No evidence for cardiotoxicity of miltefosine^☆

Dear Editor,

In a recent article, Barroso et al.¹ reported on the comparison of cardiotoxicity between N-methyl glucamine antimoniate, better known as meglumine antimoniate, and miltefosine. As the authors indicate, antimonial compounds are notorious for their extensive toxicity, particularly cardiotoxicity, leading to pronounced prolongation of corrected QT interval (QTc) and risk of developing abnormal heart rhythms that can cause sudden death.

The only significant result the authors report is a decreased relative risk in QTc > 440 msec for meglumine antimoniate (n=38) compared to miltefosine (n=15) on day 7 of treatment. Looking at it longitudinally for the miltefosine-regimen, the proportion of patients with QTc > 440 msec appeared to increase in the first week of treatment, but thereafter completely disappeared: 1/15, 5/15, 0/15, 0/15, for day 0, 7, 14, and 21, respectively, while it steadily increased in the meglumine antimoniatetreated group, culminating to 35.3% of patients with an abnormal QTc. Instead of looking at relative risk at each of the measured time points, assessing longitudinal changes within treatment groups would potentially have been a more relevant way of analyzing and interpreting these data.

The authors suggest that the cardiotoxicity of miltefosine has been described before, but to the best of my knowledge, this is not the case. The phase 3 study² to which the authors refer reports no abnormalities in electrocardiography, with a 14 msec increase in QTc from baseline during miltefosine. Such a clinically non-relevant increase in QTc is seen for many anti-infective drugs, also for those not exhibiting cardiotoxicity, probably due to recovery from infection and waning of fever, which can have a prolonging effect itself on QTc.³

From a pharmacokinetic angle, there is little rationale for a QTc prolongation only in the first treatment week. Miltefosine keeps accumulating during the 28-day treatment regimen, reaching a steady state in the last week of treatment.⁴ Maximal drug concentrations in the first week are < 50% of those expected in the fourth week of treatment. Moreover, no mechanisms of cardiotoxicity are known from pre-clinical and clinical pharmacological research on miltefosine. Recently, a dedicated study investigating the effect of miltefosine on QTc in 42 Bolivian mucocutaneous leishmaniasis patients was concluded. While results remain to be published, the updated FDA miltefosine label mentions no evidence of QTc prolongation or increases >20 msec from baseline were observed in this study.

The conclusion should be that there is no convincing evidence nor pharmacokinetic-pharmacodynamic rationale that miltefosine causes cardiotoxicity.

• Financial support
  None declared.
• ☆
  Study conducted at the Department of Pharmacy & Pharmacology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam, The Netherlands.

References

• ¹
  Barroso DH, Gomes CM, da Silva AM, Sampaio RNR. Comparison of cardiotoxicity between n-methyl-glucamine and miltefosine in the treatment of American cutaneous leishmaniasis. An Bras Dermatol. 2021;96:502–4.
• ²
  Sundar S, Jha T, Thakur C, Engel J, Sindermann H, Fischer C, et al. Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med. 2002;347:1739–46.
• ³
  Motulsky H. Intuitive biostatistics: a nonmathematical guide to statistical thinking. 4th ed. USA: Oxford University Press; 2018.
• ⁴
  Dorlo TP, Balasegaram M, Beijnen JH, de Vries PJ. Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J Antimicrob Chemother. 2012;67:2576–97.
• ⁵
  Martins SS, Barroso DH, Rodrigues BC, da Motta JDOC, Freire GSM, Pereira Lida, et al. A pilot randomized clinical trial: oral miltefosine and pentavalent antimonials associated with pentoxifylline for the treatment of American tegumentary leishmaniasis. Front Cell Infect Microbiol. 2021;11:700323.

Publication Dates

• Publication in this collection
  29 July 2022
• Date of issue
  Jul-Aug 2022

History

• Received
  25 Jan 2022
• Accepted
  25 Mar 2022
• Published
  30 May 2022