Impact of the organic cation transporter 2 inhibitor cimetidine on the single-dose pharmacokinetics of the glucosylceramide synthase inhibitor lucerastat in healthy subjects.
Purpose: Lucerastat is an orally available glucosylceramide synthase inhibitor with a potential to provide substrate reduction therapy for Fabry patients independent of their α-galactosidase A genotype. In humans, lucerastat is mainly eliminated as unchanged parent compound through renal excretion b...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 76; no. 3; pp. 431 - 438 |
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| Autores principales: | , , , |
| Formato: | research tables/charts Journal Article |
| Publicado: |
Springer Nature
Mar2020
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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=141663156&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 141663156 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Mar2020 vid: 76 iid: 3 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 141663156 141663156 141663156 10.1007/s00228-019-02808-9 141663156 ppf: 431 ppct: 7 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Impact of the organic cation transporter 2 inhibitor cimetidine on the single-dose pharmacokinetics of the glucosylceramide synthase inhibitor lucerastat in healthy subjects. aug: au: Boof, Marie-Laure Halabi, Atef Ufer, Mike Dingemanse, Jasper affil: Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123, Allschwil, Switzerland sug: subj: Cimetidine Administration and Dosage Lipids Transferases Pharmacokinetics Patient Safety Evaluation Drug Tolerance Evaluation Drug Combinations Organic Cation Transport Proteins Antagonists and Inhibitors Human Male Confidence Intervals Descriptive Statistics Drug Interactions Male ab: Purpose: Lucerastat is an orally available glucosylceramide synthase inhibitor with a potential to provide substrate reduction therapy for Fabry patients independent of their α-galactosidase A genotype. In humans, lucerastat is mainly eliminated as unchanged parent compound through renal excretion both by active secretion and passive filtration. In vitro studies indicated that lucerastat is a substrate of human organic cation transporter 2 (OCT2) mainly expressed in the kidney. Methods: Therefore, this clinical study, conducted in 14 healthy male subjects, investigated the effect of 800 mg twice-daily oral administration of the OCT2 inhibitor cimetidine at steady state on the single-dose pharmacokinetics (PK) of 500 mg lucerastat. The safety and tolerability of lucerastat administered alone and concomitantly with cimetidine were also evaluated. Results: Exposure to lucerastat was slightly higher upon co-administration of cimetidine indicated by geometric mean area under the plasma concentration-time curve from zero to infinity (AUC0–∞) ratio of 1.22 (90% confidence interval [CI] 1.16–1.28). Cimetidine delayed the time to reach maximum lucerastat concentrations (tmax) by 1 h but did not affect its elimination half-life (t½) or maximum plasma concentration (Cmax) as geometric mean ratios were 1.00 (0.91–1.10) and 1.04 (0.92–1.17), respectively, at cimetidine steady state. Lucerastat was safe and well tolerated when given alone and in combination with cimetidine. Conclusion: These results indicate that the single-dose PK of lucerastat are not changed to a clinically relevant extent by cimetidine-mediated OCT2 inhibition, allowing the concomitant use of OCT2 inhibitors with lucerastat without any need for dose adjustment. Trial registration: EudraCT: 2017-003725-14; ClinicalTrials.gov: NCT03380455 pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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