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Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir
Romain Coriat, … , François Goldwasser, Frédéric Batteux
Romain Coriat, … , François Goldwasser, Frédéric Batteux
Published December 20, 2013
Citation Information: J Clin Invest. 2014;124(1):262-272. https://doi.org/10.1172/JCI68730.
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Clinical Research and Public Health

Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir

Abstract

Background. The majority of patients receiving the platinum-based chemotherapy drug oxaliplatin develop peripheral neurotoxicity. Because this neurotoxicity involves ROS production, we investigated the efficacy of mangafodipir, a molecule that has antioxidant properties and is approved for use as an MRI contrast enhancer.

Methods. The effects of mangafodipir were examined in mice following treatment with oxaliplatin. Neurotoxicity, axon myelination, and advanced oxidized protein products (AOPPs) were monitored. In addition, we enrolled 23 cancer patients with grade ≥2 oxaliplatin-induced neuropathy in a phase II study, with 22 patients receiving i.v. mangafodipir following oxaliplatin. Neuropathic effects were monitored for up to 8 cycles of oxaliplatin and mangafodipir.

Results. Mangafodipir prevented motor and sensory dysfunction and demyelinating lesion formation. In mice, serum AOPPs decreased after 4 weeks of mangafodipir treatment. In 77% of patients treated with oxaliplatin and mangafodipir, neuropathy improved or stabilized after 4 cycles. After 8 cycles, neurotoxicity was downgraded to grade ≥2 in 6 of 7 patients. Prior to enrollment, patients received an average of 880 ± 239 mg/m2 oxaliplatin. Patients treated with mangafodipir tolerated an additional dose of 458 ± 207 mg/m2 oxaliplatin despite preexisting neuropathy. Mangafodipir responders managed a cumulative dose of 1,426 ± 204 mg/m2 oxaliplatin. Serum AOPPs were lower in responders compared with those in nonresponders.

Conclusion. Our study suggests that mangafodipir can prevent and/or relieve oxaliplatin-induced neuropathy in cancer patients.

Trial registration. Clinicaltrials.gov NCT00727922.

Funding. Université Paris Descartes, Ministère de la Recherche et de l’Enseignement Supérieur, and Assistance Publique-Hôpitaux de Paris.

Authors

Romain Coriat, Jérôme Alexandre, Carole Nicco, Laurent Quinquis, Evelyne Benoit, Christiane Chéreau, Hervé Lemaréchal, Olivier Mir, Didier Borderie, Jean-Marc Tréluyer, Bernard Weill, Joel Coste, François Goldwasser, Frédéric Batteux

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The therapeutic and neurotoxic potential of mangafodipir in oxaliplatin-induced neuropathy

Submitter: Jan Olof G. Karlsson | janolof.karlsson@ktias.com

Authors: Per Jynge, Judy L. Aschner, and Michael Aschner

Linköping University

Published January 22, 2014

The recent JCI publication by Coriat and coworkers1 and a prior case report by Yri et al.2 describe treatment of oxaliplatin-induced peripheral neuropathy with intravenous mangafodipir. Both publications suggest that the manganese superoxide dismutase (MnSOD) mimetic activity of mangafodipir3-4  protects against oxaliplatin-induced peripheral neuropathy.

Regrettably, the paper by Coriat et al.1 fails to adequately consider the potential for manganese (Mn)-induced toxicity upon repeated use of mangafodipir. Mn toxicity, recapitulating neurological features of Parkinson’s disease (PD), is a well-known phenomenon5-6. Mn neurotoxicity is well established in patients receiving parental nutrition, where doses exceeding 1 µmol/day (corresponding to 14 nmol/kg in a 70-kilogram person) are associated with elevated risk for developing neurological symptoms7-8. Mn accumulates in the brain with an elimination half-life exceeding 50 days6. The threshold for cumulative intravenous Mn toxicity in monkeys is well-defined (5 mg/kg), corresponding to ~100 µmol/kg5.  

Neurological symptoms correlate well with accumulation of Mn in the basal ganglia, seen as hyperintensity on a T1-weighted MRI5,7. The patient in the aforementioned case report2  recieved mangafodipir in 14 of 15 chemotherapy cycles, resulting in an accumulated dose of 140 µmol/kg. Brain MRI after 14 cycles showed increased T1-weighted signal intensity in the basal ganglia. This patient manifested PD-like neuropsychological symptoms2.

Coriat et al.1 reported that the mean plasma Mn content increased from 11.8±5.5 nM to 19.8±4.3 nM after eight cycles of mangafodipir co-treatment, all within normal reference values. However, plasma Mn is considered a weak predictor of Mn neurotoxicity7. A much more reliable predictor is brain T1-weighted MRI.

A cavalier attitude about the potential for Mn neurotoxicity with repeated exposures to mangafodipir seems ill-advised. Treatment with mangafodipir should be considered within the context of a robust risk-benefit analysis, including brain MRI and neuropsychological testing. It is premature to use mangafodipir in adjuvant oxaliplatin-based therapy of colon cancer patients outside of well-designed randomized controlled trials with both efficacy and safety endpoints.

Mn bound to fodipir is likely non-neurotoxic, but Mn released from the chelator may pass the blood-brain-barrier, causing neurotoxicity. About 80% of the Mn content of mangafodipir is released upon intravenous administration9. It is possible to stabilize mangafodipir by replacing 4/5 of its Mn content with calcium, resulting in a compound known as calmangafodipir10. At equivalent intravenous Mn doses, calmangafodipir causes considerably less Mn release and retention in the rat brain and is significantly more efficacious than mangafodipir10. Calmangafodipir is at present in a phase IIb clinical study in colorectal cancer patients undergoing oxaliplatin plus 5-FU palliative chemotherapy.

 

Authors: Jan Olof G. Karlsson1, Per Jynge1, Judy L. Aschner2, and Michael Aschner3

1Divison of Drug Research/Pharmacology, Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden. 2 Department of Pediatrics and 3 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

 

Conflict of interest: Jan Olof G. Karlsson and Per Jynge are two of the founders of PledPharma AB and own shares in this company. Karlsson and Jynge are inventors on two granted patent families (e.g., US6258828 and US6147094) covering the therapeutic use of mangafodipir in cancer treatment, which are owned by GE Healthcare. Karlsson is inventor on one granted patent family (e.g., US8377969) and two patent applications (WO2011004323 and WO2013102806) covering the therapeutic use of PLED derivatives in cancer, which are owned by PledPharma AB. Jynge is a medical advisor in PledPharma. Karlsson is a former employee of GE Healthcare and PledPharma AB. Judy Aschner and Michael Aschner declare no conflict of interest.

 

References

  1. Coriat R, et al. Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir. J Clin Invest. 2014;124(1):262-272.
  2. Yri OE, Vig J, Hegstad E, Hovde O, Pignon I, Jynge P. Mangafodipir as a cytoprotective adjunct to chemotherapy—a case report. Acta Oncol. 2009;48(4):633–635.
  3. Brurok H, et al. Manganese dipyridoxyl diphosphate: MRI contrast agent with antioxidative and cardioprotective properties. Biochem Biophys Res Commun. 1999;254(3): 768-772.
  4. Bedda S, et al. Mangafodipir prevents liver injury induced by acetaminophen in the mouse. J Hepatol. 2003;39(5): 765-772.
  5. Aschner M, Erikson KM, Dorman DC. Manganese dosimetry: species differences and implications for neurotoxicity. Crit Rev Toxicol. 2005;35(1):1-32.
  6. Newland MC. Animal models of manganese's neurotoxicity. Neurotoxicology. 1999;20(2-3):415-432.
  7. Takagi Y, Okada A, Sando K, Wasa M, Yoshida H, Hirabuki N. Evaluation of indexes of in vivo manganese status and the optimal intravenous dose for adult patients undergoing home parenteral nutrition. Am J Clin Nutr. 2002;75(1):112-118.
  8. Aschner JL, Aschner M. Nutritional aspects of manganese homeostasis. Mol Aspects Med. 2005;26(4-5):353-362.
  9. Toft KG, et al. Metabolism and pharmacokinetics of MnDPDP in man. Acta Radiol. 1997;38(4): 677–689.
  10. Karlsson JO, Kurz T, Flechsig S, Näsström J, Andersson RG. Superior therapeutic index of calmangafodipir in comparison to mangafodipir as a chemotherapy adjunct. Transl Oncol. 2012;5(6):492-502.

 

 

 

 

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