{"title":"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。","authors":"","doi":"10.1111/bcp.16295","DOIUrl":null,"url":null,"abstract":"<p><b>16</b></p><p><b>Pharmacokinetics of molnupiravir and favipiravir in plasma separation cards from patients with COVID-19: Agile CST-2 and CST-6</b></p><p>Beth Thompson<sup>1</sup>, Laura Else<sup>1</sup>, Elizabeth Challenger<sup>1</sup>, Richard Fitzgerald<sup>1,2</sup>, Helen Reynolds<sup>1,2</sup>, Laura Dickinson<sup>1</sup>, Colin Hale<sup>2</sup>, Tom Fletcher<sup>2,3</sup>, Tim Rowland<sup>2,3</sup> and Saye Khoo<sup>1,2</sup></p><p><sup>1</sup><i>University of Liverpool;</i> <sup>2</sup><i>Royal Liverpool University Hospital;</i> <sup>3</sup><i>Liverpool School of Tropical Medicine</i></p><p><b>Background:</b> Molnupiravir (MPV) and favipiravir (FVP) are broadly active antiviral ribonucleoside analogues. Both have demonstrated efficacy in treatment of COVID-19 and have been investigated for use against other high-consequence infections. Collection of liquid plasma (L-PL) in remote settings, where diseases like haemorrhagic fevers are endemic, can be challenging. HemaSep dried blood spots (HS-DBS) offer a useful alternative to L-PL, separating plasma upon contact as a distinct outer ring (HS-PL) and shipped at ambient temperatures. HS-DBS were collected alongside L-PL in the AGILE CST-2/CST-6 clinical trials to evaluate the pharmacokinetics of single and repeat doses of these agents in patients with confirmed COVID-19 disease.</p><p><b>Materials and methods:</b> AGILE-CST-2 and CST-6 were open-label 2:1 randomized controlled phase I trials comparing MPV and FVP, respectively, with standard of care, designed to determine the optimal dose for treatment of symptomatic COVID-19 patients (CST-2; <i>n</i> = 12, CST-6; <i>n</i> = 16). MPV was orally delivered twice daily (BD) for 10 doses, with dose escalations (300/600/800 mg BD) across three cohorts, whereas FVP was intravenously administered BD for 14 doses, with dose escalations across four cohorts (600/1200/1800/2400 mg). Paired L-PL and HS-DBS were collected over 0–4 h post-dose (CST-2) and 0–12 h post-dose (CST-6) following administration of single (day 1) and multiple doses (day 5–CST-2; day 3–CST-6). HS-PL were excised and extracted with 50:50 acetonitrile:1 mM ammonium acetate (CST-2) and acetonitrile (CST-6). Concentrations of MPV active metabolite ß-d-N4-hydroxycytidine (NHC) and FVP were quantified using LC-MS (NHC-HS-PL: 2.5–250 ng/sample, L-PL: 2.5-5000 ng/mL; FVP-HS-PL: 50-5000 ng/sample, L-PL: 1000-100 000 ng/mL). HS-PL values were normalized to ng/mL and pharmacokinetic parameters (C<sub>max</sub>, AUC<sub>last</sub>) derived using non-compartmental analysis. Linear regression and Bland–Altman plots were used to compare methods.</p><p><b>Results:</b> NHC L-PL geometric mean Cmax increased with each dosing cohort (<i>n</i> = 4/cohort) 300/600/800 mg [day 1: 1197/2440/3447 ng/mL; day 5: 1065/1865/3546 ng/mL]. The mean difference between all HS-PL and L-PL NHC was 27% (−69%–143%). HS-PL C<sub>max</sub> were: day 1, 1749/2441/4986 ng/mL; day 5, 1559/1992/4618 ng/mL. Intersubject variability within each dosing cohort was <61% (L-PL) and <90% (HS-PL). L-PL and HS-PL concentrations (<i>r</i> = .967; <i>p</i> = <.001; <i>n</i> = 81) and AUC<sub>last</sub> (r = .958; <i>p</i> = <.001; <i>n</i> = 23) were highly correlated with a mean difference of 1.32 ng/mL between the two methods.</p><p>FVP L-PL geometric mean C<sub>ma</sub>x increased between days and with increasing doses 600/1200/1800/2400 mg [day 1: 16 481/28 006/52 044/88 486 ng/mL; day 3: 11 713/61 907/85362.4/195066.5 ng/mL]. The mean difference between all HS-PL and L-PL FVP was −6% (−115%–72%). HS-PL concentrations were [day 1: 14 307/38 107/57 448/90 607 ng/mL; day 3: 15 216/62 019/78 527/145 964 ng/mL]. Intersubject variability within each dosing cohort was <60% (L-PL) and <48% (HS-PL). FVP L-PL and HS-PL concentrations were highly correlated (<i>r</i> = .965; <i>p</i> = <.001; <i>n</i> = 124) (AUC<sub>last</sub>; <i>r</i> = .942; <i>p</i> = <.001; <i>n</i> = 32). The mean difference between the two methods was 1.08 ng/mL.</p><p><b>Conclusion:</b> HemaSep DBS are a useful alternative to L-PL for collection and transport of clinical samples for studies of high-risk infections in field settings, as NHC and FVP concentrations were correlated with respective L-PL values, with a minimal mean difference between methods. HS-PL concentrations were generally higher than respective L-PL, likely due to variable plasma ring volumes.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"90 S1","pages":"13"},"PeriodicalIF":3.1000,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16295","citationCount":"0","resultStr":"{\"title\":\"Pharmacokinetics of molnupiravir and favipiravir in plasma separation cards from patients with COVID-19: Agile CST-2 and CST-6\",\"authors\":\"\",\"doi\":\"10.1111/bcp.16295\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><b>16</b></p><p><b>Pharmacokinetics of molnupiravir and favipiravir in plasma separation cards from patients with COVID-19: Agile CST-2 and CST-6</b></p><p>Beth Thompson<sup>1</sup>, Laura Else<sup>1</sup>, Elizabeth Challenger<sup>1</sup>, Richard Fitzgerald<sup>1,2</sup>, Helen Reynolds<sup>1,2</sup>, Laura Dickinson<sup>1</sup>, Colin Hale<sup>2</sup>, Tom Fletcher<sup>2,3</sup>, Tim Rowland<sup>2,3</sup> and Saye Khoo<sup>1,2</sup></p><p><sup>1</sup><i>University of Liverpool;</i> <sup>2</sup><i>Royal Liverpool University Hospital;</i> <sup>3</sup><i>Liverpool School of Tropical Medicine</i></p><p><b>Background:</b> Molnupiravir (MPV) and favipiravir (FVP) are broadly active antiviral ribonucleoside analogues. Both have demonstrated efficacy in treatment of COVID-19 and have been investigated for use against other high-consequence infections. Collection of liquid plasma (L-PL) in remote settings, where diseases like haemorrhagic fevers are endemic, can be challenging. HemaSep dried blood spots (HS-DBS) offer a useful alternative to L-PL, separating plasma upon contact as a distinct outer ring (HS-PL) and shipped at ambient temperatures. HS-DBS were collected alongside L-PL in the AGILE CST-2/CST-6 clinical trials to evaluate the pharmacokinetics of single and repeat doses of these agents in patients with confirmed COVID-19 disease.</p><p><b>Materials and methods:</b> AGILE-CST-2 and CST-6 were open-label 2:1 randomized controlled phase I trials comparing MPV and FVP, respectively, with standard of care, designed to determine the optimal dose for treatment of symptomatic COVID-19 patients (CST-2; <i>n</i> = 12, CST-6; <i>n</i> = 16). MPV was orally delivered twice daily (BD) for 10 doses, with dose escalations (300/600/800 mg BD) across three cohorts, whereas FVP was intravenously administered BD for 14 doses, with dose escalations across four cohorts (600/1200/1800/2400 mg). Paired L-PL and HS-DBS were collected over 0–4 h post-dose (CST-2) and 0–12 h post-dose (CST-6) following administration of single (day 1) and multiple doses (day 5–CST-2; day 3–CST-6). HS-PL were excised and extracted with 50:50 acetonitrile:1 mM ammonium acetate (CST-2) and acetonitrile (CST-6). Concentrations of MPV active metabolite ß-d-N4-hydroxycytidine (NHC) and FVP were quantified using LC-MS (NHC-HS-PL: 2.5–250 ng/sample, L-PL: 2.5-5000 ng/mL; FVP-HS-PL: 50-5000 ng/sample, L-PL: 1000-100 000 ng/mL). HS-PL values were normalized to ng/mL and pharmacokinetic parameters (C<sub>max</sub>, AUC<sub>last</sub>) derived using non-compartmental analysis. Linear regression and Bland–Altman plots were used to compare methods.</p><p><b>Results:</b> NHC L-PL geometric mean Cmax increased with each dosing cohort (<i>n</i> = 4/cohort) 300/600/800 mg [day 1: 1197/2440/3447 ng/mL; day 5: 1065/1865/3546 ng/mL]. The mean difference between all HS-PL and L-PL NHC was 27% (−69%–143%). HS-PL C<sub>max</sub> were: day 1, 1749/2441/4986 ng/mL; day 5, 1559/1992/4618 ng/mL. Intersubject variability within each dosing cohort was <61% (L-PL) and <90% (HS-PL). L-PL and HS-PL concentrations (<i>r</i> = .967; <i>p</i> = <.001; <i>n</i> = 81) and AUC<sub>last</sub> (r = .958; <i>p</i> = <.001; <i>n</i> = 23) were highly correlated with a mean difference of 1.32 ng/mL between the two methods.</p><p>FVP L-PL geometric mean C<sub>ma</sub>x increased between days and with increasing doses 600/1200/1800/2400 mg [day 1: 16 481/28 006/52 044/88 486 ng/mL; day 3: 11 713/61 907/85362.4/195066.5 ng/mL]. The mean difference between all HS-PL and L-PL FVP was −6% (−115%–72%). HS-PL concentrations were [day 1: 14 307/38 107/57 448/90 607 ng/mL; day 3: 15 216/62 019/78 527/145 964 ng/mL]. Intersubject variability within each dosing cohort was <60% (L-PL) and <48% (HS-PL). FVP L-PL and HS-PL concentrations were highly correlated (<i>r</i> = .965; <i>p</i> = <.001; <i>n</i> = 124) (AUC<sub>last</sub>; <i>r</i> = .942; <i>p</i> = <.001; <i>n</i> = 32). The mean difference between the two methods was 1.08 ng/mL.</p><p><b>Conclusion:</b> HemaSep DBS are a useful alternative to L-PL for collection and transport of clinical samples for studies of high-risk infections in field settings, as NHC and FVP concentrations were correlated with respective L-PL values, with a minimal mean difference between methods. HS-PL concentrations were generally higher than respective L-PL, likely due to variable plasma ring volumes.</p>\",\"PeriodicalId\":9251,\"journal\":{\"name\":\"British journal of clinical pharmacology\",\"volume\":\"90 S1\",\"pages\":\"13\"},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2024-10-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bcp.16295\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"British journal of clinical pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/bcp.16295\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"British journal of clinical pharmacology","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/bcp.16295","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
Pharmacokinetics of molnupiravir and favipiravir in plasma separation cards from patients with COVID-19: Agile CST-2 and CST-6
16
Pharmacokinetics of molnupiravir and favipiravir in plasma separation cards from patients with COVID-19: Agile CST-2 and CST-6
Beth Thompson1, Laura Else1, Elizabeth Challenger1, Richard Fitzgerald1,2, Helen Reynolds1,2, Laura Dickinson1, Colin Hale2, Tom Fletcher2,3, Tim Rowland2,3 and Saye Khoo1,2
1University of Liverpool;2Royal Liverpool University Hospital;3Liverpool School of Tropical Medicine
Background: Molnupiravir (MPV) and favipiravir (FVP) are broadly active antiviral ribonucleoside analogues. Both have demonstrated efficacy in treatment of COVID-19 and have been investigated for use against other high-consequence infections. Collection of liquid plasma (L-PL) in remote settings, where diseases like haemorrhagic fevers are endemic, can be challenging. HemaSep dried blood spots (HS-DBS) offer a useful alternative to L-PL, separating plasma upon contact as a distinct outer ring (HS-PL) and shipped at ambient temperatures. HS-DBS were collected alongside L-PL in the AGILE CST-2/CST-6 clinical trials to evaluate the pharmacokinetics of single and repeat doses of these agents in patients with confirmed COVID-19 disease.
Materials and methods: AGILE-CST-2 and CST-6 were open-label 2:1 randomized controlled phase I trials comparing MPV and FVP, respectively, with standard of care, designed to determine the optimal dose for treatment of symptomatic COVID-19 patients (CST-2; n = 12, CST-6; n = 16). MPV was orally delivered twice daily (BD) for 10 doses, with dose escalations (300/600/800 mg BD) across three cohorts, whereas FVP was intravenously administered BD for 14 doses, with dose escalations across four cohorts (600/1200/1800/2400 mg). Paired L-PL and HS-DBS were collected over 0–4 h post-dose (CST-2) and 0–12 h post-dose (CST-6) following administration of single (day 1) and multiple doses (day 5–CST-2; day 3–CST-6). HS-PL were excised and extracted with 50:50 acetonitrile:1 mM ammonium acetate (CST-2) and acetonitrile (CST-6). Concentrations of MPV active metabolite ß-d-N4-hydroxycytidine (NHC) and FVP were quantified using LC-MS (NHC-HS-PL: 2.5–250 ng/sample, L-PL: 2.5-5000 ng/mL; FVP-HS-PL: 50-5000 ng/sample, L-PL: 1000-100 000 ng/mL). HS-PL values were normalized to ng/mL and pharmacokinetic parameters (Cmax, AUClast) derived using non-compartmental analysis. Linear regression and Bland–Altman plots were used to compare methods.
Results: NHC L-PL geometric mean Cmax increased with each dosing cohort (n = 4/cohort) 300/600/800 mg [day 1: 1197/2440/3447 ng/mL; day 5: 1065/1865/3546 ng/mL]. The mean difference between all HS-PL and L-PL NHC was 27% (−69%–143%). HS-PL Cmax were: day 1, 1749/2441/4986 ng/mL; day 5, 1559/1992/4618 ng/mL. Intersubject variability within each dosing cohort was <61% (L-PL) and <90% (HS-PL). L-PL and HS-PL concentrations (r = .967; p = <.001; n = 81) and AUClast (r = .958; p = <.001; n = 23) were highly correlated with a mean difference of 1.32 ng/mL between the two methods.
FVP L-PL geometric mean Cmax increased between days and with increasing doses 600/1200/1800/2400 mg [day 1: 16 481/28 006/52 044/88 486 ng/mL; day 3: 11 713/61 907/85362.4/195066.5 ng/mL]. The mean difference between all HS-PL and L-PL FVP was −6% (−115%–72%). HS-PL concentrations were [day 1: 14 307/38 107/57 448/90 607 ng/mL; day 3: 15 216/62 019/78 527/145 964 ng/mL]. Intersubject variability within each dosing cohort was <60% (L-PL) and <48% (HS-PL). FVP L-PL and HS-PL concentrations were highly correlated (r = .965; p = <.001; n = 124) (AUClast; r = .942; p = <.001; n = 32). The mean difference between the two methods was 1.08 ng/mL.
Conclusion: HemaSep DBS are a useful alternative to L-PL for collection and transport of clinical samples for studies of high-risk infections in field settings, as NHC and FVP concentrations were correlated with respective L-PL values, with a minimal mean difference between methods. HS-PL concentrations were generally higher than respective L-PL, likely due to variable plasma ring volumes.
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Published on behalf of the British Pharmacological Society, the British Journal of Clinical Pharmacology features papers and reports on all aspects of drug action in humans: review articles, mini review articles, original papers, commentaries, editorials and letters. The Journal enjoys a wide readership, bridging the gap between the medical profession, clinical research and the pharmaceutical industry. It also publishes research on new methods, new drugs and new approaches to treatment. The Journal is recognised as one of the leading publications in its field. It is online only, publishes open access research through its OnlineOpen programme and is published monthly.
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