Author(s): Ali Tafazoli [*] aff1 aff2
allogeneic hematopoietic stem cell transplantation; cyclosporine; graft versus host disease; pharmacokinetics; review
Cyclosporine (CsA) has been used extensively for immune suppression in allogeneic hematopoietic stem cell transplantation (HSCT) for prevention and treatment of graft versus host disease (GvHD) [1,2 ].
Patient response to cyclosporine especially in HSCT is very unpredictable. There are numerous studies in literature that tried to define aspects, causes and consequences of cyclosporine performance variegations among different patients and interestingly even in single cases on different occasions. Also, pharmacokinetic (PK) specifications of HSCT population cause inapplicability of solid organ transplantation data which is more abundant.
Despite augmentation of clinical experiences for CsA use in recent years, and development of some guidelines as well, unfortunately there are still lots of uncertainties about its appropriate method of administration, dosing and monitoring [3-8 ].
The aim of this review is to gather sparse data about different PK-related aspects of cyclosporine use for HSCT recipients to help optimization of clinical practice and show new horizons for research in the future.
In order to find the most relevant data, 'PubMed' as a highly accredited database was explored without any limitation in time or language. With the search command (('Cyclosporine'[Mesh]) and 'Hematopoietic Stem Cell Transplantation'[Mesh]) and 'Pharmacokinetics'[Mesh], only 23 journal articles were obtained that constructed the core concepts of this review. Five articles were excluded because their major focus was on everolimus and mycophenolate. Coverage of different aspects in CsA use and prevention of missing the relevant data required widening of the search process, because of limitation of specific PK studies in marrow transplant setting. Therefore two other search commands were tried ('Cyclosporine'[Majr]) and 'Transplantation, Homologous'[Majr] and ('Cyclosporine'[Majr]) and 'Hematopoietic Stem Cell Transplantation'[Majr] that yielded 78 and 122 result outputs, respectively and all of them were screened. Of these, 37 articles that were closely associated to the topic used and others ignored including most of nonhuman studies, irrelevant and repeated ones. The rest of the references were chosen from 'Google Scholar' for further explanation of the topics whenever acquired data by systematic search was insufficient. At the end, 200 references gathered together as a specialized database for this clinical issue.
Results & discussion
Causes of complexity in CsA use
There are several explanations for obstacles hindering a straight forward CsA therapy and study of them is helpful in reaching evidence-based guidelines. These complexities and related data are summarized in Table 1.
Variations in CsA PKs observed in all aspects of drug absorptions, distribution, clearance (Cl) and elimination that make generalization of median population values for individuals impossible [9,10 ]. Willemze et al . generally pictured CsA PK [11 ] by a slow, incomplete and variable absorption to reach an inconsistent peak blood level (Cmax ) at an unpredictable time (Tmax ), called absorption phase. Then gradually blood content of drug decreases with large volume of distribution (Vd ) that shows drug transfer from circulating blood to tissues, generally apart from the site of action,...