A naïve pooled data approach for extrapolation of Phase 0 microdose trials to therapeutic dosing regimens
Abstract Microdosing is a strategy to obtain knowledge of human pharmacokinetics prior to Phase I clinical trials. The most frequently used method to extrapolate microdose (≤100 μg) pharmacokinetics to therapeutic doses is based on linear extrapolation from a noncompartmental analysis (NCA) with a t...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-02-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13446 |
| _version_ | 1811164880671080448 |
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| author | Lisa van derHeijden Merel vanNuland Jos Beijnen Alwin Huitema Thomas Dorlo |
| author_facet | Lisa van derHeijden Merel vanNuland Jos Beijnen Alwin Huitema Thomas Dorlo |
| author_sort | Lisa van derHeijden |
| collection | DOAJ |
| description | Abstract Microdosing is a strategy to obtain knowledge of human pharmacokinetics prior to Phase I clinical trials. The most frequently used method to extrapolate microdose (≤100 μg) pharmacokinetics to therapeutic doses is based on linear extrapolation from a noncompartmental analysis (NCA) with a two‐fold acceptance criterion between pharmacokinetic metrics of the extrapolated microdose and the therapeutic dose. The major disadvantage of NCA is the assumption of linear extrapolation of NCA metrics. In this study, we used a naïve pooled data (NPD) modeling approach to extrapolate microdose pharmacokinetics to therapeutic pharmacokinetics. Gemcitabine and anastrozole were used as examples of intravenous and oral drugs, respectively. Data from microdose studies were used to build a parent‐metabolite model for gemcitabine and its metabolite 2′,2′‐difluorodeoxyuridine (dFdU) and a model for anastrozole. The pharmacokinetic microdose models were extrapolated to therapeutic doses. Extrapolation of the microdose showed differences in pharmacokinetic shape for gemcitabine and dFdU between the simulated and observed therapeutic concentrations, whereas the observed therapeutic concentrations for anastrozole were captured by the extrapolation. This study demonstrated the possible use and feasibility of an NPD modeling approach for the evaluation and application of microdose studies in early drug development. Last, physiologically‐based pharmacokinetic modeling might be an alternative for microdose extrapolation of drugs with complex pharmacokinetics such as gemcitabine. |
| first_indexed | 2024-04-10T15:29:24Z |
| format | Article |
| id | doaj.art-aaf34c4b3c5a4baf998072fbc42281c1 |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-04-10T15:29:24Z |
| publishDate | 2023-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-aaf34c4b3c5a4baf998072fbc42281c12023-02-14T07:32:57ZengWileyClinical and Translational Science1752-80541752-80622023-02-0116225826810.1111/cts.13446A naïve pooled data approach for extrapolation of Phase 0 microdose trials to therapeutic dosing regimensLisa van derHeijden0Merel vanNuland1Jos Beijnen2Alwin Huitema3Thomas Dorlo4Department of Pharmacy & Pharmacology Antoni van Leeuwenhoek/The Netherlands Cancer Institute Amsterdam The NetherlandsDepartment of Pharmacy & Pharmacology Antoni van Leeuwenhoek/The Netherlands Cancer Institute Amsterdam The NetherlandsDepartment of Pharmacy & Pharmacology Antoni van Leeuwenhoek/The Netherlands Cancer Institute Amsterdam The NetherlandsDepartment of Pharmacy & Pharmacology Antoni van Leeuwenhoek/The Netherlands Cancer Institute Amsterdam The NetherlandsDepartment of Pharmacy & Pharmacology Antoni van Leeuwenhoek/The Netherlands Cancer Institute Amsterdam The NetherlandsAbstract Microdosing is a strategy to obtain knowledge of human pharmacokinetics prior to Phase I clinical trials. The most frequently used method to extrapolate microdose (≤100 μg) pharmacokinetics to therapeutic doses is based on linear extrapolation from a noncompartmental analysis (NCA) with a two‐fold acceptance criterion between pharmacokinetic metrics of the extrapolated microdose and the therapeutic dose. The major disadvantage of NCA is the assumption of linear extrapolation of NCA metrics. In this study, we used a naïve pooled data (NPD) modeling approach to extrapolate microdose pharmacokinetics to therapeutic pharmacokinetics. Gemcitabine and anastrozole were used as examples of intravenous and oral drugs, respectively. Data from microdose studies were used to build a parent‐metabolite model for gemcitabine and its metabolite 2′,2′‐difluorodeoxyuridine (dFdU) and a model for anastrozole. The pharmacokinetic microdose models were extrapolated to therapeutic doses. Extrapolation of the microdose showed differences in pharmacokinetic shape for gemcitabine and dFdU between the simulated and observed therapeutic concentrations, whereas the observed therapeutic concentrations for anastrozole were captured by the extrapolation. This study demonstrated the possible use and feasibility of an NPD modeling approach for the evaluation and application of microdose studies in early drug development. Last, physiologically‐based pharmacokinetic modeling might be an alternative for microdose extrapolation of drugs with complex pharmacokinetics such as gemcitabine.https://doi.org/10.1111/cts.13446 |
| spellingShingle | Lisa van derHeijden Merel vanNuland Jos Beijnen Alwin Huitema Thomas Dorlo A naïve pooled data approach for extrapolation of Phase 0 microdose trials to therapeutic dosing regimens Clinical and Translational Science |
| title | A naïve pooled data approach for extrapolation of Phase 0 microdose trials to therapeutic dosing regimens |
| title_full | A naïve pooled data approach for extrapolation of Phase 0 microdose trials to therapeutic dosing regimens |
| title_fullStr | A naïve pooled data approach for extrapolation of Phase 0 microdose trials to therapeutic dosing regimens |
| title_full_unstemmed | A naïve pooled data approach for extrapolation of Phase 0 microdose trials to therapeutic dosing regimens |
| title_short | A naïve pooled data approach for extrapolation of Phase 0 microdose trials to therapeutic dosing regimens |
| title_sort | naive pooled data approach for extrapolation of phase 0 microdose trials to therapeutic dosing regimens |
| url | https://doi.org/10.1111/cts.13446 |
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