Parametric and Nonparametric Population Pharmacokinetic Models to Assess Probability of Target Attainment of Imipenem Concentrations in Critically Ill Patients

Population pharmacokinetic modeling and simulation (M&S) are used to improve antibiotic dosing. Little is known about the differences in parametric and nonparametric M&S. Our objectives were to compare (1) the external validation of parametric and nonparametric models of imipenem in critically ill patients and (2) the probability of target attainment (PTA) calculations using simulations of both models. The M&S software used was NONMEM 7.2 (parametric) and Pmetrics 1.5.2 (nonparametric). The external predictive performance of both models was adequate for eGFRs ≥ 78 mL/min but insufficient for lower eGFRs, indicating that the models (developed using a population with eGFR ≥ 60 mL/min) could not be extrapolated to lower eGFRs. Simulations were performed for three dosing regimens and three eGFRs (90, 120, 150 mL/min). Fifty percent of the PTA results were similar for both models, while for the other 50% the nonparametric model resulted in lower MICs. This was explained by a higher estimated between-subject variability of the nonparametric model. Simulations indicated that 1000 mg q6h is suitable to reach MICs of 2 mg/L for eGFRs of 90–120 mL/min. For MICs of 4 mg/L and for higher eGFRs, dosing recommendations are missing due to largely different PTA values per model. The consequences of the different modeling approaches in clinical practice should be further investigated.

Dose Tailoring of Vancomycin Through Population Pharmacokinetic Modeling Among Surgical Patients in Pakistan

Background: Vancomycin is a narrow therapeutic agent, and it is necessary to optimize the dose to achieve safe therapeutic outcomes. The purpose of this study was to identify the significant covariates for vancomycin clearance and to optimize the dose among surgical patients in Pakistan.Methods: Plasma concentration data of 176 samples collected from 58 surgical patients treated with vancomycin were used in this study. A population pharmacokinetic model was developed on NONMEM® using plasma concentration–time data. The effect of all available covariates was evaluated on the pharmacokinetic parameters of vancomycin by stepwise covariate modeling. The final model was evaluated using bootstrap, goodness-of-fit plots, and visual predictive checks.Results: The pharmacokinetics of vancomycin followed a one-compartment model with first-order elimination. The vancomycin clearance (CL) and volume of distribution (Vd) were 2.45 L/h and 22.6 l, respectively. Vancomycin CL was influenced by creatinine clearance (CRCL) and body weight of the patients; however, no covariate was significant for its effect on the volume of distribution. Dose tailoring was performed by simulating dosage regimens at a steady state based on the CRCL of the patients. The tailored doses were 400, 600, 800, and 1,000 mg for patients with a CRCL of 20, 60, 100, and 140 ml/min, respectively.Conclusion: Vancomycin CL is influenced by CRCL and body weight of the patient. This model can be helpful for the dose tailoring of vancomycin based on renal status in Pakistani patients.

1118. Population Pharmacokinetics of Contezolid Acefosamil and Contezolid – Rationale for a Safe and Effective Loading Dose Regimen

Background Contezolid (CZD) is a novel oral oxazolidnone with comparable activity and potentially improved safety compared to current oxazolidinones. The intravenous (IV) double prodrug contezolid acefosamil (CZDa) is converted via MRX-1352 to active CZD. CZDa paired with CZD holds promise as a safe and effective treatment for serious Gram-positive infections such as those caused by methicillin-resistant Staphylococcus aureus. Sequential therapy with CZDa IV followed by CZD oral (PO) offers flexible treatment options in hospital and outpatient settings for conditions such as diabetic foot infections. We aimed to design a CZDa/CZD dosage regimen leveraging population pharmacokinetic modeling (PopPK). Methods PopPK simultaneously fit data from 184 adult subjects. These were 1) plasma concentrations (by LC-MS/MS) of MRX-1352, CZD, and its metabolite MRX-1320 from 66 healthy subjects receiving CZDa (150-2400 mg IV) for up to 10 days, 2) CZD and MRX-1320 concentrations from 44 healthy subjects receiving single CZD PO doses of 400, 800, or 1200 mg with and without food or multiple doses Q12h for up to 28 days, and 3) CZD concentrations from 74 Phase 2 patients receiving CZD 800 mg PO Q12h. PopPK and Monte Carlo simulations were used to optimize CZD exposures. Results CZDa was rapidly converted to MRX-1352, which was converted less rapidly to CZD. CZD was well absorbed and food enhanced its bioavailability. For CZD 800 mg PO with food, apparent total clearance of CZD was 13.1 L/h (22% coefficient of variation) in healthy subjects and 14.5 L/h (53% CV) in patients. The apparent volume of distribution at steady-state was 20.5 L. A loading dose of CZDa 2000 mg IV, then CZDa 1000 mg IV Q12h, and followed by CZD 800 mg PO Q12h achieved areas under the curve (AUC) between 75 and 100 mg*h/L (medians; Figure) on all study days. Compared to CZD AUCs, the MRX-1352 AUCs during IV dosing were higher. While the median MRX-1320 AUCs were lower (18 to 48 mg*h/L), some accumulation was predicted in ~5% of subjects. Conclusion A loading dose of CZDa 2000 mg IV followed by either CZDa 1000 mg IV or CZD 800 mg PO Q12h was predicted to reliably achieve efficacious CZD exposures on day 1 and maintain those exposures throughout therapy. This regimen will be evaluated in Phase 3 studies in complicated skin infections and diabetic foot infections. Disclosures Jürgen B. Bulitta, PhD, MicuRx Pharmaceuticals, Inc. (Consultant) Barry HAFKIN, MD, MicuRx Pharmaceuticals Inc. (Consultant)

Population Pharmacokinetic Modeling and Dose Optimization of Vancomycin in Chinese Patients with Augmented Renal Clearance

Patients with augmented renal clearance (ARC) have been described as having low vancomycin concentration. However, the pharmacokinetic model that best describes vancomycin in patients with ARC has not been clarified. The purpose of this study is to determine the pharmacokinetic of vancomycin in Chinese adults and the recommend dosage for patients with different renal function, including patients with ARC. We retrospectively collected 424 vancomycin serum concentrations from 209 Chinese patients and performed a population pharmacokinetic model using NONMEM 7.4.4. The final model indicated that the clearance rate of vancomycin increased together with the creatinine clearance, and exhibited a nearly saturated curve at higher creatinine clearance. The estimated clearance of vancomycin was between 3.46 and 5.58 L/h in patients with ARC, with 5.58 being the maximum theoretical value. The central volume of distribution increased by more than three times in patients admitted to Intensive Care Unit. Monte Carlo simulations were conducted to explore the probability of reaching the target therapeutic range (24-h area under the curve: 400–650 mg·h/L, trough concentration: 10–20 mg/L) when various dose regimens were administered. The simulations indicated that dose should increase together with the creatinine clearance until 180 mL/min. These findings may contribute to improving the efficacy and safety of vancomycin in patients with ARC.