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Microneedle biosensors for real-time, minimally invasive drug monitoring of phenoxymethylpenicillin: a first-in-human evaluation in healthy volunteers

Timothy M Rawson, Sally A N Gowers, David M E Freeman, Richard C Wilson, Sanjiv Sharma Orcid Logo, Mark Gilchrist, Alasdair MacGowan, Andrew Lovering, Mark Bayliss, Mathew Kyriakides, Pantelis Georgiou, Anthony E G Cass, Danny O'Hare, Alison H Holmes

The Lancet Digital Health, Volume: 1, Issue: 7, Pages: e335 - e343

Swansea University Author: Sanjiv Sharma Orcid Logo

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DOI (Published version): 10.1016/s2589-7500(19)30131-1

Abstract

Background: We report the first-in-human evaluation of realtime penicillin monitoring using a microneedle-based beta-lactam biosensor.Methods: Participants taking phenoxymethylpenicillin (penicillin-V) at steady state had venous blood (via cannula, T=- 30,0,10,20,30,45,60,90,120,150,180,210,240mins)...

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Published in: The Lancet Digital Health
ISSN: 2589-7500
Published: Elsevier BV 2019
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2023-02-21T16:37:39.5930388</datestamp><bib-version>v2</bib-version><id>51460</id><entry>2019-08-19</entry><title>Microneedle biosensors for real-time, minimally invasive drug monitoring of phenoxymethylpenicillin: a first-in-human evaluation in healthy volunteers</title><swanseaauthors><author><sid>b6b7506358522f607b171ec9c94757b7</sid><ORCID>0000-0003-3828-737X</ORCID><firstname>Sanjiv</firstname><surname>Sharma</surname><name>Sanjiv Sharma</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2019-08-19</date><deptcode>MEDE</deptcode><abstract>Background: We report the first-in-human evaluation of realtime penicillin monitoring using a microneedle-based beta-lactam biosensor.Methods: Participants taking phenoxymethylpenicillin (penicillin-V) at steady state had venous blood (via cannula, T=- 30,0,10,20,30,45,60,90,120,150,180,210,240mins) and extracellular fluid (ECF; via microdialysis, every 15mins) pharmacokinetic (PK) samples taken during one dosing interval. During this period, a solid microneedle betalactam biosensor was worn to provide real-time monitoring of ECF penicillin-V concentration. Penicillin-V concentration data obtained from the microneedles was calibrated using locally-estimated-scatter-plot smoothing and compared to free blood and microdialysis (gold standard) data. Penicillin-V PK for each method was evaluated using noncompartmental analysis. Area-under-the-concentration-time-curve (AUC), Cmax, and tmax were compared. Bias and limits of agreement were investigated with Bland-Altman plots. Microneedle biosensor limits of detection were estimated. The study was approved by London-HarrowRegional ethics committee (Ref:18/LO/0054, NCT03847610).Findings: Ten healthy volunteers participated. Mean (SD) age was 42 (14) years. Seven (70%) were male. Penicillin-V ECF determined through microdialysis and microneedle methods demonstrated similar Cmax (0.74mg/L vs. 0.64mg/L, p=0.53; 95%CI: -0.24;0.44), tmax (1.18hrs vs. 1.10hrs, p=0.79; 95%CI:-0.52;0.67), and AUC (1.54mg*h/L vs. 1.67 mg*h/L p=0.79;95%CI:-1.10;0.85). In total, 440 time points were compared with mean (95%CI) difference between measurements -0.15 mg/L (95%CI:-0.11;0.20). Mean (SD) penicillin-V AUC values for free serum and microneedle PK were similar at 1.77 (0.59) mg*h/L and 1.67 (1.06) mg*h/L, respectively (p=0.81; 95%CI:-0.77;0.97). Percentage coefficient of variation betweensensors within individuals was median (IQR) 7 (4-17)%. Limit of detection for the microneedles was estimated at 0.17 mg/L.Interpretation: This demonstrates proof-of-concept of real-time, microneedle sensing of penicillin in vivo. Future work will explore microneedle use in patient populations, their role in data generation to inform dosing recommendations, and their incorporation into closed-loop control systems for automated drug delivery.</abstract><type>Journal Article</type><journal>The Lancet Digital Health</journal><volume>1</volume><journalNumber>7</journalNumber><paginationStart>e335</paginationStart><paginationEnd>e343</paginationEnd><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>2589-7500</issnPrint><issnElectronic/><keywords/><publishedDay>30</publishedDay><publishedMonth>11</publishedMonth><publishedYear>2019</publishedYear><publishedDate>2019-11-30</publishedDate><doi>10.1016/s2589-7500(19)30131-1</doi><url>http://dx.doi.org/10.1016/s2589-7500(19)30131-1</url><notes/><college>COLLEGE NANME</college><department>Biomedical Engineering</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDE</DepartmentCode><institution>Swansea University</institution><apcterm/><funders/><projectreference/><lastEdited>2023-02-21T16:37:39.5930388</lastEdited><Created>2019-08-19T08:52:52.1792914</Created><path><level id="1">Faculty of Science and Engineering</level><level id="2">School of Engineering and Applied Sciences - Biomedical Engineering</level></path><authors><author><firstname>Timothy M</firstname><surname>Rawson</surname><order>1</order></author><author><firstname>Sally A N</firstname><surname>Gowers</surname><order>2</order></author><author><firstname>David M E</firstname><surname>Freeman</surname><order>3</order></author><author><firstname>Richard C</firstname><surname>Wilson</surname><order>4</order></author><author><firstname>Sanjiv</firstname><surname>Sharma</surname><orcid>0000-0003-3828-737X</orcid><order>5</order></author><author><firstname>Mark</firstname><surname>Gilchrist</surname><order>6</order></author><author><firstname>Alasdair</firstname><surname>MacGowan</surname><order>7</order></author><author><firstname>Andrew</firstname><surname>Lovering</surname><order>8</order></author><author><firstname>Mark</firstname><surname>Bayliss</surname><order>9</order></author><author><firstname>Mathew</firstname><surname>Kyriakides</surname><order>10</order></author><author><firstname>Pantelis</firstname><surname>Georgiou</surname><order>11</order></author><author><firstname>Anthony E G</firstname><surname>Cass</surname><order>12</order></author><author><firstname>Danny</firstname><surname>O'Hare</surname><order>13</order></author><author><firstname>Alison H</firstname><surname>Holmes</surname><order>14</order></author></authors><documents><document><filename>51460__15498__66910aefae77417b8b6482c0441d71b4.pdf</filename><originalFilename>rawson2019(2).pdf</originalFilename><uploaded>2019-10-07T14:31:07.7130000</uploaded><type>Output</type><contentLength>1532590</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><embargoDate>2019-10-07T00:00:00.0000000</embargoDate><copyrightCorrect>false</copyrightCorrect><language>eng</language></document></documents><OutputDurs/></rfc1807>
spelling 2023-02-21T16:37:39.5930388 v2 51460 2019-08-19 Microneedle biosensors for real-time, minimally invasive drug monitoring of phenoxymethylpenicillin: a first-in-human evaluation in healthy volunteers b6b7506358522f607b171ec9c94757b7 0000-0003-3828-737X Sanjiv Sharma Sanjiv Sharma true false 2019-08-19 MEDE Background: We report the first-in-human evaluation of realtime penicillin monitoring using a microneedle-based beta-lactam biosensor.Methods: Participants taking phenoxymethylpenicillin (penicillin-V) at steady state had venous blood (via cannula, T=- 30,0,10,20,30,45,60,90,120,150,180,210,240mins) and extracellular fluid (ECF; via microdialysis, every 15mins) pharmacokinetic (PK) samples taken during one dosing interval. During this period, a solid microneedle betalactam biosensor was worn to provide real-time monitoring of ECF penicillin-V concentration. Penicillin-V concentration data obtained from the microneedles was calibrated using locally-estimated-scatter-plot smoothing and compared to free blood and microdialysis (gold standard) data. Penicillin-V PK for each method was evaluated using noncompartmental analysis. Area-under-the-concentration-time-curve (AUC), Cmax, and tmax were compared. Bias and limits of agreement were investigated with Bland-Altman plots. Microneedle biosensor limits of detection were estimated. The study was approved by London-HarrowRegional ethics committee (Ref:18/LO/0054, NCT03847610).Findings: Ten healthy volunteers participated. Mean (SD) age was 42 (14) years. Seven (70%) were male. Penicillin-V ECF determined through microdialysis and microneedle methods demonstrated similar Cmax (0.74mg/L vs. 0.64mg/L, p=0.53; 95%CI: -0.24;0.44), tmax (1.18hrs vs. 1.10hrs, p=0.79; 95%CI:-0.52;0.67), and AUC (1.54mg*h/L vs. 1.67 mg*h/L p=0.79;95%CI:-1.10;0.85). In total, 440 time points were compared with mean (95%CI) difference between measurements -0.15 mg/L (95%CI:-0.11;0.20). Mean (SD) penicillin-V AUC values for free serum and microneedle PK were similar at 1.77 (0.59) mg*h/L and 1.67 (1.06) mg*h/L, respectively (p=0.81; 95%CI:-0.77;0.97). Percentage coefficient of variation betweensensors within individuals was median (IQR) 7 (4-17)%. Limit of detection for the microneedles was estimated at 0.17 mg/L.Interpretation: This demonstrates proof-of-concept of real-time, microneedle sensing of penicillin in vivo. Future work will explore microneedle use in patient populations, their role in data generation to inform dosing recommendations, and their incorporation into closed-loop control systems for automated drug delivery. Journal Article The Lancet Digital Health 1 7 e335 e343 Elsevier BV 2589-7500 30 11 2019 2019-11-30 10.1016/s2589-7500(19)30131-1 http://dx.doi.org/10.1016/s2589-7500(19)30131-1 COLLEGE NANME Biomedical Engineering COLLEGE CODE MEDE Swansea University 2023-02-21T16:37:39.5930388 2019-08-19T08:52:52.1792914 Faculty of Science and Engineering School of Engineering and Applied Sciences - Biomedical Engineering Timothy M Rawson 1 Sally A N Gowers 2 David M E Freeman 3 Richard C Wilson 4 Sanjiv Sharma 0000-0003-3828-737X 5 Mark Gilchrist 6 Alasdair MacGowan 7 Andrew Lovering 8 Mark Bayliss 9 Mathew Kyriakides 10 Pantelis Georgiou 11 Anthony E G Cass 12 Danny O'Hare 13 Alison H Holmes 14 51460__15498__66910aefae77417b8b6482c0441d71b4.pdf rawson2019(2).pdf 2019-10-07T14:31:07.7130000 Output 1532590 application/pdf Version of Record true 2019-10-07T00:00:00.0000000 false eng
title Microneedle biosensors for real-time, minimally invasive drug monitoring of phenoxymethylpenicillin: a first-in-human evaluation in healthy volunteers
spellingShingle Microneedle biosensors for real-time, minimally invasive drug monitoring of phenoxymethylpenicillin: a first-in-human evaluation in healthy volunteers
Sanjiv Sharma
title_short Microneedle biosensors for real-time, minimally invasive drug monitoring of phenoxymethylpenicillin: a first-in-human evaluation in healthy volunteers
title_full Microneedle biosensors for real-time, minimally invasive drug monitoring of phenoxymethylpenicillin: a first-in-human evaluation in healthy volunteers
title_fullStr Microneedle biosensors for real-time, minimally invasive drug monitoring of phenoxymethylpenicillin: a first-in-human evaluation in healthy volunteers
title_full_unstemmed Microneedle biosensors for real-time, minimally invasive drug monitoring of phenoxymethylpenicillin: a first-in-human evaluation in healthy volunteers
title_sort Microneedle biosensors for real-time, minimally invasive drug monitoring of phenoxymethylpenicillin: a first-in-human evaluation in healthy volunteers
author_id_str_mv b6b7506358522f607b171ec9c94757b7
author_id_fullname_str_mv b6b7506358522f607b171ec9c94757b7_***_Sanjiv Sharma
author Sanjiv Sharma
author2 Timothy M Rawson
Sally A N Gowers
David M E Freeman
Richard C Wilson
Sanjiv Sharma
Mark Gilchrist
Alasdair MacGowan
Andrew Lovering
Mark Bayliss
Mathew Kyriakides
Pantelis Georgiou
Anthony E G Cass
Danny O'Hare
Alison H Holmes
format Journal article
container_title The Lancet Digital Health
container_volume 1
container_issue 7
container_start_page e335
publishDate 2019
institution Swansea University
issn 2589-7500
doi_str_mv 10.1016/s2589-7500(19)30131-1
publisher Elsevier BV
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Biomedical Engineering{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Biomedical Engineering
url http://dx.doi.org/10.1016/s2589-7500(19)30131-1
document_store_str 1
active_str 0
description Background: We report the first-in-human evaluation of realtime penicillin monitoring using a microneedle-based beta-lactam biosensor.Methods: Participants taking phenoxymethylpenicillin (penicillin-V) at steady state had venous blood (via cannula, T=- 30,0,10,20,30,45,60,90,120,150,180,210,240mins) and extracellular fluid (ECF; via microdialysis, every 15mins) pharmacokinetic (PK) samples taken during one dosing interval. During this period, a solid microneedle betalactam biosensor was worn to provide real-time monitoring of ECF penicillin-V concentration. Penicillin-V concentration data obtained from the microneedles was calibrated using locally-estimated-scatter-plot smoothing and compared to free blood and microdialysis (gold standard) data. Penicillin-V PK for each method was evaluated using noncompartmental analysis. Area-under-the-concentration-time-curve (AUC), Cmax, and tmax were compared. Bias and limits of agreement were investigated with Bland-Altman plots. Microneedle biosensor limits of detection were estimated. The study was approved by London-HarrowRegional ethics committee (Ref:18/LO/0054, NCT03847610).Findings: Ten healthy volunteers participated. Mean (SD) age was 42 (14) years. Seven (70%) were male. Penicillin-V ECF determined through microdialysis and microneedle methods demonstrated similar Cmax (0.74mg/L vs. 0.64mg/L, p=0.53; 95%CI: -0.24;0.44), tmax (1.18hrs vs. 1.10hrs, p=0.79; 95%CI:-0.52;0.67), and AUC (1.54mg*h/L vs. 1.67 mg*h/L p=0.79;95%CI:-1.10;0.85). In total, 440 time points were compared with mean (95%CI) difference between measurements -0.15 mg/L (95%CI:-0.11;0.20). Mean (SD) penicillin-V AUC values for free serum and microneedle PK were similar at 1.77 (0.59) mg*h/L and 1.67 (1.06) mg*h/L, respectively (p=0.81; 95%CI:-0.77;0.97). Percentage coefficient of variation betweensensors within individuals was median (IQR) 7 (4-17)%. Limit of detection for the microneedles was estimated at 0.17 mg/L.Interpretation: This demonstrates proof-of-concept of real-time, microneedle sensing of penicillin in vivo. Future work will explore microneedle use in patient populations, their role in data generation to inform dosing recommendations, and their incorporation into closed-loop control systems for automated drug delivery.
published_date 2019-11-30T04:03:21Z
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