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Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs

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Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs Clin Pharmacokinet DOI 10.1007/s40262-017-0570-0 REVIEW ARTICLE Clinical Pharmacokinetics of Systemically Administered Antileishmanial Drugs 1,2 2,3 1,2,3 1,4 Anke E. Kip • Jan H. M. Schellens • Jos H. Beijnen • Thomas P. C. Dorlo Ó The Author(s) 2017. This article is an open access publication Abstract This review describes the pharmacokinetic half-life, potentially due to intracellular conversion to properties of the systemically administered antileishma- trivalent antimony. Pentamidine is the only antileish- nial drugs pentavalent antimony, paromomycin, pen- manial drug metabolised by cytochrome P450 enzymes. tamidine, miltefosine and amphotericin B (AMB), Paromomycin is excreted by the kidneys unchanged and including their absorption, distribution, metabolism and is eliminated fastest of all antileishmanial drugs. Milte- excretion and potential drug–drug interactions. This fosine pharmacokinetics are characterized by a long overview provides an understanding of their clinical terminal half-life and extensive accumulation during pharmacokinetics, which could assist in rationalising and treatment. AMB pharmacokinetics differ per drug for- optimising treatment regimens, especially in combining mulation, with a fast renal and faecal excretion of AMB multiple antileishmanial drugs in an attempt to increase deoxylate but a much slower clearance of liposomal efficacy and shorten treatment duration. Pentavalent AMB resulting in an approximately ten-fold higher antimony pharmacokinetics are characterised by rapid exposure. AMB and pentamidine pharmacokinetics have renal excretion of unchanged drug and a long terminal 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 Electronic supplementary material The online version of this patients after systemic administration. Pharmacokinetic article (doi:10.1007/s40262-017-0570-0) contains supplementary material, which is available to authorized users. data on special patient populations such as HIV co-in- fected patients are mostly lacking. More research in & Thomas P. C. Dorlo these areas will help improve clinical outcomes by [email protected] informed dosing and combination of drugs. 1 Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek Hospital/MC Slotervaart, Amsterdam, The Netherlands 2 Division of Pharmacoepidemiology and Clinical Pharmacology, Faculty of Science, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands 3 Department of Clinical Pharmacology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands 4 Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden A. E. Kip et al. 1 Introduction Key Points Leishmaniasis is a neglected tropical disease caused by the Due to very limited treatment options for Leishmania parasite and can cause diverse clinical mani- leishmaniasis patients, optimisation of current drug festations depending on the subspecies responsible for the dosages and drug combinations is of utmost infection and the host immune response. The two main importance, for which this review provides a solid types are the systemic disease visceral leishmaniasis (VL) pharmacokinetic basis. and the skin infection cutaneous leishmaniasis (CL). Sev- eral drugs (Table 1) are currently used in clinical practice This review describes the absorption, distribution, in treatment of both VL and CL [1, 2] but clinical guide- metabolism and excretion, as well as the clinical lines differ by region. Clinical results obtained in one area pharmacokinetics and potential drug–drug of endemicity cannot be extrapolated to other geographical interactions of the antileishmanial drugs pentavalent areas as efficacies have been shown to vary widely between antimonials, paromomycin, pentamidine, miltefosine countries and parasite subspecies (reviewed in Croft and and amphotericin B in the context of leishmaniasis. Olliaro [3] and Sundar and Singh [4]). The pharmacokinetics of two out of five Rising levels of resistance against antimonials, mostly in antileishmanial drugs have never been evaluated in India, and potentially miltefosine, is a great pitfall in the leishmaniasis patients. Exposure–response studies treatment of leishmaniasis patients [4, 5]. Available treatment and pharmacokinetic data in special patient options are limited, especially in vulnerable patient popula- populations such as HIV co-infected patients are tions such as paediatric leishmaniasis patients and HIV lacking. More research in this area will patients co-infected with VL. Therefore, several new combi- improve clinical outcomes via informed dosing nations of drugs are currently being tested to improve the regimens and combinations of drugs. efficacy of antileishmanial therapies. Furthermore, combina- tion therapies could possibly shorten treatment duration. Table 1 Overview of antileishmanial drugs systemically administered in treatment of visceral and/or cutaneous leishmaniasis (only includes information in human subjects, unless indicated otherwise) Antileishmanial Formulations Route of Distribution Metabolism Excretion drug administration Highest Skin accumulation Pentavalent Sodium IM/IV Liver, thyroid, heart Confirmed Intracellular Renal clearance antimonials stibugluconate reduction to SbIII (SSG) Meglumine Antimoniate (MA) Paromomycin Paromomycin IM Not reported Not reported Not metabolized Renal clearance sulphate Pentamidine Pentamidine IM/IV Kidney, liver, spleen, Not reported CYP1A1 Not excreted unchanged dimesylate adrenal glands (CYP2D6, Pentamidine CYP3A5 and isethionate CYP4A11) Miltefosine Miltefosine Oral Not reported (rats/ Not reported Intracellularly by Not excreted unchanged mice: kidney, liver, (in rats: phospholipase D (metabolised to spleen, intestines, confirmed) endogenous compounds) adrenal) Amphotericin D-AMB IV Liver, spleen Not reported Metabolism not D-AMB: urinary excretion a B L-AMB (in rats: well-studied. (21%); faecal excretion confirmed) Liposomes (43%) engulfed by RES L-AMB: urinary excretion (5%); faecal excretion (4%) CYP cytochrome P450, D-AMB amphotericin B deoxylate, IM intramuscular, IV intravenous, L-AMB liposomal amphotericin B, RES Retic- uloendothelial system a More lipid formulations exist of amphotericin B, but these are outside the scope of this review Clinical Pharmacokinetics of Antileishmanial Drugs Pharmacokinetics provide a scientific framework for Pharmacokinetic studies based on bio-assays were exclu- choosing the appropriate (combination of) drugs and their ded due to low sensitivity and problems with potential co- dosage. The clinical pharmacokinetics of antileishmanial measurements of the effect of metabolites. Many pharma- drugs, however, remain largely unexplored [6]. The aim of cokinetic studies have been conducted for AMB, and for this review is to give a comprehensive overview of the this reason we excluded studies with fewer than ten sub- pharmacokinetic characteristics relating to the absorption, jects or patients, studies with continuous infusion and distribution, metabolism and excretion (ADME) of system- studies on neonates\3 kg based on their limited relevance ically administered antileishmanial drugs currently being in the context of the treatment of leishmaniasis. Studies on used in the clinic as a basis to further rationalise the therapy experimental formulations were excluded for all drugs, for leishmaniasis. Albeit the pharmacokinetics of miltefos- such as a pharmacokinetic study on the experimental ine [7] and liposomal amphotericin B (L-AMB, with focus generic sodium stibogluconate (SSG) formulation ‘Ulam- on treatment of fungal infections [8]) have previously been ina’ composed of the pentachloride of antimony plus N- reviewed, our aim was to discuss the antileishmanial drugs methylglucamine [10], as no records have been found of collectively in the context of leishmaniasis. the commercialisation of this formulation. We have composed a summary of all pharmacokinetic studies performed, providing the reported primary and secondary pharmacokinetic parameters in overview tables. 3 Absorption, Distribution, Metabolism The pharmacokinetics in special patient populations rele- and Excretion (ADME) and Clinical vant in treatment of leishmaniasis are described: paediatric Pharmacokinetics patients, HIV co-infected patients, pregnant patients and patients with renal failure. Furthermore, potential drug– 3.1 Pentavalent Antimonials drug interactions between antileishmanial drugs, as well as between antileishmanial and antiretroviral drugs are dis- Pentavalent antimonials (pentavalent Sb/SbV) have been cussed. When information in humans is lacking, in vitro first-line treatment against CL and VL in the majority of and in vivo animal studies are examined. endemic regions for decades, though increasing drug In this review we solely focus on systemically admin- resistance has compromised its efficacy [3, 4]. Pentavalent istered drugs, as the majority of these drugs are adminis- antimonials are administered intramuscularly (IM) or tered in both CL and VL. Topical formulations were intravenously (IV) in systemic treatment of both CL and omitted due to its sole applicability to CL patients. The VL. It is marketed in two formulations: SSG (marketed as
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