Central Volume Of Distribution Research Articles

Caspofungin Population Pharmacokinetic Analysis in Plasma and Peritoneal Fluid in Septic Patients with Intra-Abdominal Infections: A Prospective Cohort Study.

The aim of this study was to report the pharmacokinetics (PK) of caspofungin in plasma and peritoneal fluid and to identify optimal dosing strategies in septic patients with intra-abdominal infections. Eleven patients with secondary peritonitis with septic shock received the standard dosing regimen of caspofungin. Total caspofungin plasma and peritoneal concentrations were subject to a population PK analysis using Pmetrics®. Monte Carlo simulations were performed considering the ratio of 24-h total drug exposure above the minimum inhibitory concentration (AUC24/MIC) in plasma and comparing simulated concentrations versus MIC in peritoneal fluid. Fat-free mass (FFM) was retained in the final model of caspofungin, reporting a total clearance (standard deviation) of 0.78 (0.17)L/h and a central volume of distribution of 9.36 (2.61)L. The peritoneal fluid/plasma ratio of caspofungin was 33% on the first day of therapy (AUC24 73.92 (21.93) and 26.03 (9.88)mg*h/L for plasma and peritoneal data, respectively). Dosing simulations supported the use of standard dosing regimens for patients with an FFM <50kg for the most susceptible candida species (C. albicans and C. glabrata). For higher FFM, a loading dose of 70 or 100 mg, with a maintenance dose of 70 mg, reached AUC24/MIC ratios for these species. There is moderate penetration of caspofungin into the peritoneal cavity (33%). For empirical treatment, a dose escalation of 100 mg loading dose on the first day is suggested for higher FFM to ensure adequate concentrations into the abdominal cavity for the most susceptible candida species.

Population Pharmacokinetics of Ponatinib in Healthy Adult Volunteers and Patients With Hematologic Malignancies and Model-Informed Dose Selection for Pediatric Development.

The BCR‐ABL1 inhibitor ponatinib is approved for the treatment of adults with chronic myeloid leukemia or Philadelphia chromosome–positive acute lymphoblastic leukemia, including those with the T315I mutation. We report a population pharmacokinetic model‐based analysis for ponatinib and its application to inform dose selection for pediatric development. Plasma concentration–time data were collected from 260 participants (86 healthy volunteers; 174 patients with hematologic malignancies) enrolled across 7 clinical trials. Data were analyzed using nonlinear mixed‐effects modeling. Ponatinib pharmacokinetics were described by a 2‐compartment model with first‐order elimination from the central compartment. The final model included body weight and age as covariates on the apparent central volume of distribution; however, exposure variability explained by these covariates was small compared with overall variability in the population. None of the covariates evaluated, including sex, age (19‐85 years), race, body weight (40.7‐152.0 kg), total bilirubin (0.1‐3.16 mg/dL), alanine aminotransferase (6‐188 U/L), albumin (23.0‐52.5 g/L), and creatinine clearance (≥28 mL/min) had clinically meaningful effects on apparent oral clearance. Simulations based on the final model predicted that daily doses of 15 to 45 mg result in steady‐state average concentrations that are in the pharmacological range for BCR‐ABL1 inhibition and approximate or exceed concentrations associated with suppression of T315I mutant clones. The final model was adapted using allometric scaling to inform dose selection for pediatric development. Clinicaltrials.gov identifier: NCT00660920; NCT01667133; NCT01650805

Population Pharmacokinetics of Melphalan in a Large Cohort of Autologous and Allogeneic Hematopoietic Cell Transplantation Recipients: Towards Individualized Dosing Regimens.

High-dose melphalan is an integral part of conditioning chemotherapy prior to both autologous and allogeneic hematopoietic cell transplantation. While underexposure may lead to relapse, overexposure may lead to toxicities include mucositis, diarrhea, bone marrow suppression, and rarely sinusoidal obstruction syndrome. In this study, we describe the population pharmacokinetics of high-dose melphalan as a first step towards individualized dosing. Melphalan samples were collected in patients receiving an allogeneic or autologous hematopoietic cell transplantation between August 2016 and August 2020 at the Memorial Sloan Kettering Cancer Center. A population-pharmacokinetic model was developed using NONMEM. Based on a total of 3418 samples from 452 patients receiving a median cumulative dose of 140 mg/m2, a two-compartment population-pharmacokinetic model was developed. Fat-free mass was a covariate for clearance, central volume of distribution, and inter-compartmental clearance, while glomerular filtration rate predicted clearance. Simulation studies showed that based on fixed body surface area-based dosing, renal impairment has a higher impact in increasing melphalan exposure compared with obesity. The proposed model adequately describes the population pharmacokinetics of melphalan in adult patients receiving a hematopoietic cell transplantation. This model can be used to define the therapeutic window of melphalan, and subsequently to develop individualized dosing regimens aiming for that therapeutic window in all patients.

Ampicillin Pharmacokinetics in Peripartum and Laboring Women.

Ampicillin is used for multiple peripartum indications including prevention of neonatal group B streptococcus (GBS) and treatment of chorioamnionitis. Despite its widespread use in obstetrics, existing pharmacokinetic data for ampicillin do not address contemporary indications or dosing paradigms for this population. We sought to characterize the pharmacokinetic profile of ampicillin administered to laboring women. Using whole blood dried blood spot sampling technique, maternal blood samples were collected at specified times from 31 women receiving intravenous (IV) ampicillin for peripartum indications. Women received either a 2-g loading dose with 1-g administered every 4 hours (GBS) or 2-g every 6 hours (chorioamnionitis). Pharmacokinetics were analyzed via a population approach with nonlinear mixed-effect modeling. The data were best described by a two-compartment model with first-order elimination, with the following whole blood parameters: central volume of distribution (V1), 75.2 L (95% confidence interval [CI]: 56.3-93.6); clearance (CL), 82.4 L/h (95% CI: 59.7-95.7); intercompartmental clearance (Q), 20.9 L/h (95% CI: 16.2-38.2); and peripheral volume of distribution (V2), 61.1 L (95% CI: 26.1-310.5). Interpatient variation in CL and V1 was large (42.0 and 56.7%, respectively). Simulations of standard dosing strategies demonstrated over 98% of women are predicted to achieve an estimated free plasma concentration above mean inhibitory concentration (MIC) of 0.5 μg/mL for more than 50% of the dosing interval. Although large variation in the pharmacokinetics of ampicillin in pregnant women exists, as predicted by our model, current standard dosing strategies achieve adequate exposure for GBS in nearly all patients. · IV ampicillin is widely used in obstetrics.. · Pharmacokinetic studies are lacking.. · Ampicillin pharmacokinetics were established.. · Ampicillin clearance and volume of distribution are high.. · Current ampicillin dosing strategies are sufficient..

Advancement of pharmacokinetic models of iohexol in patients aged 70\xa0years or older with impaired kidney function

Plasma clearance of iohexol is a pivotal metric to quantify glomerular filtration rate (GFR), but the optimal timing and frequency of plasma sampling remain to be assessed. In this study, we evaluated the impact of a Bayesian estimation procedure on iohexol clearance estimates, and we identified an optimal sampling strategy based on data in individuals aged 70+. Assuming a varying number of random effects, we re-estimated previously developed population pharmacokinetic two- and three-compartment models in a model development group comprising 546 patients with iohexol concentration data up to 300 min post injection. Model performance and optimal sampling times were assessed in an evaluation group comprising 104 patients with reduced GFR and concentration data up to 1440 min post injection. Two- and three-compartment models with random effects for all parameters overestimated clearance values (bias 5.07 and 4.40 mL/min, respectively) and underpredicted 24-h concentrations (bias − 14.5 and − 12.0 µg/ml, respectively). Clearance estimates improved distinctly when limiting random effects of the three-compartment model to clearance and central volume of distribution. Two blood samples, one early and one 300 min post injection, were sufficient to estimate iohexol clearance. A simplified three-compartment model is optimal to estimate iohexol clearance in elderly patients with reduced GFR.

Abstract 10571: Phase 1 Single-Dose Study to Evaluate Apixaban in Pediatric Subjects at Risk for Venous or Arterial Thrombotic Disorder

Introduction: Standard-of-care antithrombotics in pediatric subjects (peds) include unfractionated/LMW heparin, aspirin, and vitamin K antagonists. Apixaban, a direct factor Xa (FXa) inhibitor indicated for VTE treatment (tx) and prevention in adults, may be an effective and convenient oral tx option with an acceptable safety profile in peds. Objectives: To evaluate pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of apixaban in peds at risk for venous or arterial thrombotic disorder; to support dose selection for apixaban pediatric program trials. Methods: This phase 1 study (NCT01707394) enrolled peds aged &lt; 18 years (y) at risk for venous/arterial thrombotic disorder into groups by age. Peds undergoing tx/procedures or with conditions that may affect bleeding risk or apixaban exposure were excluded. A single apixaban dose (based on BSA; targeted to achieve adult exposures with apixaban 2.5 mg) was administered: 0.1 mg sprinkle capsule for age &lt; 28 days (d); 0.4 mg/mL solution for ages 28 d to &lt; 18 y (dose range: 1.08-2.19 mg/m 2 ). Endpoints included PK, safety, tolerability, and PD (anti-FXa activity). For PK/PD, 4-6 blood samples were collected ≤ 26 h after dosing. A population PK (PPK) model developed with data from adults and peds was used to evaluate PK. Apparent oral clearance (CL/F) included a fixed maturation function based on published data. Results: From Jan 2013 to Jun 2019, 49 peds aged 9 d to 16 y received an apixaban dose. All AEs (n = 15) resolved; most were mild/moderate; none were bleeding-related. SAEs (1 seizure; 1 limb venous thrombosis) were not tx-related. Apixaban CL/F and apparent central volume of distribution increased less than proportionally with body weight. Apixaban CL/F increased with age, reaching adult values in ages 12 to &lt; 18 y. Maturation affected CL/F most notably in ages &lt; 9 months. Plasma anti-FXa activity values were linearly related to apixaban concentrations with no apparent age-related differences, comparable to adults. Conclusions: Single apixaban doses were generally safe and well tolerated in peds. Study data and PPK model supported dose selection for phase 2/3 multiple-dose pediatric trials.

The Influence of Underlying Disease on Rituximab Pharmacokinetics May be Explained by Target-Mediated Drug Disposition.

Rituximab is an anti-CD20 monoclonal antibody approved in several diseases, including chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), rheumatoid arthritis (RA), and anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). The influence of underlying disease on rituximab pharmacokinetics has never been investigated for several cancer and non-cancer diseases simultaneously. This study aimed at assessing this influence using an integrated semi-mechanistic model accounting for target-mediated elimination of rituximab. Rituximab concentration-time data from five studies previously published in patients with CLL, DLBCL, FL, RA, and AAV were described using a two-compartment model with irreversible binding of rituximab to its target antigen. Both underlying disease and target antigen measurements were assessed as covariates. Central volume of distribution was [95% confidence interval] 1.7-fold [1.6-1.9] higher in DLBCL than in RA, FL, and CLL, and it was 1.8-fold [1.6-2.1] higher in RA, FL, and CLL than in AAV. First-order elimination rate constants were 1.8-fold [1.7-2.0] and 1.3-fold [1.2-1.5] higher in RA, DLBCL, and FL than in CLL and AAV, respectively. Baseline latent antigen level (L0) was 54-fold [30-94], 20-fold [11-36], and 29-fold [14-64] higher in CLL, DLBCL, and FL, respectively, than in RA and AAV. In lymphoma, L0 increased with baseline total metabolic tumor volume (p = 6.10-7). In CLL, the second-order target-mediated elimination rate constant (kdeg) increased with baseline CD20 count on circulating B cells (CD20cir, p = 0.0081). Our results show for the first time that rituximab pharmacokinetics is strongly influenced by underlying disease and disease activity. Notably, neoplasms are associated with higher antigen amounts that result in decreased exposure to rituximab compared to inflammatory diseases. Our model might be used to estimate unbound target amounts in upcoming studies.

Dose Optimization of Vancomycin for Critically Ill Patients Undergoing CVVH: A Prospective Population PK/PD Analysis

The optimal dose of vancomycin in critically ill patients receiving continuous venovenous hemofiltration (CVVH) remains unclear. The objective of this study was to identify factors that significantly affect pharmacokinetic profiles and to further investigate the optimal dosage regimens for critically ill patients undergoing CVVH based on population pharmacokinetics and pharmacodynamic analysis. A prospective population pharmacokinetic analysis was performed at the surgical intensive care unit in a level A tertiary hospital. We included 11 critically ill patients undergoing CVVH and receiving intravenous vancomycin. Serial blood samples were collected from each patient, with a total of 131 vancomycin concentrations analyzed. Nonlinear mixed effects models were developed using NONMEM software. Monte Carlo Simulation was used to optimize vancomycin dosage regimens. A two-compartment model with first-order elimination was sufficient to characterize vancomycin pharmacokinetics for CVVH patients. The population typical vancomycin clearance (CL) was 1.15 L/h and the central volume of distribution was 16.9 L. CL was significantly correlated with ultrafiltration rate (UFR) and albumin level. For patients with normal albumin and UFR between 20 and 35 mL/kg/h, the recommended dosage regimen was 10 mg/kg qd. When UFR was between 35 and 40 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. For patients with hypoalbuminemia and UFR between 20 and 25 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. When UFR was between 25 and 40 mL/kg/h, the recommended dosage regimen was 10 mg/kg q12h. We recommend clinicians choosing the optimal initial vancomycin dosage regimens for critically ill patients undergoing CVVH based on these two covariates.

Pharmacokinetics and Monte Carlo Simulation of Meropenem in Critically Ill Adult Patients Receiving Extracorporeal Membrane Oxygenation.

Objectives: There have been few clinical studies of ECMO-related alterations of the PK of meropenem and conflicting results were reported. This study investigated the pharmacokinetics (PK) of meropenem in critically ill adult patients receiving extracorporeal membrane oxygenation (ECMO) and used Monte Carlo simulations to determine appropriate dosage regimens. Methods: After a single 0.5 or 1 g dose of meropenem, 7 blood samples were drawn. A population PK model was developed using nonlinear mixed-effects modeling. The probability of target attainment was evaluated using Monte Carlo simulation. The following treatment targets were evaluated: the cumulative percentage of time during which the free drug concentration exceeds the minimum inhibitory concentration of at least 40% (40% fT>MIC), 100% fT>MIC, and 100% fT>4xMIC. Results: Meropenem PK were adequately described by a two-compartment model, in which creatinine clearance and ECMO flow rate were significant covariates of total clearance and central volume of distribution, respectively. The Monte Carlo simulation predicted appropriate meropenem dosage regimens. For a patient with a creatinine clearance of 50–130 ml/min, standard regimen of 1 g q8h by i. v. infusion over 0.5 h was optimal when a MIC was 4 mg/L and a target was 40% fT>MIC. However, the standard regimen did not attain more aggressive target of 100% fT>MIC or 100% fT>4xMIC. Conclusion: The population PK model of meropenem for patients on ECMO was successfully developed with a two-compartment model. ECMO patients exhibit similar PK with patients without ECMO. If more aggressive targets than 40% fT>MIC are adopted, dose increase may be needed.

Micafungin Population PK Analysis in Healthy and Septic Pigs: Can the Septic Porcine Model Predict the Micafungin PK in Septic Patients?

To describe micafungin pharmacokinetic (PK) alterations of sepsis induced in piglets and to determine whether the porcine septic model is able to predict the PK of micafungin in septic patients at the plasma and peritoneal sites. From healthy (n = 8) and septic piglet group (n = 16), total micafungin concentrations were subject to a population PK analysis using Monolix®. Data from 16 septic humans patients from others studies was used to compare micafungin PK between septic piglets and septic patients. Sepsis induced in piglets slightly alters the total clearance and the volume of distribution, while inter-compartment clearance is increased (from 3.88 to 5.74 L/h) as well as the penetration into peritoneal cavity (from 61 to 90%). In septic human patients, PK parameters are similar except for the Vd, which is corrected by an allometric factor based on the body weight of each species. Micafungin penetration into peritoneal cavity of humans is lower than in septic piglets (40 versus 90%). The sepsis induced in the porcine model alters the PK of micafungin comparable to that in humans. In addition, micafungin PK is similar between these two species at the plasma level taking into account the allometric relationship of the body weight of these species on the central volume of distribution. The porcine septic plasma model would be able to predict the micafungin PK in the septic patients. However, further studies on peritoneal penetration are necessary to characterize this inter-species difference.

Population pharmacokinetic model-guided optimization of intravenous voriconazole dosing regimens in critically ill patients with liver dysfunction.

This study aimed to establish a population pharmacokinetic (PPK) model of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction and to explore the optimal dosing strategies in specific clinical scenarios for invasive fungal infections (IFIs) caused by common Aspergillus and Candida species. Prospective pharmacokinetics study. The intensive care unit in a tertiary-care medical center. A total of 297 plasma VRC concentrations from 26 critically ill patients with liver dysfunction were included in the PPK analysis. Model-based simulations with therapeutic range of 2-6mg/L as the plasma trough concentration (Cmin ) target and the free area under the concentration-time curve from 0 to 24h (ƒAUC24 ) divided by the minimum inhibitory concentration (MIC) (ie, ƒAUC24 /MIC) ≥25 as the effective target were performed to optimize VRC dosing regimens for Child-Pugh class A and B (CP-A/B) and Child-Pugh class C (CP-C) patients. A two-compartment model with first-order elimination adequately described the data. Significant covariates in the final model were body weight on both central and peripheral distribution volume and Child-Pugh class on clearance. Intravenous VRC loading dose of 5mg/kg every 12h (q12h) for the first day was adequate for CP-A/B and CP-C patients to attain the Cmin target at 24h. The maintenance dose regimens of 100mg q12h or 200mg q24h for CP-A/B patients and 50mg q12h or 100mg q24h for CP-C patients could obtain the probability of effective target attainment of >90% at an MIC ≤0.5mg/L and achieve the cumulative fraction of response of >90% against C.albicans, C.parapsilosis, C.glabrata, C.krusei, A.fumigatus, and A.flavus. Additionally, the daily VRC doses could be increased by 50mg for CP-A/B and CP-C patients at an MIC of 1mg/L, with plasma Cmin monitored closely to avoid serious adverse events. It is recommended that an appropriate alternative antifungal agent or a combination therapy could be adopted when an MIC ≥2mg/L is reported, or when the infection is caused by C.tropicalis but the MIC value is not available. For critically ill patients with liver dysfunction, the loading dose of intravenous VRC should be reduced to 5mg/kg q12h. Additionally, based on the types of fungal pathogens and their susceptibility to VRC, the adjusted maintenance dose regimens with lower doses or longer dosing intervals should be considered for CP-A/B and CP-C patients.

Development of a new pharmacokinetic model for target-concentration controlled infusion of vancomycin in critically ill patients.

The aim of this prospective study was to construct a new pharmacokinetic model of vancomycin for target-concentration controlled infusion (TCI). As the first loading dose, 25mg/kg of vancomycin was administered during 60-90min. Arterial blood samples were obtained at pre-set intervals to measure the serum concentrations of vancomycin. Population pharmacokinetic analysis was performed using the NONMEM software (ICON Development Solutions). In total, 197 serum concentration measurements from 22 patients were used to characterise the pharmacokinetics of vancomycin. A three-compartment mammillary model best described the pharmacokinetics of vancomycin in critically ill patients. The ideal body weight was a significant covariate for the central and slow peripheral volume of distribution. The weight and age converted to categorical variables at a cut-off of 65years were a significant covariate for the clearance. Based on the results of stochastic simulation, the TCI method maintained the therapeutic concentration range for the longest duration. In addition, assuming that vancomycin was administered by the TCI method for 7days, the dose was reduced by about 15% compared with the standard administration methods. The daily area under the curve values were maintained between 500mg·h/L and 600mg·h/L. TCI has the potential to become a new infusion method for patient-tailored dosing in critically ill patients. To administer vancomycin via TCI in clinical practice, the newly constructed pharmacokinetic model should undergo proper external validation.

Population pharmacokinetics of cefepime in critically ill patients receiving extracorporeal membrane oxygenation (an ASAP ECMO study)

ObjectivesThis study aimed to describe the population pharmacokinetics (PK) of cefepime during extracorporeal membrane oxygenation (ECMO) and through dosing simulations, identify a maximally effective and safe dosing strategy. MethodsSerial cefepime plasma concentrations were measured in patients on ECMO, and data were analysed using a population PK approach with Pmetrics®. Dosing simulations were used to identify the optimal dosing strategy that achieved target trough concentrations (Cmin) of 8–20 mg/L. Six patients were enrolled, of which one was receiving renal replacement therapy. Cefepime was best described in a two-compartment model, with total body weight and creatinine clearance (CrCL) as significant predictors of PK parameters. The mean clearance and central volume of distribution were 2.42 L/h and 15.09 L, respectively. ResultsBased on simulations, patients with CrCL of 120 mL/min receiving 1 g 8-hourly dosing achieved a 40–44% probability of efficacy (Cmin > 8 mg/L) and 1–6% toxicity (Cmin > 20 mg/L). Patients with CrCL 30 mL/min and 65 mL/min receiving 1 g 12-hourly dosing achieved an 84–92% and 46–53% probability of efficacy and 8–44% and 1–8% probability of toxicity, respectively. Simulations demonstrated a lower probability of efficacy and higher probability of toxicity with decreasing patient weight. ConclusionThis study reported reduced cefepime clearance in patients receiving ECMO, resulting in an increased risk of cefepime toxicity. To avoid drug accumulation, modified dosing regimens should be used in critically ill patients on ECMO. Clinicians should adopt therapeutic drug monitoring when treating less susceptible organisms and in patients with reduced renal clearance on ECMO.

Population Pharmacokinetics of Levetiracetam and Dosing Evaluation in Critically Ill Patients with Normal or Augmented Renal Function.

Levetiracetam is a broad-spectrum antiepileptic drug commonly used in intensive care units (ICUs). The objective of this study is to evaluate the adequacy of levetiracetam dosing in patients with normal or augmented renal clearance (ARC) admitted to the ICU by population modelling and simulation. A multicentre prospective study including twenty-seven critically ill patients with urinary creatinine clearance (CrCl) > 50 mL/min and treated with levetiracetam was developed. Levetiracetam plasma concentrations were best described by a two-compartment model. The parameter estimates and relative standard errors (%) were clearance (CL) 3.5 L/h (9%), central volume of distribution (V1) 20.7 L (18%), intercompartmental clearance 31.9 L/h (22%), and peripheral volume of distribution 33.5 L (13%). Interindividual variability estimates were, for the CL, 32.7% (21%) and, for V1, 56.1% (29%). The CrCl showed significant influence over CL. Simulations showed that the administration of at least 500 mg every 8 h or 1000 mg every 12 h are needed in patients with normal renal function. Higher doses (1500 or 2000 mg, every 8 h) are needed in patients with ARC. Critically ill patients with normal or ARC treated with levetiracetam could be at high risk of being underdosed.

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.

Population Pharmacokinetics and Dosing Simulation of Vancomycin Administered by Continuous Injection in Critically Ill Patient.

Background: Vancomycin is widely used for empirical antimicrobial therapy in critically ill patients with sepsis. Continuous infusion (CI) may provide more stable exposure than intermittent infusion, but optimal dosing remains challenging. The aims of this study were to perform population pharmacokinetic (PK) analysis of vancomycin administered by CI in intensive care unit (ICU) patients to identify optimal dosages. Methods: Patients who received vancomycin by CI with at least one measured concentration in our center over 16 months were included, including those under continuous renal replacement therapy (CRRT). Population PK was conducted and external validation of the final model was performed in a dataset from another center. Simulations were conducted with the final model to identify the optimal loading and maintenance doses for various stages of estimated creatinine clearance (CRCL) and in patients on CRRT. Target exposure was defined as daily AUC of 400–600 mg·h/L on the second day of therapy (AUC24–48 h). Results: A two-compartment model best described the data. Central volume of distribution was allometrically scaled to ideal body weight (IBW), whereas vancomycin clearance was influenced by CRRT and CRCL. Simulations performed with the final model suggested a loading dose of 27.5 mg/kg of IBW. The maintenance dose ranged from 17.5 to 30 mg/kg of IBW, depending on renal function. Overall, simulation showed that 55.8% (95% CI; 47–64%) of patients would achieve the target AUC with suggested dosages. Discussion: A PK model has been validated for vancomycin administered by CI in ICU patients, including patients under CRRT. Our model-informed precision dosing approach may help for early optimization of vancomycin exposure in such patients.

Voriconazole Pharmacokinetics Are Not Altered in Critically Ill Patients with Acute-on-Chronic Liver Failure and Continuous Renal Replacement Therapy: An Observational Study.

Infection and sepsis are a main cause of acute-on-chronic liver failure (ACLF). Besides bacteria, molds play a role. Voriconazole (VRC) is recommended but its pharmacokinetics (PK) may be altered by ACLF. Because ACLF patients often suffer from concomitant acute renal failure, we studied the PK of VRC in patients receiving continuous renal replacement therapy (RRT) with ACLF and compared it to PK of VRC in critically ill patients with RRT without concomitant liver failure (NLF). In this prospective cohort study, patients received weight-based VRC. Pre- and post-dialysis membrane, and dialysate samples obtained at different time points were analyzed by high-performance liquid chromatography. An integrated dialysis pharmacometric model was used to model the available PK data. The recommended, 50% lower, and 50% higher doses were analyzed by Monte-Carlo simulation (MCS) for day 1 and at steady-state with a target trough concentration (TC) of 0.5–3mg/L. Fifteen patients were included in this study. Of these, 6 patients suffered from ACLF. A two-compartment model with linear clearance described VRC PK. No difference for central (V1) or peripheral (V2) volumes of distribution or clearance could be demonstrated between the groups. V1 was 80.6L (95% confidence interval: 62.6–104) and V2 106L (65–166) with a body clearance of 4.7L/h (2.87–7.81) and RRT clearance of 1.46L/h (1.29–1.64). MCS showed TC below/within/above target of 10/74/16% on day 1 and 9/39/52% at steady-state for the recommended dose. A 50% lower dose resulted in 26/72/1% (day 1) and 17/64/19% at steady-state and 7/57/37% and 7/27/67% for a 50% higher dose. VRC pharmacokinetics are not significantly influenced by ACLF in critically ill patients who receive RRT. Maintenance dose should be adjusted in both groups. Due to the high interindividual variability, therapeutic drug monitoring seems inevitable.

Population pharmacokinetics of cefotaxime in intensive care patients

PurposeTo characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates.MethodsThis work was based on data from cefotaxime-treated patients included in the ACCIS (Antibiotic Concentrations in Critical Ill ICU Patients in Sweden) study. Clinical data from 51 patients at seven different ICUs in Sweden, given cefotaxime (1000–3000 mg given 2–6 times daily), were collected from the first day of treatment for up to three consecutive days. In total, 263 cefotaxime samples were included in the population pharmacokinetic analysis.ResultsA two-compartment model with linear elimination, proportional residual error and inter-individual variability (IIV) on clearance and central volume of distribution best described the data. The typical individual was 64 years, with body weight at ICU admission of 92 kg and estimated creatinine clearance of 94 mL/min. The resulting typical value of clearance was 11.1 L/h, central volume of distribution 5.1 L, peripheral volume of distribution 18.2 L and inter-compartmental clearance 14.5 L/h. The estimated creatinine clearance proved to be a significant covariate on clearance (p < 0.001), reducing IIV from 68 to 49%.ConclusionA population pharmacokinetic model was developed to describe cefotaxime pharmacokinetics and associated variability in adult ICU patients. The estimated creatinine clearance partly explained the IIV in cefotaxime clearance. However, the remaining unexplained IIV is high and suggests a need for dose individualisation using therapeutic drug monitoring where the developed model, after evaluation of predictive performance, may provide support.

Gentamicin Population Pharmacokinetics in Pediatric Patients-A Prospective Study with Data Analysis Using the saemix Package in R.

The aminoglycoside gentamicin is used for the empirical treatment of pediatric infections. It has a narrow therapeutic window. In this prospective study at University Children’s Hospital Zurich, Switzerland, we aimed to characterize the pharmacokinetics of gentamicin in pediatric patients and predict plasma concentrations at typical recommended doses. We recruited 109 patients aged from 1 day to 14 years, receiving gentamicin (7.5 mg/kg at age ≥ 7 d or 5 mg/kg). Plasma levels were determined 30 min, 4 h and 24 h after the infusion was stopped and then transferred, together with patient data, to the secure BioMedIT node Leonhard Med. Population pharmacokinetic modeling was performed with the open-source R package saemix on the SwissPKcdw platform in Leonhard Med. Data followed a two-compartment model. Bodyweight, plasma creatinine and urea were identified as covariates for clearance, with bodyweight as a covariate for central and peripheral volumes of distribution. Simulations with 7.5 mg/kg revealed a 95% CI of 13.0–21.2 mg/L plasma concentration at 30 min after the stopping of a 30-min infusion. At 24 h, 95% of simulated plasma levels were <1.8 mg/L. Our study revealed that the recommended dosing is appropriate. It showed that population pharmacokinetic modeling using R provides high flexibility in a secure environment.

Population pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide metabolite in patients with autoimmune glomerulonephritis.

To develop a simultaneous population pharmacokinetic model of cyclophosphamide (CY) and 4-hydroxycyclophosphamide (4-OH) in patients with glomerulonephritis. In total, 23 patients participated in a pharmacokinetic evaluation using dense plasma sampling. A population pharmacokinetic model was developed in Monolix Suite 2020R1 that simultaneously describes the kinetics of CY and 4-OH. Several structural and residual error models were evaluated and patient variables were tested as potential covariates. The final model was selected based on visual predictive check and bootstrap. Simulations of plasma concentrations for various doses were conducted. A model including two compartments for CY and one for 4-OH was found to best describe the data. A proportional error model for both compounds was chosen. The following estimates were found for the main CY pharmacokinetic parameters: total clearance, 13.3 l/h with inter-individual variability (IIV) 32%, and central volume of distribution, 59.8 l with IIV 12%. The metabolite elimination rate constant was 4.3 h-1 with IIV 36% and the proportion of metabolism 64%. Sex was a significant covariate on the central volume of CY, with females exhibiting 25% lower value than males. A population pharmacokinetic model was developed for CY and 4-OH in patients with autoimmune glomerulonephritis. Simulations using various dose regimens allow for informed dosing before the initiation of therapy.