Pediatr Transplantation 2015: 19: 3–4
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12394
Editorial
Dried blood spots for therapeutic drug monitoring of tacrolimus and sirolimus in pediatric patients In this issue of Pediatric Transplantation, Dickerson et al. evaluated the use of dried blood spots for therapeutic drug monitoring (TDM) of the immunosuppressant drugs tacrolimus and sirolimus (1). Tacrolimus and sirolimus are commonly used antirejection drugs, both of which are known to have a narrow therapeutic window (2). Accordingly, frequent TDM is essential for successful immunosuppressive treatment as low blood concentrations are associated with graft rejection, while high blood concentrations are associated with adverse events such as nephrotoxicity (3). The reliance on frequent TDM for therapeutic efficacy places a significant burden on children and their families who are required to travel to medical centers for frequent appointments. In the case of rural settings, this often means traveling over great distances to clinics to meet the strict trough sampling time points, which are usually very early in the morning or late in the evening. Dickerson et al. elegantly describe and assess the utility of dried blood spots for the TDM of tacrolimus and sirolimus in an effort to allow for remote monitoring of blood concentrations. The major conclusions derived from this study were that tacrolimus and sirolimus blood concentrations analyzed from dried blood spots were only minimally lower (0.6 ng/mL for tacrolimus, 0.8 ng/mL for sirolimus) than samples analyzed from venous blood samples. These minimal differences are not likely clinically relevant in patient care. This is a potentially important finding in that the use of dried blood spots for TDM would significantly reduce the sample blood volume required and eliminate the need for patients to routinely travel to medical centers for blood sampling. Despite the promise of this strategy, there are several important limitations that must be
considered. First, there was a moderate difference in measured sirolimus levels between dried blood spots and venous blood samples at higher sirolimus concentrations (up to approximately 5 ng/mL). Interpretation of the difference in drug levels by the treating clinician may cause an unnecessary dosage adjustment, which could impact efficacy or toxicity. Although the mean concentration difference between dried blood spot and venous blood analysis is minimal, patients at the upper extremes in this study, of modest sample size, appear to exhibit a greater variation in concentration. Future studies will need to determine whether this trend continues over broader ranges of sirolimus concentration and whether these changes are likely to produce meaningful differences in the interpretation of reported sirolimus concentration. It is well known that ontogeny in drug disposition pathways varies with age (4, 5). Tacrolimus and sirolimus are fundamental examples that dosing drugs in children often substantially differs from adults. Both tacrolimus and sirolimus exhibit markedly increased clearance in children compared to adults, likely owing to differences in drug metabolism pathways (6, 7). Consequently, the dosage of tacrolimus and sirolimus in pediatric populations often exceeds those of adults. It is well appreciated that drugs undergoing extensive first-pass metabolism are subject to drug–drug interactions when inducers or inhibitors are coadministered. As children appear to have increased metabolic clearance of tacrolimus and sirolimus, they may be more prone to drug–drug interactions compared with adult patients taking interacting drugs. A limitation of using dried blood spots and remote sampling is the increased turnaround time from sampling to the time the attending clinician receives the report. Most clinical laboratories report results for tacrolimus and 3
Editorial
sirolimus TDM within 24 h. Remote sampling relies on regular mail to send dried blood spots to clinical laboratories. In this study, remote sampling delayed TDM by a median of 4.5 days and one sample was reported to be lost in the mail. In the rare case of a significant drug–drug interaction, this delay may prove to be serious as blood concentrations can change dramatically and rapidly following administration of an interacting drug (8, 9). The last potential limitation of a remote sampling strategy using dried blood spots is patient adherence. It is well recognized that patient adherence to drug regimens is an important predictor of long-term successful outcome. Children and adolescents who have had solid organ transplants are known to suffer from non-adherence to therapy (10). In the current study by Dickerson et al., a certified phlebotomist was responsible for taking blood samples in a clinical setting. As acknowledged by the authors, it is unknown what impact sample collection by the patient or family members will have on the analysis. In addition to concerns surrounding spot quality, future studies should evaluate adherence to the timing of sample collection in relation to dosing. There may be difficulties interpreting results from patients that do not provide a true trough sample, and it may result in their dose being unnecessarily altered. In this study, Dickerson et al. have provided the framework for remote sampling for tacrolimus and sirolimus TDM using dried blood spots. They were able to demonstrate that in general, samples analyzed from capillary blood samples correlate well with those obtained from traditional venipuncture. This approach is likely to greatly enhance the quality of life for pediatric transplant patients and their families. Although a promising strategy, future studies are required before adopting this into clinical practice.
4
Bradley L. Urquhart1 and Michael J. Knauer2 Departments of Physiology and Pharmacology, Paediatrics and Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada 2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada E-mail: [email protected]
1
References 1. DICKERSON JSM, JACOT K, STACK J, SADILKOVA J, LAW Y, JACK R. Tacrolimus and sirolimus in capillary dried blood spots allows for remote monitoring. Pediatr Transplant 2015: 19: 101–106. 2. SHAW LM, HOLT DW, KEOWN P, VENKATARAMANAN R, YATSCOFF RW. Current opinions on therapeutic drug monitoring of immunosuppressive drugs. Clin Ther 1999: 21: 1632– 1652; discussion 1631. 3. VENKATARAMANAN R, SHAW LM, SARKOZI L, et al. Clinical utility of monitoring tacrolimus blood concentrations in liver transplant patients. J Clin Pharmacol 2001: 41: 542– 551. 4. FILLER G, BENDRICK-PEART J, CHRISTIANS U. Pharmacokinetics of mycophenolate mofetil and sirolimus in children. Ther Drug Monit 2008: 30: 138–142. 5. DE WILDT SN, TIBBOEL D, LEEDER JS. Drug metabolism for the paediatrician. Arch Dis Child 2014: doi: 10.1136/archdischild-2013-305212. 6. FILLER G, BENDRICK-PEART J, STROM T, ZHANG YL, JOHNSON G, CHRISTIANS U. Characterization of sirolimus metabolites in pediatric solid organ transplant recipients. Pediatr Transplant 2009: 13: 44–53. 7. WALLEMACQ PE, VERBEECK RK. Comparative clinical pharmacokinetics of tacrolimus in paediatric and adult patients. Clin Pharmacokinet 2001: 40: 283–295. 8. RUSCHITZKA F, MEIER PJ, TURINA M, LUSCHER TF, NOLL G. Acute heart transplant rejection due to Saint John’s wort. Lancet 2000: 355: 548–549. 9. ZHAO W, BAUDOUIN V, FAKHOURY M, STORME T, DESCHENES G, JACQZ-AIGRAIN E. Pharmacokinetic interaction between tacrolimus and amlodipine in a renal transplant child. Transplantation 2012: 93: e29–30. 10. SHEMESH E, ANNUNZIATO RA, SHNEIDER BL, et al. Improving adherence to medications in pediatric liver transplant recipients. Pediatr Transplant 2008: 12: 316–323.
Copyright of Pediatric Transplantation is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12394
Editorial
Dried blood spots for therapeutic drug monitoring of tacrolimus and sirolimus in pediatric patients In this issue of Pediatric Transplantation, Dickerson et al. evaluated the use of dried blood spots for therapeutic drug monitoring (TDM) of the immunosuppressant drugs tacrolimus and sirolimus (1). Tacrolimus and sirolimus are commonly used antirejection drugs, both of which are known to have a narrow therapeutic window (2). Accordingly, frequent TDM is essential for successful immunosuppressive treatment as low blood concentrations are associated with graft rejection, while high blood concentrations are associated with adverse events such as nephrotoxicity (3). The reliance on frequent TDM for therapeutic efficacy places a significant burden on children and their families who are required to travel to medical centers for frequent appointments. In the case of rural settings, this often means traveling over great distances to clinics to meet the strict trough sampling time points, which are usually very early in the morning or late in the evening. Dickerson et al. elegantly describe and assess the utility of dried blood spots for the TDM of tacrolimus and sirolimus in an effort to allow for remote monitoring of blood concentrations. The major conclusions derived from this study were that tacrolimus and sirolimus blood concentrations analyzed from dried blood spots were only minimally lower (0.6 ng/mL for tacrolimus, 0.8 ng/mL for sirolimus) than samples analyzed from venous blood samples. These minimal differences are not likely clinically relevant in patient care. This is a potentially important finding in that the use of dried blood spots for TDM would significantly reduce the sample blood volume required and eliminate the need for patients to routinely travel to medical centers for blood sampling. Despite the promise of this strategy, there are several important limitations that must be
considered. First, there was a moderate difference in measured sirolimus levels between dried blood spots and venous blood samples at higher sirolimus concentrations (up to approximately 5 ng/mL). Interpretation of the difference in drug levels by the treating clinician may cause an unnecessary dosage adjustment, which could impact efficacy or toxicity. Although the mean concentration difference between dried blood spot and venous blood analysis is minimal, patients at the upper extremes in this study, of modest sample size, appear to exhibit a greater variation in concentration. Future studies will need to determine whether this trend continues over broader ranges of sirolimus concentration and whether these changes are likely to produce meaningful differences in the interpretation of reported sirolimus concentration. It is well known that ontogeny in drug disposition pathways varies with age (4, 5). Tacrolimus and sirolimus are fundamental examples that dosing drugs in children often substantially differs from adults. Both tacrolimus and sirolimus exhibit markedly increased clearance in children compared to adults, likely owing to differences in drug metabolism pathways (6, 7). Consequently, the dosage of tacrolimus and sirolimus in pediatric populations often exceeds those of adults. It is well appreciated that drugs undergoing extensive first-pass metabolism are subject to drug–drug interactions when inducers or inhibitors are coadministered. As children appear to have increased metabolic clearance of tacrolimus and sirolimus, they may be more prone to drug–drug interactions compared with adult patients taking interacting drugs. A limitation of using dried blood spots and remote sampling is the increased turnaround time from sampling to the time the attending clinician receives the report. Most clinical laboratories report results for tacrolimus and 3
Editorial
sirolimus TDM within 24 h. Remote sampling relies on regular mail to send dried blood spots to clinical laboratories. In this study, remote sampling delayed TDM by a median of 4.5 days and one sample was reported to be lost in the mail. In the rare case of a significant drug–drug interaction, this delay may prove to be serious as blood concentrations can change dramatically and rapidly following administration of an interacting drug (8, 9). The last potential limitation of a remote sampling strategy using dried blood spots is patient adherence. It is well recognized that patient adherence to drug regimens is an important predictor of long-term successful outcome. Children and adolescents who have had solid organ transplants are known to suffer from non-adherence to therapy (10). In the current study by Dickerson et al., a certified phlebotomist was responsible for taking blood samples in a clinical setting. As acknowledged by the authors, it is unknown what impact sample collection by the patient or family members will have on the analysis. In addition to concerns surrounding spot quality, future studies should evaluate adherence to the timing of sample collection in relation to dosing. There may be difficulties interpreting results from patients that do not provide a true trough sample, and it may result in their dose being unnecessarily altered. In this study, Dickerson et al. have provided the framework for remote sampling for tacrolimus and sirolimus TDM using dried blood spots. They were able to demonstrate that in general, samples analyzed from capillary blood samples correlate well with those obtained from traditional venipuncture. This approach is likely to greatly enhance the quality of life for pediatric transplant patients and their families. Although a promising strategy, future studies are required before adopting this into clinical practice.
4
Bradley L. Urquhart1 and Michael J. Knauer2 Departments of Physiology and Pharmacology, Paediatrics and Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada 2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada E-mail: [email protected]
1
References 1. DICKERSON JSM, JACOT K, STACK J, SADILKOVA J, LAW Y, JACK R. Tacrolimus and sirolimus in capillary dried blood spots allows for remote monitoring. Pediatr Transplant 2015: 19: 101–106. 2. SHAW LM, HOLT DW, KEOWN P, VENKATARAMANAN R, YATSCOFF RW. Current opinions on therapeutic drug monitoring of immunosuppressive drugs. Clin Ther 1999: 21: 1632– 1652; discussion 1631. 3. VENKATARAMANAN R, SHAW LM, SARKOZI L, et al. Clinical utility of monitoring tacrolimus blood concentrations in liver transplant patients. J Clin Pharmacol 2001: 41: 542– 551. 4. FILLER G, BENDRICK-PEART J, CHRISTIANS U. Pharmacokinetics of mycophenolate mofetil and sirolimus in children. Ther Drug Monit 2008: 30: 138–142. 5. DE WILDT SN, TIBBOEL D, LEEDER JS. Drug metabolism for the paediatrician. Arch Dis Child 2014: doi: 10.1136/archdischild-2013-305212. 6. FILLER G, BENDRICK-PEART J, STROM T, ZHANG YL, JOHNSON G, CHRISTIANS U. Characterization of sirolimus metabolites in pediatric solid organ transplant recipients. Pediatr Transplant 2009: 13: 44–53. 7. WALLEMACQ PE, VERBEECK RK. Comparative clinical pharmacokinetics of tacrolimus in paediatric and adult patients. Clin Pharmacokinet 2001: 40: 283–295. 8. RUSCHITZKA F, MEIER PJ, TURINA M, LUSCHER TF, NOLL G. Acute heart transplant rejection due to Saint John’s wort. Lancet 2000: 355: 548–549. 9. ZHAO W, BAUDOUIN V, FAKHOURY M, STORME T, DESCHENES G, JACQZ-AIGRAIN E. Pharmacokinetic interaction between tacrolimus and amlodipine in a renal transplant child. Transplantation 2012: 93: e29–30. 10. SHEMESH E, ANNUNZIATO RA, SHNEIDER BL, et al. Improving adherence to medications in pediatric liver transplant recipients. Pediatr Transplant 2008: 12: 316–323.
Copyright of Pediatric Transplantation is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
