LB-019 - CAN PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING COMPLEMENT THERAPEUTIC DRUG MONITORING FOR DIGOXIN DOSE OPTIMIZATION IN PATIENTS WITH RENAL IMPAIRMENT?

Y. Chen¹, Y. Huang², Y. Lan³, Y. Ho²; ¹Department of Pharmacy, National Taiwan University Hospital, Taipei, Taiwan, ²National Taiwan University College of Medicine, Taipei, Taiwan, ³National Taiwan University College of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan, Taiwan.

Background: Digoxin is a cardiac glycoside indicated for heart failure and atrial fibrillation. Therapeutic drug monitoring (TDM) is often applied to patients prescribed with digoxin due to its narrow therapeutic index and dosing variabilities frequently observed in certain disease state (e.g., chronic kidney disease, CKD) and polypharmacy users. Additionally, digoxin is a substrate of drug transporters such as p-glycoprotein which may further complicate dosing appropriateness especially in CKD. The objectives of the study are to establish a digoxin PBPK model for clinical use and to examine whether physiologically based pharmacokinetics (PBPK) can be applied to estimate patients’ digoxin concentrations.

Methods: Encrypted medical records, including demographics, comorbidities, digoxin prescription details, comedications, and certain laboratory data, of patients with digoxin prescription and TDM data were acquired from a medical center after obtaining ethics approval. Relevant virtual populations in the Simcyp Simulator were used for simulating serum digoxin concentrations according to individual patient’s demographics, eGFR, and exact digoxin regimen. The resulting patients’ digoxin concentration-time profiles were checked and compared to respective TDM observed values for comparability appraisal.

Results: The digoxin PBPK model was finalized by optimizing iteratively using clinical pharmacokinetic (PK) data from 102 studies. Medical records, including detailed medication profiles of fourteen patients, were collated for digoxin PBPK simulation. A typical PK profile is shown in the Figure. Overall, most of the observed TDM data points (yellow dot) are close to the simulated mean (green line) and fell within the simulated 5th and 95th percentile (dashed grey line) ranges. For varying degree of eGFR, i.e., Healthy Volunteer (n = 5), Renal Impaired_Mild (n = 3), Renal Impaired_Moderate (n = 3), Renal Impaired_Severe (n = 3), the satisfactory predictability was 88.9% (8 in 9), 100% (3 in 3), 66.7% (2 in 3), and 66.7% (2 in 3), respectively.

Conclusion: PBPK holds potential for digoxin dose optimization in clinical settings. Retrospective validating using larger TDM cohort and prospective trials in real-life patients is awaited prior to wider applications.