External validation of population pharmacokinetic models of tacrolimus in Thai adult liver transplant recipients.

OBJECTIVE: Several population pharmacokinetic models of tacrolimus in liver transplant patients were built, and their predictability was evaluated in their settings. However, the extrapolation in the prediction was unclear. This study aimed to evaluate the predictive performance of published tacrolimus models in adult liver transplant recipients using data from the Thai population as an external dataset. METHODS: The selected published models were systematically searched and evaluated for their quality. The external dataset of patients who underwent the first liver transplant and received immediate-release tacrolimus was used to assess the predictive performance of each selected model. Trough concentrations between 3 and 6 months were retrospectively collected to evaluate the predictability of each model using prediction-based diagnostics, simulation-based diagnostics, and Bayesian forecasting. RESULTS: Sixty-seven patients with 360 trough concentrations and eight selected published models were included in this study. None of the models met the predictive precision criteria in prediction-based diagnostics. Meanwhile, four published population pharmacokinetic models showed a normal distribution in NPDE testing. Regarding Bayesian forecasting, all models improved their forecasts with at least one prior information data point. CONCLUSION: Bayesian forecasting is more accurate and precise than other testing methods for predicting drug concentrations. However, none of the evaluated models provides satisfactory predictive performance for generalization to Thai liver transplant patients. This underscores the need for future research to develop population PK models tailored to the Thai population. Such efforts should consider the inclusion of nonlinear pharmacokinetics and region-specific factors, including genetic variability, to improve model accuracy and applicability.

Population Pharmacokinetics and Pharmacodynamics of Vancomycin in Pediatric Patients With Various Degrees of Renal Function.

OBJECTIVE: Although vancomycin dosage recommendations in the pediatric setting for methicillin-resistant Staphylococcus aureus (MRSA) infection indicate that ≥60 mg/kg/day is correlated to a desired area under the vancomycin concentration time curve from 0 to 24 hours to minimum inhibitory concentration ratio (AUC0-24 hr/MIC) ≥400, for some patients this dosage is inadequate or relates to toxicity. This study purposed to explore vancomycin dosing for pediatrics with various degrees of renal function. METHODS: Routine monitoring data were retrospectively collected from patients, aged 1 month to 18 years. Population pharmacokinetic analysis was performed by using non-linear mixed-effect model with NONMEM software, and Monte Carlo simulation was conducted by using Crystal Ball software. RESULTS: Two hundred twelve patients with 348 vancomycin serum concentrations were included. Median age was 3.5 years (IQR, 0.9-10.9), median weight was 14.0 kg (IQR, 7.2-30.4), with baseline estimated glomerular filtration rate (eGFR) ranging from 15.5 to 359.3 mL/min/1.73 m2. A 1-compartment model with first-order elimination sufficiently described vancomycin PK. The dosing targeting AUC0-24hr/MIC ≥400 and AUC0-24hr <800 mg•h/L for pediatric patients with eGFRs of 15 to 29, 30 to 59, 60 to 89, 90 to 129, and 130 to 160 mL/min/1.73 m2 was 12.5, 25, 40, 60, and 70 mg/kg/day, respectively. All vancomycin dosing obtained >85% of the cumulative fraction of response across the MIC distribution of MRSA. CONCLUSIONS: Vancomycin dosing of 12.5, 25, 40, 60, and 70 mg/kg/day is suggested for pediatric patients with eGFRs of 15 to 29, 30 to 59, 60 to 89, 90 to 129, and 130 to 160 mL/min/1.73 m2, respectively.

Population pharmacokinetics and pharmacodynamics of piperacillin in critically ill patients during the early phase of sepsis.

This study aimed to characterize the population pharmacokinetics (PKs) of piperacillin and investigate probability of target attainment (PTA) and cumulative fraction of response (CFR) of various dosage regimens in critically ill patients during the early phase of sepsis. Forty-eight patients treated with piperacillin/tazobactam were recruited. Five blood samples were drawn before and during 0-0.5, 0.5-2, 2-4 and 4-6 or 8 h after administration. Population PKs was analyzed using NONMEM®. The PTA of 90%fT>MIC target and CFR were determined by Monte Carlo simulation. The two compartment model best described the data. Piperacillin clearance (CL) was 5.37 L/h, central volume of distribution (V1) was 9.35 L, and peripheral volume of distribution was 7.77 L. Creatinine clearance (CLCr) and mean arterial pressure had a significant effect on CL while adjusted body weight had a significant impact on V1. Subtherapeutic concentrations can occur during the early phase of sepsis in critically ill patients with normal renal function. The usual dosage regimen, 4 g of piperacillin infused over 0.5 h every 6 h, could not achieve the target for susceptible organisms with MIC 16 mg/L in patients with CLCr ≥ 60 mL/min. Our proposed regimen for the patients with CLCr 60-120 mL/min was an extended 2 h infusion of 4 g of piperacillin every 6 h. Most regimens provided CFR ≥ 90% for the E. coli infection while there was no dosage regimen achieved a CFR of 90% for the P. aeruginosa infection.

Evaluation of FOCEI and SAEM Estimation Methods in Population Pharmacokinetic Analysis Using NONMEM® Across Rich, Medium, and Sparse Sampling Data.

BACKGROUND AND OBJECTIVES: First-order conditional estimation with interaction (FOCEI) is one of the most commonly used estimation methods in nonlinear mixed effects modeling, while the stochastic approximation expectation maximization (SAEM) is the newer estimation algorithm. This work aimed to compare the performance of FOCEI and SAEM methods when using NONMEM® with the classical one- and two-compartment models across rich, medium, and sparse data. METHODS: One- and two-compartment models of the previous studies were used to simulate data in three scenarios: rich, medium, and sparse data. For each scenario, there were 100 data sets, containing 100 individuals in each data set. Every data set was estimated with both FOCEI and SAEM methods. The simulation and estimation were performed using NONMEM®. The completion rates, percentage of relative estimation errors (%RERs), root mean square errors (RMSEs), and runtimes were considered to assess the completion, accuracy, precision, and speed of estimation, respectively. RESULTS: Both FOCEI and SAEM methods provided comparable completion rates, median %RERs (ranged from - 9.03 to 3.27% for FOCEI and - 9.17 to 3.27% for SAEM) and RMSEs (ranged from 0.0004 to 1.244 for FOCEI and 0.0004 to 1.131 for SAEM) for most parameters in both models across three scenarios. The run times were much shorter with FOCEI (ranged from 0.18 to 0.98 min) compared to SAEM method (ranged from 4.64 to 12.03 min). CONCLUSIONS: For the classical one- and two-compartment models, FOCEI method exhibited comparable performance similar to SAEM method but with significantly shorter runtimes across rich, medium, and sparse sampling scenarios.

Population Pharmacokinetics and Pharmacodynamics Modeling To Optimize Dosage Regimens of Sulbactam in Critically Ill Patients with Severe Sepsis Caused by Acinetobacter baumannii.

Sulbactam is being considered as an alternative concomitant medication with other effective antibiotics for the treatment of multidrug-resistant (MDR) Acinetobacter baumannii infections. Pathophysiological changes in critically ill patients with severe sepsis, resulting in altered pharmacokinetic (PK) patterns for antibiotics, are important factors in determining therapeutic success. The aims of this study were (i) to examine the population PK parameters and (ii) to assess the probability of target attainment (PTA) for sulbactam in patients with severe sepsis caused by A. baumannii PK studies were carried out following administration of 2 g of sulbactam every 12 h on the 4th day of drug administration in 27 patients, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the plasma drug concentration remained above the MIC (T>MIC) and 60% T>MIC The central and peripheral volumes of distribution were 14.56 and 9.55 liters, respectively, and total clearances of sulbactam were 2.26 liters/h and 7.64 liters/h in patients aged >65 years and ≤65 years, respectively. The high PTAs (≥90%) for targets of 40% T>MIC and 60% T>MIC with a MIC of 4 µg/ml were observed when sulbactam was administered by a 4-h infusion of 1 g every 12 h and 1 g every 8 h, respectively. Sulbactam would be an alternative antibiotic option to coadminister with colistin for the treatment of infections caused by MDR A. baumannii However, for pathogens with MICs of >4 µg/ml, higher dosage regimens of sulbactam are required.

Population pharmacokinetics and Monte Carlo dosing simulations of meropenem during the early phase of severe sepsis and septic shock in critically ill patients in intensive care units.

Pathophysiological changes during the early phase of severe sepsis and septic shock in critically ill patients, resulting in altered pharmacokinetic (PK) patterns for antibiotics, are important factors influencing therapeutic success. The aims of this study were (i) to reveal the population PK parameters and (ii) to assess the probability of target attainment (PTA) for meropenem. The PK studies were carried out following administration of 1 g of meropenem every 8 h during the first 24 h of severe sepsis and septic shock in nine patients, and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the free plasma drug concentration remains above the MIC (fT>MIC) and 80% fT>MIC. The volume of distribution (V) and total clearance (CL) of meropenem in these patients were 23.7 liters and 7.82 liters/h, respectively. For pathogens with MICs of 4 µg/ml, the PTAs of 40% fT>MIC following administration of meropenem as a 1-h infusion of 1 g every 8 h and a 4-h infusion of 0.5 g every 8 h were 92.52% and 90.29%, respectively. For pathogens with MICs of 2 µg/ml in immunocompromised hosts, the PTAs of 80% fT>MIC following administration of 1-h and 4-h infusions of 2 g of meropenem every 8 h were 84.32% and 94.72%, respectively. These findings indicated that the V of meropenem was greater and the CL of meropenem was lower than the values obtained in a previous study with healthy subjects. The maximum recommended dose, i.e., 2 g of meropenem every 8 h, may be required for treatment of life-threatening infections in this patient population.