A Comparison of the Pharmacokinetics and Tolerability of Riluzole after Repeat Dose Administration in Healthy Elderly and Young Volunteers

Liboux, A. Le; Cachia, J.-P.; Kirkesseli, Stéphane; Gautier, Juliette; Guimart, C.; Montay, G.; Peeters, Pierre; Groen, Ewout J N; Jonkman, J. H. G.; Wemer, J.

doi:10.1177/009127009903900507

Cited by 44 publications

(3 citation statements)

References 9 publications

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“…Following centrifugation for 10 min at 1,500 × g at 4°C within 30 min of blood collection, the plasma was aliquoted and stored at −80°C. Concentrations of sorafenib and riluzole in plasma were analyzed using a validated liquid chromatography-tandem mass spectrometry method (LC-MS/MS) as described previously [ 41 , 42 ], with the lower limits of quantitation at 31 ng/mL and 1.9 ng/mL, respectively.…”

Section: Methodsmentioning

confidence: 99%

A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850

et al. 2023

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Background: Overexpression of metabotropic glutamate receptor 1 (GRM1) has been implicated in the pathogenesis of multiple cancers. Riluzole, an inhibitor of glutamate release, showed synergistic antitumor activity in combination with the multi-kinase inhibitor sorafenib in preclinical models. This phase I trial identified the toxicity profile, dose-limiting toxicities, maximum tolerated dose (MTD), and pharmacokinetic and pharmacodynamic properties of riluzole combined with sorafenib in patients with advanced cancers. Patients and Methods: Patients with refractory solid tumors were enrolled utilizing a 3+3 dose-escalation design. Riluzole was given at 100 mg PO BID in combination with sorafenib, beginning at 200 mg PO daily and escalating in 200 mg increments per level in 28-day cycles. Restaging evaluations were performed every 2 cycles. Results: 35 patients were enrolled over 4 dose levels. The MTD was declared at dose level 3 (riluzole: 100 mg PO BID; sorafenib: 400 mg AM/200 mg PM). Pharmacokinetic analyses did not reveal definitive evidence of drug-drug interactions. Consistent decreases in phospho-forms of ERK and AKT in tumor tissue analyses with accompanying decrease in GRM1 expression and increase in pro-apoptotic BIM suggest target engagement by the combination. Best responses included a partial response in 1 (2.9%) patient with pancreatic acinar cell carcinoma with a KANK4-RAF1 fusion, and stable disease in 11 (36%) patients. Conclusion: Combination therapy with riluzole and sorafenib was safe and tolerable in patients with advanced solid tumors. The partial response in a patient with a RAF1 fusion suggests that further exploration in a genomically selected cohort may be warranted.

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Section: Methodsmentioning

confidence: 99%

A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850

et al. 2023

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“…The maximal measured plasma concentration (C max ) and area under the concentration–time curve (AUC) for riluzole were linearly related to dose, and a high‐fat meal significantly reduced the rate and extent of absorption of riluzole 10 . Riluzole tablet PK parameters were not significantly affected by age or sex, with the exception of having a shorter terminal elimination half‐life (t 1/2 ) in elderly subjects 11 . Metabolism of riluzole occurs predominantly through the cytochrome P450 isoenzyme CYP1A2 to form N‐hydroxyriluzole, with relatively little metabolism via glucuronidation 12 .…”

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confidence: 99%

“… 10 Riluzole tablet PK parameters were not significantly affected by age or sex, with the exception of having a shorter terminal elimination half‐life (t 1/2 ) in elderly subjects. 11 Metabolism of riluzole occurs predominantly through the cytochrome P450 isoenzyme CYP1A2 to form N‐hydroxyriluzole, with relatively little metabolism via glucuronidation. 12 A sublingual formulation of riluzole was found to be bioequivalent to the tablet formulation and appeared to be less affected by a high‐fat meal.…”

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Pharmacokinetics, Bioavailability, and Swallowing Safety With Riluzole Oral Film

Wymer

Apple

Harrison

et al. 2022

Clinical Pharm in Drug Dev

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Dysphagia is highly prevalent in patients with amyotrophic lateral sclerosis (ALS). Riluzole is a US Food and Drug Administration-approved treatment for ALS. Riluzole oral film (ROF; Exservan TM ) contains riluzole in a polymer-based film matrix. The ROF is administered by placing on the tongue, where it dissolves and the drug is ingested with the saliva. Two clinical trials assessed the safety and tolerability of the ROF. Bioavailability and pharmacokinetics (PK) were evaluated in an open-label, randomized, single-dose, replicate crossover study of 50 mg of ROF and riluzole 50-mg tablets in 32 healthy volunteers. The second study was a videofluoroscopic swallowing examination conducted with nine patients with ALS before and after receiving a single dose of 50 mg of ROF. The primary outcome was change on penetration-aspiration scale (PAS) scores from pre-to post-dose. Overall, the PK parameters for ROF and riluzole tablets were comparable between treatments and administrations when administered under fasting conditions. Administration of ROF with food resulted in a 15% reduction in area under the curve and a 45% reduction in maximum serum concentration. A total of 44 treatment-emergent adverse events (AEs) were reported in the study; all were mild in severity. No serious AEs were observed and no subjects discontinued due to AEs. In the swallowing study, very little numerical or categorical change was observed following the dose of ROF. No evidence of deterioration of swallowing function was observed post-dose. The ROF was bioequivalent to riluzole tablets, was well tolerated, and had no detrimental effect on swallowing.

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A validated HPLC assay to monitor riluzole plasma or serum concentrations in patients with amyotrophic lateral sclerosis

Kan

Spieksma

Groeneveld

et al. 2004

Biomedical Chromatography

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A specific, accurate and precise high-performance liquid chromatographic assay was developed for the determination of riluzole, a drug used to treat patients with amyotrophic lateral sclerosis. Samples were treated by extraction with dichloromethane followed by reversed-phase chromatography with ultraviolet detection at 260 nm. Preset validation criteria were met from 20 to 2000 ng/mL with a linear response curve. Extraction recovery of riluzole was 65-76%. The accuracy of the method was 102-103%. Intra- and inter-day coefficients of variation were in the ranges 2.8-4.9% and 1.8-9.7%. A detection limit of 5 ng/mL was found. Determination of concentrations in serum and plasma resulted in similar results below 500 ng/mL. At higher values a matrix effect cannot be excluded. This presented method can be used to monitor plasma or serum levels in ALS patients treated with riluzole.

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A Comparison of the Pharmacokinetics and Tolerability of Riluzole after Repeat Dose Administration in Healthy Elderly and Young Volunteers

Cited by 44 publications

References 9 publications

A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850

A phase I trial of riluzole and sorafenib in patients with advanced solid tumors: CTEP #8850

Pharmacokinetics, Bioavailability, and Swallowing Safety With Riluzole Oral Film

A validated HPLC assay to monitor riluzole plasma or serum concentrations in patients with amyotrophic lateral sclerosis

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