Clinical Therapy Dose Optimization of Sublingual Buprenorphine in Poorly Adherent Pregnant Patients: A PBPK Translational Modelling Study

Tobechi Brendan Nnanna

doi:doi:10.11648/j.ijpc.20241004.11

Research Article |

| Peer-Reviewed

Clinical Therapy Dose Optimization of Sublingual Buprenorphine in Poorly Adherent Pregnant Patients: A PBPK Translational Modelling Study

Tobechi Brendan Nnanna^*

Published in International Journal of Pharmacy and Chemistry (Volume 10, Issue 4)

Received: 21 November 2024 Accepted: 6 December 2024 Published: 31 December 2024

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Abstract

Plasma levels of sublingual buprenorphine utilized in the therapy of opioid use disorder, has been demonstrated to undergo gestation-associated decline in vivo, to an extent influenced by upheavals physiologically across gestational trimesters. However, based on extant literature, a dearth of knowledge exists in the optimization of buprenorphine therapeutic modalities, pharmacokinetic interactions and posological scrutiny, necessary for successful regimen adherence. A physiologically-based pharmacokinetic modelling methodology in a virtual clinical trial premise was utilized to investigate gestational upheavals in peak plasma buprenorphine concentrations, followed by a pharmacokinetic drug-drug interaction investigation and dose optimization strategy, to maintain buprenorphine levels above proposed thresholds of 1ng/ml and below 22.2ng/ml adjudicated as a fatality limit. A fold decline (> 1.3fold) in buprenorphine mean peak plasma concentration (92% - 74%) was evident for the model predicted buprenorphine metrics across selected gestational weeks to term in line with the model predicted increases in physiological upheavals occurring across gestation which may influence the changes. The rifampicin mediated drug-drug interaction on buprenorphine levels initially resulted in fold decreases (>1.5 fold) over a twenty-four hour duration, in concert with escalating physiological metrics across gestational trimesters. The interaction perpetrated with Clarithromycin dosing resulted in fold increases (> 2-fold) in the plasma concentration as well as an increase in other metrics associated with buprenorphine kinetics. The dose optimization approach maintained majority of subjects (>90%) with the extensive metabolizer (EM) phenotype above 1ng/ml and below 22.2ng/ml in the 8mg – 24mg dose ranges albeit with 1% and 3% in the 28mg and 32mg doses above the fatality limit respectively. This study demonstrates the utility of physiologically based pharmacokinetic methods to predict the time course of administered buprenorphine in plasma during gestation which could aid clinician decisions in a translational manner, in order to optimize therapeutic modalities in the therapy of opioid use disorder.

Published in	International Journal of Pharmacy and Chemistry (Volume 10, Issue 4)
DOI	10.11648/j.ijpc.20241004.11
Page(s)	46-79
Creative Commons	This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.
Copyright	Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

Buprenorphine, Drug Interactions, Dose, Optimization, Pharmacokinetics, Phenotype, Pregnancy, PBPK

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Nnanna, T. B. (2024). Clinical Therapy Dose Optimization of Sublingual Buprenorphine in Poorly Adherent Pregnant Patients: A PBPK Translational Modelling Study. International Journal of Pharmacy and Chemistry, 10(4), 46-79. https://doi.org/10.11648/j.ijpc.20241004.11

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Nnanna, T. B. Clinical Therapy Dose Optimization of Sublingual Buprenorphine in Poorly Adherent Pregnant Patients: A PBPK Translational Modelling Study. Int. J. Pharm. Chem. 2024, 10(4), 46-79. doi: 10.11648/j.ijpc.20241004.11

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Nnanna TB. Clinical Therapy Dose Optimization of Sublingual Buprenorphine in Poorly Adherent Pregnant Patients: A PBPK Translational Modelling Study. Int J Pharm Chem. 2024;10(4):46-79. doi: 10.11648/j.ijpc.20241004.11

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@article{10.11648/j.ijpc.20241004.11,
  author = {Tobechi Brendan Nnanna},
  title = {Clinical Therapy Dose Optimization of Sublingual Buprenorphine in Poorly Adherent Pregnant Patients: A PBPK Translational Modelling Study
},
  journal = {International Journal of Pharmacy and Chemistry},
  volume = {10},
  number = {4},
  pages = {46-79},
  doi = {10.11648/j.ijpc.20241004.11},
  url = {https://doi.org/10.11648/j.ijpc.20241004.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijpc.20241004.11},
  abstract = {Plasma levels of sublingual buprenorphine utilized in the therapy of opioid use disorder, has been demonstrated to undergo gestation-associated decline in vivo, to an extent influenced by upheavals physiologically across gestational trimesters. However, based on extant literature, a dearth of knowledge exists in the optimization of buprenorphine therapeutic modalities, pharmacokinetic interactions and posological scrutiny, necessary for successful regimen adherence. A physiologically-based pharmacokinetic modelling methodology in a virtual clinical trial premise was utilized to investigate gestational upheavals in peak plasma buprenorphine concentrations, followed by a pharmacokinetic drug-drug interaction investigation and dose optimization strategy, to maintain buprenorphine levels above proposed thresholds of 1ng/ml and below 22.2ng/ml adjudicated as a fatality limit. A fold decline (> 1.3fold) in buprenorphine mean peak plasma concentration (92% - 74%) was evident for the model predicted buprenorphine metrics across selected gestational weeks to term in line with the model predicted increases in physiological upheavals occurring across gestation which may influence the changes. The rifampicin mediated drug-drug interaction on buprenorphine levels initially resulted in fold decreases (>1.5 fold) over a twenty-four hour duration, in concert with escalating physiological metrics across gestational trimesters. The interaction perpetrated with Clarithromycin dosing resulted in fold increases (> 2-fold) in the plasma concentration as well as an increase in other metrics associated with buprenorphine kinetics. The dose optimization approach maintained majority of subjects (>90%) with the extensive metabolizer (EM) phenotype above 1ng/ml and below 22.2ng/ml in the 8mg – 24mg dose ranges albeit with 1% and 3% in the 28mg and 32mg doses above the fatality limit respectively. This study demonstrates the utility of physiologically based pharmacokinetic methods to predict the time course of administered buprenorphine in plasma during gestation which could aid clinician decisions in a translational manner, in order to optimize therapeutic modalities in the therapy of opioid use disorder.
},
 year = {2024}
}

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TY  - JOUR
T1  - Clinical Therapy Dose Optimization of Sublingual Buprenorphine in Poorly Adherent Pregnant Patients: A PBPK Translational Modelling Study

AU  - Tobechi Brendan Nnanna
Y1  - 2024/12/31
PY  - 2024
N1  - https://doi.org/10.11648/j.ijpc.20241004.11
DO  - 10.11648/j.ijpc.20241004.11
T2  - International Journal of Pharmacy and Chemistry
JF  - International Journal of Pharmacy and Chemistry
JO  - International Journal of Pharmacy and Chemistry
SP  - 46
EP  - 79
PB  - Science Publishing Group
SN  - 2575-5749
UR  - https://doi.org/10.11648/j.ijpc.20241004.11
AB  - Plasma levels of sublingual buprenorphine utilized in the therapy of opioid use disorder, has been demonstrated to undergo gestation-associated decline in vivo, to an extent influenced by upheavals physiologically across gestational trimesters. However, based on extant literature, a dearth of knowledge exists in the optimization of buprenorphine therapeutic modalities, pharmacokinetic interactions and posological scrutiny, necessary for successful regimen adherence. A physiologically-based pharmacokinetic modelling methodology in a virtual clinical trial premise was utilized to investigate gestational upheavals in peak plasma buprenorphine concentrations, followed by a pharmacokinetic drug-drug interaction investigation and dose optimization strategy, to maintain buprenorphine levels above proposed thresholds of 1ng/ml and below 22.2ng/ml adjudicated as a fatality limit. A fold decline (> 1.3fold) in buprenorphine mean peak plasma concentration (92% - 74%) was evident for the model predicted buprenorphine metrics across selected gestational weeks to term in line with the model predicted increases in physiological upheavals occurring across gestation which may influence the changes. The rifampicin mediated drug-drug interaction on buprenorphine levels initially resulted in fold decreases (>1.5 fold) over a twenty-four hour duration, in concert with escalating physiological metrics across gestational trimesters. The interaction perpetrated with Clarithromycin dosing resulted in fold increases (> 2-fold) in the plasma concentration as well as an increase in other metrics associated with buprenorphine kinetics. The dose optimization approach maintained majority of subjects (>90%) with the extensive metabolizer (EM) phenotype above 1ng/ml and below 22.2ng/ml in the 8mg – 24mg dose ranges albeit with 1% and 3% in the 28mg and 32mg doses above the fatality limit respectively. This study demonstrates the utility of physiologically based pharmacokinetic methods to predict the time course of administered buprenorphine in plasma during gestation which could aid clinician decisions in a translational manner, in order to optimize therapeutic modalities in the therapy of opioid use disorder.

VL  - 10
IS  - 4
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Tobechi Brendan Nnanna

Clinical Pharmacology & Pharmaceutical Research Unit, PYCAD Pharmacy, Nigeria

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Nnanna, T. B. (2024). Clinical Therapy Dose Optimization of Sublingual Buprenorphine in Poorly Adherent Pregnant Patients: A PBPK Translational Modelling Study. International Journal of Pharmacy and Chemistry, 10(4), 46-79. https://doi.org/10.11648/j.ijpc.20241004.11

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Nnanna, T. B. Clinical Therapy Dose Optimization of Sublingual Buprenorphine in Poorly Adherent Pregnant Patients: A PBPK Translational Modelling Study. Int. J. Pharm. Chem. 2024, 10(4), 46-79. doi: 10.11648/j.ijpc.20241004.11

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Nnanna TB. Clinical Therapy Dose Optimization of Sublingual Buprenorphine in Poorly Adherent Pregnant Patients: A PBPK Translational Modelling Study. Int J Pharm Chem. 2024;10(4):46-79. doi: 10.11648/j.ijpc.20241004.11

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@article{10.11648/j.ijpc.20241004.11,
  author = {Tobechi Brendan Nnanna},
  title = {Clinical Therapy Dose Optimization of Sublingual Buprenorphine in Poorly Adherent Pregnant Patients: A PBPK Translational Modelling Study
},
  journal = {International Journal of Pharmacy and Chemistry},
  volume = {10},
  number = {4},
  pages = {46-79},
  doi = {10.11648/j.ijpc.20241004.11},
  url = {https://doi.org/10.11648/j.ijpc.20241004.11},
  eprint = {https://article.sciencepublishinggroup.com/pdf/10.11648.j.ijpc.20241004.11},
  abstract = {Plasma levels of sublingual buprenorphine utilized in the therapy of opioid use disorder, has been demonstrated to undergo gestation-associated decline in vivo, to an extent influenced by upheavals physiologically across gestational trimesters. However, based on extant literature, a dearth of knowledge exists in the optimization of buprenorphine therapeutic modalities, pharmacokinetic interactions and posological scrutiny, necessary for successful regimen adherence. A physiologically-based pharmacokinetic modelling methodology in a virtual clinical trial premise was utilized to investigate gestational upheavals in peak plasma buprenorphine concentrations, followed by a pharmacokinetic drug-drug interaction investigation and dose optimization strategy, to maintain buprenorphine levels above proposed thresholds of 1ng/ml and below 22.2ng/ml adjudicated as a fatality limit. A fold decline (> 1.3fold) in buprenorphine mean peak plasma concentration (92% - 74%) was evident for the model predicted buprenorphine metrics across selected gestational weeks to term in line with the model predicted increases in physiological upheavals occurring across gestation which may influence the changes. The rifampicin mediated drug-drug interaction on buprenorphine levels initially resulted in fold decreases (>1.5 fold) over a twenty-four hour duration, in concert with escalating physiological metrics across gestational trimesters. The interaction perpetrated with Clarithromycin dosing resulted in fold increases (> 2-fold) in the plasma concentration as well as an increase in other metrics associated with buprenorphine kinetics. The dose optimization approach maintained majority of subjects (>90%) with the extensive metabolizer (EM) phenotype above 1ng/ml and below 22.2ng/ml in the 8mg – 24mg dose ranges albeit with 1% and 3% in the 28mg and 32mg doses above the fatality limit respectively. This study demonstrates the utility of physiologically based pharmacokinetic methods to predict the time course of administered buprenorphine in plasma during gestation which could aid clinician decisions in a translational manner, in order to optimize therapeutic modalities in the therapy of opioid use disorder.
},
 year = {2024}
}

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TY  - JOUR
T1  - Clinical Therapy Dose Optimization of Sublingual Buprenorphine in Poorly Adherent Pregnant Patients: A PBPK Translational Modelling Study

AU  - Tobechi Brendan Nnanna
Y1  - 2024/12/31
PY  - 2024
N1  - https://doi.org/10.11648/j.ijpc.20241004.11
DO  - 10.11648/j.ijpc.20241004.11
T2  - International Journal of Pharmacy and Chemistry
JF  - International Journal of Pharmacy and Chemistry
JO  - International Journal of Pharmacy and Chemistry
SP  - 46
EP  - 79
PB  - Science Publishing Group
SN  - 2575-5749
UR  - https://doi.org/10.11648/j.ijpc.20241004.11
AB  - Plasma levels of sublingual buprenorphine utilized in the therapy of opioid use disorder, has been demonstrated to undergo gestation-associated decline in vivo, to an extent influenced by upheavals physiologically across gestational trimesters. However, based on extant literature, a dearth of knowledge exists in the optimization of buprenorphine therapeutic modalities, pharmacokinetic interactions and posological scrutiny, necessary for successful regimen adherence. A physiologically-based pharmacokinetic modelling methodology in a virtual clinical trial premise was utilized to investigate gestational upheavals in peak plasma buprenorphine concentrations, followed by a pharmacokinetic drug-drug interaction investigation and dose optimization strategy, to maintain buprenorphine levels above proposed thresholds of 1ng/ml and below 22.2ng/ml adjudicated as a fatality limit. A fold decline (> 1.3fold) in buprenorphine mean peak plasma concentration (92% - 74%) was evident for the model predicted buprenorphine metrics across selected gestational weeks to term in line with the model predicted increases in physiological upheavals occurring across gestation which may influence the changes. The rifampicin mediated drug-drug interaction on buprenorphine levels initially resulted in fold decreases (>1.5 fold) over a twenty-four hour duration, in concert with escalating physiological metrics across gestational trimesters. The interaction perpetrated with Clarithromycin dosing resulted in fold increases (> 2-fold) in the plasma concentration as well as an increase in other metrics associated with buprenorphine kinetics. The dose optimization approach maintained majority of subjects (>90%) with the extensive metabolizer (EM) phenotype above 1ng/ml and below 22.2ng/ml in the 8mg – 24mg dose ranges albeit with 1% and 3% in the 28mg and 32mg doses above the fatality limit respectively. This study demonstrates the utility of physiologically based pharmacokinetic methods to predict the time course of administered buprenorphine in plasma during gestation which could aid clinician decisions in a translational manner, in order to optimize therapeutic modalities in the therapy of opioid use disorder.

VL  - 10
IS  - 4
ER  -

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