A high intra-patient variability in tacrolimus exposure is associated with poor long-term outcome of kidney transplantation Teun van Gelder Depts. of Pharmacy and Nephrology Erasmus MC, Rotterdam, the Netherlands

Disclosures Name: Teun van Gelder, MD, Erasmus Medical Center Rotterdam, Netherlands Commercial Interests & Nature of Relationships: Sandoz, Roche, Novartis, Astellas, Siemens, Thermo-Fischer, Teva, Chiesi: Consultant/Speaker received honoraria Chiesi, Astellas: Research Grant Support, study on transplant related diseases

Variability in tacrolimus pharmacokinetics Inter-patient variability

Variability in tacrolimus pharmacokinetics Inter-patient variability Intra-patient variability

Intra-patient tacrolimus variability The fluctuation in Tac concentrations within an individual over a certain period of time during which the Tac dose is unchanged

High intra-patient tacrolimus variability Concentrations will often be outside the therapeutic range Too low: increased risk of rejection Too high: increased risk of toxicity May be associated with inferior outcomes after transplantation

How to calculate intra-patient variability?

Intra-patient variability in Tacrolimus exposure

Follow-up study Nauras Shuker

Follow-up study Enlarge the number of patients (1/2000 – 12/2010), longer follow-up IPV calculated using Tac levels obtained between 6-12 months Composite endpoint “event” Graft loss Doubling of serum creatinine >month 12 Late BPAR or transplant glomerulopathy Shuker, Transpl Int. 2016 May 18. [Epub ahead of print]

Follow-up study Median follow-up 5.5 yr (range 0.06 – 14.1 yr) 4823 person yrs at risk 188 of 808 patients (23.3%) events: 68 graft loss 12 doubling of serum creatinine 108 late BPAR or TGP Shuker, Transpl Int. 2016 May 18. [Epub ahead of print]

Median IPV = 16.2% Low IPV High IPV (n = 808) 16.2%

High IPV is associated with worse graft outcome.

Multivariable Cox regression analysis Shuker, Transpl Int. 2016 May 18. [Epub ahead of print]

Estimated hazard ratios

Estimated hazard ratios

What to do about it? Possible interventions. Improving adherence Discuss variability with your patient Hurdles in taking drugs at the right time? Dietary changes? Higher target concentration range? From twice-daily to once-daily dosing?

Conclusion: A higher intra-patient variability is associated with poor long term outcome. Lower tacrolimus concentrations are associated with poor long term outcome.

Questions?