Changes of mycophenolic acid (MPA) pharmacokinetics with aging were investigated in rats. We also compared the effect of concomitant amoxicillin/clavulanate combination (CVA/AMPC) on the pharmacokinetics of MPA in 4-week-old and 12-week-old rats (the package insert of CVA/AMPC warns of possible interaction with MPA). Four-week-old rats showed a 1.4-fold higher total body clearance of MPA and a lower volume of distribution of MPA (65%), compared to the values in 12-week-old rats. However, the difference in MPA pharmacokinetics disappeared when enterohepatic circulation was eliminated by bile duct cannulation (BDC). Concomitant CVA/AMPC significantly reduced plasma MPA concentration in intact rats of both age groups, and the age-dependent difference of MPA pharmacokinetics was no longer apparent. The effect of CVA/AMPC was not seen in rats that had undergone BDC, suggesting that the drug-drug interaction can be attributed to inhibition of enterohepatic circulation by CVA/AMPC. These results indicate that the aging-related alteration of MPA pharmacokinetics is a consequence of immature enterohepatic circulation in 4-week-old rats. Higher doses of MPA may be necessary in juveniles.

Background Atrial fibrillation (AF) is a risk factor for ischemic stroke (IS). We developed a novel risk score of IS (HELT-E2S2 score) in non-valvular atrial fibrillation (NVAF) patients from the combined database of 5 major AF registries in Japan. However, this score does not include echocardiographic (Echo) parameters that have been reported to be risk factors of IS, such as left atrial diameter (LAD) enlargement or increased relative wall thickness (RWT) of left ventricle (LV). Purpose To investigate the predictive value of Echo parameters in Japanese patients with NVAF. Methods After excluding patients without the Echo data, 6,032 NVAF patients were analyzed in the present study. LAD was measured in the parasternal long axis view at the end-ventricular systole. RWT was calculated as (2x posterior wall thickness)/ LV end-diastolic dimension. We compared clinical characteristics and the incidence of IS between NVAF patients divided by LAD level (High/Low LAD group) and RWT level (High/Low RWT group). To balance the follow-up period among the registries, event data from individuals whose follow-up period exceeded 730 days were excluded from the analysis. Results The optimal cut-off value of LAD and RWT to predict the incidence of IS with the receiver operating characteristic analysis was 43.3 mm and 0.4167, respectively. Between the High/Low LAD groups (High LAD: n=2,640 vs. Low LAD: n=3,392), age (70.3±12.1 vs. 68.3±12.5 years; p<0.001), CHA2DS2-VASc score (3.02±1.84 vs. 2.57±1.78; p<0.001), HELT-E2S2 score (2.20±1.31 vs. 1.55±1.33; p<0.001), the prescription of oral anticoagulants (OACs) (69.5 vs. 51.5%; p<0.001), LV ejection fraction (60.4±13.4 vs. 64.4±10.7%; p<0.001) and RWT (0.401±0.091 vs. 0.396±0.082; p=0.02) were significantly different. Between the High/Low RWT groups (High RWT: n=2,293 vs. Low RWT: n=3,739), percentage of female (35.6 vs. 27.8%; p<0.001), age (71.2±12.1 vs. 68.0±12.4 years; p<0.001), CHA2DS2-VASc score (3.08±1.82 vs. 2.58±1.79; p<0.001), HELT-E2S2 score (2.10±1.39 vs. 1.67±1.31; p<0.001), the prescription of OACs (62.6 vs. 57.4%; p<0.001), LV ejection fraction (65.5±9.9 vs. 60.9±13.0%; p<0.001) and LAD (43.0±8.1 vs. 42.4±8.3; p=0.004) were significantly different. In Kaplan-Meier analysis, the incidence of IS was different between the groups during the median follow-up period of 730 days (High LAD vs. Low LAD; 1.82 vs. 1.00 per 100 person-years; p<0.001, by log-rank test, High RWT vs. Low RWT; 1.86 vs. 1.06; p<0.001) (Figure). Both High LAD (hazard ratio: 1.65, 95% CI: 1.12–2.46; p=0.01) and High RWT (hazard ratio: 1.43, 95% CI: 1.01–2.04; p=0.045) were independent predictors of the incidence of IS after adjustment by the components of the HELT-E2S2 score and other clinically relevant variables including co-existing diseases, gender, and the prescription of OACs (Table). Conclusion Echo parameters, LAD and RWT, were independently associated with the incidence of IS among Japanese patients with NVAF. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Japan Agency for Medical Research and Development