Total and Free Blood and Plasma Concentration Changes in Pregnancy for Medicines Highly Bound to Plasma Proteins: Application of Physiologically Based Pharmacokinetic Modelling to Understand the Impact on Efficacy
Free drug concentrations are generally considered the pharmacologically active moiety and are important for cellular diffusion and distribution. Pregnancy-related changes in plasma protein binding and blood partitioning are due to decreases in plasma albumin, alpha-1-acid glycoprotein, and haematocr...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-10-01
|
| Series: | Pharmaceutics |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4923/15/10/2455 |
| _version_ | 1827720112946282496 |
|---|---|
| author | Paola Coppola Andrew Butler Susan Cole Essam Kerwash |
| author_facet | Paola Coppola Andrew Butler Susan Cole Essam Kerwash |
| author_sort | Paola Coppola |
| collection | DOAJ |
| description | Free drug concentrations are generally considered the pharmacologically active moiety and are important for cellular diffusion and distribution. Pregnancy-related changes in plasma protein binding and blood partitioning are due to decreases in plasma albumin, alpha-1-acid glycoprotein, and haematocrit; this may lead to increased free concentrations, tissue distribution, and clearance during pregnancy. In this paper we highlight the importance and challenges of considering changes in total and free concentrations during pregnancy. For medicines highly bound to plasma proteins, such as tacrolimus, efavirenz, clindamycin, phenytoin, and carbamazepine, differential changes in concentrations of free drug during pregnancy may be clinically significant and have important implications for dose adjustment. Therapeutic drug monitoring usually relies on the measurement of total concentrations; this can result in dose adjustments that are not necessary when changes in free concentrations are considered. We explore the potential of physiologically based pharmacokinetic (PBPK) models to support the understanding of the changes in plasma proteins binding, using tacrolimus and efavirenz as example drug models. The exposure to either drug was predicted to be reduced during pregnancy; however, the decrease in the exposure to the total tacrolimus and efavirenz were significantly larger than the reduction in the exposure to the free drug. These data show that PBPK modelling can support the impact of the changes in plasma protein binding and may be used for the simulation of free concentrations in pregnancy to support dosing decisions. |
| first_indexed | 2024-03-10T20:57:54Z |
| format | Article |
| id | doaj.art-b758e5d4e7d743dd8e1a20b9264a7619 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T20:57:54Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-b758e5d4e7d743dd8e1a20b9264a76192023-11-19T17:44:46ZengMDPI AGPharmaceutics1999-49232023-10-011510245510.3390/pharmaceutics15102455Total and Free Blood and Plasma Concentration Changes in Pregnancy for Medicines Highly Bound to Plasma Proteins: Application of Physiologically Based Pharmacokinetic Modelling to Understand the Impact on EfficacyPaola Coppola0Andrew Butler1Susan Cole2Essam Kerwash3Medicines and Healthcare Products Regulatory Agency (MHRA), 10 South Colonnade, London E14 4PU, UKMedicines and Healthcare Products Regulatory Agency (MHRA), 10 South Colonnade, London E14 4PU, UKMedicines and Healthcare Products Regulatory Agency (MHRA), 10 South Colonnade, London E14 4PU, UKMedicines and Healthcare Products Regulatory Agency (MHRA), 10 South Colonnade, London E14 4PU, UKFree drug concentrations are generally considered the pharmacologically active moiety and are important for cellular diffusion and distribution. Pregnancy-related changes in plasma protein binding and blood partitioning are due to decreases in plasma albumin, alpha-1-acid glycoprotein, and haematocrit; this may lead to increased free concentrations, tissue distribution, and clearance during pregnancy. In this paper we highlight the importance and challenges of considering changes in total and free concentrations during pregnancy. For medicines highly bound to plasma proteins, such as tacrolimus, efavirenz, clindamycin, phenytoin, and carbamazepine, differential changes in concentrations of free drug during pregnancy may be clinically significant and have important implications for dose adjustment. Therapeutic drug monitoring usually relies on the measurement of total concentrations; this can result in dose adjustments that are not necessary when changes in free concentrations are considered. We explore the potential of physiologically based pharmacokinetic (PBPK) models to support the understanding of the changes in plasma proteins binding, using tacrolimus and efavirenz as example drug models. The exposure to either drug was predicted to be reduced during pregnancy; however, the decrease in the exposure to the total tacrolimus and efavirenz were significantly larger than the reduction in the exposure to the free drug. These data show that PBPK modelling can support the impact of the changes in plasma protein binding and may be used for the simulation of free concentrations in pregnancy to support dosing decisions.https://www.mdpi.com/1999-4923/15/10/2455pharmacokineticspregnancyprotein bindingfree concentrationstotal concentrationsPBPK |
| spellingShingle | Paola Coppola Andrew Butler Susan Cole Essam Kerwash Total and Free Blood and Plasma Concentration Changes in Pregnancy for Medicines Highly Bound to Plasma Proteins: Application of Physiologically Based Pharmacokinetic Modelling to Understand the Impact on Efficacy Pharmaceutics pharmacokinetics pregnancy protein binding free concentrations total concentrations PBPK |
| title | Total and Free Blood and Plasma Concentration Changes in Pregnancy for Medicines Highly Bound to Plasma Proteins: Application of Physiologically Based Pharmacokinetic Modelling to Understand the Impact on Efficacy |
| title_full | Total and Free Blood and Plasma Concentration Changes in Pregnancy for Medicines Highly Bound to Plasma Proteins: Application of Physiologically Based Pharmacokinetic Modelling to Understand the Impact on Efficacy |
| title_fullStr | Total and Free Blood and Plasma Concentration Changes in Pregnancy for Medicines Highly Bound to Plasma Proteins: Application of Physiologically Based Pharmacokinetic Modelling to Understand the Impact on Efficacy |
| title_full_unstemmed | Total and Free Blood and Plasma Concentration Changes in Pregnancy for Medicines Highly Bound to Plasma Proteins: Application of Physiologically Based Pharmacokinetic Modelling to Understand the Impact on Efficacy |
| title_short | Total and Free Blood and Plasma Concentration Changes in Pregnancy for Medicines Highly Bound to Plasma Proteins: Application of Physiologically Based Pharmacokinetic Modelling to Understand the Impact on Efficacy |
| title_sort | total and free blood and plasma concentration changes in pregnancy for medicines highly bound to plasma proteins application of physiologically based pharmacokinetic modelling to understand the impact on efficacy |
| topic | pharmacokinetics pregnancy protein binding free concentrations total concentrations PBPK |
| url | https://www.mdpi.com/1999-4923/15/10/2455 |
| work_keys_str_mv | AT paolacoppola totalandfreebloodandplasmaconcentrationchangesinpregnancyformedicineshighlyboundtoplasmaproteinsapplicationofphysiologicallybasedpharmacokineticmodellingtounderstandtheimpactonefficacy AT andrewbutler totalandfreebloodandplasmaconcentrationchangesinpregnancyformedicineshighlyboundtoplasmaproteinsapplicationofphysiologicallybasedpharmacokineticmodellingtounderstandtheimpactonefficacy AT susancole totalandfreebloodandplasmaconcentrationchangesinpregnancyformedicineshighlyboundtoplasmaproteinsapplicationofphysiologicallybasedpharmacokineticmodellingtounderstandtheimpactonefficacy AT essamkerwash totalandfreebloodandplasmaconcentrationchangesinpregnancyformedicineshighlyboundtoplasmaproteinsapplicationofphysiologicallybasedpharmacokineticmodellingtounderstandtheimpactonefficacy |