Effect of pharmacokinetic model misspecification on antibiotic probability of target attainment predicted by Monte Carlo simulation .

Objective: The first aim of this study was to compare the predictability of efficacy by Monte Carlo simulation between a true one-compartment model and a true two-compartment model for doripenem. The second aim was to explore how we can identify the usefulness of a one-compartment model when the pharmacokinetic/pharmacodynamic (PK/PD) indices between three misspecified one-compartment models and a true two-compartment model are compared.

Materials And Methods: The reported two-compartment model parameters of two doripenem studies and a vancomycin study were used to generate 200 virtual concentration-time profiles for each study. Sparse and dense sampling designs were selected to build the one- and two-compartment models, respectively. The probability of target attainment (PTA) for the PK/PD indices were compared between the one- and two-compartment models of the same drug, applying the clinical breakpoint distribution of minimum inhibitory concentrations (MICs).

Results: The simulated concentration-time profiles reproduced the original data well. In addition, PTAs were similar between the one- and two-compartment models when infusion time and MIC were the same in the doripenem studies. For vancomycin simulations, the maximum difference was 65.9% between a misspecified one-compartment model and the true two-compartment model.

Conclusion: When a misspecified one-compartment model was established with sparse sampling data, the PTA was significantly different from that of the two-compartment model. Thus, a useful PK model must be verified through diagnostic plots and visual predictive checks and the range of sampling time should be sufficient to explain the PK of a drug.