Comparison of different methods to assess tacrolimus concentration intra-patient variability as potential marker of medication non-adherence

Barbora Kostalova; Katerina Mala-Ladova; Sylvie Dusilova Sulkova; Kris Denhaerynck; Sabina De Geest; Josef Maly

doi:10.3389/fphar.2022.973564

Comparison of different methods to assess tacrolimus concentration intra-patient variability as potential marker of medication non-adherence

Front Pharmacol. 2022 Oct 13:13:973564. doi: 10.3389/fphar.2022.973564. eCollection 2022.

Authors

Barbora Kostalova¹, Katerina Mala-Ladova¹, Sylvie Dusilova Sulkova², Kris Denhaerynck³, Sabina De Geest^{3

4}, Josef Maly¹

Affiliations

¹ Department of Social and Clinical Pharmacy, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czechia.
² Department of Nephrology, University Hospital Hradec Kralove and Faculty of Medicine Hradec Kralove, Charles University, Hradec Kralove, Czechia.
³ Department Public Health, Institute of Nursing Science, University of Basel, Basel, Switzerland.
⁴ Academic Center for Nursing and Midwifery, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium.

Abstract

Background and objective: Non-adherence to tacrolimus commonly manifests as low drug concentrations and/or high intra-patient variability (IPV) of concentrations across multiple measurements. We aimed to compare several methods of tacrolimus IPV calculation and evaluate how well each reflects blood concentration variation due to medication non-adherence in kidney transplant recipients. Methods: This Czech single-center retrospective longitudinal study was conducted in 2019. All outpatients ≥18 years of age, ≥3 months post-transplant, and on tacrolimus-based regimens were approached. After collecting seven consecutive tacrolimus concentrations we asked participating patients to self-report adherence to immunosuppressants (BAASIS^© scale). The IPV of tacrolimus was calculated as the medication level variability index (MLVI), the coefficient of variation (CV), the time-weighted CV, and via nonlinearly modeled dose-corrected trough levels. These patient-level variables were analyzed using regression analysis. Detected nonlinearities in the dose-response curve were controlled for by adding tacrolimus dosing and its higher-order terms as covariates, along with self-reported medication adherence levels. Results: Of 243 patients using tacrolimus, 42% (n = 102) reported medication non-adherence. Non-adherence was associated with higher CVs, higher time-weighted CVs, and lower dose-corrected nonlinearly modeled trough levels; however, it was not associated with MLVIs. All of the significant operationalizations suggested a weak association that was similar across the applied methods. Discussion and conclusion: Implementation non-adherence was reflected by higher CV or time-weighted CV and by lower blood concentrations of tacrolimus. As an additional tool for identifying patients at risk for non-adherence, simple IPV calculations incorporated into medical records should be considered in everyday clinical practice.

Keywords: immunosuppression; intra-patient variability; kidney transplantation; medication adherence; tacrolimus; tacrolimus immunosuppression.