Ibudilast for prevention of oxaliplatin-induced acute neurotoxicity: a pilot study assessing preliminary efficacy, toler
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ORIGINAL ARTICLE
Ibudilast for prevention of oxaliplatin‑induced acute neurotoxicity: a pilot study assessing preliminary efficacy, tolerability and pharmacokinetic interactions in patients with metastatic gastrointestinal cancer Christina Teng1,2,8 · Stephanie E. Reuter3 · Prunella L. Blinman1,8 · Haryana M. Dhillon4 · Peter Galettis5 · Nicholas Proschogo6 · Andrew J. McLachlan7 · Janette L. Vardy1,4,8 Received: 15 June 2020 / Accepted: 6 September 2020 / Published online: 19 September 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Purpose This prospective, open-label, sequential ‘before vs. after’ pilot study was conducted to provide preliminary efficacy and tolerability data for ibudilast in the prevention of oxaliplatin-induced neurotoxicity in patients with metastatic upper gastrointestinal or colorectal cancer. Any potential impact of ibudilast on oxaliplatin and 5-fluorouracil pharmacokinetics was also explored. Methods Participants were administered a chemotherapy cycle (FOLFOX or CapeOx), followed by a chemotherapy cycle with co-administration of ibudilast 30 mg b.i.d. p.o. Efficacy was assessed on Day 3 and end of cycle using the OxaliplatinSpecific Neurotoxicity Scale (OSNS) and additional clinical/patient-reported neurotoxicity measures. A population pharmacokinetic approach was used to determine oxaliplatin and 5-fluorouracil pharmacokinetics with and without ibudilast. Results Sixteen participants consented; 14 completed both chemotherapy cycles. Across all measures, the majority of participants experienced either an improvement or no worsening of neurotoxicity with ibudilast treatment. Based on OSNS assessments, acute neurotoxicity was unchanged in 12/14 participants and improved in 2/14 participants. The 90% confidence interval (CI) of the dose-normalised ratio of oxaliplatin AUC (90% CI 95.0–109%) and 5-fluorouracil AUC (90% CI 66.5–173%) indicated no significant impact of ibudilast on systemic exposure. Conclusion This pilot study indicated ibudilast co-administration may improve or stabilise oxaliplatin-induced neurotoxicity. Given the expected worsening of symptoms in patients with continued chemotherapy, this represents a signal of effect that warrants further investigation. Pharmacokinetic analysis indicates ibudilast has no significant effect on oxaliplatin pharmacokinetics, and is unlikely to influence pharmacokinetics of 5-fluorouracil. Clinical trial registration Trial registration number: UTN U1111-1209-0075 and ANZCTRN12618000232235 (registered 13/02/2018). Keywords Oxaliplatin · Chemotherapy-induced peripheral neuropathy · Neurotoxicity · Gastrointestinal cancer · Colorectal cancer · Pharmacokinetics
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00280-020-04143-8) contains supplementary material, which is available to authorized users. * Janette L. Vardy [email protected] Extended author information available on the last page of the article
Oxaliplatin-containing chemotherap
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