1. 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

2. 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

3. Variability in tacrolimus pharmacokinetics
Inter-patient variability

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

5. 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

6. 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

7. How to calculate intra-patient variability?

8. Intra-patient variability in Tacrolimus exposure

9. Follow-up study
Nauras Shuker

10. 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 May 18. [Epub ahead of print]

11. 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 May 18. [Epub ahead of print]

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

13. High IPV is associated with worse graft outcome.

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

15. Estimated hazard ratios

16. Estimated hazard ratios

19. 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?

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

21. Questions?