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Administrative data

Description of key information

Human clinical trials conducted for the treatment of leishmaniasis, usually involving i.v. or i.m. administration.

Out of the 7 key human studies, 5 were conducted with the standard dosing regimen (20 mg/kg bw/d Sb(V)) and 2 studies with dose regimens in the range 10 to 20 mg/kg bw/d Sb(V). In human trials regarded as supportive, 10 were conducted with the standard regimen and 6 studies with varying dose regimens in the range 5 to 60 mg/kg bw/d Sb(V). Based on the evaluation of side effects described in these studies, a dose level of 10 mg/kg bw/d Sb(V) can be identified as LOAEL (lowest observed adverse effect level).

At 10 mg/kg bw/d Sb(V), mainly mild common and reversible side effects including arthralgia, neuralgic pain, joint and muscle stiffness as well as increased transaminase levels were seen, but did not result in termination of treatment. However, changes in cardiovascular parameters like flattening of T-waves were also observed. The maximum duration of treatment was 40 days.

At dose levels > 20 mg/kg bw/d Sb(V), side effects were very variable and dependent on the state of the patients and duration of treatment. In some studies severe, but reversible, side effects were observed (nausea, anorexia, severe bone and muscle pain, hypotension and arrhythmia, pancreatitis, transaminitis, haematological suppressions) resulting in discontinuation of treatment in some cases. ECG measurements showed changes of T-waves and in some patients QTc prolongation. Very few cases of death related to cardiotoxicity were described.

Additional information

Background

Pentavalent antimonials have been used for more than 5 decades for the treatment of leishmaniasis, a parasitic disease. The objective was to screen all available literature on human exposure to pentavalent therapeutic drugs and to document the extent of published clinical trials in humans with these substances, and to assess the feasibility whether and under which circumstances these data could be used for the derivation of a DNEL, and possibly in derogation from animal testing.

It is explicitly noted here that because of the poor oral bioavailability of antimony, the clinical use has always been associated with either i. v. or i. m. treatment regimes over an extended period of time.

Literature review

Based on the above literature search, a total of 263 publications with possible relevance for the assessment of human health effects that occur during treatment with pentavalent antimonials were retrieved. Of these, 93 were found to be single case reports which were not considered further for lack of statistical relevance. One report was found to lack relevance for this project since it deals with a trivalent antimonial substance.

Finally, a set of 32 clinical trials remained which have been performed throughout the world for the treatment of leishmaniosis, predominantly with either Pentostam (SSG, sodium stibogluconate) or Meglumine antimoniate (MA).

Outcome

The majority of trials used a dosing regimen with SSG or MA that is also recommended by WHO, corresponding to a dose of 20 mg/kg/bw/d of Sb(V), which is administered either intravenously or intramuscularly usually for a period of 20 days. Whereas there are other studies that used either shorter treatment periods or lower dosages, these are either less well documented or curing rates may have been compromised. In addition to the above, there are several studies which used the same dosing regimen, but with extended durations up to 120 days.

In conclusion, it is reasonable to state that human clinical trials data exist for periods of up to 120 days which would correspond to subchronic exposure. Tentatively, a LOAEL of 20 Sb(V) could be derived from this.

The (non-exhaustive) list of side-effects includes observations related more to the route of administration (pain in injection sites, rashes), but also more seriously arthralgia, myalgia, asthenia, pancreatitis, jaundice, headache, nausea, hematologic and cardiac effects suppression (44 %). Despite most of them being described as reversible, they are nevertheless a clear indication of adverse effects, rendering the dose administered a LOAEL rather than a NOAEL.

In total 32 trials were evaluated and 7 key studies and further 16 supportive studies were identified for determination of a LOAEL. Unfortunately, it was not always entirely clear whether statements related to the dose levels given refer to the compounds SSG or MA or pentavalent antimony Sb(V). Out of the 23 studies regarded as relevant, 10 dose regimens were clearly related to antimony, and in a further 11 studies reference was given to either WHO or standard recommendations for treatment of leishmaniasis. Only in 2 cases it was not possible to clearly identify whether treatment was related to the compound or the active substance. However, there is sufficient evidence that the WHO recommendation of 20 mg/kg bw/d Sb(V) was used as standard therapy or in some cases variations in the range of 5 to 60 mg/kg bw/d Sb(V).

Evaluation of adverse effects in the different studies ranged from only clinical examinations and monitoring up to more complete evaluations including haematology, clinical chemistry and urine parameters as well as ECG measurements. Treatment of patients with leishmaniasis by pentavalent antimony drugs resulted in the following most common systemic side effects, of which cardiotoxicity is the most severe finding: cardiotoxicity, pancreatitis, anorexia, nausea, abdominal pain, arthralgia and myalgia, malaise, headache, lethargy, elevated transaminase levels (hepatotoxicity) and depression of haematologic cell lines. The severity of cardiovascular side effects is very much dependent on the state of the patients with slight changes in the amplitude of T-waves in otherwise healthy subjects up to QTc prolongation, ventricular arrhythmias, torsade de pointes and sudden death in patients with predisposition to cardiac diseases.

Out of the 7 key studies, 5 were conducted with the standard dosing regimen and 2 studies with dose regimens in the range 10 to 20 mg/kg bw/d Sb(V). In studies regarded as supportive, 10 were conducted with the standard regimen and 6 studies with varying dose regimens in the range 5 to 60 mg/kg bw/d Sb(V). Based on the evaluation of the side effects described in these studies, a dose level of 10 mg/kg bw/d Sb(V) can be identified as LOAEL. There is only one study available with a dose level of 5 mg/kg bw/d, but this dose level was given only to 12 patients and was therefore not considered. At 10 mg/kg bw/d Sb(V) mainly mild common and reversible side effects including arthralgia, neuralgic pain, joint and muscle stiffness, increased transaminase levels were seen, but did not result in termination of treatment. However, changes in cardiovascular parameters like flattening of T-waves were also observed. The maximum duration of treatment was 40 days.

At dose levels>20 mg/kg bw/d Sb(V), side effects were very variable and dependent on the state of the patients and duration of treatment. In some studies severe, but reversible, side effects were observed (nausea, anorexia, severe bone and muscle pain, hypotension and arrhythmia, pancreatitis, transaminitis, haematological suppressions) resulting in discontinuation of treatment in some cases. ECG measurements showed changes of T-waves and in some patients QTc prolongation. A very few cases of death related to cardiotoxicity were described.

Evaluation of toxicokinetic data

Pentavalent antimony is almost not bioavailable when it is given orally. Therefore treatment of patients with leishmaniasis is always by the parenteral route (i.m. or i.v.). It can be assumed that bioavailability is 100% following i.v. exposure. Only a few studies regarded as relevant were conducted with i.m. administrations, and since the profile of side effects was similar following the i.v. and i.m. route, also 100% bioavailability can be assumed for this route. There are no toxicokinetic data available for i.m. injection in the EU RAR report on diantimony trioxide.

EU RAR (May 2008) for diantimony trioxide:

“From human trials there is no quantitative data available for absorption following the inhalation route. However, based on the levels of antimony found in the liver and taking into account that antimony was not measured in e. g. bone marrow, thyroid or in urine in the Leffler study it can be concluded that the absorption must have been > 12.6%. ”

“Based on data on physical particle size and density for 8 different samples of diantimony trioxide and with the use of the MPPD model and values on gastrointestinal tract absorption a value of 6.82 % have been calculated for inhalation absorption. This way of calculating inhalation absorption figures has previously been used in the EU RARs on zinc compounds, therefore6.82 %inhalation absorption is proposed. ”

“There is one study which has measured the absorption of diantimony trioxide after oral exposure to diantimony trioxide particle suspension. In this study, absorption after oral dosing was low; only 0.3% after administration of 100 mg/ kg bw and 0.05% after administration of 1000 mg/ kg bw. It should however, be noted that the exposure levels in this study in rats are at least 2-3 orders of magnitude higher than the exposure levels for humans”. “Instead, we also propose to consider the data published on intestinal absorption of more soluble antimony compounds than diantimony trioxide. Although all these studies have been performed with different study protocols which do not meet current standards they indicate an average intestinal absorption of 3-8 % (0.15-40 %). Considering the above data and the poor solubility of diantimony trioxide an oral absorption of 1% is proposed for diantimony trioxide.”

Furthermore there is one study in which the oral absorption of soluble pentavalent antimony compounds is assessed to be less than 1% (Felicetti, 1974), based upon which ICRP (1981) concluded 1% oral absorption for all pentavalent antimony compounds. Thus, a bioavailability of 1% following oral absorption is further used in the risk assessment.