Helen Reynolds3, Justin Chiong3, Henry Pertinez6, Andrew Owen6, Geoff Saunders7, Gareth Griffiths7, Saye Khoo3 and Tom Fletcher11Liverpool School of Tropical Medicine; 2NIHR Liverpool Clinical Research Facility; 3Centre for Experimental Therapeutics (TherEx), Department of Pharmacology and Therapeutics, Institute of Integrative, Systems and Molecular Biology, University of Liverpool; 4PHARMExcel; 5Bangor University; 6Centre of Excellence for Long-acting Therapeutics (CELT), University of Liverpool; 7Southampton Clinical Trials Unit, University of SouthamptonBackground: AGILE is a phase Ib/IIa platform for rapidly evaluating candidate therapeutics for the treatment of COVID-19. In this trial (NCT04746183), we evaluated the safety and optimal dose of a novel intravenous (IV) formulation of favipiravir (FVP) in hospitalized participants with SARS-CoV-2.Materials and methods: CST-6 was a dose-escalating, open-label, randomized, controlled Bayesian adaptive phase Ib trial carried out at the NIHR Liverpool Clinical Research Facility. Participants (hospitalized adults with PCR-confirmed SARS-CoV-2 infection within 14 days of onset of symptomatic COVID-19) were randomized 2:1 in groups of six participants (n = 4 FVP, n = 2 SoC) to 600, 1200, 1800 and 2400 mg doses of IV FVP twice daily for 7 days or standard of care (SoC). Throughout the study period, clinical data, safety evaluations, virology and pharmacokinetics were collected at predefined timepoints. FVP was quantified using validated LC-MS methods with FVP concentrations expressed as ng/mL. The primary outcome was safety, with toxicity considered to be unacceptable if the probability of 30% or greater dose-limiting toxicity related to FVP over controls was 25% or greater, as calculated by the Bayesian model. Secondary outcomes included clinical progression scores, pharmacokinetic parameters and virological endpoints.Results: Of 30 participants screened, 24 were enrolled between 10 September 2022 and 1 November 2023 [10/24 female; median age was 74 years (range 52–93)]. FVP was well tolerated at all doses, despite a high background rate of adverse events reflecting the frailty and c","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"8-9"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16288","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399420","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

Adherence insights from TAF/FTC-based art co-encapsulated with an ingestible sensor among virologically suppressed persons 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.16291

{"title":"Adherence insights from TAF/FTC-based art co-encapsulated with an ingestible sensor among virologically suppressed persons with HIV","authors":"","doi":"10.1111/bcp.16291","DOIUrl":"10.1111/bcp.16291","url":null,"abstract":"12Adherence insights from TAF/FTC-based art co-encapsulated with an ingestible sensor among virologically suppressed persons with HIVRyan Coyle1, Vincent Mainella1, Mary Morrow1, Sarah Mann1, Stefanie Schwab1, Corwin Coppinger1, Nicholas Barker1, Samuel Ellis1, Tony Carnes2, Pamela Alpert2, Lucas Ellison1, Lane Bushman1, Kristina Brooks1, Samantha MaWhinney1, Jose Castillo-Mancilla1 and Peter Anderson11University of Colorado Anschutz Medical Campus; 2etectRxBackground: QUANTI-TAF (NCT04065347) measured adherence for approximately 16 weeks using digital pills with ingestible sensors (ID-Cap System, etectRx) paired with tenofovir diphosphate/emtricitabine triphosphate (TFV-DP/FTC-TP) concentrations in dried blood spots (DBS) among 84 persons with HIV (PWH) receiving daily oral tenofovir alafenamide/emtricitabine (TAF/FTC)-based antiretroviral therapy (ART) for ≥6 months. This analysis focused on digital pill adherence patterns.Material and methods: We categorized each recorded dose by interval length (>36 h [late/missed]; 36–18 h [on-time]; <18 h [early/stacked]). Chi-squared tests compared the proportion of observed dosing intervals and detected vs. manually entered doses. Kaplan–Meier analysis evaluated digital pill system use from enrolment to end of study, censored at week 16. We used generalized estimating equations with a logit link to calculate the odds ratio (OR [95% CI]) of a missed dose according to day of the week, or between Sunday–Thursday and Friday–Saturday. We summarized HIV-1 RNA, adherence and TFV-DP/FTC-TP in DBS at visits with suppressed HIV-1 RNA (<200 copies/mL) and low (<85%) cumulative (enrolment to visit) digital pill adherence as proportion (%) or median (IQR).Results: Overall, adherence was 93% (8650 recorded doses/9280 expected). Dosing intervals were mostly on-time (7991 [92%]), with smaller numbers of late/missed doses (356 [4%]) or early/stacked doses (303 [4%]), p < .0001. Significantly more doses were detected (7948 [92%]) than manually entered (702 [8%]), p < .0001. The proportion of participants on-study was 84/84 (100%) at week 4, 81/84 (96%) at week 8, 77/84 (92%) at week 12 and 73/84 (87%) at week 16. Median (IQR) cumulative adherence was 100% (100%–100%) at week 4 and 99% (96%–100%) at week 12 and at week 16. The OR (95% CI) for a missed dose was higher on Friday compared with Monday (1.35 [1.02, 1.79]; p = .04) or Tuesday (1.34 [1.04, 1.73]; p = .03), and on Saturday compared with Sunday (1.39 [1.08, 1.79]; p = .01), Monday (1.58 [1.14, 2.19]; p = .006), Tuesday (1.57 [1.23, 2.02]; p = .0004), Wednesday (1.38 [1.01, 1.88]; p = .04), or Thursda","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"10-11"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16291","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399423","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

Case report: Dolutegravir dosing post-Roux-en-Y gastric bypass surgery 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.16314

{"title":"Case report: Dolutegravir dosing post-Roux-en-Y gastric bypass surgery","authors":"","doi":"10.1111/bcp.16314","DOIUrl":"10.1111/bcp.16314","url":null,"abstract":"35Case report: Dolutegravir dosing post-Roux-en-Y gastric bypass surgeryJennifer HawkesNorthern HealthBackground: Adequacy of dolutegravir drug exposure when administered after the duodenum (such as Roux-en-Y jejunostomy tube or Roux-en-Y gastric bypass surgery) is largely unknown. In addition, various gastrointestinal modifications including changes in gastric volume, acidity, emptying time, enterohepatic circulation and delayed entry of bile acids may be present post-surgery. Existing data are limited to individual case reports or case series with the timing of collection post-surgery varying. Pharmacokinetics are more likely to be altered in the early stages post-surgery. There is evidence of decreased exposure of dolutegravir following a Roux-en-Y gastric bypass surgery. In some cases, a temporary increase in dolutegravir dose to 50 mg BID may be considered.Case report: A 53-year-old white male with HIV on antiretroviral therapy with dolutegravir/abacavir/lamivudine FDC and recent non-adherence with 1 month of missed doses is admitted for emergency Roux-en-Y gastric bypass surgery due to a septic shock and perforated gastric viscus with a suspected gastric tumour. He is non-obese and had a low BMI of 18.5. He was not virologically suppressed at the time of the surgery with an HIV VL 560 copies/mL and a CD4 count of 160 cells/mm3. The dolutegravir dose was increased to 50 mg BID with food post-surgery to mitigate potential decreased levels. Dolutegravir trough levels were measured at 7 days' post-dose increase (steady state), which was 2 weeks' post-surgery. A reduction in dolutegravir trough concentrations were observed compared to reference Cmin levels prior to the AM dose but not the supper dose (1137 and 2167 ng/mL vs. reference of 2120 ng/mL). A target dolutegravir trough has not yet been established nor has a dose limiting toxicity. His HIV viral load re-suppressed to <40 copies/mL at 1 month post-surgery and has remained suppressed at 2, 3 and 5 months' post-surgery with an increase of CD4 cells to 290 cells/mm3 at 5 months' post-surgery.It was decided to continue dolutegravir BID long term in this patient due to one level being at reference and one below reference, the challenges with obtaining new steady-state levels, tolerability of the regimen and ongoing intermittent non-adherence.Conclusion: This case study continues to highlight the importance of performing pharmacokinetic assessments in patients with the potential for impaired drug absorption to ensure antiretroviral success. Dolutegravir BID has been shown to be well tolerated for long-term use; however, there is the potential to reduce the dose in the future based on adherence and therapeutic drug monitoring.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"23-24"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16314","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399446","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

Minimal impact of pregnancy on rilpivirine pharmacokinetics: A POPPK approach 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.16293

{"title":"Minimal impact of pregnancy on rilpivirine pharmacokinetics: A POPPK approach","authors":"","doi":"10.1111/bcp.16293","DOIUrl":"10.1111/bcp.16293","url":null,"abstract":"14Minimal impact of pregnancy on rilpivirine pharmacokinetics: A POPPK approachMinh Lê1, Benjamin Kably1, Roland Tubiana2, Jade Ghosn3, Quentin Le Hingrat4, Marc Wirden5, Zeliea Julia3, Naima Hamani2, Laurent Mandelbrot6 and Gilles Peytavin11AP-HP, Hôpital Bichat, Pharmacology; 2AP-HP, Hôpital Pitié Salpétrière, Infectious Diseases; 3AP-HP, Hôpital Bichat, Infectious Diseases; 4AP-HP, Hôpital Bichat, Virology; 5AP-HP, Hôpital Pitié Salpétrière, Virology; 6AP-HP, Hôpital Louis Mourier, ObstetricsBackground: Rilpivirine is the most popular non-nucleoside transcriptase inhibitor (NNRTI) recommended to prevent the risk of mother-to-child transmission of HIV. However, a decrease of rilpivirine plasma exposure in the second trimester could be expected due to an increased metabolism and/or elimination in pregnant women. The latter could compromise the efficacy of the ARV strategy. The objectives were to assess maternal rilpivirine plasma concentrations during pregnancy and postpartum.Material and methods: A multicentre, cross-sectional cohort was conducted from 2020 to 2023. Pregnant women living with HIV receiving rilpivirine 25 mg once-daily containing regimen were enrolled. Plasma concentrations of rilpivirine were determined by UPLC-MS/MS (Waters Acquity) during the three trimesters (Tn) of pregnancy and postpartum. The gestational age was recorded for each sample. A population pharmacokinetic approach was performed using Monolix 2023R1 suite to analyse the plasma concentrations. Rilpivirine trough plasma concentrations (C24h) were estimated using individual parameters. Rilpivirine C24h were interpreted using an efficacy threshold of 50 ng/mL. The results are presented as median (IQR).Results: Seventy-two (97% sub-Saharan African) pregnant women were enrolled: age 34 years old (28–38). All were receiving FTC/TFV (as TDF or TAF) associated NRTIs with no boosted PI/r or reported CYP3A4 inhibitor. For these women, 222 plasma concentrations were determined corresponding to 20 at T1, 85 at T2, 92 at T3 and 25 postpartum. Population pharmacokinetic parameters (RSE%) were ka 1 h-1 (fixed), V/F 727 L (10.7%), CL/F 6.4 L/h (9.1%). Inter-individual variabilities were 39% (22.7%) and 53% (14.5%) for V/F and CL/F, respectively. Between-occasion variabilities were 73% (8.2%) and 24% (14.1%) for V/F and CL/F, respectively. Additive and proportional errors were 3.7 ng/mL (46.5%) and 0.08 (36.1%), respectively. There was no effect of gestational age or trimester on ka, V/F or CL/F parameters to improve the between-occasion variabilities. Rilpivirine estimated C24h were 90 ng/mL (50–103). Among the 72 patients, 14% of patients presented C24h below the 50 ng/mL. All women pr","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"12"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16293","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399425","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

Population pharmacokinetics of ainuovirine and exposure–response analysis in the HIV-infected individuals 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.16309

{"title":"Population pharmacokinetics of ainuovirine and exposure–response analysis in the HIV-infected individuals","authors":"","doi":"10.1111/bcp.16309","DOIUrl":"10.1111/bcp.16309","url":null,"abstract":"30Population pharmacokinetics of ainuovirine and exposure–response analysis in the HIV-infected individualsSu Bin1, Sun Jin1, Zhang Yihang1, Jiang Taiyi1, Xia Wei1, Zhang Tong1, Sun Lijun1, Wu Hao1, Qin Hong2 and Yun Xinming21Beijing Youan Hospital, Capital Medical University; 2Jiangsu Aidea Pharmaceutical Co., LtdObjective: Ainuovirine (ANV) is a novel new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of human immunodeficiency virus type 1 (HIV-1) infection. This study aimed to evaluate the population pharmacokinetic profile and exposure-response relationship of ANV among people living with HIV (PLWH).Methods: Plasma concentration–time data from phase 1 and phase 3 clinical trials of ANV were pooled for developing the population pharmacokinetic (PopPK) model. Exposure estimates obtained from the final model were used in exposure–response analysis for virologic and safety responses.Results: ANV exhibited a non-linear pharmacokinetic profile, which was best described by a two-compartment model with first-order elimination. There were no significant covariates correlated to the pharmacokinetic parameters of ANV. The PopPK parameter estimate (RSE%) for CL/F was 6.46 L/h (15.0), and the clearance of ANV increased after multiple doses. The exposure–response model revealed no significant correlation between the virologic response (HIV-RNA < 50 copies/mL) at 48 weeks and the exposure, but the incidence of adverse events increased with the increasing exposure.Conclusions: Our PopPK model supported ANV 150 mg once daily as the recommended dose for PLWH, requiring no dose adjustment for the studied factors. Optimization of ANV dose may be warranted in clinical practice due to an increasing trend in adverse reactions with increasing exposure.Keywords: ainuovirine, expose–response model, HIV, population pharmacokinetics","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"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.16309","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399441","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

Effect of fluconazole on the pharmacokinetics of ainuovirine in healthy adult subjects 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.16316

{"title":"Effect of fluconazole on the pharmacokinetics of ainuovirine in healthy adult subjects","authors":"","doi":"10.1111/bcp.16316","DOIUrl":"10.1111/bcp.16316","url":null,"abstract":"37Effect of fluconazole on the pharmacokinetics of ainuovirine in healthy adult subjectsLi Linghua, Huang Jianfei, Lei Yan, Cai Weiping, Meng Yu, Xiao Lei, Zhao Yi, Lin Weitong, He Yaozu, Huang Kaipeng and Qin HongGuangzhou Eighth People's Hospital, Guangzhou Medical UniversityIntroduction: Ainuovirine (ANV) is a newly developed next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for used in combination therapy for people living with HIV (PLWH) in China, which is metabolized by CYP2C19. The aim of this phase 1 study was to assess the drug–drug interaction (DDI) and safety of ainuovirine when co-administered with fluconazole, a strong CYP2C19 inhibitor, by experimentally obtained in healthy adult subjects and a physiologically based pharmacokinetics (PBPK) model was developed for dose prediction of ainuovirine.Methods: This was a single-centre, open-label, parallel-group, fixed-sequence, two-period study in healthy subjects (aged 20–45 years). Thirty-six healthy subjects were allocated into two groups. In group A, 18 healthy subjects received oral ainuovirine (150 mg) once daily in period 1 (days 1–7), followed by co-administration with oral fluconazole (200 mg) once daily in period 2 (days 8–14). In group B, 18 healthy subjects received oral fluconazole (200 mg) once daily in period 1 (days 1–7), followed by co-administration with oral ainuovirine (150 mg) once daily in period 2 (days 8–14). Blood samples were collected before and after dosing. A PBPK model (PK-SIM® version 11.2, Open Systems Pharmacology, USA) of ainuovirine and fluconazole was developed and validated to predict their DDIs.Results: All subjects (N = 36) completed the study. In group A, when co-administered with fluconazole, geometric means of ainuovirine pharmacokinetics parameters Cmin,ss, AUC0–24,ss increased up to 233.0% and 349.6%, respectively, vs. ainuovirine alone, whereas the median Tmax,ss was unaffected. In group B, there were no apparent effects of ainuovirine on Cmax,ss, AUC0–24,ss and Tmax,ss for fluconazole. Possible treatment-related adverse events (AEs) assessed by investigators were fewer in group A (83.3%) vs. group B (94.4%), no death or grade ≥3 serious AE was reported. The PBPK modelling supports a dose reduction by half for co-administration of ainuovirine and strong CYP2C19 inhibitors such as fluconazole.Conclusion: Co-administration of ainuovirine with fluconazole significantly increased ainuovirine systemic exposure, whereas ainuovirine did not appear to affect the exposure of fluconazole. The PBPK modelling supports a dose reduction by half (i.e. 75 mg) for coadministration of ainuovirine and strong CYP2C19 inhibitors such as fluconazole.Keywords: ainuovirine, CPY2C19, drug–drug interactions, fluconazole, pharmacokinetics","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"24-25"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16316","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399448","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

Cabotegravir PopPK analysis of adults and adolescents living with HIV/at risk for HIV receiving prep 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.16317

{"title":"Cabotegravir PopPK analysis of adults and adolescents living with HIV/at risk for HIV receiving prep","authors":"","doi":"10.1111/bcp.16317","DOIUrl":"10.1111/bcp.16317","url":null,"abstract":"38Cabotegravir PopPK analysis of adults and adolescents living with HIV/at risk for HIV receiving prepAmy Cheung1,2, Yu-Wei Lin1,2, Isabelle Deprez1,2, Susan Ford2, Jon Collins3, Rashmi Mehta2, Mark Bush3, Kelong Han2, Cindy McCoig3, Conn Harrington3, Lionel Tan3, Aditya Gaur4, Carolyn Bolton5, Lynda Stranix-Chibanda6, Sybil Hosek7, Mark Marzinke8, Brookie Best9, Edmund Capparelli9, IMPAACT 2017 Study Team10, HPTN 084-01 Study Team11 and HPTN 083-01 Study Team111Certara; 2GlaxoSmithKline; 3ViiV Healthcare; 4St. Jude Children's Hospital; 5Centre for Infectious Disease Research in Zambia; 6University of Zimbabwe; 7Stroger Hospital of Cook County; 8The John's Hopkins University; 9University of California; 10The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network; 11The HIV Prevention Trials Network (HPTN)Background: Cabotegravir (CAB) is an integrase strand transfer inhibitor approved in adults and adolescents (12 to <18 years) weighing >35 kg as long-acting injectable (LAI) HIV-1 prevention and for treatment in combination with rilpivirine. An existing CAB population pharmacokinetic (PopPK) model was limited to adult PK (Han 2023). We set out to extend and optimize that existing PopPK model for adolescents (12 to <18 years) by incorporating available adolescent PK data from the IMPAACT 2017/MOCHA (NCT03497676) and HPTN 083/084-01(NCT04824131/NCT02720094) clinical trials.Materials and methods: PK data following oral lead-in (30 mg once daily, QD for at least 4 weeks) and LAI treatment (an initial 600 mg 4-week loading dose followed by 400 mg Q4W or 600 mg Q8W) from 147 adolescents with HIV (IMPAACT 2017) and 62 HIV-negative adolescents (HPTN 083/084–01) with weight of 35.2–168 kg, body mass index (BMI) of 15.8–51.6 kg/m2 and 12–17 years were added to adult data (n = 1647). The PopPK model parameters were re-estimated based on this pooled dataset using NONMEM 7.3. The updated PopPK model was used to simulate PK profiles for CAB for Q4W and Q8W regimens in adolescents and adults. Individual exposure metrics (e.g. Ctau,ss) were derived and compared between adolescents and adults.Results: A two-compartment model with 1st-order absorption adequately described CAB PK in adolescents and adults. No new covariates were identified as compared to the adult PopPK model. Weight and smoking status were significant determinants of CL/F, and only weight was a determinant of Vc/F, Vp/F and Q/F. Need","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"25"},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16317","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399449","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

Evaluation of the effect of CYP2D6 and OCT1 polymorphisms on the pharmacokinetics of tramadol: Implications for clinical safety and dose rationale in paediatric chronic pain. 评估 CYP2D6 和 OCT1 多态性对曲马多药代动力学的影响：对儿科慢性疼痛的临床安全性和剂量合理性的影响。

IF 3.1 3区医学

British journal of clinical pharmacology Pub Date : 2024-10-09 DOI: 10.1111/bcp.16201

Paul Healy, Karel Allegaert, Oscar Della Pasqua

{"title":"Evaluation of the effect of CYP2D6 and OCT1 polymorphisms on the pharmacokinetics of tramadol: Implications for clinical safety and dose rationale in paediatric chronic pain.","authors":"Paul Healy, Karel Allegaert, Oscar Della Pasqua","doi":"10.1111/bcp.16201","DOIUrl":"https://doi.org/10.1111/bcp.16201","url":null,"abstract":"Aims: Our investigation aimed to assess the dose rationale of tramadol in paediatric patients considering the effect of CYP2D6/OCT1 polymorphisms on systemic exposure. Recommendations were made for the oral dose of tramadol to be used in a prospective study in children (3 months to < 18 years old) with chronic pain.Methods: Intravenous pharmacokinetic and genotype data from neonatal patients (n = 46) were available for this analysis. The time course of tramadol and O-desmethyltramadol (M1) concentrations was characterized using a nonlinear mixed effects approach in conjunction with extrapolation principles. Clinical trial simulations were then implemented to explore the effects of polymorphism, maturation and developmental growth on the disposition of tramadol and M1. Reported efficacious exposure range in adult subjects were used as reference.Results: The pharmacokinetics of tramadol and M1 was characterized by a two-compartment model. The total clearance of tramadol (CLPP) comprised CYP2D6-mediated metabolism (CLPM) and other pathways (CLPO). Age-related changes in CLPM, CLPO and M1 clearance (CLMO) were described by a sigmoid function, with CYP2D6 as a covariate on CLPP and CLPM, and OCT1 on CLMO. Simulation scenarios including different CYP2D6/OCT1 combinations revealed that steady-state concentrations are above the putative ranges for analgesia in >15% and >70% of subjects after doses of 3 and 8 mg/kg, respectively.Conclusions: In the absence of genotyping, reference exposure ranges can be used to define the dose rationale for tramadol in paediatric chronic pain. However, a starting dose of 0.5 mg/kg/day should be considered, followed by stepwise titration to the desired analgesic response.","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388153","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