Post-transplant patients receiving immunosuppressive drugs—often for the rest of their lives—require regular therapeutic drug monitoring (TDM), given the narrow therapeutic interval of these drugs as well as the risk of graft rejection at low exposure and toxic effects at high levels. However, current techniques lack standardization, allowing for great variability.
To address this problem, researchers at Karolinska University Hospital in Sweden used a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to simultaneously analyze immunosuppressive drugs as part of their TDM service. They reported on their 5-year experience in 142,000 routine patient samples in a recent article in Clinical Biochemistry.
The article also compared the results of the LC-MS/MS method with the previous immunoassays used (CEDIA for ciclosporin, EMIT-2000 for tacrolimus, and MEIA for sirolimus) in 572 samples.
The comparison demonstrated 20.6% lower values for tacrolimus and 28.6% lower values for ciclosporin concentrations on average when measured with LC-MS/MS compared with the previous immunoassays. Average sirolimus values were 9% higher and everolimus values 19.9% lower with the MS approach compared with the immunoassay method.
Such disparities between the two methods reduced the therapeutic window from 5 to 15 ng/mL to 4 to 12 ng/mL for tacrolimus, and from 60 to 120 ng/mL to 45 to 90 ng/mL for most stable kidney transplant patients on ciclosporin. No change was suggested for sirolimus, while an interval of 2.5 to 7 ng/mL was suggested for everolimus.
Beyond more accurate results, the dual multiplexing offered a higher capacity per MS instrument and reduced average turnaround times from more than 6 hours to just below 4 hours, with considerably shorter median times, as well.
The MS method also enjoyed wide acceptance among clinicians, the authors wrote, and stimulated the development of several clinical collaboration projects.
With the availability of a backup system, the lab was able to provide the service 7 days a week with a short turnaround time and no shutdown incidents during the 5.5 years they reported on.
In addition, the researchers wrote, the system was cost-effective, with a 20% price reduction possible in comparison to using commercial immunoassay agents.
As the authors wrote, “Our experience is that the switchover to an LC-MS/MS method has made it possible to provide a more reliable and effective laboratory service.” However, they cautioned, before considering such a change, laboratories must ensure they have in-house access to bioanalytical and LC-MS expertise.
Even though the method proved to be sufficient for routine use, the authors concluded, “we think there is still room for considerable improvement in the design of LC-MS methods for the analytical task of measuring immunosuppressive drugs in blood.”