A Multicenter Randomized Bioequivalence Study of a Novel Ready-to-Use Temozolomide Oral Suspension vs. Temozolomide Capsules
Background: Temozolomide (TMZ) oral suspension (Ped-TMZ, KIZFIZO<sup>®</sup>) is being developed for the treatment of relapsed or refractory neuroblastoma, a rare cancer affecting infants and young children. The study assessed the safety and the bioequivalence of this novel pediatric for...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-11-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/15/12/2664 |
| _version_ | 1827573830030196736 |
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| author | François Ducray Carole Ramirez Marie Robert Maxime Fontanilles Charlotte Bronnimann Olivier Chinot Florian Estrade Xavier Durando Stéphanie Cartalat Jeremy Bastid Hugues Bienayme Caroline Lemarchand |
| author_facet | François Ducray Carole Ramirez Marie Robert Maxime Fontanilles Charlotte Bronnimann Olivier Chinot Florian Estrade Xavier Durando Stéphanie Cartalat Jeremy Bastid Hugues Bienayme Caroline Lemarchand |
| author_sort | François Ducray |
| collection | DOAJ |
| description | Background: Temozolomide (TMZ) oral suspension (Ped-TMZ, KIZFIZO<sup>®</sup>) is being developed for the treatment of relapsed or refractory neuroblastoma, a rare cancer affecting infants and young children. The study assessed the safety and the bioequivalence of this novel pediatric formulation with existing TMZ oral capsules. Methods: In vitro dissolution profiles and the bioequivalence were evaluated following the European Medicines Agency “Guidelines on the investigation of Bioequivalence”. The phase I, multicenter, randomized, open-label, crossover, single-dose bioequivalence study enrolled 36 adult patients with glioblastoma multiforme or lower-grade glioma. Each patient received 200 mg/m<sup>2</sup> Ped-TMZ suspension and TMZ capsules (Temodal<sup>®</sup>) on 2 consecutive days, with the order being randomly assigned. Fourteen blood samples were collected up to 10 h post-dosing. Bioequivalence was assessed by comparing the 90% confidence interval for the ratio of the geometric means of maximum TMZ plasma concentration (C<sub>max</sub>) and the area under the curve (AUCt). Other endpoints included further pharmacokinetic parameters and safety. Results: Both formulations exhibited a fast in vitro dissolution profile with more than 85% of TMZ dissolved within 15 min. For the bioequivalence study, thirty patients completed the trial as per the protocol. The ratio of Ped-TMZ/TMZ capsule geometric means (90% CI) for AUCt and C<sub>max</sub> were 97.18% (95.05–99.35%) and 107.62% (98.07–118.09%), respectively, i.e., within the 80–125% bioequivalence limits. No buccal toxicity was associated with Ped-TMZ liquid formulation. Conclusions: This study showed that Ped-TMZ oral suspension and TMZ oral capsule treatment are immediate release and bioequivalent medicines. There were also no unexpected safety signals or local toxicity (funded by ORPHELIA Pharma; ClinicalTrials.gov number, NCT04467346). |
| first_indexed | 2024-03-08T20:26:45Z |
| format | Article |
| id | doaj.art-29256ebc25c84872bd21f0f213c1dcc0 |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-08T20:26:45Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-29256ebc25c84872bd21f0f213c1dcc02023-12-22T14:31:53ZengMDPI AGPharmaceutics1999-49232023-11-011512266410.3390/pharmaceutics15122664A Multicenter Randomized Bioequivalence Study of a Novel Ready-to-Use Temozolomide Oral Suspension vs. Temozolomide CapsulesFrançois Ducray0Carole Ramirez1Marie Robert2Maxime Fontanilles3Charlotte Bronnimann4Olivier Chinot5Florian Estrade6Xavier Durando7Stéphanie Cartalat8Jeremy Bastid9Hugues Bienayme10Caroline Lemarchand11Service de Neuro-Oncologie, Hôpital Neurologique, Hospices Civils de Lyon, Centre de Recherche en Cancérologie UMR INSERM 1052 CNRS 5286, Université Claude Bernard Lyon 1, 69008 Lyon, FranceServices de Neurologie et D’oncologie Médicale, CHU et ICHUSE de Saint-Etienne, 42055 Saint-Etienne, FranceInstitut de Cancérologie de l’Ouest, Medical Oncology, 44800 Saint Herblain, FranceINSERM U1245 Unit, Cancer Centre Henri Becquerel, Université Rouen Normandie, 76038 Rouen, FranceCHU de Bordeaux, Service D’oncologie Médicale, Hôpital Saint André, 33075 Bordeaux, FranceAix-Marseille Université, Neuro-Oncology Department, APHM, CNRS, Institut de Neurophysiopathologie, CHU Timone, Service de Neuro-Oncologie, 13385 Marseille, FranceCentre Eugène Marquis, 35042 Rennes, FranceINSERM U1240 IMoST, University of Clermont Auvergne, 63001 Clermont-Ferrand, FranceService de Neuro-Oncologie, Hôpital Neurologique, Hospices Civils de Lyon, Centre de Recherche en Cancérologie UMR INSERM 1052 CNRS 5286, Université Claude Bernard Lyon 1, 69008 Lyon, FranceORPHELIA Pharma, 75005 Paris, FranceORPHELIA Pharma, 75005 Paris, FranceORPHELIA Pharma, 75005 Paris, FranceBackground: Temozolomide (TMZ) oral suspension (Ped-TMZ, KIZFIZO<sup>®</sup>) is being developed for the treatment of relapsed or refractory neuroblastoma, a rare cancer affecting infants and young children. The study assessed the safety and the bioequivalence of this novel pediatric formulation with existing TMZ oral capsules. Methods: In vitro dissolution profiles and the bioequivalence were evaluated following the European Medicines Agency “Guidelines on the investigation of Bioequivalence”. The phase I, multicenter, randomized, open-label, crossover, single-dose bioequivalence study enrolled 36 adult patients with glioblastoma multiforme or lower-grade glioma. Each patient received 200 mg/m<sup>2</sup> Ped-TMZ suspension and TMZ capsules (Temodal<sup>®</sup>) on 2 consecutive days, with the order being randomly assigned. Fourteen blood samples were collected up to 10 h post-dosing. Bioequivalence was assessed by comparing the 90% confidence interval for the ratio of the geometric means of maximum TMZ plasma concentration (C<sub>max</sub>) and the area under the curve (AUCt). Other endpoints included further pharmacokinetic parameters and safety. Results: Both formulations exhibited a fast in vitro dissolution profile with more than 85% of TMZ dissolved within 15 min. For the bioequivalence study, thirty patients completed the trial as per the protocol. The ratio of Ped-TMZ/TMZ capsule geometric means (90% CI) for AUCt and C<sub>max</sub> were 97.18% (95.05–99.35%) and 107.62% (98.07–118.09%), respectively, i.e., within the 80–125% bioequivalence limits. No buccal toxicity was associated with Ped-TMZ liquid formulation. Conclusions: This study showed that Ped-TMZ oral suspension and TMZ oral capsule treatment are immediate release and bioequivalent medicines. There were also no unexpected safety signals or local toxicity (funded by ORPHELIA Pharma; ClinicalTrials.gov number, NCT04467346).https://www.mdpi.com/1999-4923/15/12/2664temozolomideoral suspensionbioequivalencepediatric formulation |
| spellingShingle | François Ducray Carole Ramirez Marie Robert Maxime Fontanilles Charlotte Bronnimann Olivier Chinot Florian Estrade Xavier Durando Stéphanie Cartalat Jeremy Bastid Hugues Bienayme Caroline Lemarchand A Multicenter Randomized Bioequivalence Study of a Novel Ready-to-Use Temozolomide Oral Suspension vs. Temozolomide Capsules Pharmaceutics temozolomide oral suspension bioequivalence pediatric formulation |
| title | A Multicenter Randomized Bioequivalence Study of a Novel Ready-to-Use Temozolomide Oral Suspension vs. Temozolomide Capsules |
| title_full | A Multicenter Randomized Bioequivalence Study of a Novel Ready-to-Use Temozolomide Oral Suspension vs. Temozolomide Capsules |
| title_fullStr | A Multicenter Randomized Bioequivalence Study of a Novel Ready-to-Use Temozolomide Oral Suspension vs. Temozolomide Capsules |
| title_full_unstemmed | A Multicenter Randomized Bioequivalence Study of a Novel Ready-to-Use Temozolomide Oral Suspension vs. Temozolomide Capsules |
| title_short | A Multicenter Randomized Bioequivalence Study of a Novel Ready-to-Use Temozolomide Oral Suspension vs. Temozolomide Capsules |
| title_sort | multicenter randomized bioequivalence study of a novel ready to use temozolomide oral suspension vs temozolomide capsules |
| topic | temozolomide oral suspension bioequivalence pediatric formulation |
| url | https://www.mdpi.com/1999-4923/15/12/2664 |
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