An article published by Nils T. Vethe et al in the October 2019 issue of Therapeutic Drug Monitoring, reported on the successful validation of 10 µL Mitra® devices from 26-27 renal transplant recipients to measure therapeutic drug levels of the anti-rejection drug, tacrolimus.
The paper, entitled “Tacrolimus can be reliably measured with volumetric absorptive capillary microsampling throughout the dose interval in renal transplant recipients,” describes an analytical and clinical validation comparing wet blood to dried Mitra microsamples.
During the study, over 600 blood microsamples collected by study participants at home were compared to a similar number of samples taken in the clinic and sent directly to the Oslo University Hospital laboratory.
This therapeutic drug monitoring (TDM) study showed that both trough level measurements and PK measurements provided equivalent results from dried capillary blood samples compared to venous samples collected via venipuncture blood draws.
The results demonstrated both accuracy and precision within accepted criteria. Further, the Mitra dried blood microsamples showed stability over 1-2 months when stored at ambient temperatures.
Additionally, the researchers found that processing of Mitra samples was more efficient than processing of traditional wet samples, with increased options for automation.
The very first solid organ transplant was conducted in 1954 at at the Peter Bent Brigham Hospital in Boston by Dr. Joseph E. Murray at Harvard Medical School in Massachusetts, where he conducted a kidney transplant between identical twins, Richard and Ronald Herrick. Receiving a new kidney from his brother via the successful operation added years to Richard Herrick’s life and ushered in a new dawn of transplant science.
Over the ensuing years, this area of medical science has advanced even further. Indeed, in 2019 it was estimated that as many as 39,500 kidney transplantations were conducted in the US alone. Similar numbers were reported for Europe.
The success of the world’s first successful organ transplant was attributed to the genetic similarity and histocompatibility of the identical Herrick twins. However, organ rejection was a real concern even when tissue typing between the donor and recipient was so close.
Indeed, back in the 1950s, very little was known about organ rejection and how to overcome it. In the past 50 years, much research on preventing organ rejection in transplant patients has been conducted. In 1971, the calcineurin inhibitor cyclosporine was discovered and isolated from the fungus Tolypocladium inflatum.
In 1983, after additional research and development, the drug was approved for clinical use as a preventative against organ rejection. Cyclosporine is still used for this purpose to this day.
Calcineurin inhibitors continue to be a key class of drugs used in the prevention of graft rejection. These inhibitors work by actively suppressing specific T-cell immune interactions. The most popular calcineurin inhibitor used in renal transplants is the macrolide, tacrolimus. Tacrolimus was first isolated from a soil sample in the Tsukuba region of Japan in 1984.
The drug was commercialized by Astellas Pharmaceuticals. In 1994, tacrolimus was approved by the US Food and Drug Administration (FDA) as a therapeutic drug for patients who had undergone liver transplantation. This application was later approved for use in patients with other transplanted organs.
Graft recipients in present times are often given a cocktail of drugs which include steroids, mycophenolate and a calcineurin inhibitor such as tacrolimus. Due to the narrow therapeutic index of calcineurin inhibitors, tacrolimus and similar drugs need to be carefully monitored.
In fact, as highlighted in the paper by Vethe et al, there can be a 10-fold difference in dosing between patients. For this reason, post-transplant dose changes are often required throughout a patient’s lifetime, thus requiring regular therapeutic drug monitoring (TDM).
In the initial days of a successful graft, blood testing is carried out several times per week to assess drug levels. As the graft stabilizes over time, drug monitoring is gradually reduced to occur about every 2-3 months. This transition typically happens around 6-12 months post-transplant.
This regular TDM schedule (and related dose adjustments), helps to prevent drug-induced chemotoxicity which would otherwise result in the following complications: hypertension, post-transplant diabetes mellitus, neurotoxicity, and nephrotoxicity. Alternatively, too low a dose of the administered tacrolimus can lead to acute organ rejection due to over-activity of donor-specific antibodies.
There are two primary reasons for taking TDM and testing out of the clinic. The first reason is logistics. The Oslo team highlighted the following challenges with the current in-clinic system of blood draws for therapeutic drug monitoring.
The second reason for taking TDM out of the clinic is to minimize exposure of immunosuppressed patients to contagions that could lead to dangerous infections, such as COVID-19 caused by the SARS-CoV-2 virus. Enabling these vulnerable patients to complete a majority of their maintenance care at home keeps them out of high-risk environments.
The Oslo study illustrates that the current “wet sampling” situation is time-consuming and carries a higher risk for transplant recipients, so Vethe et al proposed that home sampling would be more patient-friendly and would save time and money. Indeed, they highlighted a previous study that had conducted a cost evaluation of home monitoring in pediatric TDM.
In the conclusions of their 2016 paper the authors stated, “From a societal perspective, total costs per blood draw decrease drastically with home sampling. Patient costs are reduced to zero and costs related to loss of productivity are decreased by >95%.”
The team from Oslo also highlighted that home sampling would allow for limited sampling strategies by measuring AUC. The team also noted that dried blood spot (DBS, which was used in previous studies for tacrolimus measurements), was hampered by a type of “hematocrit effect,” or HCT bias. This was particularly an issue for renal grafts, due to observed large shifts in HCT levels post transplantation.
However, because Mitra devices enable a volumetric approach to microsampling with their VAMS® tips, it was proposed that these devices would overcome the observed HCT hurdle and indeed they did.
To 1) develop a VAMS method for measuring trough levels with the same performance as methods for liquid blood, and 2) to develop a future model requiring quantification throughout the dose model for renal transplant patients.
The study team developed a method from VAMS extracts involving the same reagents for protein precipitation dried blood sample preparation compared to standard liquid blood samples. This made the method very compatible when compared to the standard LC-MS/MS method.
The work reported by Nils T. Vethe et al in Oslo demonstrated that a rich dataset could be obtained from Mitra devices which was comparable to data from wet samples. This, coupled with the benefits of home sampling, could usher in an AUC approach to TDM of anti-rejection drugs possibly interspersed with trough measurements over the course of each 12 months. Sampling from home will allow the patient to spend less time travelling to clinic and waiting for blood results.
Given the success that other centers have had in developing similar methodologies, such as a program at Wythenshawe Hospital in the UK, home sampling for tacrolimus measurements may become the gold standard for combining convenience with accuracy in TDM.
Furthermore, patients in the Oslo study reported no difficulties in using Mitra devices when sampling at home, as reported in a follow-up paper by the same group in Oslo focusing on the PK data. This finding was echoed in a paper from the Mayo Clinic in 2020, where 100 transplant patients were surveyed and 82% preferred capillary sampling with Mitra devices compared to 3% who preferred venous sampling and only 13% who had no preference.
Furthermore, this patient preference also was reported in a recent paper published in Australia. The findings from Oslo and other transplant groups globally certainly paint a very bright future for at-home TDM sampling for research of transplant recipients.
This study paper was summarized for our readers by James Rudge, PhD, Neoteryx Technical Director. This is curated content. To learn more about the important research outlined in this review, visit the original article published in Therapeutic Drug Monitoring.