Comparative analysis of ampicillin plasma and dried blood spot pharmacokinetics in neonates

Jennifer Le; Brenda Poindexter; Janice E. Sullivan; Matthew Laughon; Paula Delmore; Martha Blackford; Ram Yogev; Laura P. James; Chiara Melloni; Barrie Harper; Jeff Mitchell; Daniel K. Benjamin; Felix Boakye-Agyeman; Michael Cohen-Wolkowiez

doi:10.1097/FTD.0000000000000466

Comparative analysis of ampicillin plasma and dried blood spot pharmacokinetics in neonates

Jennifer Le, Brenda Poindexter, Janice E. Sullivan, Matthew Laughon, Paula Delmore, Martha Blackford, Ram Yogev, Laura P. James, Chiara Melloni, Barrie Harper, Jeff Mitchell, Daniel K. Benjamin, Felix Boakye-Agyeman, Michael Cohen-Wolkowiez

Pediatrics

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

Background: Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. The utility of DBS to determine the population pharmacokinetics (pop-PK) of ampicillin, as well as accuracy versus plasma samples, was evaluated. Methods: An open-label, multicenter, opportunistic, prospective study was conducted in neonates. Ampicillin concentrations from plasma and DBS (CONC_Plasma and CONC_DBS) were measured by liquid chromatographic tandem mass spectrometry and analyzed using pop-PK and statistical (including transformation) approaches. Results: A total of 29 paired plasma and DBS samples from 18 neonates were analyzed. The median (range) gestational age and postnatal age were 37 (27-41) weeks and 8 (1-26) days, respectively. The geometric mean of CONC_DBS to CONC_Plasma ratio was 0.56. Correlation analysis demonstrated strong association between CONC_Plasma and CONC_DBS (r² = 0.902, analysis of variance P < 0.001). Using linear regression transformation, the estimated CON-C_Plasma (eCONC_Plasma) was derived using (CONC_DBS 2 3.223)/0.51. The median bias and geometric mean ratio improved to 211% and 0.88 (Wilcoxon signed-rank test, P < 0.001), respectively, when comparing eCONC_Plasma to CONC_Plasma. Furthermore, using pop-PK modeling, the median bias (interquartile range) for clearance and individual predicted concentrations improved to 8% (211 to 50) and 28% (234 to 11), respectively, when eCONC_Plasma was used. Conclusions: After transformation, DBS sampling accurately predicted ampicillin exposure in neonates.

Original language	English (US)
Pages (from-to)	103-108
Number of pages	6
Journal	Therapeutic drug monitoring
Volume	40
Issue number	1
DOIs	https://doi.org/10.1097/FTD.0000000000000466
State	Published - Feb 2018

Funding

J. Le (primary author) receives support from NICHD and NIAID (1U54HD090259 and 1K23AI089978) and subagreement from Duke University (HHSN27500027). M. Laughon receives support from the US government for his work in pediatric and neonatal clinical pharmacology (Government Contract HHSN267200700051C, PI: Benjamin under the Best Pharmaceuticals for Children Act) and from NICHD (1K23HL092225-01). D. K. Benjamin receives support from the National Institutes of Health (award 2K24HD058735-06), National Institute of Child Health and Human Development (HHSN275201000003I), National Institute of Allergy and Infectious Diseases (HHSN272201500006I), ECHO Program (1U2COD023375-01), and the National Center for Advancing Translational Sciences (1U24TR001608-01); he also receives research support from Cempra Pharmaceuticals (subaward to HHSO100201300009C) and industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/ coi.jsp). M. Cohen-Wolkowiez receives support for research from the National Institutes of Health (1R01-HD076676-01A1), the National Institute of Allergy and Infectious Disease (HHSN272201500006I and HHSN272201300017I), the National Institute of Child Health and Human Development (HHSN275201000003I), the Biomedical Advanced Research and Development Authority (HHSO100201300009C), and industry for drug development in adults and children (www. dcri.duke.edu/research/coi.jsp). The remaining authors declare no conflict of interest. J. Le (primary author) receives support from NICHD and NIAID (1U54HD090259 and 1K23AI089978) and subagreement from Duke University (HHSN27500027). M. Laughon receives support from the US government for his work in pediatric and neonatal clinical pharmacology (Government Contract HHSN267200700051C, PI: Benjamin under the Best Pharmaceuticals for Children Act) and from NICHD (1K23HL092225-01). D. K. Benjamin receives support from the National Institutes of Health (award 2K24HD058735-06), National Institute of Child Health and Human Development (HHSN275201000003I), National Institute of Allergy and Infectious Diseases (HHSN272201500006I), ECHO Program (1U2COD023375-01), and the National Center for Advancing Translational Sciences (1U24TR001608-01); he also receives research support from Cempra Pharmaceuticals (subaward to HHSO100201300009C) and industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/ coi.jsp). M. Cohen-Wolkowiez receives support for research from the National Institutes of Health (1R01-HD076676-01A1), the National Institute of Allergy and Infectious Disease (HHSN272201500006I and HHSN272201300017I), the National Institute of Child Health and Human Development (HHSN275201000003I), the Biomedical Advanced Research and Development Authority (HHSO100201300009C), and industry for drug development in adults and children (www.dcri.duke.edu/research/coi.jsp). The remaining authors declare no conflict of interest. This work was funded under NICHD contract HHSN275201000003I for the Pediatric Trials Network (PI Benjamin). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The assay measuring ampicillin concentrations was performed at OpAns Laboratory (Durham, NC).

Keywords

Ampicillin
Dried blood spot
Neonates
Pharmacokinetic modeling

ASJC Scopus subject areas

Pharmacology (medical)
Pharmacology

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10.1097/FTD.0000000000000466

Cite this

Le, J., Poindexter, B., Sullivan, J. E., Laughon, M., Delmore, P., Blackford, M., Yogev, R., James, L. P., Melloni, C., Harper, B., Mitchell, J., Benjamin, D. K., Boakye-Agyeman, F., & Cohen-Wolkowiez, M. (2018). Comparative analysis of ampicillin plasma and dried blood spot pharmacokinetics in neonates. Therapeutic drug monitoring, 40(1), 103-108. https://doi.org/10.1097/FTD.0000000000000466

@article{a373039bac9a476991610d3163dfb9ab,

title = "Comparative analysis of ampicillin plasma and dried blood spot pharmacokinetics in neonates",

abstract = "Background: Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. The utility of DBS to determine the population pharmacokinetics (pop-PK) of ampicillin, as well as accuracy versus plasma samples, was evaluated. Methods: An open-label, multicenter, opportunistic, prospective study was conducted in neonates. Ampicillin concentrations from plasma and DBS (CONCPlasma and CONCDBS) were measured by liquid chromatographic tandem mass spectrometry and analyzed using pop-PK and statistical (including transformation) approaches. Results: A total of 29 paired plasma and DBS samples from 18 neonates were analyzed. The median (range) gestational age and postnatal age were 37 (27-41) weeks and 8 (1-26) days, respectively. The geometric mean of CONCDBS to CONCPlasma ratio was 0.56. Correlation analysis demonstrated strong association between CONCPlasma and CONCDBS (r2 = 0.902, analysis of variance P < 0.001). Using linear regression transformation, the estimated CON-CPlasma (eCONCPlasma) was derived using (CONCDBS 2 3.223)/0.51. The median bias and geometric mean ratio improved to 211% and 0.88 (Wilcoxon signed-rank test, P < 0.001), respectively, when comparing eCONCPlasma to CONCPlasma. Furthermore, using pop-PK modeling, the median bias (interquartile range) for clearance and individual predicted concentrations improved to 8% (211 to 50) and 28% (234 to 11), respectively, when eCONCPlasma was used. Conclusions: After transformation, DBS sampling accurately predicted ampicillin exposure in neonates.",

keywords = "Ampicillin, Dried blood spot, Neonates, Pharmacokinetic modeling",

author = "Jennifer Le and Brenda Poindexter and Sullivan, {Janice E.} and Matthew Laughon and Paula Delmore and Martha Blackford and Ram Yogev and James, {Laura P.} and Chiara Melloni and Barrie Harper and Jeff Mitchell and Benjamin, {Daniel K.} and Felix Boakye-Agyeman and Michael Cohen-Wolkowiez",

year = "2018",

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doi = "10.1097/FTD.0000000000000466",

language = "English (US)",

volume = "40",

pages = "103--108",

journal = "Therapeutic drug monitoring",

issn = "0163-4356",

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Le, J, Poindexter, B, Sullivan, JE, Laughon, M, Delmore, P, Blackford, M, Yogev, R, James, LP, Melloni, C, Harper, B, Mitchell, J, Benjamin, DK, Boakye-Agyeman, F & Cohen-Wolkowiez, M 2018, 'Comparative analysis of ampicillin plasma and dried blood spot pharmacokinetics in neonates', Therapeutic drug monitoring, vol. 40, no. 1, pp. 103-108. https://doi.org/10.1097/FTD.0000000000000466

TY - JOUR

T1 - Comparative analysis of ampicillin plasma and dried blood spot pharmacokinetics in neonates

AU - Le, Jennifer

AU - Poindexter, Brenda

AU - Sullivan, Janice E.

AU - Laughon, Matthew

AU - Delmore, Paula

AU - Blackford, Martha

AU - Yogev, Ram

AU - James, Laura P.

AU - Melloni, Chiara

AU - Harper, Barrie

AU - Mitchell, Jeff

AU - Benjamin, Daniel K.

AU - Boakye-Agyeman, Felix

AU - Cohen-Wolkowiez, Michael

PY - 2018/2

Y1 - 2018/2

N2 - Background: Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. The utility of DBS to determine the population pharmacokinetics (pop-PK) of ampicillin, as well as accuracy versus plasma samples, was evaluated. Methods: An open-label, multicenter, opportunistic, prospective study was conducted in neonates. Ampicillin concentrations from plasma and DBS (CONCPlasma and CONCDBS) were measured by liquid chromatographic tandem mass spectrometry and analyzed using pop-PK and statistical (including transformation) approaches. Results: A total of 29 paired plasma and DBS samples from 18 neonates were analyzed. The median (range) gestational age and postnatal age were 37 (27-41) weeks and 8 (1-26) days, respectively. The geometric mean of CONCDBS to CONCPlasma ratio was 0.56. Correlation analysis demonstrated strong association between CONCPlasma and CONCDBS (r2 = 0.902, analysis of variance P < 0.001). Using linear regression transformation, the estimated CON-CPlasma (eCONCPlasma) was derived using (CONCDBS 2 3.223)/0.51. The median bias and geometric mean ratio improved to 211% and 0.88 (Wilcoxon signed-rank test, P < 0.001), respectively, when comparing eCONCPlasma to CONCPlasma. Furthermore, using pop-PK modeling, the median bias (interquartile range) for clearance and individual predicted concentrations improved to 8% (211 to 50) and 28% (234 to 11), respectively, when eCONCPlasma was used. Conclusions: After transformation, DBS sampling accurately predicted ampicillin exposure in neonates.

AB - Background: Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. The utility of DBS to determine the population pharmacokinetics (pop-PK) of ampicillin, as well as accuracy versus plasma samples, was evaluated. Methods: An open-label, multicenter, opportunistic, prospective study was conducted in neonates. Ampicillin concentrations from plasma and DBS (CONCPlasma and CONCDBS) were measured by liquid chromatographic tandem mass spectrometry and analyzed using pop-PK and statistical (including transformation) approaches. Results: A total of 29 paired plasma and DBS samples from 18 neonates were analyzed. The median (range) gestational age and postnatal age were 37 (27-41) weeks and 8 (1-26) days, respectively. The geometric mean of CONCDBS to CONCPlasma ratio was 0.56. Correlation analysis demonstrated strong association between CONCPlasma and CONCDBS (r2 = 0.902, analysis of variance P < 0.001). Using linear regression transformation, the estimated CON-CPlasma (eCONCPlasma) was derived using (CONCDBS 2 3.223)/0.51. The median bias and geometric mean ratio improved to 211% and 0.88 (Wilcoxon signed-rank test, P < 0.001), respectively, when comparing eCONCPlasma to CONCPlasma. Furthermore, using pop-PK modeling, the median bias (interquartile range) for clearance and individual predicted concentrations improved to 8% (211 to 50) and 28% (234 to 11), respectively, when eCONCPlasma was used. Conclusions: After transformation, DBS sampling accurately predicted ampicillin exposure in neonates.

KW - Ampicillin

KW - Dried blood spot

KW - Neonates

KW - Pharmacokinetic modeling

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Comparative analysis of ampicillin plasma and dried blood spot pharmacokinetics in neonates

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