Intrapatient variability of aminoglycoside pharmacokinetic parameters in simulated extended-interval aminoglycoside dosing

Introduction: There is intrapatient variability of aminoglycoside pharmacokinetic (PK) parameters in critically ill patients (CIP). We simulated extended-interval aminoglycoside dosing from multiple traditional dosing (TD) studies using Barnes and Jewish (BJ) and Hartford (H) dosing strategies to assess aminoglycoside PK variability in CIP using these dosing methods. Methods: CIP with 2-3 PK studies were included. Exclusions were CrCL<20 ml/min, hemodialysis, and BJ or H nomogram recommendations for TD. From the simulations, a 10 hour aminoglycoside level (Cp) was used to adjust the dosing interval, if necessary, using the BJ or H nomogram and the simulation was repeated. Cmax, Cmax:MIC2, Cmin, time Cp<2, time Cp<0.5, were compared to assess intrapatient variability using two way ANOVA. Variables were also assessed for correlation using Pearson Correlation. Results: Intrapatient variability occurred in BJ Cmax and Cmax:MIC2 between analysis 2 and 3 (p<0.05) and in H Cmax between analysis 1 and 3 (p<0.01)and 2 and 3 (p<0.01). Correlation between dose and Vd was not significant between BJ study 2(r=0.197, p=ns) and 3 (r=0.01, p=ns) and in H studies 1 (r=0.01, p=ns), 2(r=0.06, p=ns), and 3 (r=0.035, p=ns). Conclusion: Intrapatient PK variability exists with BJ and H dosing strategies in CIP. Vd can not be assumed to achieve desired Cmax in CIP. We do not recommend BJ and H dosing strategies in CIP. BJ1(n=43) BJ2(n=43) BJ3(n=25) H1(n=37) H2(n=36) H3(n=21) Cmax 15.2±5.6 14.3±4.1 17.2±6.6 20.2±7.1 19.9±6.1 25.2±9.9 Cmax:MIC ₂ 7.6±2.8 7.15±2.1 8.6±3.3 10.1±3.6 9.9±3.0 12.6±5.0 TCp<2.0 16.9±5.5 15.8±5.5 15.1±6.0 14.4±3.8 14.4±4.4 14.1±6 TCp<0.5 7.5±5.5 6.3±5.2 6.4±5.2 6.12±4 5.5±4.7 6.2±4.8 Cmln 0.23±0.23 0.33±0,36 0.38±0.43 0.27±0.29 0.32±0.43 0.36±0.45.