Quantifying the impact of nonadherence patterns on exposure to oral immunosuppressants

J Ross Maclean¹, Marc Pfister^2,3, Zexun Zhou², Amit Roy², Vickie A Tuomari¹, Michael Heifets^1
1Department of Global Development and Medical Affairs, Bristol-Myers Squibb; ²Clinical Pharmacology & Pharmacometrics, Bristol-Myers Squibb, Princeton, NJ, USA; ³Quantitative Solutions, Bridgewater, NJ, USA

Background and objectives: Nonadherence to oral immunosuppressive drugs in renal transplant patients remains a major challenge. The objective of this study was to develop an adherence-exposure model that 1) quantifies the impact of nonadherence patterns on cyclosporine levels and 2) identifies nonadherence patterns that are associated with unfavorable transplantation outcomes.
Design, setting, participants, and measurements: This model quantified variability in drug exposure, expressed as the coefficient of variation (CV%), for time-averaged and trough cyclosporine levels (C_avg and C_min, respectively), and percentage of days spent below the therapeutic C_min target. Simulated patterns of nonadherence closely matched those observed in clinical practice for four nonadherence clusters and an "Others" category.
Results: Patients in simulated nonadherence clusters 1–3 spent a mean (standard deviation) 5.8% (4.9), 9.0% (5.0), and 6.5% (3.4) of days below the C_min target, compared with 76.8% (6.5) for cluster 4 and 38.3% (6.4) for the "Others" category. Mean (standard deviation) CV% values for C_min were 24.1 (7.9), 35.4 (11.7), and 34.1 (10.6) for clusters 1–3, compared with 136.4 (23.6) for cluster 4 and 64.8 (10.3) for the "Others" category. Findings for C_avg were similar.
Conclusion: Based on nonadherence patterns and known relationships between CV% for C_min and C_avg, and transplantation outcomes, patients in cluster 4 and the "Others" category are expected to be at high risk of allograft rejection. The proposed drug adherence-exposure model is useful to identify high-risk patients who can be targeted for interventions aimed at enhancing drug adherence to optimize clinical long-term outcomes.

Keywords: immunosuppressive agents, logistic models, kidney transplantation, cyclosporine