Pharmacokinetics of experimental pentavalent antimony after intramuscular administration in adult volunteers

Dagert, José Vicente Scorza; Scorza, J. V.; Vicuña-Fernández, Nelson; Peña, Yaneira Petit de; López, Sabrina; Bendezú, Herminia; Rojas, Elina; Vásquez, Laura; Pérez, Belén

doi:10.1016/j.curtheres.2006.06.005

Cited by 21 publications

(14 citation statements)

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“…Many pharmacokinetic studies have been conducted for AMB, and for this reason we excluded studies with fewer than ten subjects or patients, studies with continuous infusion and studies on neonates <3 kg based on their limited relevance in the context of the treatment of leishmaniasis. Studies on experimental formulations were excluded for all drugs, such as a pharmacokinetic study on the experimental generic sodium stibogluconate (SSG) formulation ‘Ulamina’ composed of the pentachloride of antimony plus N -methylglucamine [ 10 ], as no records have been found of the commercialisation of this formulation.…”

Section: Methodsmentioning

confidence: 99%

Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs

et al. 2017

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This review describes the pharmacokinetic properties of the systemically administered antileishmanial drugs pentavalent antimony, paromomycin, pentamidine, miltefosine and amphotericin B (AMB), including their absorption, distribution, metabolism and excretion and potential drug–drug interactions. This overview provides an understanding of their clinical pharmacokinetics, which could assist in rationalising and optimising treatment regimens, especially in combining multiple antileishmanial drugs in an attempt to increase efficacy and shorten treatment duration. Pentavalent antimony pharmacokinetics are characterised by rapid renal excretion of unchanged drug and a long terminal half-life, potentially due to intracellular conversion to trivalent antimony. Pentamidine is the only antileishmanial drug metabolised by cytochrome P450 enzymes. Paromomycin is excreted by the kidneys unchanged and is eliminated fastest of all antileishmanial drugs. Miltefosine pharmacokinetics are characterized by a long terminal half-life and extensive accumulation during treatment. AMB pharmacokinetics differ per drug formulation, with a fast renal and faecal excretion of AMB deoxylate but a much slower clearance of liposomal AMB resulting in an approximately ten-fold higher exposure. AMB and pentamidine pharmacokinetics have never been evaluated in leishmaniasis patients. Studies linking exposure to effect would be required to define target exposure levels in dose optimisation but have only been performed for miltefosine. Limited research has been conducted on exposure at the drug’s site of action, such as skin exposure in cutaneous leishmaniasis patients after systemic administration. Pharmacokinetic data on special patient populations such as HIV co-infected patients are mostly lacking. More research in these areas will help improve clinical outcomes by informed dosing and combination of drugs.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0570-0) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs

et al. 2017

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“…The antimony treatment cure rate in ACL has been reported in meta-analyses as 76.5% (23 studies, 1,133 patients) in patients receiving 20mgSb5+/kg/day over 20 days [ 16 ], and as 75.7% in a case-controlled prospective study (119 patients) [ 13 ]. Reasons for antimony treatment failure (ATF) in ACL imply host inherent features such as age [ 13 ], drug depuration rates [ 17 ], immunological stage, drug activation and treatment adherence [ 18 ]. Natural variation in antimony susceptibility between different strains of Leishmania spp .…”

Section: Introductionmentioning

confidence: 99%

Clinical and Parasitological Features of Patients with American Cutaneous Leishmaniasis that Did Not Respond to Treatment with Meglumine Antimoniate

et al. 2016

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BackgroundAmerican cutaneous leishmaniasis (ACL) is a complicated disease producing about 67.000 new cases per year. The severity of the disease depends on the parasite species; however in the vast majority of cases species confirmation is not feasible. WHO suggestion for ACL produced by Leishmania braziliensis, as first line treatment, are pentavalent antimonial derivatives (Glucantime or Sodium Stibogluconate) under systemic administration. According to different authors, pentavalent antimonial derivatives as treatment for ACL show a healing rate of about 75% and reasons for treatment failure are not well known.MethodsIn order to characterise the clinical and parasitological features of patients with ACL that did not respond to Glucantime, a cross-sectional observational study was carried out in a cohort of 43 patients recruited in three of the Colombian Army National reference centers for complicated ACL. Clinical and paraclinical examination, and epidemiological and geographic information were recorded for each patient. Parasitological, histopathological and PCR infection confirmation were performed. Glucantime IC50 and in vitro infectivity for the isolated parasites were estimated.ResultsPredominant infecting Leishmania species corresponds to L. braziliensis (95.4%) and 35% of the parasites isolated showed a significant decrease in in vitro Glucanatime susceptibility associated with previous administration of the medicament. Lesion size and in vitro infectivity of the parasite are negatively correlated with decline in Glucantime susceptibility (Spearman: r = (-)0,548 and r = (-)0,726; respectively).ConclusionA negative correlation between lesion size and parasite resistance is documented. L. braziliensis was found as the main parasite species associated to lesion of patients that underwent treatment failure or relapse. The indication of a second round of treatment in therapeutic failure of ACL, produced by L. braziliensis, with pentavalent antimonial derivatives is discussable.

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“…Particularly, MA is a depot drug, with gradual accumulation. The therapeutic effect of antimony is provided by the fraction accumulated in the tissues [22, 23]. PA present an initial absorption phase, followed by a phase of rapid elimination of more than 80% of the administered dose within six to eight hours [4], and finally a slow elimination phase with a half-life of 76 hours [22].…”

Section: Discussionmentioning

confidence: 99%

Alterations in Evoked Otoacoustic Emissions by the Use of Meglumine Antimoniate in American Tegumentary Leishmaniasis Patients

et al. 2017

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IntroductionTegumentary Leishmaniasis (TL) is a neglected, non-contagious, infectious disease, caused by different protozoa species of the Leishmania genus that affects skin and mucous membranes. Meglumine Antimoniate (MA), the first drug of choice for TL treatment in Brazil, has already been associated with cochlear toxicity, which is defined as damages of the cochlea caused by exposure to chemical substances, resulting in reversible or irreversible hearing loss. Auditory monitoring for cochlear toxicity aims at the early detection of auditory disorders, enabling, when possible, hearing to be preserved or an early auditory rehabilitation. Although otoacoustic emissions (OAEs) are used in this monitoring, there is no consensus on the criteria that define cochlear toxicity by this examination. The objective of this study was to describe the characteristics of the OAEs in cochlear toxicity monitoring in TL patients using MA.MethodsProspective and longitudinal study of auditory monitoring of 35 patients with parasitological diagnosis of TL, with liminal tonal audiometry, high frequency audiometry, immitanciometry, distortion product evoked otoacoustic emissions (DPEOAEs) and transient evoked otoacoustic emissions (TEOAEs) before treatment, at the end of treatment, one month after the end of treatment and two months after the end of treatment.Results80% male, with median age of 44 years (IIQ: 22–59). In the pre-treatment evaluation: 11.4% complained of hearing loss and 20% of tinnitus, 48.6% presented auditory alterations in liminal tonal audiometry (LTA, 65.2% in high frequency audiometry (HFA), 26.6% in DPEOAE and 51.4% in TEOAE. No association was verified between genre and alterations in the EOAE examinations. We observed that patients that presented disorders in DPEOAE examinations were 17 years older than those without alterations and that patients that showed disorders in TEOAEO examinations were 34 years older than those without disorders. The presence of alterations in DPEOAE and TEOAE before beginning treatment was associated with each other and with the presence of alterations in LTA and HFA, and only DPEOAE was associated with hearing loss. We observed a significantly higher number of alterations of DPEOAE at the end of treatment than during pre-treatment and values of the ratio signal/noise significantly smaller at the end of treatment than during pre-treatment in the frequencies of 2 kHz (difference of 1.7dB; p = 0.016) and 4 kHz (difference of 2.45dB; p = 0.016) in DPEOAE and in the range 1.75/2.5 kHz in TEOAE (difference of 2.9dB; p = 0.039).ConclusionThe ototoxic signals observed in our study using EOAE indicated that both, DPEOAE and TEOAE are adequate and sensitive techniques for clinical monitoring of ototoxicity by MA. Their application is very simple, and their results help the physician to take the most adequate steps for each patient, thus avoiding permanent hearing damage.

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Pharmacokinetics of experimental pentavalent antimony after intramuscular administration in adult volunteers

Abstract: The investigational generic SbV, Ulamina, was associated with linearelimination after IM administration of a single 5-mg/kg dose. A 2-compartment pharmacokinetic model was observed in these volunteers; the mean t½β, was 17.45 hours and the mean Vd was 6.6 L/kg.

Cited by 21 publications

References 16 publications

Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs

Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs

Clinical and Parasitological Features of Patients with American Cutaneous Leishmaniasis that Did Not Respond to Treatment with Meglumine Antimoniate

Alterations in Evoked Otoacoustic Emissions by the Use of Meglumine Antimoniate in American Tegumentary Leishmaniasis Patients

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