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.

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Pharmacokinetics of Micafungin in Critically Ill Patients

Scientific Reports ◽

10.1038/s41598-019-53093-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Silke Gastine ◽

Christian Lanckohr ◽

Magalie Blessou ◽

Dagmar Horn ◽

Manfred Fobker ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Compartment Model ◽

Volume Of Distribution ◽

Study Cohort ◽

Linear Mixed Effects ◽

Two Compartment Model ◽

The Status ◽

Linear Elimination ◽

Central Volume

AbstractWe investigated covariates of pharmacokinetics of micafungin in critically ill patients. After application of micafungin, plasma samples were collected. Non-linear mixed effects modelling (NONMEM 7.3) was used to develop the pharmacokinetic model. Using this model, the adequacy of a fixed 100 mg dosing regimen was evaluated in the study cohort. A two-compartment model with linear elimination was found to describe the obtained data. SOFA score was identified as a significant covariate on both clearance and central volume of distribution, respectively. Patients in highly critical condition, represented by a SOFA above 10 showed a 30.8% lower central volume of distribution than the less critically ill patients. For patients with bilirubin levels above 4 mg/dl, clearance was decreased by 21.1%. Renal replacement therapy (RRT) did not influence micafungin clearance or the volumes of distribution. In a posthoc evaluation of the modeled population, 100 mg micafungin was suitable when assessing the PKPD targets (AUC/MIC) for C. albicans and C. glabrata, with insufficient target attainment for C. parapsilosis. Micafungin pharmacokinetics appear not to be influenced by the status of RRT. A dose of 100 mg micafungin is suitable for infections with C. albicans and C. glabrata in critically ill patients.

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Population Pharmacokinetics of Unbound Ceftolozane and Tazobactam in Critically Ill Patients without Renal Dysfunction

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01265-19 ◽

2019 ◽

Vol 63 (10) ◽

Cited By ~ 10

Author(s):

Fekade B. Sime ◽

Melissa Lassig-Smith ◽

Therese Starr ◽

Janine Stuart ◽

Saurabh Pandey ◽

...

Keyword(s):

Creatinine Clearance ◽

Population Pharmacokinetics ◽

Critically Ill ◽

Rate Constant ◽

Critically Ill Patients ◽

Plasma Concentrations ◽

Peripheral Compartment ◽

Parameter Estimates ◽

Pharmacokinetic Data ◽

Dosing Regimens

ABSTRACT Evaluation of dosing regimens for critically ill patients requires pharmacokinetic data in this population. This prospective observational study aimed to describe the population pharmacokinetics of unbound ceftolozane and tazobactam in critically ill patients without renal impairment and to assess the adequacy of recommended dosing regimens for treatment of systemic infections. Patients received 1.5 or 3.0 g ceftolozane-tazobactam according to clinician recommendation. Unbound ceftolozane and tazobactam plasma concentrations were assayed, and data were analyzed with Pmetrics with subsequent Monte Carlo simulations. A two-compartment model adequately described the data from twelve patients. Urinary creatinine clearance (CLCR) and body weight described between-patient variability in clearance and central volume of distribution (V), respectively. Mean ± standard deviation (SD) parameter estimates for unbound ceftolozane and tazobactam, respectively, were CL of 7.2 ± 3.2 and 25.4 ± 9.4 liters/h, V of 20.4 ± 3.7 and 32.4 ± 10 liters, rate constant for distribution of unbound ceftolozane or tazobactam from central to peripheral compartment (Kcp) of 0.46 ± 0.74 and 2.96 ± 8.6 h−1, and rate constant for distribution of unbound ceftolozane or tazobactam from peripheral to central compartment (Kpc) of 0.39 ± 0.37 and 26.5 ± 8.4 h−1. With dosing at 1.5 g and 3.0 g every 8 h (q8h), the fractional target attainment (FTA) against Pseudomonas aeruginosa was ≥85% for directed therapy (MIC ≤ 4 mg/liter). However, for empirical coverage (MIC up to 64 mg/liter), the FTA was 84% with the 1.5-g q8h regimen when creatinine clearance is 180 ml/min/1.73 m2, whereas the 3.0-g q8h regimen consistently achieved an FTA of ≥85%. For a target of 40% of time the free drug concentration is above the MIC (40% fT>MIC), 3g q8h by intermittent infusion is suggested unless a highly susceptible pathogen is present, in which case 1.5-g dosing could be used. If a higher target of 100% fT>MIC is required, a 1.5-g loading dose plus a 4.5-g continuous infusion may be adequate.

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Population Pharmacokinetics of Piperacillin in the Early Phase of Septic Shock: Does Standard Dosing Result in Therapeutic Plasma Concentrations?

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01347-15 ◽

2015 ◽

Vol 59 (11) ◽

pp. 7018-7026 ◽

Cited By ~ 14

Author(s):

Kristina Öbrink-Hansen ◽

Rasmus Vestergaard Juul ◽

Merete Storgaard ◽

Marianne Kragh Thomsen ◽

Tore Forsingdal Hardlei ◽

...

Keyword(s):

Septic Shock ◽

Renal Function ◽

Plasma Concentrations ◽

Compartment Model ◽

Pharmacokinetic Profile ◽

Population Pharmacokinetic ◽

Relative Standard Error ◽

Content Type ◽

Relative Standard ◽

Dosing Regimens

ABSTRACTAntibiotic dosing in septic shock patients poses a challenge for clinicians due to the pharmacokinetic (PK) variability seen in this patient population. Piperacillin-tazobactam is often used for empirical treatment, and initial appropriate dosing is crucial for reducing mortality. Accordingly, we determined the pharmacokinetic profile of piperacillin (4 g) every 8 h, during the third consecutive dosing interval, in 15 patients treated empirically for septic shock. We developed a population pharmacokinetic model to assess empirical dosing and to simulate alternative dosing regimens and modes of administration. Time above the MIC (T>MIC) predicted for each patient was evaluated against clinical breakpoint MIC forPseudomonas aeruginosa(16 mg/liter). Pharmacokinetic-pharmacodynamic (PK/PD) targets evaluated were 50%fT>4×MIC and 100%fT>MIC. A population PK model was developed using NONMEM, and data were best described by a two-compartment model. Central and intercompartmental clearances were 3.6 liters/h (relative standard error [RSE], 15.7%) and 6.58 liters/h (RSE, 16.4%), respectively, and central and peripheral volumes were 7.3 liters (RSE, 11.8%) and 3.9 liters (RSE, 9.7%), respectively. Piperacillin plasma concentrations varied considerably between patients and were associated with levels of plasma creatinine. Patients with impaired renal function were more likely to achieve predefined PK/PD targets than were patients with preserved or augmented renal function. Simulations of alternative dosing regimens showed that frequent intermittent bolus dosing as well as dosing by extended and continuous infusion increases the probability of attaining therapeutic plasma concentrations. For septic shock patients with preserved or augmented renal function, dose increment or prolonged infusion of the drug needs to be considered. (This study has been registered at ClinicalTrials.gov under registration no. NCT02306928.)

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Compartmental Pharmacokinetic Analysis of Oral Amprenavir with Secondary Peaks

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00570-06 ◽

2007 ◽

Vol 51 (5) ◽

pp. 1822-1826 ◽

Cited By ~ 16

Author(s):

Olanrewaju Okusanya ◽

Alan Forrest ◽

Robin DiFrancesco ◽

Sanela Bilic ◽

Susan Rosenkranz ◽

...

Keyword(s):

Plasma Concentrations ◽

Compartment Model ◽

Central Compartment ◽

Volume Of Distribution ◽

Information Criteria ◽

Secondary Peak ◽

Pharmacokinetic Analysis ◽

Therapeutic Drug ◽

Healthy Human ◽

Two Compartment Model

ABSTRACT Amprenavir is a protease inhibitor that has been shown to have secondary peaks postulated to be due to enterohepatic recycling. We propose a model to describe the pharmacokinetics of amprenavir which accommodates the secondary peak(s). A total of 82 healthy human immunodeficiency virus (HIV)-seronegative subjects were administered a single 600-mg dose of amprenavir as part of adult AIDS Clinical Trials Group protocol A5043. Serial blood samples were obtained over 24 h. Samples were analyzed for amprenavir and fit to a compartmental model using ADAPT II software, with all relevant parameters conditional with respect to bioavailability. The model accommodated secondary peaks by incorporating clearance out of the central compartment with delayed instantaneous release back into the gut compartment. The data were weighted by the inverse of the estimated measurement error variance; model discrimination was determined using Akaike's Information Criteria. A total of 76 subjects were evaluable in the study analysis. The data were best fit by a two-compartment model, with 98.7% of the subjects demonstrating a secondary peak. Amprenavir had a mean total clearance of 1.163 liters/h/kg of body weight (0.7), a central volume of distribution of 1.208 liters/kg (0.8), a peripheral volume of distribution of 8.2 liters/kg (0.81), and distributional clearance of 0.04 liters/h/kg (0.81). The time to the secondary peak was 7.86 h (0.17), and clearance into a recycling compartment was 0.111 liters/kg/h (0.74). Amprenavir pharmacokinetics has been well described using a two-compartment model with clearance to a recycling compartment and release back into the gut. The nature of the secondary peaks may be an important consideration for the interpretation of amprenavir plasma concentrations during therapeutic drug monitoring.

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Optimization of fluconazole dosing for the prevention and treatment of invasive candidiasis based on the pharmacokinetics of fluconazole in critically-ill patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01554-20 ◽

2020 ◽

Author(s):

J. M. Boonstra ◽

A. G. Märtson ◽

I Sandaradura ◽

J. G. Kosterink ◽

T. S. van der Werf ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Plasma Concentrations ◽

Organ Transplant ◽

Compartment Model ◽

Pharmacokinetic Analysis ◽

Solid Organ ◽

Time Curve ◽

Final Population ◽

The Mean

Background: The efficacy of fluconazole is related to the area under the plasma concentration-time curve over the minimum inhibitory concentration of the microorganism. Physiological changes in critically ill patients may affect the exposure of fluconazole and therefore dosing adjustments might be needed. Objective: The aim of this study was to evaluate variability in fluconazole drug concentration in ICU patients and to develop a pharmacokinetic model to support personalized fluconazole dosing. Methods: A prospective observational pharmacokinetic study was performed in critically ill patients receiving fluconazole either as prophylaxis or as treatment. The association between fluconazole exposure and patient variables was studied. Pharmacokinetic modeling was performed with nonparametric adaptive grid (NPAG) algorithm using R package Pmetrics. Results: Data from 33 patients were available for pharmacokinetic analysis. Patients on dialysis and solid organ transplant patients had a significantly lower exposure to fluconazole. The population was best described with a one-compartment model, where the mean volume of distribution was 51.52 L (SD 19.81) and the mean clearance was 0.767 L/h (SD 0.46). Creatinine clearance was tested as a potential covariate in the model, but was not included in the final population model. A significant positive correlation was found between the fluconazole exposure (AUC) and the Cmin. Conclusion: Substantial variability in fluconazole plasma concentrations in critically-ill adults was observed, where the majority of patients were underexposed. Fluconazole Cmin TDM guided dosing can be used to optimize therapy in critically ill patients.

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Pregnancy-Related Effects on Tenofovir Pharmacokinetics: a Population Study with 186 Women

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05244-11 ◽

2011 ◽

Vol 56 (2) ◽

pp. 857-862 ◽

Cited By ~ 29

Author(s):

Sihem Benaboud ◽

Déborah Hirt ◽

Odile Launay ◽

Emmanuelle Pannier ◽

Ghislaine Firtion ◽

...

Keyword(s):

Pregnant Women ◽

Compartment Model ◽

Volume Of Distribution ◽

Therapeutic Drug ◽

Parameter Estimates ◽

Population Parameter ◽

Linear Absorption ◽

Two Compartment Model ◽

Apparent Clearance ◽

Elimination Clearance

ABSTRACTAccording to the European AIDS Clinical Society, tenofovir disoproxil fumarate can be used in HIV-infected pregnant women if started prior to pregnancy, although no data are available on the pharmacokinetics of tenofovir (TFV) during pregnancy. The aim of this study was to describe TFV pharmacokinetics in HIV-infected women and to evaluate the effect of pregnancy on TFV disposition. Samples were collected according to a therapeutic drug monitoring in 186 women, including 46 pregnant women treated with TFV and retrospectively analyzed by a population approach. TFV pharmacokinetics were ascribed to an open two-compartment model with linear absorption and elimination. The mean population parameter estimates (between-subject variability) were as follows: absorption rate constant, 0.56 h−1; elimination clearance, 59.9 liters h−1(0.436); central volume of distribution, 552 liters (1.96); intercompartmental clearance, 172 liters/h; and peripheral volume of distribution, 1,390 liters. Pregnant women had a 39% higher apparent clearance compared to nonpregnant women. Apparent clearance significantly decreased with age. In order to obtain an exposure similar to the known exposure in adults and guarantee similar trough concentrations (Cmin) as observed in adults, an increase in the TFV dose should be considered for women from the second trimester to delivery.

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Effect of Obesity on the Population Pharmacokinetics of Meropenem in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00531-16 ◽

2016 ◽

Vol 60 (8) ◽

pp. 4577-4584 ◽

Cited By ~ 16

Author(s):

Abdulaziz S. Alobaid ◽

Steven C. Wallis ◽

Paul Jarrett ◽

Therese Starr ◽

Janine Stuart ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Compartment Model ◽

Central Compartment ◽

Lower Probability ◽

Peripheral Compartment ◽

Morbidly Obese ◽

Parameter Estimates ◽

Population Pk ◽

Intercompartmental Clearance

ABSTRACTSevere pathophysiological changes in critical illness can lead to dramatically altered antimicrobial pharmacokinetics (PK). The additional effect of obesity on PK potentially increases the challenge for effective dosing. The aim of this prospective study was to describe the population PK of meropenem for a cohort of critically ill patients, including obese and morbidly obese patients. Critically ill patients prescribed meropenem were recruited into the following three body mass index (BMI) groups: nonobese (18.5 to 29.9 kg/m2), obese (30.0 to 39.9 kg/m2), and morbidly obese (≥40 kg/m2). Serial plasma samples were taken, and meropenem concentrations were determined using a validated chromatographic method. Population PK analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Nineteen critically ill patients with different BMI categories were enrolled. The patients' mean ± standard deviation (SD) age, weight, and BMI were 49 ± 15.9 years, 95 ± 22.0 kg, and 33 ± 7.0 kg/m2, respectively. A two-compartment model described the data adequately. The mean ± SD parameter estimates for the final covariate model were as follows: clearance (CL), 15.5 ± 6.0 liters/h; volume of distribution in the central compartment (V1), 11.7 ± 5.8 liters; intercompartmental clearance from the central compartment to the peripheral compartment, 25.6 ± 35.1 liters h−1; and intercompartmental clearance from the peripheral compartment to the central compartment, 8.32 ± 12.24 liters h−1. Higher creatinine clearance (CLCR) was associated with a lower probability of target attainment, with BMI having little effect. Although obesity was found to be associated with an increasedV1, dose adjustment based on CLCRappears to be more important than patient BMI.

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Linezolid Concentrations in Plasma and Subcutaneous Tissue are Reduced in Obese Patients, Resulting in a Higher Risk of Underdosing in Critically Ill Patients: A Controlled Clinical Pharmacokinetic Study

Journal of Clinical Medicine ◽

10.3390/jcm9041067 ◽

2020 ◽

Vol 9 (4) ◽

pp. 1067 ◽

Cited By ~ 1

Author(s):

Philipp Simon ◽

David Busse ◽

David Petroff ◽

Christoph Dorn ◽

Lisa Ehmann ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Therapeutic Target ◽

Subcutaneous Tissue ◽

Plasma Concentrations ◽

Volume Of Distribution ◽

Pharmacokinetic Analysis ◽

Obese Patients ◽

Clinical Model ◽

Dosing Regimens

Background: Linezolid is used for the treatment of soft tissue infections in critically ill patients. However, data for characterizing the pharmacokinetics (PK) and assessing whether effective concentrations are reached at the target site are lacking. We hypothesized that current dosing regimens do not lead to effective concentrations in the plasma and interstitial fluid (ISF) of subcutaneous tissue in obese patients. Methods: As a controlled clinical model, critically ill obese and non-obese patients undergoing intra-abdominal surgery received 600 mg linezolid as a single infusion. Concentrations in the plasma and microdialysate from the ISF of subcutaneous tissue were determined up to 8 h after dosing. Pharmacokinetic analysis was performed by non-compartmental methods. As a therapeutic target, we used fAUC/MIC > 80. Results: Fifteen obese (BMI: 48.7 ± 11.2 kg/m2) and 15 non-obese (23.9 ± 2.1 kg/m2) patients were analyzed. AUC0–8 in ISF decreased by −1.69 mg*h/L (95% CI: −2.59 to −0.79, p < 0.001) for every 10 kg increase in weight. PK in obese patients were characterized by lower maximal plasma concentrations (median 3.8 vs. 8.3 mg/L, p < 0.001) and a higher volume of distribution (41.0 vs. 30.8 L, p < 0.001), and the therapeutic target was not reached for MIC ≥ 1 mg/L in ISF and ≥ 2 mg/L in plasma. Conclusions: Increasing the weight led to a decrease of linezolid concentrations in the plasma and subcutaneous tissue. The current dosing regimen does not seem to produce sufficient concentrations to kill bacteria with MIC ≥ 2 mg/L, especially as empirical antimicrobial therapy in critically ill obese patients.

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Pharmacokinetics of Intravenous Posaconazole in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00242-18 ◽

2018 ◽

Vol 62 (6) ◽

pp. e00242-18 ◽

Cited By ~ 6

Author(s):

Fekade B. Sime ◽

Janine Stuart ◽

Jenie Butler ◽

Therese Starr ◽

Steven C. Wallis ◽

...

Keyword(s):

Single Dose ◽

Steady State ◽

Critically Ill ◽

Critically Ill Patients ◽

Central Venous Access ◽

Plasma Concentrations ◽

Parameter Estimates ◽

Pharmacokinetic Data ◽

Albumin Concentration ◽

Data Set

ABSTRACT To date, there is no information on the intravenous (i.v.) posaconazole pharmacokinetics for intensive care unit (ICU) patients. This prospective observational study aimed to describe the pharmacokinetics of a single dose of i.v. posaconazole in critically ill patients. Patients with no history of allergy to triazole antifungals and requiring systemic antifungal therapy were enrolled if they were aged ≥18 years, central venous access was available, they were not pregnant, and they had not received prior posaconazole or drugs interacting with posaconazole. A single dose of 300 mg posaconazole was administered over 90 min. Total plasma concentrations were measured from serial plasma samples collected over 48 h, using a validated chromatographic method. The pharmacokinetic data set was analyzed by noncompartmental methods. Eight patients (7 male) were enrolled with the following characteristics: median age, 46 years (interquartile range [IQR], 40 to 51 years); median weight, 68 kg (IQR, 65 to 82 kg); and median albumin concentration, 20 g/liter (IQR, 18 to 24 g/liter). Median (IQR) pharmacokinetic parameter estimates were as follows: observed maximum concentration during sampling period (Cmax), 1,702 ng/ml (1,352 to 2,141 ng/ml); area under the concentration-time curve from zero to infinity (AUC0–∞), 17,932 ng · h/ml (13,823 to 27,905 ng · h/ml); clearance (CL), 16.8 liters/h (11.1 to 21.7 liters/h); and volume of distribution (V), 529.1 liters (352.2 to 720.6 liters). The V and CL were greater than 2-fold and the AUC0–∞ was 39% of the values reported for heathy volunteers. The AUC0–∞ was only 52% of the steady-state AUC0–24 reported for hematology patients. The median of estimated average steady-state concentrations was 747 ng/ml (IQR, 576 to 1,163 ng/ml), which is within but close to the lower end of the previously recommended therapeutic range of 500 to 2,500 ng/ml. In conclusion, we observed different pharmacokinetics of i.v. posaconazole in this cohort of critically ill patients compared to those in healthy volunteers and hematology patients.

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The Population Pharmacokinetics of Meropenem in Adult Patients With Rifampicin-Sensitive Pulmonary Tuberculosis

Frontiers in Pharmacology ◽

10.3389/fphar.2021.637618 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ahmed A. Abulfathi ◽

Veronique de Jager ◽

Elana van Brakel ◽

Helmuth Reuter ◽

Nikhil Gupte ◽

...

Keyword(s):

Body Weight ◽

Creatinine Clearance ◽

Population Pharmacokinetics ◽

Goodness Of Fit ◽

Compartment Model ◽

Parameter Estimates ◽

Final Model ◽

Once Daily ◽

Two Compartment Model ◽

Relative Standard

Background: Meropenem is being investigated for repurposing as an anti-tuberculosis drug. This study aimed to develop a meropenem population pharmacokinetics model in patients with pulmonary tuberculosis and identify covariates explaining inter-individual variability.Methods: Patients were randomized to one of four treatment groups: meropenem 2 g three times daily plus oral rifampicin 20 mg/kg once daily, meropenem 2 g three times daily, meropenem 1 g three times daily, and meropenem 3 g once daily. Meropenem was administered by intravenous infusion over 0.5–1 h. All patients also received oral amoxicillin/clavulanate together with each meropenem dose, and treatments continued daily for 14 days. Intensive plasma pharmacokinetics sampling over 8 h was conducted on the 14th day of the study. Nonlinear mixed-effects modeling was used for data analysis. The best model was chosen based on likelihood metrics, goodness-of-fit plots, and parsimony. Covariates were tested stepwise.Results: A total of 404 concentration measurements from 49 patients were included in the analysis. A two-compartment model parameterized with clearance (CL), inter-compartmental clearance (Q), and central (V1) and peripheral (V2) volumes of distribution fitted the data well. Typical values of CL, Q, V1, and V2 were 11.8 L/h, 3.26 L/h, 14.2 L, and 3.12 L, respectively. The relative standard errors of the parameter estimates ranged from 3.8 to 35.4%. The covariate relations included in the final model were creatinine clearance on CL and allometric scaling with body weight on all disposition parameters. An effect of age on CL as previously reported could not be identified.Conclusion: A two-compartment model described meropenem population pharmacokinetics in patients with pulmonary tuberculosis well. Covariates found to improve model fit were creatinine clearance and body weight but not rifampicin treatment. The final model will be used for an integrated pharmacokinetics/pharmacodynamics analysis linking meropenem exposure to early bactericidal activity.

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