Siponimod pharmacokinetics, safety, and tolerability in combination with the potent CYP3A4 inhibitor itraconazole in healthy subjects with different CYP2C9 genotypes.
Purpose: To evaluate the PK and safety of siponimod, a substrate of CYP2C9/3A4, in the presence or absence of a CYP3A4 inhibitor, itraconazole. Methods: This was an open-label study in healthy subjects (aged 18–50 years; genotype: CYP2C9 *1*2 [cohort 1; n = 17] or *1*3 [cohort 2; n = 13]). Subjects...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 75; no. 11; pp. 1565 - 1575 |
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| Autores principales: | , , , , , |
| Formato: | clinical trial research tables/charts Journal Article |
| Publicado: |
Springer Nature
Nov2019
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=139325440&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 139325440 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Nov2019 vid: 75 iid: 11 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 139325440 139325440 139325440 10.1007/s00228-019-02729-7 139325440 ppf: 1565 ppct: 10 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Siponimod pharmacokinetics, safety, and tolerability in combination with the potent CYP3A4 inhibitor itraconazole in healthy subjects with different CYP2C9 genotypes. aug: au: Gardin, Anne Shakeri-Nejad, Kasra Feller, Andrea Huth, Felix Neelakantham, Srikanth Dumitras, Swati affil: Novartis Institutes for Biomedical Research, Basel, Switzerland sug: subj: Antifungal Agents Pharmacokinetics Receptors, Cell Surface Pharmacokinetics Genotype Drug Effects Drug Therapy, Combination Patient Safety Human Adolescence Adult Middle Age Clinical Trials Antifungal Agents Administration and Dosage Receptors, Cell Surface Administration and Dosage Receptors, Cell Surface Metabolism Confidence Intervals Receptors, Cell Surface Adverse Effects Receptors, Cell Surface Blood Drug Interactions Adolescent: 13-18 years Adult: 19-44 years Middle Aged: 45-64 years ab: Purpose: To evaluate the PK and safety of siponimod, a substrate of CYP2C9/3A4, in the presence or absence of a CYP3A4 inhibitor, itraconazole. Methods: This was an open-label study in healthy subjects (aged 18–50 years; genotype: CYP2C9 *1*2 [cohort 1; n = 17] or *1*3 [cohort 2; n = 13]). Subjects received siponimod 0.25-mg single dose in treatment period 1 (days 1–14), itraconazole 100 mg twice daily in treatment period 2 (days 15–18), and siponimod 0.25-mg single dose (day 19) with itraconazole until day 31 (cohort 1) or day 35 (cohort 2) in treatment period 3. PK of siponimod alone and with itraconazole and safety were assessed. Results: Overall, 29/30 subjects completed the study. In treatment period 1, geometric mean AUCinf, T1/2, and median Tmax were higher while systemic clearance was lower in cohort 2 than cohort 1. In treatment period 3, siponimod AUC decreased by 10% (geo-mean ratio [90% confidence intervals]: 0.90 [0.84; 0.96]) and 24% (0.76 [0.69; 0.82]) in cohorts 1 and 2, respectively. Siponimod Cmax was similar between treatment periods 1 and 3. In both cohorts, the Cmax and AUC of the metabolites (M17, M3, and M5) decreased in the presence of itraconazole. All adverse events were mild. Conclusions: The minor albeit significant reduction in plasma exposure of siponimod and its metabolites by itraconazole was unexpected. While the reason is unclear, the results suggest that coadministration of the two drugs would not cause a considerable increase of siponimod exposure independent of CYP2C9 genotype. pubtype: Academic Journal doctype: clinical trial research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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