BTS Report 2014: Variability: does it impact outcomes?

Maria Dalby reporting on the Oral Presentation by Marc Clancy, Western Infirmary, Glasgow – Although the mainstay of clinical immunosuppression since the 1980s, calcineurin inhibitors (CNIs) are narrow therapeutic index drugs and small changes in systemic exposure can have significant consequences in terms of pharmacodynamics response. Marc Clancy, transplant surgeon from Glasgow, explained the concept of individual patient variability in the oral availability of CNIs and the consequences of over- and under-immunosuppression.

A number of factors have been shown to affect tacolimus trough levels. Inter-patient variability is typically caused by factors such as age, body mass index (BMI), genetic polymorphisms, or drug- drug interactions [1-7], which cannot be easily modified. In contrast, factors causing intra-patient variability (IPV) such as the timing of intake of drug and adherence to treatment can be addressed with relatively small interventions which can make a significant clinical difference for the overall outcome.

Intra-patient variability is a common and well-known issue in transplantation recipients. In the SYMPHONY study, intra-patient variability – that is, the average difference between an individual patient’s measured trough level values and mean value – was 28% in the low-dose tacrolimus arm, and only 11% of patients remained entirely within their target range for tacrolimus trough levels for the first two months of treatment [8, 9]. Results based on cyclosporine data show that an IPV of 28% in trough levels is associated with significantly higher rates of acute rejection [10]. A study in paediatric patients showed that the IPV of tacrolimus trough levels in patients experiencing acute rejection was 53%, compared with only 30% in patients without rejection [11]; overall, greater IPV in tacrolimus trough levels is strongly associated with graft failure [12, 13].

Marc Clancy’s own experience in the West of Scotland bears out the findings reported in the literature, with rates of acute rejection almost doubling and graft survival decreasing from 99% to 92% in patients with IPV over 27% in the first six months post-transplantation [14]. Recognising that the first 12 months post-transplantation constitute a very ‘noisy’ period with a lot of clinical management that can interfere with tacrolimus levels, Marc Clancy and his team have continued to monitor renal transplant recipients in the West of Scotland in a retrospective study. At approximately four years of follow-up, patients in the high-variability (mean IPV 24% 6–12 months post-transplant) arm were significantly more likely to have lost their graft (hazard ratio [HR] 3.69; p=0.004) or experienced acute rejection (HR 1.97; p=0.004) compared with patients with low variability (mean IPV 11% 6–12 months post-transplant). Patients in the low-variability arm also achieved significantly better renal function during follow-up. Marc Clancy and his team hypothesised that this variation may in fact be a surrogate for treatment adherence – however, censoring for pre-dialysis phosphate variability as a marker of compliance showed no significant difference.

The once-daily formulation of tacrolimus has been shown to cause less variability in tacrolimus trough levels [15] and area under the plasma curve (AUC) [16] compared with the twice-daily formulation. The latter is of particular interest, since even small variations in AUC may represent significant variability in exposure. Marc Clancy finished by concluding that even small slips from the narrow path of CNI immunosuppression may lead to significant loss of graft function and that prospective studies to reduce variability and improve treatment adherence are justified.

References

1.         Venkataramanan, R., et al., Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet, 1995. 29(6): p. 404-30.

2.         Schiff, J., E. Cole, and M. Cantarovich, Therapeutic monitoring of calcineurin inhibitors for the nephrologist. Clin J Am Soc Nephrol, 2007. 2(2): p. 374-84.

3.         Antignac, M., et al., Population pharmacokinetics and bioavailability of tacrolimus in kidney transplant patients. Br J Clin Pharmacol, 2007. 64(6): p. 750-7.

4.         de Jonge, H., M. Naesens, and D.R. Kuypers, New insights into the pharmacokinetics and pharmacodynamics of the calcineurin inhibitors and mycophenolic acid: possible consequences for therapeutic drug monitoring in solid organ transplantation. Ther Drug Monit, 2009. 31(4): p. 416-35.

5.         Scholten, E.M., et al., AUC-guided dosing of tacrolimus prevents progressive systemic overexposure in renal transplant recipients. Kidney Int, 2005. 67(6): p. 2440-7.

6.         Dew, M.A., et al., Rates and risk factors for nonadherence to the medical regimen after adult solid organ transplantation. Transplantation, 2007. 83(7): p. 858-73.

7.         Vasquez, E.M., et al., Medication noncompliance after kidney transplantation. Am J Health Syst Pharm, 2003. 60(3): p. 266-9.

8.         Ekberg, H., et al., The challenge of achieving target drug concentrations in clinical trials: experience from the Symphony study. Transplantation, 2009. 87(9): p. 1360-6.

9.         Ekberg, H., et al., Relationship of tacrolimus exposure and mycophenolate mofetil dose with renal function after renal transplantation. Transplantation, 2011. 92(1): p. 82-7.

10.        Waiser, J., et al., Impact of the variability of cyclosporin A trough levels on long-term renal allograft function. Nephrol Dial Transplant, 2002. 17(7): p. 1310-7.

11.        Hsiau, M., et al., Monitoring nonadherence and acute rejection with variation in blood immunosuppressant levels in pediatric renal transplantation. Transplantation, 2011. 92(8): p. 918-22.

12.        Borra, L.C., et al., High within-patient variability in the clearance of tacrolimus is a risk factor for poor long-term outcome after kidney transplantation. Nephrol Dial Transplant, 2010. 25(8): p. 2757-63.

13.        Pollock-Barziv, S.M., et al., Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children. Pediatr Transplant, 2010. 14(8): p. 968-75.

14.        Stevenson, K.S. and e. al., Oral presentation at ESOT. 2011.

15.        Wu, M.J., et al., Lower variability of tacrolimus trough concentration after conversion from prograf to advagraf in stable kidney transplant recipients. Transplantation, 2011. 92(6): p. 648-52.

16.        Stifft, F., et al., Lower Variability in 24-Hour Exposure During Once-Daily Compared to Twice-Daily Tacrolimus Formulation in Kidney Transplantation. Transplantation, 2013.