Population Pharmacokinetics and Pharmacodynamic Target Attainment of Isavuconazole against Aspergillus fumigatus and Aspergillus flavus in Adult Patients with Invasive Fungal Diseases: Should Therapeutic Drug Monitoring for Isavuconazole Be Considered as Mandatory as for the Other Mold-Active Azoles?

Isavuconazole is a newer broad-spectrum triazole approved for the treatment of invasive fungal disease. The objective of this study was to conduct a population pharmacokinetic and pharmacodynamic analysis of isavuconazole in a retrospective cohort of hospitalized patients. A nonlinear mixed-effect approach with Monte Carlo simulations was conducted to assess the probability of target attainment (PTA) of an area under the concentration–time curve (AUC24 h)/minimum inhibitory concentration (MIC) ratio of 33.4 (defined as efficacy threshold against A. fumigatus and A. flavus) associated with a maintenance dose (MD) of 100, 200 and 300 mg daily after loading. The cumulative fraction of response (CFR) against the EUCAST MIC distributions of A. fumigatus and A. flavus was calculated as well. The proportion of trough concentrations (Ctrough) exceeding a defined threshold of toxicity (>5.13 mg/L) was estimated. A total of 50 patients, with a median age of 61.5 years, provided 199 plasma isavuconazole concentrations. Invasive pulmonary aspergillosis was the prevalent type of infection and accounted for 80% (40/50) of cases. No clinical covariates were retained by the model. With the standard MD of 200 mg daily, CFRs were always ≥90% during the first two months of treatment. The risk of Ctrough < 1.0 mg/L was around 1%, and that of Ctrough > 5.13 mg/L was 27.7 and 39.2% at 28 and 60 days, respectively, due to isavuconazole accumulation over time. Our findings suggest that TDM for isavuconazole should not be considered as mandatory as for the other mold-active azoles voriconazole and posaconazole.

Average IGF-1 Prediction for Once-Weekly Lonapegsomatropin in Children with Growth Hormone Deficiency

Context Serum IGF-1 levels are relatively constant in somatropin-treated children with growth hormone deficiency (GHD), and guide dose adjustments for clinical efficacy and long-term safety. IGF-1 levels following treatment with long-acting growth hormones such as lonapegsomatropin (TransCon hGH), a once-weekly somatropin prodrug, exhibit a characteristic profile over the dosing interval. Objective Develop a method to predict average IGF-1 in lonapegsomatropin-treated GHD children to interpret IGF-1 data based on a single sample obtained any time at steady state. Design A population nonlinear mixed-effect pharmacodynamic model for IGF-1 was developed based on two randomized, open-label trials of lonapegsomatropin in GHD children and used to develop a linear mixed model with Taylor series to fit simulated IGF-1 profiles of lonapegsomatropin-treated children. Setting and Patients 49,896 IGF-1 sample data simulated from 105 lonapegsomatropin-treated GHD children were utilized for the final prediction model. Intervention Dose range of lonapegsomatropin was 0.14–0.30 hGH mg/kg/week. Main Outcome Measure Weekly average IGF-1 was calculated using IGF-1 profiles simulated from the nonlinear pharmacodynamic model. Predicted average IGF-1 was obtained by linear mixed model with Taylor series. Results The nonlinear mixed-effect model provided satisfactory model fit. The linear mixed model with Taylor series fit simulated IGF-1 data well, with a relatively straightforward prediction formula. IGF-1 values sampled at ~4.5 days post-dose coincided with weekly average IGF-1 at steady state. Conclusion A formula to predict average IGF-1 from a single sample of IGF-1 at steady state was established to aid clinicians in interpreting IGF-1 levels in GHD children administered lonapegsomatropin.

Population Pharmacokinetics And Bayesian Estimation of Mycophenolate Mofetil In Patients With Autoimmune Hepatitis

Background: Mycophenolate mofetil (MMF) is the most widely used second-line agent in auto-immune hepatitis (AIH). It is generally titrated up to patient response and continued for at least two years following complete liver enzyme normalization. However, in this maintenance phase individual dose adjustment to reach mycophenolic acid (MPA) exposure with the best benefit-risk probability may avoid adverse outcomes. The aim of the present study was to develop population pharmacokinetic (popPK) models and Maximum A-Posteriori Bayesian estimators (MAP-BEs) to estimate MPA inter-dose area under the curve (AUC0-12h) in AIH patients administered MMF using nonlinear mixed effect modelling. Methods: We analysed 50 MPA PK profiles from 34 different patients, together with some demographic, clinical, and laboratory test data. The median number of samples per profile, immediately preceding and following the morning MMF dose, was 7 [4 – 10]. PopPK modeling was performed using parametric, top-down, nonlinear mixed effect modelling with NONMEM 7.3. MAP-BEs were developed based on the the best popPK model and the best limited sampling strategy (LSS) selected among several. Results: The pharmacokinetic data were best described by a 2-compartment model, Erlang distribution to describe the absorption phase, and a proportional error. The best MAP-BE relied on the LSS at 0.33, 1 and 3 hours after mycophenolate mofetil dose administration and was very accurate (bias=5.6%) and precise (RMSE<20%). Conclusion: The precise and accurate Bayesian estimator developed in this study for AIH patients on MMF can be used to improve the therapeutic management of these patients.

The relationship between the effect-site concentration of propofol and sedation scale in children: a pharmacodynamic modeling study

Background Continuous infusion of propofol has been used to achieve sedation in children. However, the relationship between the effect-site concentration (Ce) of propofol and sedation scale has not been previously examined. The objective of this study was to investigate the relationship between the Ce of propofol and the University of Michigan Sedation Scale (UMSS) score in children with population pharmacodynamic modeling. Methods A total of 30 patients (aged 3 to 6 years) who underwent surgery under general anesthesia with propofol and remifentanil lasting more than 1 h were enrolled in this study. Sedation levels were evaluated using the UMSS score every 20 s by a 1 μg/mL stepwise increase in the Ce of propofol during the induction of anesthesia. The pharmacodynamic relationship between the Ce of propofol and UMSS score was analyzed by logistic regression with nonlinear mixed-effect modeling. Results The estimated Ce50 (95% confidence interval) of propofol to yield UMSS scores equal to or greater than n were 1.84 (1.54–2.14), 2.64 (2.20–3.08), 3.98 (3.66–4.30), and 4.78 (4.53–5.03) μg/mL for n = 1, 2, 3, and 4, respectively. The slope steepness for the relationship of the Ce versus sedative response to propofol (95% confidence interval) was 5.76 (4.00–7.52). Conclusions We quantified the pharmacodynamic relationship between the Ce of propofol and UMSS score, and this finding may be helpful to predict the sedation score at the target Ce of propofol in children. Trial registration http://www.clinicaltrials.gov (No.: NCT03195686, Date of registration: 22/06/2017).

Optimized Dosing Regimens of Meropenem in Septic Children Receiving Extracorporeal Life Support

Objectives: To develop a population pharmacokinetic model of meropenem in children with sepsis receiving extracorporeal life support (ECLS) and optimize the dosage regimen based on investigating the probability of target attainment (PTA).Methods: The children with sepsis were prospectively enrolled in a pediatric intensive care unit from January 2018 to December 2019. The concentration-time data were fitted using nonlinear mixed effect model approach by NONMEM program. The stochastic simulation considering various scenarios based on proposed population pharmacokinetics model were conducted, and the PTAs were calculated to optimize the dosage regimens.Results: A total of 25 children with sepsis were enrolled, of whom13 received ECMO, 9 received CRRT, and 4 received ECMO combined with CRRT. 12 children received a two-step 3-h infusion and 13 children received 1-h infusion. Bodyweight and creatinine clearance had significant impacts on the PK parameters. ECMO intervention was not related to the PK properties. If 100%T &gt; MIC was chosen as target, children receiving 40 mg/kg q8h over a 3 h-infusion only reached the PTA up to 77.4%. If bacteria with MIC 2 mg/L were to be treated with meropenem and the PTA target was 50%T &gt; MIC, a dose of 40 mg/kg q8h for 1 h infusion would be necessary.Conclusions: The PK properties of meropenem in septic children receiving extracorporeal life support were best described. We recommended the opitimized dosing regimens for septic children receiving ECLS depending on the PTA of PK target 50%T &gt; MIC and 100%T &gt; MIC, for children with sepsis during ECLS with different body weight, estimated creatinine clearance (eCRCL) and MIC of bacteria.

Bayesian multi-response nonlinear mixed-effect model: application of two recent HIV infection biomarkers

Since the discovery of the human immunodeficiency virus (HIV) 35 years ago, the epidemic is still ongoing in France. To monitor the dynamics of HIV transmission and assess the impact of prevention campaigns, the main indicator is the incidence. One method to estimate the HIV incidence is based on biomarker values at diagnosis and their dynamics over time. Estimating the HIV incidence from biomarkers first requires modeling their dynamics since infection using external longitudinal data. The objective of the work presented here is to estimate the joint dynamics of two biomarkers from the PRIMO cohort. We thus jointly modeled the dynamics of two biomarkers (TM and V3) using a multi-response nonlinear mixed-effect model. The parameters were estimated using Bayesian Hamiltonian Monte Carlo inference. This procedure was first applied to the real data of the PRIMO cohort. In a simulation study, we then evaluated the performance of the Bayesian procedure for estimating the parameters of multi-response nonlinear mixed-effect models.

Clinical Application of Vancomycin PPK Model in Patients with Neutropenia

Background: To explore the clinical application of a population pharmacokinetics (PPK) model of vancomycin in patients with hematological diseases who developed neutropenia.Methods: Patients with neutropenia treated at the Department of Hematology in our hospital were included in the PPK model study. A nonlinear mixed effect modeling approach (NONMEM) was used to establish the PPK model of those patients. Monte Carlo simulation was also carried out. A total of 64 patients were divided into model group and non-model group for clinical application research. The model group was given the first dose of 1g q8h, and the non-model group was given 1g q12h as the empiric therapy; the follow-up dose adjustment was made according to the concentration results.Results: This two-compartment model showed good stability and accuracy. The average concentrations in the model group and the non-model group were significantly different, i.e., 13.45±4.07 μg/ml, 60.71% reaching the target concentration vs. 9.85±3.76 μg/ml, 27.78% reaching the target concentration, respectively (all P<0.05). This suggested that for patients with neutropenia and CLCR≥90 ml/min/1.73m2, the first dose of 1g q8h may help to reach the target concentration as soon as possible.Conclusions: Our PPK model of vancomycin in patients with hematologic diseases who developed neutropenia can be used to realize the individualized application of vancomycin in this population.