Alternative Matrices for Therapeutic Drug Monitoring of Immunosuppressive Agents Using LC–MS/MS

Abstract

Immunosuppressive drugs used in solid organ transplants typically have narrow therapeutic windows and high intra- and intersubject variability. To ensure satisfactory exposure, therapeutic drug monitoring (TDM) plays a pivotal role in any successful posttransplant maintenance therapy. Currently, recommendations for optimum immunosuppressant concentrations are based on blood/plasma measurements. However, they introduce many disadvantages, including poor prediction of allograft survival and toxicity, a weak correlation with drug concentrations at the site of action and the invasive nature of the sample collection. Thus, alternative matrices have been investigated. This paper reviews tandem-mass spectrometry (LC–MS/MS) methods used for the quantification of immunosuppressant drugs utilizing nonconventional matrices, namely oral fluids, fingerprick blood and intracellular and intratissue sampling. The advantages, disadvantages and clinical application of such alternative mediums are discussed. Additionally, sample extraction techniques and basic chromatography information regarding these methods are presented in tabulated form.

First UHPLC-MS/MS method coupled with automated online SPE for quantification both of tacrolimus and everolimus in peripheral blood mononuclear cells and its application on samples from co-treated pediatric patients.

“…Tacrolimus and EVE have a narrow therapeutic index; therefore, TDM is highly recommended . Nowadays, their TDM is routinely performed only in whole blood .…”

“…Immunosuppressant drugs used in solid organ transplant include tacrolimus (TAC, FK506) and everolimus (EVE, RAD001), characterized by a narrow therapeutic index, potential drug interactions and significant inter‐patient and intra‐patient variability . The incidence and severity of their side effects correlate with high exposure, while under dosed patients show a greater risk for allograft rejection . After the approval of new immunosuppressant drugs (like EVE), the necessity to understand how to manage the switch from a drug to the new one in difficult to treat patients became mandatory.…”

“…Whereas both targets are in the cytoplasm of lymphocytes, a closer link to drug efficacy could be expected from direct quantification within this compartment, as compared with whole blood or even tissue concentrations . Measurement of TAC and EVE concentrations at the target sites has been proposed as a possible approach to avoid organ rejection . In fact, both the fraction of TAC associated with leukocytes and its unbound concentration were observed to be significantly lower during episodes of rejection, rather than during periods of stable graft function .…”

Development and Validation of A HPLC-UV Method for Dissolution Testing of Ciclosporin: Its Application to The Measurement of Brand and Generic Versions from Different Countries

“…Therefore, a dissolution method of rupturing the capsule in medium and then measuring the content of ciclosporin in the dissolution medium would give rise to more reproducible results. Several methods have been developed to measure ciclosporin in biological matrices [14,15]. However, our methos are tailored for quantification of ciclopsorin in dissolution testing.…”

Recent advances in analytical methods for the therapeutic drug monitoring of immunosuppressive drugs

“…The Passing-Bablok regression revealed no significant deviation from linearity (Cusum test, P = 0.11). Thus, this method was deemed suitable for usage in the TDM of CsA.3.3 | Non-traditional samplesIn recent years, research on non-traditional samples has received significant attention, especially using dried blood spot (DBS) samples5 and saliva39 for measuring ISDs. The DBS sampling technique has been greatly accelerated with the high sensitivity and specificity offered by LC-MS/MS, even if only a limited amount of sample is available for analysis.…”