Optimization of meropenem continuous infusion based on Monte Carlo simulation integrating with degradation study

Abstract

Objective: Meropenem degradation poses a challenge to continuous infusion (CI) implementation. However, data about the impact of degradation on the probability of target attainment (PTA) of meropenem has been limited. This study evaluated the stability of meropenem brands and the consequence of in-bottle degradation on PTA in different environmental scenarios.

Method: Seven meropenem generic brands prepared at concentrations of 1 g/48mL and 2 g/48mL in saline were examined at 25, 30, and 37°C over 8 h. A linear mixed-effects model was used to estimate degradation rate constant and potential covariates. In-bottle stability data was subsequently integrated as input for a deterministic and stochastic simulation using a published population pharmacokinetic model of critical illness. The impact of the degradation on target attainment at 98%fT>MIC was assessed.

Results: Time, temperature, and infusion concentration were factors affecting the stability of the meropenem solution for all products. The differences in the degradation of seven generics were subtle, so their simulated plasma concentrations were equal. Meropenem CI with 8 h renewal infusion achieved a higher PTA than the extended 3 h infusion, even at the highest degradation condition. The impact of meropenem degradation on PTA was minimal vis-à-vis the meropenem dose, patient's renal function, and microbial susceptibility. Meropenem degradation reduced PTA by an observable magnitude in patients with augmented renal clearance and difficult-to-treat pathogens. Dose escalation up to 1.5-2g every 8 h could restore this reduction to the target 90% PTA.

Conclusion: Meropenem CI with 8 h of renewal infusion, considering stability even in tropical areas, was feasible to maximize the efficacy to difficult-to-treat pathogens.

Fig 1. Schematic illustrating the integration of the in-bottle degradation and the two-compartment population pharmacokinetic model.

The drug input from the bottle was simulated with different infusion dose regimens altered by degradation. The drug distribution and elimination followed the published pharmacokinetic model [7]. Dose, k_deg, t, T_inf, Vc, Vp, Cl, Q denoted prescribed dose (mg), degradation rate constant (h^-1), time (h), length of infusion (h), central’s volume of distribution (L), peripheral’s volume of distribution (L), total clearance (L/h) and inter-compartmental clearance (L/h), respectively.

Fig 2. Diagnostic plots of the best-fit model.

A. Goodness of fit plot. B. Standardized residuals plot. C. Normal Q-Q plot.

Fig 3. The remaining percentage of meropenem concentration for 7 brands by time under the investigated conditions.

Fig 4

A. Meropenem simulated concentration profiles and B. The ratio of steady-state minimum concentration. Data were generated in different investigated conditions due to the decay process (C_min) and steady-state concentration without degradation (C_no-deg) for a typical patient (Clcr = 80.8 mL/min, body weight = 70 kg, serum albumin = 2.8 g/dL) applying continuous infusion with different infusion lengths (1 g every 3, 6, or 8 h) after a loading dose of 500 mg over 30 min.

Fig 5. PTA treatment day 1 of 1 g every 8 h after LD of 500 mg over 30 min with various infusion lengths (3 h, 6 h, 8 h) and PK/PD target of 98%fT>MIC.

Data were for a typical patient (Clcr = 80.8 mL/min, body weight = 70 kg, serum albumin = 2.8 g/dL) without and with degradation process at different conditions. Abbreviations: PTA, probability of target attainment; MIC, minimum inhibitory concentration.

Fig 6. Impact of creatinine clearance on PTA of meropenem continuous infusion.

PTA was evaluated at treatment day 1 with a target of 98%fT>MIC for Clcr-based grouped patients (weight of 70 kg and serum albumin of 2.8 g/dL). A continuous infusion with 1 g every 8 h after an LD of 500 mg over 30 min was used, with or without degradation process at different conditions. Abbreviations: PTA, probability of target attainment; MIC, minimum inhibitory concentration; Clcr, creatinine clearance.

Fig 7. Impact of prescribed dose on PTA of meropenem continuous infusion.

PTA was evaluated at treatment day 1 with a target of 98%fT>MIC for a total daily dose of 3, 4.5, and 6 g administered via continuous infusion after a loading dose of 500 mg over 30 min. Three temperatures (25, 30, and 37°C) and four periods of bottle renewal (3, 4, 6, and 8 h) were evaluated for elevated MIC pathogens (8 and 16 mg/L) and Clcr-based grouped patients (weight of 70 kg and serum albumin of 2.8 g/dL). Infusion concentration was kept at 1 g/48mL. Red, orange, yellow, and green colors are used when PTA < 50%, 50% ≤ PTA < 80%, 80% ≤ PTA < 90%, and PTA ≥ 90%, respectively. Abbreviations: PTA, probability of target attainment; MIC, minimum inhibitory concentration; Clcr, creatinine clearance.