British journal of clinical pharmacology最新文献

{"title":"The effect of P-glycoprotein, breast cancer resistance protein and CYP3A4 modulators on the pharmacokinetics of the TLR-7 agonist vesatolimod in people living with HIV","authors":"","doi":"10.1111/bcp.16298","DOIUrl":"10.1111/bcp.16298","url":null,"abstract":"<p><b>19</b></p><p><b>The effect of P-glycoprotein, breast cancer resistance protein and CYP3A4 modulators on the pharmacokinetics of the TLR-7 agonist vesatolimod in people living with HIV</b></p><p>Yanan Zheng<sup>1</sup>, Mary Wire<sup>1</sup>, Buyun Chen<sup>1</sup>, Christiaan de Vries<sup>1</sup>, Olayemi Oisyemi<sup>2</sup>, Kimberly Cruz<sup>3</sup>, Howard Hassman<sup>4</sup>, Juan Rondon<sup>5</sup>, Daina Lim<sup>1</sup>, Steve West<sup>1</sup>, Jia Hao<sup>1</sup>, Yiding Hu<sup>1</sup>, Yurong Lai<sup>1</sup> and Ramesh Palaparthy<sup>1</sup></p><p><sup>1</sup><i>Gilead Sciences, Inc.;</i> <sup>2</sup><i>Triple Research Institute;</i> <sup>3</sup><i>Advanced Pharma CR, LLC;</i> <sup>4</sup><i>CenExel HRI;</i> <sup>5</sup><i>Clinical Pharmacology of Miami, LLC</i></p><p><b>Background:</b> Vesatolimod (VES) is a Toll-like receptor 7 (TLR-7) agonist being evaluated as an immunomodulator to enhance antiviral responses in the clear-and-control HIV cure strategy. Per nonclinical data, VES is a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and CYP3A. Cobicistat (COBI; a P-gp, BCRP, and strong CYP3A inhibitor), voriconazole (VOR; a strong CYP3A inhibitor) and rifabutin (RFB; a moderate CYP3A inducer) have the potential to alter VES plasma concentrations, and these medications may be administered to people living with HIV (PLWH) as part of antiretroviral therapy (ART) or to treat fungal or bacterial infections.</p><p><b>Materials and methods:</b> NCT05458102 was an open-label study to evaluate the effect of P-gp/BCRP/CYP3A4 modulators on VES pharmacokinetics (PK) in virologically suppressed PLWH on stable ART. In cohort 1, the following study drugs were administered orally in three periods sequentially: period 1, VES 2 mg; period 2, COBI 150 mg once daily for 5 days with VES 2 mg co-administered on day 2; period 3, VOR 400 mg twice daily on day 1 and 200 mg twice daily on days 2–6 with VES 2 mg co-administered on day 3. In cohort 2, the following study drugs were administered orally in two periods sequentially: period 1, VES 6 mg; period 2, RFB 300 mg once daily for 9 days with VES 2 mg co-administered on day 6. VES PK samples were collected over 96 h after each dose of VES. VES PK parameters were estimated using noncompartmental analysis and compared between treatments using an analysis of variance.</p><p><b>Results:</b> In cohort 1 (<i>N</i> = 15), when VES was co-administered with COBI, median T<sub>max</sub> occurred 1.5 h earlier and the geometric least squares mean (GLSM) VES AUC, C<sub>max</sub>, and t1/2 increased 4.3-, 7.5- and 1.2-fold, respectively. When VES was co-administered with VOR, there was no change in median Tmax or in GLSM VES AUC<sub>inf</sub>, C<sub>max</sub>, and t1/2.</p><p>In cohort 2 (<i>N</i> = 2), when VES was co-administered with RFB, median VES T<sub>max</sub> occurred 3.85 h earlier and individual increases in VES AUC and C<sub>max</sub> were 26- and 98-fold and 2.6- and 10-fold, r","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16298","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical research for saliva-based therapeutic drug monitoring of linezolid.","authors":"Yuki Inoue, Hitoshi Kashiwagi, Yuki Sato, Shunsuke Nashimoto, Tsutomu Endo, Masahiko Takahata, Miki Komatsu, Mitsuru Sugawara, Yoh Takekuma","doi":"10.1111/bcp.16278","DOIUrl":"https://doi.org/10.1111/bcp.16278","url":null,"abstract":"<p><strong>Aims: </strong>Linezolid is primarily used to treat of methicillin-resistant Staphylococcus aureus and multidrug-resistant tuberculosis infections. Thrombocytopenia due to linezolid usage is a concern, and therapeutic drug monitoring has been reported to be effective in its prevention. Plasma concentrations provide valuable information for treatment decisions; however, collecting plasma samples can be burdensome for both patients and healthcare providers. Therefore, there is interest in saliva as an alternative for monitoring, considering its potential to replace plasma samples.</p><p><strong>Methods: </strong>Patients hospitalized at Hokkaido University Hospital and Hokkaido Spinal Cord Injury Center between April 2022 and July 2024, who received oral or intravenous linezolid treatment, were enrolled. The concentrations of linezolid were simultaneously measured in plasma and saliva samples. We determined the concentration profiles of linezolid in the saliva and examined the correlation between saliva and plasma linezolid concentrations.</p><p><strong>Results: </strong>Eighteen patients receiving linezolid were enrolled. The average of saliva/plasma (S/P) concentration ratios of linezolid were 1.018. A strong correlation was found between the salivary and plasma concentrations of linezolid (R = .833, P < .001). Notably, in patients receiving intravenous administration of linezolid, the correlation was even more pronounced (R = .885, P < .001). Additionally, when focusing on the S/P ratio of the trough concentrations in the morning and at night, the S/P ratios at night were much closer to 1.0.</p><p><strong>Conclusion: </strong>The concentrations of linezolid in plasma and saliva were similar, indicating their potential applicability in clinical settings. The monitoring of linezolid concentrations in saliva has been shown to be particularly suitable for patients receiving intravenous administration.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"2024 updates to the Québec antiretroviral therapeutic drug monitoring guidelines: Key changes over 10 years","authors":"","doi":"10.1111/bcp.16289","DOIUrl":"10.1111/bcp.16289","url":null,"abstract":"&lt;p&gt;&lt;b&gt;10&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;2024 updates to the Québec antiretroviral therapeutic drug monitoring guidelines: Key changes over 10 years&lt;/b&gt;&lt;/p&gt;&lt;p&gt;Nancy Sheehan&lt;sup&gt;1,2,3&lt;/sup&gt;, Myriam Fréchette-Le Bel&lt;sup&gt;1,4&lt;/sup&gt;, Marie-Eve Dumas&lt;sup&gt;1,4&lt;/sup&gt;, Rachel Therrien&lt;sup&gt;5&lt;/sup&gt;, Claude Fortin&lt;sup&gt;5,6&lt;/sup&gt;, Isabelle Boucoiran&lt;sup&gt;6,7&lt;/sup&gt;, Fatima Kakkar&lt;sup&gt;6,7&lt;/sup&gt;, Benoît Trottier&lt;sup&gt;5,6,8&lt;/sup&gt;, Jason Szabo&lt;sup&gt;2,9&lt;/sup&gt;, Xavier Le Guyader&lt;sup&gt;10&lt;/sup&gt;, Anne-Marie Bérard&lt;sup&gt;11&lt;/sup&gt; and Jean-Guy Baril&lt;sup&gt;6,8,11&lt;/sup&gt;&lt;/p&gt;&lt;p&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;i&gt;Québec Antiretroviral Therapeutic Drug Monitoring Program, McGill University Health Centre;&lt;/i&gt; &lt;sup&gt;2&lt;/sup&gt;&lt;i&gt;Chronic Viral Illness Service, McGill University Health Centre;&lt;/i&gt; &lt;sup&gt;3&lt;/sup&gt;&lt;i&gt;Faculté de pharmacie, Université de Montréal;&lt;/i&gt; &lt;sup&gt;4&lt;/sup&gt;&lt;i&gt;Centre hospitalier universitaire de Sherbrooke;&lt;/i&gt; &lt;sup&gt;5&lt;/sup&gt;&lt;i&gt;Clinique des infections virales chroniques, Centre hospitalier de l'Université de Montréal;&lt;/i&gt; &lt;sup&gt;6&lt;/sup&gt;&lt;i&gt;Faculté de médecine, Université de Montréal;&lt;/i&gt; &lt;sup&gt;7&lt;/sup&gt;&lt;i&gt;Centre d'infectiologie mère-enfant, Centre hospitalier universitaire Sainte-Justine;&lt;/i&gt; &lt;sup&gt;8&lt;/sup&gt;&lt;i&gt;Clinique de médecine urbaine du Quartier Latin;&lt;/i&gt; &lt;sup&gt;9&lt;/sup&gt;&lt;i&gt;Clinique médicale l'Actuel;&lt;/i&gt; &lt;sup&gt;10&lt;/sup&gt;&lt;i&gt;Programme national de mentorat sur le VIH et les hépatites;&lt;/i&gt; &lt;sup&gt;11&lt;/sup&gt;&lt;i&gt;Direction de la prévention des infections transmissibles sexuellement et par le sang, Ministère de la Santé et des Services Sociaux&lt;/i&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Background&lt;/b&gt;: Therapeutic drug monitoring (TDM) of antiretrovirals has the potential to improve virologic response and tolerability. In 2013, TDM guidelines in Québec (Canada) were published to assist clinicians. In 2016, an addendum was developed for newer antiretrovirals (dolutegravir, elvitegravir, rilpivirine). From 2018 to 2023, we underwent an update to the guidelines.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; An extensive literature review of published articles and grey literature was conducted using predefined terms. Three waves of literature review were completed (2018, 2020/2021 and 2022). After 1 August 2022, additional articles or conference proceedings were added if judged important. Indications for TDM for each antiretroviral were categorized based on strength of the recommendation (A, strongly recommended; B, moderately recommended; C, optional; D, not recommended) and quality of the evidence (I, prospective TDM trial; II, retrospective or prospective observational data; III, expert opinion or small number of cases ≤10). The rating was determined by two pharmacists by consensus. If consensus was not met, a decision was taken by the working group. Target concentrations were also reviewed. We present key changes, including the percent of recommendations in the current guidelines that were modified compared to the previous recommendations.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Older antiretrovirals (&lt;i&gt;n&lt;/i&gt; = 5) were removed and newer agents (&lt;i&gt;n&lt;/i&gt; = 6) added to the 2024 guidelines. Overall, 374 references","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16289","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, pharmacokinetics and antiviral activity of ainuovirine as 10-day monotherapy in treatment-naïve adults with HIV-1","authors":"","doi":"10.1111/bcp.16304","DOIUrl":"10.1111/bcp.16304","url":null,"abstract":"<p><b>25</b></p><p><b>Safety, pharmacokinetics and antiviral activity of ainuovirine as 10-day monotherapy in treatment-naïve adults with HIV-1</b></p><p>Su Bin¹, Wu Hao¹, Wei Xia¹, Zhang Li², Yun Xinming² and Qin Hong²</p><p>¹<i>Beijing Youan Hospital Affiliated to Capital Medical University;</i> ²<i>Jiangsu Aidea Pharmaceutical Co., Ltd</i></p><p><b>Background:</b> Ainuovirine (ANV) is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of HIV-1 infection. This study aimed to evaluate the safety, pharmacokinetics and antiviral activity of short-term ANV monotherapy in antiretroviral treatment-naive adults with HIV-1.</p><p><b>Methods:</b> A single-centre, open-label, dose-ranging study was conducted among 28 treatment-naive adults with HIV-1. Participants received ainuovirine monotherapy, at the dosage of 75, 150 or 300 mg, once daily, for 10 days.</p><p><b>Results:</b> Baseline characteristics were similar across dose cohorts (75 mg, <i>n</i> = 8; 150 mg, <i>n</i> = 10; 300 mg, <i>n</i> = 10). Across all dose cohorts, all adverse events were rated as mild to moderate in severity. No serious adverse event was reported. ANV was readily absorbed, with the maximum concentration achieved at a median time of approximately 2–3 h after dosing. The ANV exposure (AUC and C_max) increased slightly greater than the dose proportionality after single dose (day 1). Plasma ANV concentration reached the steady state at day 10 of dosing. Saturated C_max,ss, AUC_max,ss, and C_min,ss were observed at 150 and 300 mg on day 10 after repeated dosing. The inhibitory quotient (IQ) was 69.6-fold (150 mg, C_min,ss = 153.0 ng/mL) for wild type (EC50 = 2.2 ng/mL), 10.0-fold for K103N mutant (EC50 = 15.3 ng/mL) and 6.9-fold for Y181C mutant (EC50 = 22.1 ng/mL), respectively. Mean changes in HIV RNA from baseline (log10 copies/mL [90%CI]) were −1.73 [−1.90, −1.57], −1.72 [−1.87, −1.57] and −1.66 [−1.80, −1.51], respectively, on day 11.</p><p><b>Conclusion:</b> ANV demonstrated favourable safety and pharmacokinetics, and potent antiviral activity in treatment-naive adults with HIV-1. An once-daily dosing regimen of 150 mg was recommended for subsequent confirmatory efficacy trial.</p><p><b>Keywords:</b> ainuovirine, anti-HIV treatment, viral kinetics</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16304","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population pharmacokinetics of tacrolimus whole blood and peripheral blood mononuclear cell concentrations in stable kidney-transplanted patients.","authors":"Katrine Agergaard, Helle C Thiesson, Jan Carstens, Christine E Staatz, Erkka Järvinen, Flemming Nielsen, Heidi Dahl Christensen, Rikke Juhl-Sandberg, Kim Brøsen, Tore Bjerregaard Stage, Dorte Terp Andersen, Maria C Kjellsson, Troels K Bergmann","doi":"10.1111/bcp.16277","DOIUrl":"https://doi.org/10.1111/bcp.16277","url":null,"abstract":"<p><strong>Aim: </strong>Therapeutic drug monitoring of tacrolimus based on whole blood drug concentrations is routinely performed. The concentration of tacrolimus in peripheral blood mononuclear cells (PMBCs) is likely to better reflect drug exposure at the treatment target site. We aimed to describe the relationship between tacrolimus whole blood and PBMC concentrations, and the influence of patient characteristics on this relationship by developing a population pharmacokinetic model.</p><p><strong>Methods: </strong>We prospectively enrolled 63 stable adult kidney-transplanted patients and collected dense (12-h, n = 18) or sparse (4-h, n = 45) pharmacokinetic profiles of tacrolimus. PBMCs were isolated from whole blood (Ficoll density gradient centrifugation), and drug concentrations in whole blood and PBMCs were analysed using liquid chromatography-mass spectrometry. Patient genotype (CYP3A4/5, ABCB1, NR1I2) was assessed with PCR. Population pharmacokinetic modelling and statistical evaluation was performed using NONMEM.</p><p><strong>Results: </strong>Tacrolimus whole blood concentrations were well described using a two-compartment pharmacokinetic model with a lag-time and first-order absorption and elimination. Tacrolimus PBMC concentrations were best estimated from whole blood concentrations with the use of a scaling factor, the ratio of whole blood to PBMC concentrations (R_C:PBMC), which was the extent of tacrolimus distribution into PBMC. CYP3A5*1 non-expressors and NR1I2-25 385T allele expressors demonstrated higher R_C:PBMC ratios of 42.4% and 60.7%, respectively.</p><p><strong>Conclusion: </strong>Tacrolimus PBMC concentration could not be accurately predicted from whole blood concentrations and covariates because of significant residual unexplained variability in the distribution of tacrolimus into PBMCs and may need to be measured directly if required for future studies.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399386","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Absorption, distribution, metabolism and excretion of ainuovirine in healthy adults: A radiolabelled mass balance and biotransformation study","authors":"","doi":"10.1111/bcp.16315","DOIUrl":"10.1111/bcp.16315","url":null,"abstract":"<p><b>36</b></p><p><b>Absorption, distribution, metabolism and excretion of ainuovirine in healthy adults: A radiolabelled mass balance and biotransformation study</b></p><p>Miao Liyan¹, Jiang Bin¹, Sang Shibiao¹, Qin Hong² and Wu Yuechan²</p><p>¹<i>The First Affiliated Hospital of Soochow University;</i> ²<i>Jiangsu Aidea Pharmaceutical Co., Ltd</i></p><p><b>Background:</b> Ainuovirine (ANV) is a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for treatment of human immunodeficiency virus type 1 (HIV-1) infection. The absorption, distribution, metabolism and elimination of ANV was evaluated in a human radiolabelled mass balance and biotransformation study.</p><p><b>Methods:</b> A single-centre, single-dose, non-randomized, open-label study was conducted, in which six healthy males received a single dose of oral suspension containing [14C]ANV at 150 mg/approximately 100 μCi on the first day in the study under fasting condition. Whole blood, plasma, urine and faecal samples were collected at the specific time points during the study. The data of pharmacokinetic (PK) parameters of the total radioactivity in plasma, concentration ratio of total radioactivity in whole blood to plasma and mass balance were obtained by measuring the total radioactivity of [14C]ANV in plasma, whole blood, urine and faeces. The main metabolic elimination pathways and characteristics of ANV in human body were obtained by analysing the radioactive metabolite profiles in plasma, urine and faeces; and the structure of major metabolites was identified using radioisotope and mass spectrometry.</p><p><b>Results:</b> The time to maximum plasma total radioactivity (T_max) was 3.42 h; the mean maximum concentration (C_max) was 327 ng·eq./g; and the half-life of the total radioactivity terminal elimination phase (t½) was 43.5 h. Within 0–240 h, the mean cumulative excretion rate of total radioactivity was 101.64%. Specifically, the mean total excretion accounted for 28.10% of the administered dose in urine and 73.54% of the administered dose in faeces, suggesting that [14C]ANV was primarily excreted into faeces. The primary clearance pathway of [14C]ANV was mono-oxygenated to form M341, which was further glucuronidated, and metabolized by the liver, and excreted into faeces and urine. The secondary metabolic pathway was glucuronidation of the unchanged drug to form M501, which was excreted into urine.</p><p><b>Conclusions:</b> Ainuovirine is primarily metabolized by the liver and excreted into faeces and urine, with a low plasma clearance, in the human body.</p><p><b>Keywords:</b> ainuovirine, human immunodeficiency virus 1, mass balance, non-nucleoside reverse transcriptase inhibitor, pharmacokinetics</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16315","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Population pharmacokinetics of ABC/DTG/3TC FDC to support dosing in PEDS with HIV-1 (IMPAACT 2019)","authors":"","doi":"10.1111/bcp.16311","DOIUrl":"10.1111/bcp.16311","url":null,"abstract":"&lt;p&gt;&lt;b&gt;32&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Population pharmacokinetics of ABC/DTG/3TC FDC to support dosing in PEDS with HIV-1 (IMPAACT 2019)&lt;/b&gt;&lt;/p&gt;&lt;p&gt;Hardik Chandasana&lt;sup&gt;1&lt;/sup&gt;, Sven van Dijkman&lt;sup&gt;1&lt;/sup&gt;, Rashmi Mehta&lt;sup&gt;1&lt;/sup&gt;, Mark Bush&lt;sup&gt;2&lt;/sup&gt;, Helena Rabie&lt;sup&gt;3&lt;/sup&gt;, Patricia Flynn&lt;sup&gt;4&lt;/sup&gt;, Tim Cressey&lt;sup&gt;5&lt;/sup&gt;, Edward Acosta&lt;sup&gt;6&lt;/sup&gt;, Kristina Brooks&lt;sup&gt;7&lt;/sup&gt; and IMPAACT 2019 Protocol Team&lt;sup&gt;8&lt;/sup&gt;&lt;/p&gt;&lt;p&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;i&gt;GSK;&lt;/i&gt; &lt;sup&gt;2&lt;/sup&gt;&lt;i&gt;ViiV Healthcare;&lt;/i&gt; &lt;sup&gt;3&lt;/sup&gt;&lt;i&gt;University of Stellenbosch;&lt;/i&gt; &lt;sup&gt;4&lt;/sup&gt;&lt;i&gt;St. Jude Children's Research Hospital;&lt;/i&gt; &lt;sup&gt;5&lt;/sup&gt;&lt;i&gt;Chiang Mai University;&lt;/i&gt; &lt;sup&gt;6&lt;/sup&gt;&lt;i&gt;University of Alabama at Birmingham;&lt;/i&gt; &lt;sup&gt;7&lt;/sup&gt;&lt;i&gt;University of Colorado Anschutz Medical Campus;&lt;/i&gt; &lt;sup&gt;8&lt;/sup&gt;&lt;i&gt;The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network&lt;/i&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Once-daily fixed-dose combinations (FDC) containing abacavir (ABC), dolutegravir (DTG) and lamivudine (3TC) have been approved in the United States for adults and children with HIV weighing ≥6 kg (dispersible tablet [DT] and tablets). This analysis assessed the ability of previously developed ABC, DTG and 3TC paediatric population pharmacokinetic (PopPK) models using multiple formulations to describe and predict PK data in young children using DT and tablet formulations of ABC/DTG/3TC FDC in the IMPAACT 2019 study.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; IMPAACT 2019 was a phase I/II, multicentre, open-label study assessing the PK, safety, tolerability and efficacy of ABC/DTG/3TC FDC (tablets and DT) in children with HIV-1 aged &lt;12 years and weighing ≥6 to &lt;40 kg. Intensive and sparse PK samples were collected through 48 weeks (&lt;i&gt;N&lt;/i&gt; = 55 participants with 590 ABC, 598 DTG and 597 3TC observations). Existing drug-specific paediatric PopPK models for ABC (two-compartment), DTG (one-compartment) and 3TC (one-compartment) were applied to the IMPAACT 2019 plasma drug concentrations data without re-estimation (external validation) of PopPK parameters. Exposures were then simulated across weight bands for each drug and compared with predefined exposure target ranges.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Goodness of fit and visual predictive check plots demonstrated good agreement between observed concentrations for ABC, DTG and 3TC from IMPAACT 2019 and the respective PopPK models. The post hoc PK parameter estimates were comparable to the NCA PK parameter estimates from IMPAACT 2019. Thus, new PopPK models to specifically describe the IMPAACT 2019 data were not necessary. Simulated geometric mean (GM) C24h DTG exposures were consistent across the weight bands (0.74–0.95 μg/mL) for both formulations. The predicted ABC GM AUC&lt;sub&gt;0–24&lt;/sub&gt; ranged from 14.89 to 18.50 μg*h/mL for both formulations. Similarly, predicted GM AUC&lt;sub&gt;0–24&lt;/sub&gt; ranges for 3TC were consistent across the weight bands (10.50–13.20 μg*h/mL). The predicted GM exposures were within the pre-defined GM target range set for each drug and c","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16311","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experience of a nirmatrelvir/ritonavir drug–drug interaction expert advice service","authors":"","doi":"10.1111/bcp.16285","DOIUrl":"10.1111/bcp.16285","url":null,"abstract":"&lt;p&gt;&lt;b&gt;6&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experience of a nirmatrelvir/ritonavir drug–drug interaction expert advice service&lt;/b&gt;&lt;/p&gt;&lt;p&gt;Florian Lemaitre, Camille Tron, Sébastien Lalanne, Bénédicte Franck, Christelle Boglione-Kerrien, Fabrice Taïeb and Marie-Clémence Verdier&lt;/p&gt;&lt;p&gt;&lt;i&gt;Biological Pharmacologie Department, Rennes University Hospital&lt;/i&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Background&lt;/b&gt;: Nirmatrelvir/ritonavir is a protease inhibitor antiviral drug indicated in the treatment of severe acute respiratory syndrome coronavirus-2 infections in high-risk patients for a severe disease. Unfortunately, ritonavir, used to boost nirmatrelvir pharmacokinetics, can also inhibit or induce the metabolism of other co-administered drugs substrates. This may lead to a subsequent drug–drug interaction (DDI) risk and thus to adverse drug reaction. To secure the drug's prescription and help clinicians with drug indication, we developed a DDI expert advice service dedicated to nirmatrelvir/ritonavir. The aim of this study was to describe this service provided by the clinical pharmacology department of the Rennes University Hospital, Rennes, France.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Material and methods:&lt;/b&gt; We collected all DDI advices provided by the five senior clinical pharmacologists of the department regarding nirmatrelvir/ritonavir in 2022 and 2023. These advices were given by phone, email or through a tele-expertise system. The following data were gathered: patient's age and sex, renal function, date of nirmatrelvir/ritonavir initiation, clinical department requiring the expert advice, patient's treatments and advice provided. Data were presented as medians and interquartile and percentages.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; In 2022 and 2023, the expert advice services provided advices for 123 and 224 patients, respectively. These 347 advices relate on 2858 prescription lines. In 2022, advices were provided for 881 prescription lines for patients of median age of 69 years [57–76] and estimated glomerular filtration rate (eGFR) of 77 mL/min [59–91]. The main pharmacological classes were: cardiology drugs (26.8%), endocrinology drugs (16.9%) and immunosuppressive agents (13.6%). The advice was distributed as follows: treatment continuation, treatment discontinuation during the antiviral course, dosage adjustment and treatment switch in 71%, 19%, 7%, 3% of the cases, respectively. Only three patients (2.4%) were denied the drug due to contraindications. Drug monitoring was proposed in 5% of prescription lines. The top drug request was tacrolimus in 2022.&lt;/p&gt;&lt;p&gt;In 2023, advices were provided for 1977 prescription lines for patients of median age of 77 years [67–85] and estimated glomerular filtration rate (eGFR) of 77 mL/min [55–90]. The most common requests were for endocrinology drugs (22%), cardiac drugs (21%) and neurology drugs (18%). The advice was distributed as follows: treatment continuation, treatment discontinuation during the antiviral course, dosage adjustment and treatment switch in 77%, 14%, 6% and 3% of the cases, respec","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16285","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"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":"&lt;p&gt;&lt;b&gt;13&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Long-acting cabotegravir and rilpivirine plasma exposures in the clinical setting: The role of pharmacogenetics&lt;/b&gt;&lt;/p&gt;&lt;p&gt;Jessica Cusato&lt;sup&gt;1&lt;/sup&gt;, Micol Ferrara&lt;sup&gt;2&lt;/sup&gt;, Miriam Antonucci&lt;sup&gt;2&lt;/sup&gt;, Razvan Goldan&lt;sup&gt;1&lt;/sup&gt;, Sara Soloperto&lt;sup&gt;1&lt;/sup&gt;, Giovanni Di Perri&lt;sup&gt;3&lt;/sup&gt;, Antonio D'avolio&lt;sup&gt;1&lt;/sup&gt;, Andrea Calcagno&lt;sup&gt;3&lt;/sup&gt; and Stefano Bonora&lt;sup&gt;3&lt;/sup&gt;&lt;/p&gt;&lt;p&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;i&gt;Department of Medical Sciences, Laboratory of Clinical Pharmacology and Pharmacogenetics, University of Turin;&lt;/i&gt; &lt;sup&gt;2&lt;/sup&gt;&lt;i&gt;ASL Città di Torino;&lt;/i&gt; &lt;sup&gt;3&lt;/sup&gt;&lt;i&gt;Unit of Infectious Diseases, Department of Medical Sciences, University of Turin&lt;/i&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; 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/m&lt;sup&gt;2&lt;/sup&gt;) 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.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Material and methods:&lt;/b&gt; 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.&lt;/p&gt;&lt;p&gt;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.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; 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 (&lt;i&gt;p&lt;/i&gt; = .039) and UGT1A1 023 TT (&lt;i&gt;p&lt;/i&gt; = .028), 1 M CABO intracellular levels and ABCB1 1236 CT/TT (&lt;i&gt;p&lt;/i&gt; = .047), M3 ratio CABO and CYP2C19 AA (&lt;i&gt;p&lt;/i&gt; = .025) and UGT1A1 023 CT/TT (&lt;i&gt;p&lt;/i&gt; = .009), M3 RPV plasma and CYP3A4*22 (&lt;i&gt;p&lt;/i&gt; = .035), M5 ratio CABO and ABCG2 421 CA/AA (&lt;i&gt;p&lt;/i&gt; = .020), M5 plasma CABO and UGT1A1 023 TT (&lt;i&gt;p&lt;/i&gt; = .010), M9 plasma RPV and CYP3A4*22 (&lt;i&gt;p&lt;/i&gt; = .046), M11 plasma RPV and ABCB1 1236 CT/TT (&lt;i&gt;p&lt;/i&gt; = .042), M11 intracellular RPV and ABC","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.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}

{"title":"Dose linearity studies of a glecaprevir and pibrentasvir long-acting injectable formulation in Sprague Dawley rats","authors":"","doi":"10.1111/bcp.16281","DOIUrl":"10.1111/bcp.16281","url":null,"abstract":"&lt;p&gt;&lt;b&gt;2&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Dose linearity studies of a glecaprevir and pibrentasvir long-acting injectable formulation in Sprague Dawley rats&lt;/b&gt;&lt;/p&gt;&lt;p&gt;Eduardo Gallardo-Toledo&lt;sup&gt;1,2&lt;/sup&gt;, Usman Arshad&lt;sup&gt;1,2&lt;/sup&gt;, Henry Pertinez&lt;sup&gt;1,2&lt;/sup&gt;, Joanne Sharp&lt;sup&gt;1,2&lt;/sup&gt;, Joanne Herriott&lt;sup&gt;1,2&lt;/sup&gt;, Edyta Kijak&lt;sup&gt;1,2&lt;/sup&gt;, Helen Cox&lt;sup&gt;1,2&lt;/sup&gt;, Alison Savage&lt;sup&gt;2,3&lt;/sup&gt;, Catherine Unsworth&lt;sup&gt;2,3&lt;/sup&gt;, Andrew Dwyer&lt;sup&gt;2,3&lt;/sup&gt;, James Hobson&lt;sup&gt;2,3&lt;/sup&gt;, Lee Tatham&lt;sup&gt;1,2&lt;/sup&gt;, David Thomas&lt;sup&gt;4&lt;/sup&gt;, Paul Curley&lt;sup&gt;1,2&lt;/sup&gt;, Steve Rannard&lt;sup&gt;2,3&lt;/sup&gt; and Andrew Owen&lt;sup&gt;1,2&lt;/sup&gt;&lt;/p&gt;&lt;p&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;i&gt;Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, University of Liverpool;&lt;/i&gt; &lt;sup&gt;2&lt;/sup&gt;&lt;i&gt;Centre of Excellence in Long-acting Therapeutics (CELT), University of Liverpool;&lt;/i&gt; &lt;sup&gt;3&lt;/sup&gt;&lt;i&gt;Department of Chemistry, University of Liverpool;&lt;/i&gt; &lt;sup&gt;4&lt;/sup&gt;&lt;i&gt;Department of Infectious Diseases, John's Hopkins University School of Medicine&lt;/i&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;Background:&lt;/b&gt; Glecaprevir (G) and pibrentasvir (P) is a fixed-dose combination (FDC) approved to treat all six types of hepatitis C. However, patient adherence to oral treatment regimens remains a major challenge with considerably lower efficacy in clinical use than reported in RCTs. Long-acting injectables (LAI) could address poor adherence through long-term exposure of both G and P after a single administration.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Materials and methods:&lt;/b&gt; Male Sprague Dawley rats (&lt;i&gt;n&lt;/i&gt; = 4 per group) were intramuscularly dosed into both thighs with LAI suspensions of G and P alone and both drugs in an FDC (GP-FDC, 1:1 ratio) as follows: GP-FDC group (75 mg G + 75 mg P, 150 μL/thigh), G group (150 mg G, 150 μL/thigh), P group (150 mg P, 150 μL/thigh) and GP group (75 mg G, 150 μL/left thigh + 75 mg P, 150 μL/right thigh). A second set of experiments evaluated the effects of different GP-FDC active doses (18.75, 37.5 and 75 mg) on the pharmacokinetics (PK) by changing the dosing volume (0.075, 0.15 and 0.3 mL of GP-FDC at 500 mg/mL) or GP-FDC suspension strength (0.3 mL of GP-FDC at 125, 250 and 500 mg/mL). For all studies, blood samples were collected from the lateral tail vein up to 90 days' post-dose. G and P concentrations were quantified in plasma using a validated method by LC-MS/MS.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; GP-FDC showed plasma concentration–time profiles above the reported median human C&lt;sub&gt;trough&lt;/sub&gt; for both G and P over the 90 days. However, for single drug-LAI suspensions, plasma concentrations of P were above the human Ctrough over 70 days for both P alone and GP groups, whereas a more rapid drop in plasma concentrations were observed for G in both G and GP groups, after 35 and 28 days, respectively. In the second set of experiments, a linear dose-dependent PK was observed with increasing volume, with a proportional increase in the AUC&lt;sub&gt;0-tlast&lt;/sub&gt; for both G and P (G: 106, 220 and 390 μg·h/mL and P: 157, 346 a","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16281","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142399387","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}