Sultiame pharmacokinetic profile in plasma and erythrocytes after single oral doses: A pilot study in healthy volunteers
Abstract A pilot study was conducted aiming at specifying sultiame's pharmacokinetic profile, completed by in vitro assays evaluating the intraerythrocytic transfer of sultiame and by a pharmacokinetic model assessing its distribution. Single oral doses of sultiame (Ospolot® 50, 100, and 200 mg...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-02-01
|
| Series: | Pharmacology Research & Perspectives |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/prp2.558 |
| _version_ | 1818566615307911168 |
|---|---|
| author | Kim Dao Paul Thoueille Laurent A. Decosterd Thomas Mercier Monia Guidi Carine Bardinet Sébastien Lebon Eva Choong Arnaud Castang Catherine Guittet Luc‐André Granier Thierry Buclin |
| author_facet | Kim Dao Paul Thoueille Laurent A. Decosterd Thomas Mercier Monia Guidi Carine Bardinet Sébastien Lebon Eva Choong Arnaud Castang Catherine Guittet Luc‐André Granier Thierry Buclin |
| author_sort | Kim Dao |
| collection | DOAJ |
| description | Abstract A pilot study was conducted aiming at specifying sultiame's pharmacokinetic profile, completed by in vitro assays evaluating the intraerythrocytic transfer of sultiame and by a pharmacokinetic model assessing its distribution. Single oral doses of sultiame (Ospolot® 50, 100, and 200 mg) were administered in open‐label to four healthy volunteers. Serial plasma, whole blood, and urine samples were collected. A spiking experiment was also performed to characterize sultiame's exchanges between plasma and erythrocytes in vitro. Pharmacokinetic parameters were evaluated using standard noncompartmental calculations and nonlinear mixed‐effect modeling. The plasma maximal concentrations (Cmax) showed striking nonlinear disposition of sultiame, with a 10‐fold increase while doses were doubled. Conversely, whole blood Cmax increased less than dose proportionally while staying much higher than in plasma. Quick uptake of sultiame into erythrocytes observed in vivo was confirmed in vitro, with minimal efflux. A two‐compartment model with first‐order absorption, incorporating a saturable ligand to receptor binding, described the data remarkably well, indicating apparent plasma clearance of 10.0 L/h (BSV: 29%) and distribution volume of 64.8 L; saturable uptake into an intracellular compartment of 3.3 L with a maximum binding capacity of 111 mg accounted for nonlinearities observed in plasma and whole blood concentrations. Pharmacokinetic characteristics of sultiame are reported, including estimates of clearance and volume of distribution that were so far unpublished. The noticeable nonlinearity in sultiame disposition should be taken into account for the design of future studies and the interpretation of therapeutic drug monitoring results. |
| first_indexed | 2024-12-14T01:56:00Z |
| format | Article |
| id | doaj.art-16fbdfcf38e6424183c6909f159e209d |
| institution | Directory Open Access Journal |
| issn | 2052-1707 |
| language | English |
| last_indexed | 2024-12-14T01:56:00Z |
| publishDate | 2020-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj.art-16fbdfcf38e6424183c6909f159e209d2022-12-21T23:21:11ZengWileyPharmacology Research & Perspectives2052-17072020-02-0181n/an/a10.1002/prp2.558Sultiame pharmacokinetic profile in plasma and erythrocytes after single oral doses: A pilot study in healthy volunteersKim Dao0Paul Thoueille1Laurent A. Decosterd2Thomas Mercier3Monia Guidi4Carine Bardinet5Sébastien Lebon6Eva Choong7Arnaud Castang8Catherine Guittet9Luc‐André Granier10Thierry Buclin11Service of Clinical Pharmacology Lausanne University HospitalUniversity of Lausanne Lausanne SwitzerlandService of Clinical Pharmacology Lausanne University HospitalUniversity of Lausanne Lausanne SwitzerlandService of Clinical Pharmacology Lausanne University HospitalUniversity of Lausanne Lausanne SwitzerlandService of Clinical Pharmacology Lausanne University HospitalUniversity of Lausanne Lausanne SwitzerlandService of Clinical Pharmacology Lausanne University HospitalUniversity of Lausanne Lausanne SwitzerlandService of Clinical Pharmacology Lausanne University HospitalUniversity of Lausanne Lausanne SwitzerlandUnit of Paediatric Neurology and Neurorehabilitation Department Mother‐Woman‐Child Lausanne University HospitalUniversity of Lausanne Lausanne SwitzerlandService of Clinical Pharmacology Lausanne University HospitalUniversity of Lausanne Lausanne SwitzerlandAdvicenne Pharma SA Nîmes FranceAdvicenne Pharma SA Nîmes FranceAdvicenne Pharma SA Nîmes FranceService of Clinical Pharmacology Lausanne University HospitalUniversity of Lausanne Lausanne SwitzerlandAbstract A pilot study was conducted aiming at specifying sultiame's pharmacokinetic profile, completed by in vitro assays evaluating the intraerythrocytic transfer of sultiame and by a pharmacokinetic model assessing its distribution. Single oral doses of sultiame (Ospolot® 50, 100, and 200 mg) were administered in open‐label to four healthy volunteers. Serial plasma, whole blood, and urine samples were collected. A spiking experiment was also performed to characterize sultiame's exchanges between plasma and erythrocytes in vitro. Pharmacokinetic parameters were evaluated using standard noncompartmental calculations and nonlinear mixed‐effect modeling. The plasma maximal concentrations (Cmax) showed striking nonlinear disposition of sultiame, with a 10‐fold increase while doses were doubled. Conversely, whole blood Cmax increased less than dose proportionally while staying much higher than in plasma. Quick uptake of sultiame into erythrocytes observed in vivo was confirmed in vitro, with minimal efflux. A two‐compartment model with first‐order absorption, incorporating a saturable ligand to receptor binding, described the data remarkably well, indicating apparent plasma clearance of 10.0 L/h (BSV: 29%) and distribution volume of 64.8 L; saturable uptake into an intracellular compartment of 3.3 L with a maximum binding capacity of 111 mg accounted for nonlinearities observed in plasma and whole blood concentrations. Pharmacokinetic characteristics of sultiame are reported, including estimates of clearance and volume of distribution that were so far unpublished. The noticeable nonlinearity in sultiame disposition should be taken into account for the design of future studies and the interpretation of therapeutic drug monitoring results.https://doi.org/10.1002/prp2.558clearancehealthy volunteerspharmacokineticsultiamevolume of distribution |
| spellingShingle | Kim Dao Paul Thoueille Laurent A. Decosterd Thomas Mercier Monia Guidi Carine Bardinet Sébastien Lebon Eva Choong Arnaud Castang Catherine Guittet Luc‐André Granier Thierry Buclin Sultiame pharmacokinetic profile in plasma and erythrocytes after single oral doses: A pilot study in healthy volunteers Pharmacology Research & Perspectives clearance healthy volunteers pharmacokinetic sultiame volume of distribution |
| title | Sultiame pharmacokinetic profile in plasma and erythrocytes after single oral doses: A pilot study in healthy volunteers |
| title_full | Sultiame pharmacokinetic profile in plasma and erythrocytes after single oral doses: A pilot study in healthy volunteers |
| title_fullStr | Sultiame pharmacokinetic profile in plasma and erythrocytes after single oral doses: A pilot study in healthy volunteers |
| title_full_unstemmed | Sultiame pharmacokinetic profile in plasma and erythrocytes after single oral doses: A pilot study in healthy volunteers |
| title_short | Sultiame pharmacokinetic profile in plasma and erythrocytes after single oral doses: A pilot study in healthy volunteers |
| title_sort | sultiame pharmacokinetic profile in plasma and erythrocytes after single oral doses a pilot study in healthy volunteers |
| topic | clearance healthy volunteers pharmacokinetic sultiame volume of distribution |
| url | https://doi.org/10.1002/prp2.558 |
| work_keys_str_mv | AT kimdao sultiamepharmacokineticprofileinplasmaanderythrocytesaftersingleoraldosesapilotstudyinhealthyvolunteers AT paulthoueille sultiamepharmacokineticprofileinplasmaanderythrocytesaftersingleoraldosesapilotstudyinhealthyvolunteers AT laurentadecosterd sultiamepharmacokineticprofileinplasmaanderythrocytesaftersingleoraldosesapilotstudyinhealthyvolunteers AT thomasmercier sultiamepharmacokineticprofileinplasmaanderythrocytesaftersingleoraldosesapilotstudyinhealthyvolunteers AT moniaguidi sultiamepharmacokineticprofileinplasmaanderythrocytesaftersingleoraldosesapilotstudyinhealthyvolunteers AT carinebardinet sultiamepharmacokineticprofileinplasmaanderythrocytesaftersingleoraldosesapilotstudyinhealthyvolunteers AT sebastienlebon sultiamepharmacokineticprofileinplasmaanderythrocytesaftersingleoraldosesapilotstudyinhealthyvolunteers AT evachoong sultiamepharmacokineticprofileinplasmaanderythrocytesaftersingleoraldosesapilotstudyinhealthyvolunteers AT arnaudcastang sultiamepharmacokineticprofileinplasmaanderythrocytesaftersingleoraldosesapilotstudyinhealthyvolunteers AT catherineguittet sultiamepharmacokineticprofileinplasmaanderythrocytesaftersingleoraldosesapilotstudyinhealthyvolunteers AT lucandregranier sultiamepharmacokineticprofileinplasmaanderythrocytesaftersingleoraldosesapilotstudyinhealthyvolunteers AT thierrybuclin sultiamepharmacokineticprofileinplasmaanderythrocytesaftersingleoraldosesapilotstudyinhealthyvolunteers |