scholarly journals Characterizing the non-linear pharmacokinetics of miltefosine in paediatric visceral leishmaniasis patients from Eastern Africa

2020 ◽  
Vol 75 (11) ◽  
pp. 3260-3268
Author(s):  
Semra Palić ◽  
Anke E Kip ◽  
Jos H Beijnen ◽  
Jane Mbui ◽  
Ahmed Musa ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Cumulative Dose ◽  
Drug Exposure ◽  
Compartment Model ◽  
Eastern Africa ◽  
Model Following ◽  
Two Compartment Model ◽  
Non Linear ◽  
Linear Elimination ◽  
Dosing Regimens

Abstract Background Conventional miltefosine dosing (2.5 mg/kg/day) for treatment of visceral leishmaniasis (VL) is less effective in children than in adults. A higher allometric dose (median 3.2 mg/kg/day) was therefore investigated in paediatric VL patients in Eastern Africa. Results of this trial showed an unforeseen, lower than dose-proportional increase in exposure. Therefore, we performed a pooled model-based analysis of the paediatric data available from both dosing regimens to characterize observed non-linearities in miltefosine pharmacokinetics (PK). Methods Fifty-one children with VL were included in this analysis, treated with either a conventional (n = 21) or allometric (n = 30) miltefosine dosing regimen. PK data were analysed using non-linear mixed-effects modelling. Results A two-compartment model following first-order absorption and linear elimination, with two separate effects on relative oral bioavailability, was found to fit these data best. A 69% lower bioavailability at treatment start was estimated, presumably due to initial malnourishment and malabsorption. Stagnation in miltefosine accumulation in plasma, hampering increased drug exposure, was related to the increase in cumulative dose (mg/kg/day). However, the allometric regimen increased exposure 1.7-fold in the first treatment week and reduced the time to reach the PK target by 17.4%. Conclusions Miltefosine PK in children suffering from VL are characterized by dose-dependent non-linearities that obstruct the initially expected exposure levels. Bioavailability appeared to be affected by the cumulative dose, possibly as a consequence of impaired absorption. Despite this, allometric dosing led to a faster target achievement and increased exposure compared with conventional dosing.

scholarly journals Ethambutol Pharmacokinetic Variability Is Linked to Body Mass in Overweight, Obese, and Extremely Obese People

2011 ◽  
Vol 56 (3) ◽  
pp. 1502-1507 ◽  
Author(s):  
Ronald G. Hall ◽  
Mark A. Swancutt ◽  
Claudia Meek ◽  
Richard D. Leff ◽  
Tawanda Gumbo
Keyword(s):  
Body Mass ◽  
Compartment Model ◽  
Obese Patients ◽  
Obese People ◽  
Time Curve ◽  
Female Ratio ◽  
Two Compartment Model ◽  
Dosing Regimens ◽  
A Prospective Study ◽  
Male To Female

ABSTRACTWe conducted a prospective study of 18 adult volunteers (male-to-female ratio of 1) whose body mass index fell into categories of <25, 25 to 40, or >40 kg/m2, who received a single oral dose of 1,600 mg ethambutol. Only individuals with normal renal function were recruited. The minimum body mass (M) was 45.6 kg, the median was 90.8 kg, and the maximum weight was 160.4 kg. Ethambutol pharmacokinetics were best described by a two-compartment model. Inclusion of weight as a covariate dramatically improved the model, with a relative likelihood approaching infinity. The typical clearance was 42.6 liters/h. Ethambutol systemic clearance was proportional to (M/45.6)3/4and thus obeyed fractal geometry-based laws. This means that the area under the concentration-time curve (AUC) actually decreased for obese patients compared to that for leaner patients, reducing chances of concentration-dependent toxicity. On the other hand, such reduced AUCs could lead to therapy failure. Thus, new and individualized ethambutol dosing regimens need to be designed for obese and extremely obese patients.

Pharmacokinetics/Pharmacodynamics of caspofungin in plasma and peritoneal fluid of liver transplant recipients

2021 ◽  
Author(s):  
Claire Pressiat ◽  
Nawel Ait-Ammar ◽  
Matthieu Daniel ◽  
Anne Hulin ◽  
Françoise Botterel ◽  
...  
Keyword(s):  
Liver Transplant ◽  
Peritoneal Fluid ◽  
Compartment Model ◽  
Transplant Recipients ◽  
Mixed Effect ◽  
First Order ◽  
Transplant Patients ◽  
Two Compartment Model ◽  
Dosing Regimens ◽  
Liver Transplant Recipients

Background: The weaker diffusion of echinocandins in the peritoneal fluid (PF) could promote Candida resistant isolates. The aim of this study was to analyse the pharmacokinetics/pharmacodynamics (PK/PD) of caspofungin in plasma and PF of liver transplant recipients. Methods: Liver transplant patients received caspofungin as postoperative prophylaxis. Caspofungin concentrations were quantified in plasma and in PF on Days 1, 3 and 8. Data were analysed using non-linear mixed-effect modelling and Monte Carlo simulations. Area under curve (AUC) in plasma and PF were simulated under three dosing regimens. Probabilities of target attainment (PTA) were calculated using fAUC 0-24 /minimal inhibitory concentration (MIC) ratios with MICs ranging from 0.008 to 8 mg/litre. All the patients included were monitored weekly for Candida colonisation and for Candida infections. Results: Twenty patients were included. Median daily dose of caspofungin was 0.81 mg/kg. Plasma (n=395) and peritoneal (n=50) concentrations at steady state were available. A two-compartment model with first-order absorption and elimination was described. Our two-compartment model with first-order absorption and elimination model produced an effective PK/PD relationship in plasma, achieving a PTA ≥90% and MIC ranging from 0.008 to 0.12 mg/L for C. albicans and glabrata . In PF, PTAs at D8 were only optimal for a MIC of 0.008 in patients weighing 60 kg under the three dosing regimens. Among the 16 patients colonized, all MIC values were below the maximal concentration (Cmax) in plasma but not in PF. Conclusion: Peritoneal concentrations of caspofungin were low. Simulations showed that the PTA for Candida spp. in PF were not optimal, that might suggesting a potential risk of resistance.

scholarly journals Pharmacokinetics of Micafungin in Critically Ill Patients

2019 ◽  
Vol 9 (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.

scholarly journals Population pharmacokinetics of ivermectin for the treatment of scabies in Indigenous Australian children

2020 ◽  
Vol 14 (12) ◽  
pp. e0008886
Author(s):  
Amanda Gwee ◽  
Stephen Duffull ◽  
Xiao Zhu ◽  
Steven Y. C. Tong ◽  
Noel Cranswick ◽  
...  
Keyword(s):  
Young Children ◽  
Drug Exposure ◽  
Neglected Tropical Diseases ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Indigenous Australian ◽  
Time Curve ◽  
Similar Drug ◽  
Linear Elimination ◽  
Dosing Strategy

Ivermectin is a broad-spectrum antiparasitic agent used for the treatment and control of neglected tropical diseases. In Australia, ivermectin is primarily used for scabies and is licensed in children aged ≥5 years weighing >15 kg. However, young children, aged <5 years, are particularly vulnerable to scabies and its secondary complications. Therefore, this study aimed to determine an appropriate ivermectin dose for children aged 2 to 4 years and weighing ≤15 kg. We conducted a prospective, pharmacokinetic study of ivermectin in Indigenous Australian children aged between 5 and 15 years and weighing >15 kg. Doses of 200 μg/kg rounded to the nearest whole or half 3 mg tablet were given to children with scabies and ivermectin concentrations determined at two time points after dosing. A population pharmacokinetic model was developed using non-linear mixed effects modelling. A separate covariate database of children aged 2 to 4 years and weighing <15 kg was used to generate 1000 virtual patients and simulate the dose required to achieve equivalent drug exposure in young children as those aged ≥5 years. Overall, 26 children who had 48 ivermectin concentrations determined were included, 11 (42%) were male, the median age was 10.9 years and median body weight 37.6 kg. The final model was a two-compartment model with first-order absorption and linear elimination. For simulated children aged 2 to 4 years, a dose of 3 mg in children weighing 10–15 kg produced similar drug exposures to those >5 years. The median simulated area under the concentration-time curve was 976 μg∙h/L. Using modelling, we have identified a dosing strategy for ivermectin in children aged 2 to 4 years and weighing less than 15 kg that can be prospectively evaluated for safety and efficacy.

Population pharmacokinetics and dosing simulations of amoxicillin in obese adults receiving co-amoxiclav

2020 ◽  
Vol 75 (12) ◽  
pp. 3611-3618
Author(s):  
G Mellon ◽  
K Hammas ◽  
C Burdet ◽  
X Duval ◽  
C Carette ◽  
...  
Keyword(s):  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Open Label ◽  
Mixed Effect ◽  
Mean Values ◽  
Two Compartment Model ◽  
Amoxicillin Clavulanate ◽  
Dosing Regimens ◽  
Obese Subjects

Abstract Background Pneumonia, skin and soft tissue infections are more frequent in obese patients and are most often treated by co-amoxiclav, using similar dosing regimens to those used for non-obese subjects. No data are available on amoxicillin pharmacokinetics among obese subjects receiving co-amoxiclav. Materials and methods Prospective, single-centre, open-label, non-randomized, crossover pharmacokinetic trial having enrolled obese otherwise healthy adult subjects. A first dose of co-amoxiclav (amoxicillin/clavulanate 1000/200 mg) was infused IV over 30 min, followed by a second dose (1000/125 mg) administered orally, separated by a washout period of ≥24 h. We assayed concentrations of amoxicillin by a validated ultra HPLC–tandem MS technique. We estimated population pharmacokinetic parameters of amoxicillin by non-linear mixed-effect modelling using the SAEM algorithm developed by Monolix. Results Twenty-seven subjects were included in the IV study, with 24 included in the oral part of the study. Median body weight and BMI were 109.3 kg and 40.6 kg/m2, respectively. Amoxicillin pharmacokinetics were best described by a two-compartment model with first-order elimination. Mean values for clearance, central volume, intercompartmental clearance and peripheral volume were, respectively, 14.6 L/h, 9.0 L, 4.2 L/h and 6.4 L for amoxicillin. Oral bioavailability of amoxicillin was 79.7%. Amoxicillin Cmax after oral administration significantly reduced with weight (P = 0.013). Dosing simulations for amoxicillin predicted that most of the population will achieve the pharmacodynamic target of fT&gt;MIC ≥40% with the regimen of co-amoxiclav 1000/200 mg (IV) or 1000/125 mg (oral) q8h for MICs titrated up to 0.5 mg/L (IV) and 1 mg/L (oral). Conclusions Pharmacokinetic/pharmacodynamic goals for amoxicillin can be obtained in obese subjects.

scholarly journals Population Pharmacokinetics and Dosing Regimen Optimization of Meropenem in Cerebrospinal Fluid and Plasma in Patients with Meningitis after Neurosurgery

2016 ◽  
Vol 60 (11) ◽  
pp. 6619-6625 ◽  
Author(s):  
Cheng Lu ◽  
Yuyi Zhang ◽  
Mingyu Chen ◽  
Ping Zhong ◽  
Yuancheng Chen ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Population Pharmacokinetics ◽  
Compartment Model ◽  
Dosing Regimen ◽  
Target Attainment ◽  
Csf Drainage ◽  
Two Compartment Model ◽  
Dosing Regimens ◽  
Dosing Intervals ◽  
To Receive

ABSTRACTMeropenem is used to manage postneurosurgical meningitis, but its population pharmacokinetics (PPK) in plasma and cerebrospinal fluid (CSF) in this patient group are not well-known. Our aims were to (i) characterize meropenem PPK in plasma and CSF and (ii) recommend favorable dosing regimens in postneurosurgical meningitis patients. Eighty-two patients were enrolled to receive meropenem infusions of 2 g every 8 h (q8h), 1 g q8h, or 1 g q6h for at least 3 days. Serial blood and CSF samples were collected, and concentrations were determined and analyzed via population modeling. Probabilities of target attainment (PTA) were predicted via Monte Carlo simulations, using the target of unbound meropenem concentrations above the MICs for at least 40% of dosing intervals in plasma and at least of 50% or 100% of dosing intervals in CSF. A two-compartment model plus another CSF compartment best described the data. The central, intercentral/peripheral, and intercentral/CSF compartment clearances were 22.2 liters/h, 1.79 liters/h, and 0.01 liter/h, respectively. Distribution volumes of the central and peripheral compartments were 17.9 liters and 3.84 liters, respectively. The CSF compartment volume was fixed at 0.13 liter, with its clearance calculated by the observed drainage amount. The multiplier for the transfer from the central to the CSF compartment was 0.172. Simulation results show that the PTAs increase as infusion is prolonged and as the daily CSF drainage volume decreases. A 4-hour infusion of 2 g q8h with CSF drainage of less than 150 ml/day, which provides a PTA of >90% for MICs of ≤8 mg/liter in blood and of ≤0.5 mg/liter or 0.25 mg/liter in CSF, is recommended. (This study has been registered at ClinicalTrials.gov under identifier NCT02506686.)

scholarly journals Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations

2020 ◽  
Vol 75 (9) ◽  
pp. 2641-2649
Author(s):  
Nynke G L Jager ◽  
Reinier M van Hest ◽  
Jiao Xie ◽  
Gloria Wong ◽  
Marta Ulldemolins ◽  
...  
Keyword(s):  
Protein Binding ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Binding Capacity ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Population Pk ◽  
Non Linear ◽  
Dosing Regimens

Abstract Background Initial appropriate anti-infective therapy is associated with improved outcomes in patients with severe infections. In critically ill patients, altered pharmacokinetic (PK) behaviour is common and known to influence the achievement of PK/pharmacodynamic targets. Objectives To describe population PK and optimized dosing regimens for flucloxacillin in critically ill patients. Methods First, we developed a population PK model, estimated between-patient variability (BPV) and identified covariates that could explain BPV through non-linear mixed-effects analysis, using total and unbound concentrations obtained from 35 adult critically ill patients treated with intermittent flucloxacillin. Second, we validated the model using external datasets from two different countries. Finally, frequently prescribed dosing regimens were evaluated using Monte Carlo simulations. Results A two-compartment model with non-linear protein binding was developed and validated. BPV of the maximum binding capacity decreased from 42.2% to 30.4% and BPV of unbound clearance decreased from 88.1% to 71.6% upon inclusion of serum albumin concentrations and estimated glomerular filtration rate (eGFR; by CKD-EPI equation), respectively. PTA (target of 100%fT&gt;MIC) was 91% for patients with eGFR of 33 mL/min and 1 g q6h, 87% for patients with eGFR of 96 mL/min and 2 g q4h and 71% for patients with eGFR of 153 mL/min and 2 g q4h. Conclusions For patients with high creatinine clearance who are infected with moderately susceptible pathogens, therapeutic drug monitoring is advised since there is a risk of underexposure to flucloxacillin. Due to the non-linear protein binding of flucloxacillin and the high prevalence of hypoalbuminaemia in critically ill patients, dose adjustments should be based on unbound concentrations.

scholarly journals Assessment of Micafungin Dosage Regimens in Patients with Cancer Using Pharmacokinetic/Pharmacodynamic Modeling and Monte Carlo Simulation

Antibiotics ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1363
Author(s):  
Saeed Alqahtani ◽  
Asma Alfarhan ◽  
Abdullah Alsultan ◽  
Emad Alsarhani ◽  
Abdulaziz Alsubaie ◽  
...  
Keyword(s):  
High Performance ◽  
Compartment Model ◽  
Pharmacodynamic Modeling ◽  
Pharmacokinetic Parameters ◽  
Candida Spp ◽  
Patients With Cancer ◽  
Treatment And Prevention ◽  
Two Compartment Model ◽  
Linear Elimination ◽  
Empirical Antifungal Therapy

Micafungin is widely used for invasive candidiasis, especially in critically ill patients and those with cancer, and for empirical antifungal therapy in patients with neutropenic fever. This is the first study to investigate the pharmacokinetics and disposition parameters of micafungin in patients with cancer. In this observational pharmacokinetic study, blood samples were collected and analyzed using high-performance liquid chromatography. Pharmacokinetic parameters were estimated using Monolix 4.4 software. The plasma micafungin concentrations were measured in a total of 133 samples from 19 patients. In the final two-compartment model with linear elimination, the estimated micafungin clearance (CL) was significantly higher in patients with cancer than in those without cancer (1.2 vs. 0.6 L/h, p = 0.012), whereas other parameters did not significantly differ between the two groups. Aspartate and alanine transaminases and body weight significantly influenced micafungin CL in patients, with and without cancer. Overall, the probability of target attainment increased with increasing doses and decreased with higher MICs in both groups. In simulations, the patients without cancer achieved higher pharmacokinetic/pharmacodynamic targets with a 90% probability for all simulated doses, compared to the patients with cancer. Micafungin demonstrated dose-proportional linear pharmacokinetics in both the patients with and those without cancer. The estimated micafungin CL was significantly higher in patients with cancer, suggesting a need for increased dosage, especially for Candida spp. with high MICs, in these patients. Further studies should assess the efficacy and optimum dosage of micafungin for the treatment and prevention of febrile neutropenia (FN) in patients with cancer.

scholarly journals Which Analysis Approach Is Adequate to Leverage Clinical Microdialysis Data? A Quantitative Comparison to Investigate Exposure and Reponse Exemplified by Levofloxacin

2021 ◽  
Author(s):  
David Busse ◽  
André Schaeftlein ◽  
Alexander Solms ◽  
Luis Ilia ◽  
Robin Michelet ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Visual Predictive Check ◽  
Model Performance ◽  
Compartmental Analysis ◽  
Community Acquired Pneumonia ◽  
Target Site ◽  
Clinical Pharmacokinetics ◽  
Time Integral ◽  
Dosing Regimens ◽  
Therapeutic Decision Making

Abstract Purpose Systematic comparison of analysis methods of clinical microdialysis data for impact on target-site drug exposure and response. Methods 39 individuals received a 500 mg levofloxacin short-term infusion followed by 24-h dense sampling in plasma and microdialysate collection in interstitial space fluid (ISF). ISF concentrations were leveraged using non-compartmental (NCA) and compartmental analysis (CA) via (ii) relative recovery correction at midpoint of the collection interval (midpoint-NCA, midpoint-CA) and (ii) dialysate-based integrals of time (integral-CA). Exposure and adequacy of community-acquired pneumonia (CAP) therapy via pharmacokinetic/pharmacodynamic target-attainment (PTA) analysis were compared between approaches. Results Individual AUCISF estimates strongly varied for midpoint-NCA and midpoint-CA (≥52.3%CV) versus integral-CA (≤32.9%CV) owing to separation of variability in PK parameters (midpoint-CA = 46.5%–143%CVPK, integral-CA = 26.4%–72.6%CVPK) from recovery-related variability only in integral-CA (41.0%–50.3%CVrecovery). This also led to increased variability of AUCplasma for midpoint-CA (56.0%CV) versus midpoint-NCA and integral-CA (≤33.0%CV), and inaccuracy of predictive model performance of midpoint-CA in plasma (visual predictive check). PTA analysis translated into 33% of evaluated patient cases being at risk of incorrectly rejecting recommended dosing regimens at CAP-related epidemiological cut-off values. Conclusions Integral-CA proved most appropriate to characterise clinical pharmacokinetics- and microdialysis-related variability. Employing this knowledge will improve the understanding of drug target-site PK for therapeutic decision-making.

Two-Compartment Model of Cholesterol Kinetics for Establishment of Treatment Strategy of LDL Apheresis in Nephrotic Hypercholesterolemia

1994 ◽  
Vol 12 (6) ◽  
pp. 317-326 ◽  
Author(s):  
Masatomo Yashiro ◽  
Eri Muso ◽  
Munehiro Matsushima ◽  
Ryoichi Nagura ◽  
Kenji Sawanishi ◽  
...  
Keyword(s):  
Treatment Strategy ◽  
Compartment Model ◽  
Ldl Apheresis ◽  
Two Compartment Model
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