Metabolite profiling of foslevodopa/foscarbidopa in plasma of healthy human participants by LC‐HRMS indicates no major differences compared to administration of levodopa/carbidopa intestinal gel
Abstract Analysis was conducted to compare levodopa/carbidopa pharmacokinetics and drug‐related material in plasma of healthy participants after receiving a continuous infusion of Levodopa/Carbidopa Intestinal Gel (LCIG) to a continuous subcutaneous infusion of foslevodopa/foscarbidopa. Study sample...
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| Format: | Article |
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Wiley
2024-04-01
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| Series: | Pharmacology Research & Perspectives |
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| Online Access: | https://doi.org/10.1002/prp2.1190 |
| _version_ | 1797213327340863488 |
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| author | John P. Savaryn Richard L. Smith Matthew Rosebraugh Melina Neenan Richard Burton Kennan Marsh David Wagner |
| author_facet | John P. Savaryn Richard L. Smith Matthew Rosebraugh Melina Neenan Richard Burton Kennan Marsh David Wagner |
| author_sort | John P. Savaryn |
| collection | DOAJ |
| description | Abstract Analysis was conducted to compare levodopa/carbidopa pharmacokinetics and drug‐related material in plasma of healthy participants after receiving a continuous infusion of Levodopa/Carbidopa Intestinal Gel (LCIG) to a continuous subcutaneous infusion of foslevodopa/foscarbidopa. Study samples were from a randomized, open‐label, 2‐period crossover study in 20 healthy participants. Participants received either 24‐h foslevodopa/foscarbidopa SC infusion to the abdomen or LCIG delivered for 24 h to the jejunum through a nasogastric tube with jejunal extension. Serial blood samples were collected for PK. Comparability of the LD PK parameters between the two treatment regimens was determined. Selected plasma samples were pooled per treatment group and per time point for metabolite profiling. LC–MSn was performed using high‐resolution mass spectrometry to identify drug‐related material across the dosing regimens and time points. The LD PK parameter central values and 90% confidence intervals following the foslevodopa/foscarbidopa subcutaneous infusion were between 0.8 and 1.25 relative to the LCIG infusion. With LCIG administration, LD, CD, 3‐OMD, DHPA, DOPAC, and vanillacetic acid were identified in plasma at early and late time points (0.75 and 24 h); the metabolic profile after administration of foslevodopa/foscarbidopa demonstrated the same drug‐related compounds with the exception of the administered foslevodopa. 3‐OMD and vanillacetic acid levels increased over time in both treatment regimens. Relative quantification of LC–MS peak areas showed no major differences in the metabolite profiles. These results indicate that neither the addition of monophosphate prodrug moieties nor SC administration affects the circulating metabolite profile of foslevodopa/foscarbidopa compared to LCIG. |
| first_indexed | 2024-04-24T10:56:31Z |
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| issn | 2052-1707 |
| language | English |
| last_indexed | 2024-04-24T10:56:31Z |
| publishDate | 2024-04-01 |
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| series | Pharmacology Research & Perspectives |
| spelling | doaj.art-905647f03fa242e5850562a33da606012024-04-12T05:54:30ZengWileyPharmacology Research & Perspectives2052-17072024-04-01122n/an/a10.1002/prp2.1190Metabolite profiling of foslevodopa/foscarbidopa in plasma of healthy human participants by LC‐HRMS indicates no major differences compared to administration of levodopa/carbidopa intestinal gelJohn P. Savaryn0Richard L. Smith1Matthew Rosebraugh2Melina Neenan3Richard Burton4Kennan Marsh5David Wagner6AbbVie Inc. North Chicago Illinois USAAbbVie Inc. North Chicago Illinois USAAbbVie Inc. North Chicago Illinois USAAbbVie Inc. North Chicago Illinois USAAbbVie Inc. North Chicago Illinois USAAbbVie Inc. North Chicago Illinois USAAbbVie Inc. North Chicago Illinois USAAbstract Analysis was conducted to compare levodopa/carbidopa pharmacokinetics and drug‐related material in plasma of healthy participants after receiving a continuous infusion of Levodopa/Carbidopa Intestinal Gel (LCIG) to a continuous subcutaneous infusion of foslevodopa/foscarbidopa. Study samples were from a randomized, open‐label, 2‐period crossover study in 20 healthy participants. Participants received either 24‐h foslevodopa/foscarbidopa SC infusion to the abdomen or LCIG delivered for 24 h to the jejunum through a nasogastric tube with jejunal extension. Serial blood samples were collected for PK. Comparability of the LD PK parameters between the two treatment regimens was determined. Selected plasma samples were pooled per treatment group and per time point for metabolite profiling. LC–MSn was performed using high‐resolution mass spectrometry to identify drug‐related material across the dosing regimens and time points. The LD PK parameter central values and 90% confidence intervals following the foslevodopa/foscarbidopa subcutaneous infusion were between 0.8 and 1.25 relative to the LCIG infusion. With LCIG administration, LD, CD, 3‐OMD, DHPA, DOPAC, and vanillacetic acid were identified in plasma at early and late time points (0.75 and 24 h); the metabolic profile after administration of foslevodopa/foscarbidopa demonstrated the same drug‐related compounds with the exception of the administered foslevodopa. 3‐OMD and vanillacetic acid levels increased over time in both treatment regimens. Relative quantification of LC–MS peak areas showed no major differences in the metabolite profiles. These results indicate that neither the addition of monophosphate prodrug moieties nor SC administration affects the circulating metabolite profile of foslevodopa/foscarbidopa compared to LCIG.https://doi.org/10.1002/prp2.1190carbidopafoslevodopafoscarbidopahumanlevodopametabolite profiling |
| spellingShingle | John P. Savaryn Richard L. Smith Matthew Rosebraugh Melina Neenan Richard Burton Kennan Marsh David Wagner Metabolite profiling of foslevodopa/foscarbidopa in plasma of healthy human participants by LC‐HRMS indicates no major differences compared to administration of levodopa/carbidopa intestinal gel Pharmacology Research & Perspectives carbidopa foslevodopa foscarbidopa human levodopa metabolite profiling |
| title | Metabolite profiling of foslevodopa/foscarbidopa in plasma of healthy human participants by LC‐HRMS indicates no major differences compared to administration of levodopa/carbidopa intestinal gel |
| title_full | Metabolite profiling of foslevodopa/foscarbidopa in plasma of healthy human participants by LC‐HRMS indicates no major differences compared to administration of levodopa/carbidopa intestinal gel |
| title_fullStr | Metabolite profiling of foslevodopa/foscarbidopa in plasma of healthy human participants by LC‐HRMS indicates no major differences compared to administration of levodopa/carbidopa intestinal gel |
| title_full_unstemmed | Metabolite profiling of foslevodopa/foscarbidopa in plasma of healthy human participants by LC‐HRMS indicates no major differences compared to administration of levodopa/carbidopa intestinal gel |
| title_short | Metabolite profiling of foslevodopa/foscarbidopa in plasma of healthy human participants by LC‐HRMS indicates no major differences compared to administration of levodopa/carbidopa intestinal gel |
| title_sort | metabolite profiling of foslevodopa foscarbidopa in plasma of healthy human participants by lc hrms indicates no major differences compared to administration of levodopa carbidopa intestinal gel |
| topic | carbidopa foslevodopa foscarbidopa human levodopa metabolite profiling |
| url | https://doi.org/10.1002/prp2.1190 |
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