Development and validation of a high-performance liquid chromatography tandem mass spectrometry method for the quantification of the antiparasitic and antifungal drug amphotericin B in human skin tissue

Roseboom, Ignace C.; Thijssen, Bram; Rosing, Hilde; Alves, Fabiana; Sundar, Shyam; Beijnen, Jos H.; Dorlo, Thomas P. C.

doi:10.1016/j.jchromb.2022.123354

Cited by 5 publications

(13 citation statements)

References 15 publications

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“…was clinically used since 1957 [41], at first in the treatment of fungal infections. The majority bioanalytical assays of amphotericin B in various matrices used for human PK studies were detected using conventional ultraviolet (UV) detection that were more prominent before mass spectrometry (MS) detection [44,79,81,[84][85][86][87][88][89][90] was standardized. There are multiple formulations for amphotericin B, including amphotericin B lipid complex (ABLC), liposomal amphotericin B (L-AmB), amphotericin B colloidal dispersion (ABCD), and amphotericin B deoxycholate.…”

Section: Resultsmentioning

confidence: 99%

“…Considering future target site antileishmanial PK studies the development and validation of bioanalytical methods for the quantification of antileishmanial drugs in human skin tissue (CL and PKDL), spleen, liver, and bone marrow (VL), and PMBCs (leishmaniasis in general) will gain prominence. Quantification in skin tissue was to date only published for amphotericin B [90], miltefosine [37], and pentavalent antimonials [163] and is expected to contribute to future antileishmanial target site PK studies in CL and PKDL patients. Quantification in liver was described for pentavalent antimonials [151,156].…”

Section: Discussionmentioning

confidence: 99%

“…In the interest of leishmaniasis target site PK studies, quantification of amphotericin B in skin tissue has recently been developed [90]. There were six identified studies with sampling volumes of ≤50 µL for serum or heparinized/K 2 EDTA plasma samples recommended to be used in leishmaniasis patients because little blood is required from patients [47,68,79,84,85,88]…”

Section: Matrix Calibration Range and Sampling Volumementioning

confidence: 99%

“…Sample preparation consisted in most cases of protein precipitation because amphotericin B is soluble in organic solvents. For total and free fraction amphotericin B quantification in plasma, serum, urine or tissue analysis, most often simple protein precipitation was performed using methanol or acetonitrile, occasionally together with acetic acid, dimethyl sulfoxide (DMSO), ethylenediaminetetraacetic acid (EDTA) or zinc as co-solvent for precipitation improvements [42][43][44][47][48][49][50][51][52][53][55][56][57][59][60][61][62][63][64][65][66][67][68][69]72,73,75,[77][78][79][80][81][82][83][84][86][87][88]90]. Amphotericin B in the liposomal fraction samples were primarily prepared using solid-phase extraction (SPE) techniques to preserve the liposomal formulation of amphotericin B and separate the free fraction from the liposomal fraction for selective analysis [54,81,89] Figure 1: Chemical structures and names of antileishmanial drugs.…”

Section: Sample Preparationmentioning

confidence: 99%

“…PK studies involving amphotericin B drug treatment regimens were mostly performed on paediatric children or adults suffering from malignant diseases [46,48,61,63,64,68,75,81]. Furthermore, neutropenic patients were also subject of PK studies as well as patients suffering from fungal diseases [44,57,65,79,80,82,86,94] and patients suffering from leishmaniasis [90,95]. PK studies and their drug treatment regimen contained various formulations of amphotericin B in the form of deoxycholate, liposomal, and dextrose addition.…”

Section: Clinical Applicationmentioning

confidence: 99%

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Target site bioanalysis and pharmacokinetics of antileishmanial drugs

Roseboom¹

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This thesis focuses on bioanalytical method development and validation of antileishmanial drugs amphotericin B, miltefosine, and paromomycin in human plasma and human skin tissue followed by clinical target site pharmacokinetic outcomes induced by these developed bioanalytical methods. Chapter 1 provides an overview of bioanalytical quantification methods of the most relevant antileishmanial used in human pharmacokinetic studies and clinical trials. It covers (liposomal) amphotericin B, miltefosine, paromomycin, pentamidine and pentavalent antimonials and summarizes sample preparation, calibration model, separation, and detection methods in various human matrices from identified published method validations and included future perspectives in the development of antileishmanial bioanalysis. Chapter 2 presents the development and validation of a modern bioanalytical method for the quantification of paromomycin in human plasma using ion-pair ultra-high performance liquid chromatography tandem mass spectrometry. It was the first bioanalytical assay that employed a stable isotope labelled internal standard in the quantification of paromomycin. The relevance of developing a sensitive method for the quantification of paromomycin in human plasma is discussed, furthermore its supporting role in clinical pharmacokinetic studies in patients suffering from visceral leishmaniasis in Kenya. Chapter 3 discusses and presents target-site bioanalytical methods for the quantification of antileishmanial drugs in human skin tissue. Chapter 3.1 provides an overview of existing skin tissue sample pre-treatment and homogenization techniques for quantification of pharmaceutical compounds. It discusses the advantages and disadvantages of certain homogenization techniques relative to the accuracy and recovery from skin tissue of the bioanalytical method. In chapter 3.2 the development and validation of a bioanalytical method for the quantification of miltefosine in human skin tissue is presented. It describes a detailed development of a homogenization method employing enzymatic digestion by collagenase A for human skin tissue sample processing. Furthermore, its clinical applicability to target-site pharmacokinetic studies in post-kala azar dermal leishmaniasis patients in Bangladesh is demonstrated. Chapter 3.3 focuses on the development and validation of a bioanalytical method for the quantification of amphotericin B in human skin tissue with a clinical application in post-kala azar dermal leishmaniasis patients in India. Finally, chapter 3.4 provides the development and validation of a bioanalytical method for the quantification of paromomycin in human skin tissue and a clinical application in a pharmacokinetic study in post-kala-azar dermal leishmaniasis patients in Sudan. Chapter 4 explores the pharmacokinetic outcomes of target-site pharmacokinetic studies employing human skin tissue data. Chapter 4.1 evaluates miltefosine pharmacokinetic and pharmacodynamic outcomes and presents the first skin tissue model characterizing the distribution of miltefosine from blood-based matrices to skin tissue from patients suffering from post-kala azar dermal leishmaniasis in India and Bangladesh. Chapter 4.2 presents a pharmacokinetic model for liposomal amphotericin B in both human plasma and skin tissue, exploring the target-site exposure and distribution of this antileishmanial drug based on clinical pharmacokinetic data of patients suffering from post-kala azar dermal leishmaniasis in India and Bangladesh. Chapter 5 summarizes and concludes the thesis and furthermore presents the authors’ views on future perspectives for the development of bioanalytical methods for antileishmanial drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Matrix Calibration Range and Sampling Volumementioning

confidence: 99%

Section: Sample Preparationmentioning

confidence: 99%

Section: Clinical Applicationmentioning

confidence: 99%

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Target site bioanalysis and pharmacokinetics of antileishmanial drugs

Roseboom¹

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Bioanalytical methods for pharmacokinetic studies of antileishmanial drugs

Roseboom

Rosing

Beijnen

et al. 2022

Biomedical Chromatography

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Bioanalytical method development and validation for the quantification of antileishmanial drugs are pivotal to support clinical trials and provide the data necessary to conduct pharmacokinetic (PK) analysis. This review provides a comprehensive overview of published validated bioanalytical assays for the quantification of antileishmanial drugs amphotericin B, miltefosine, paromomycin, pentamidine, and pentavalent antimonials in human matrices. The applicability of the assays for leishmaniasis clinical trials as well as their relevance to PK studies with emphasis on the choice of matrix, calibration range, sample volume, sample preparation, choice of internal standards, separation, and detection was discussed for each antileishmanial drug. Given that no published bioanalytical methods included multiple antileishmanial drugs in a single assay although antileishmanial shortened combination regimens currently were under investigation, it was recommended to combine various drugs in a single bioanalytical method. Furthermore, bioanalytical method development regarding target site matrix as well as applying microsampling strategies was recommended to optimize future clinical PK studies in leishmaniasis.

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