BACKGROUND and OBJECTIVES: Despite the efforts made to optimize adherence, every transplant patient will, at least occasionally, miss doses or take them outside the prescribed times (i.e., poor execution). This study aims at quantifying the impact of poor execution on the exposure to cyclosporine (CSA) and tacrolimus (CSA) in renal transplant patients.

METHODS: Previously published and validated pharmacokinetic tools were used to simulate steady-state (SS) PK profiles of CSA and TAC when given to renal patients, who had reached either a standard or a minimized targeted exposure value (according to current clinical practices). The impact of CYP3A5 expression was also taken into account for TAC. Then, multiple situations were simulated where SS was interrupted due to a missed or delayed dose, and the impact on the exposure (trough level: C0; and area under the curve: AUC) was explored. Secondly, different strategies to restore SS efficiently were tested.

RESULTS: It was observed that: (i) a single forgotten dose can immensely impact the SS of the concentrations: 75% of decrease in the C0 for CSA and 30% for TAC; (ii) For patients being at the lowest targets of exposure, C0 values of CSA or TAC are almost undetectable at the end of the dosing interval, regardless of their CYP3A5 status; (iii) After this oversight, 3 to 5 doses are necessary to restore the SS and about 20% of the total exposure (AUC) is lost in the next 5 dosing intervals; (iv) A dose of one and a half times the usual dose should be recommended in the event of a total dose oversight in most patients, while a delay up to 4 hours has generally a minimal impact on the SS. For greater delays, an adapted dose should be recommended.

CONCLUSION: The impact of poor adherence on the exposure to two of the main prescribed immunosuppressive drugs in renal transplant patients has been quantified. Considering that intra-patient variability in the exposure is known as a predictive factor of poor graft outcome, these results can be used to provide patients with clear recommendations, both preventively and in response to their questions.

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