Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs

Abstract

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.

Antileishmanial Compounds Isolated from Psidium Guajava L. Using a Metabolomic Approach

“…These issues are at the heart of concerns of the WHO regarding the control of tropical diseases [6]. Therefore, combination therapies are used to improve the efficacy of antileishmanial therapies and can shorten treatment duration [7]. Furthering our fundamental knowledge through original approaches, herein concerning the activity of natural compounds from a promising plant species active against Leishmania spp., is vital to overcome the challenges involved in treating leishmaniasis [8].Psidium guajava Linn., or guava, is a tree belonging to the Myrtaceae family.…”

Toxicity and Anti-promastigote Activity of Benzoxazinoid Analogs Against Leishmania (Viannia) braziliensis and Leishmania (Leishmania) infantum

“…Various problems associated with the current antileishmanial therapy, i.e., high toxicity, serious adverse effects, long course, storage, and access difficulties; together with the medical, epidemiological and social importance of this zoonosis, highlights the need to study the potential antiparasitic of Bex-derived compounds against the genus Leishmania. 1,[7][8][9] Here, a set of C-2 substituted Bexs, synthesized using the pyridoxazinone and benzoxazinone core as described by Lima et al, 18 were evaluated for anti-promastigote activity against L. (V.) braziliensis and L. (L.) infantum.…”

“…7 The therapeutic arsenal used to leishmaniases is basically composed by pentavalent antimony, paromomycin, pentamidine, miltefosine, and amphotericin B. 8 However, these drugs have several limitations which include severe side effects (e.g., cardiac arrhythmias, myalgia, and pancreatitis associated to pentavalent antimonial), high toxicity, and require prolonged use. In addition patients in need of treatment exhibit a low adherence to treatment plans and there is an insufficient availability of drugs generally in endemic regions.…”

Promising nanotherapy in treating leishmaniasis

“…The pharmacokinetics studies of L-AMB were performed in immunosuppressed patients with fungal infections. It has never been conducted in leishmaniasis patients (Kip et al, 2018) Pharmacokinetics studies revealed a statistically significant relationship between mean area under curve (AUC) and probability of nephrotoxicity and a nonlinear pharmacokinetics (Lestner et al 2016). Seibel et al (2017) showed that all immunosuppressed children (40), but three, had side effects after administration of L-AMB.…”