Population pharmacokinetics of daptomycin in patients with bone and joint infection: minimal effect of rifampicin co-administration and confirmation of a sex difference

2021 ◽  
Author(s):  
Romain Garreau ◽  
Romain Bricca ◽  
Marie-Claude Gagnieu ◽  
Sandrine Roux ◽  
Anne Conrad ◽  
...  
Keyword(s):  
Joint Infection ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Individual Variability ◽  
Therapeutic Drug ◽  
Marginal Effect ◽  
Bone And Joint Infection ◽  
Two Compartment Model ◽  
Central Volume ◽  
Trough Concentrations

Abstract Background Daptomycin is increasingly used in the treatment of bone and joint infection (BJI), but its pharmacokinetics (PK) and dosage requirements have not been thoroughly investigated in this indication. Daptomycin may be co-administered with rifampicin, which raises questions about a potential drug interaction. Objectives To investigate the population PK and dosage requirements of daptomycin in patients with BJI, and examine the influence of rifampicin co-administration. Methods A population approach was used to analyse PK data from patients who received daptomycin in our regional reference for BJI. We examined the influence of available covariates, including rifampicin co-administration on daptomycin PK. Simulations performed with the final model investigated the influence of dosages and covariates on PTA for both efficacy and safety. Results A total of 1303 daptomycin concentrations from 183 patients were analysed. A two-compartment model best described the data. Significant intra-individual variability was observed. Daptomycin clearance was influenced by renal function and sex, with females having a 26% lower typical clearance than males. Central volume of distribution (V1) was influenced by body weight, age, sex and rifampicin co-administration. Typical V1 was 11% lower in patients who were co-administered rifampicin. In PK/PD simulations, sex influenced the probability of AUC24/MIC target attainment, while rifampicin had a marginal effect. Conclusions A daptomycin dosage of 8 mg/kg/24 h in women and 10 mg/kg/24 h in men should optimize efficacy but may lead to excessive trough concentrations in many patients, especially in women. Therapeutic drug monitoring appears necessary for precision dosing of daptomycin.

scholarly journals Compartmental Pharmacokinetic Analysis of Oral Amprenavir with Secondary Peaks

2007 ◽  
Vol 51 (5) ◽  
pp. 1822-1826 ◽  
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.

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

2011 ◽  
Vol 56 (2) ◽  
pp. 857-862 ◽  
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.

scholarly journals Population pharmacokinetics of cefotaxime in intensive care patients

2021 ◽  
Author(s):  
Maria Swartling ◽  
Anna-Karin Smekal ◽  
Mia Furebring ◽  
Miklos Lipcsey ◽  
Siv Jönsson ◽  
...  
Keyword(s):  
Intensive Care ◽  
Creatinine Clearance ◽  
Volume Of Distribution ◽  
Individual Variability ◽  
Pharmacokinetic Analysis ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Icu Patients ◽  
Central Volume ◽  
The Impact

Abstract Purpose To characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates. Methods This 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. Results A 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%. Conclusion A 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.

Cefepime precision dosing tool: From Standard to Precise Dose Using Nonparametric Population Pharmacokinetics

2021 ◽  
Author(s):  
Mohammad H. Alshaer ◽  
Sylvain Goutelle ◽  
Barbara Santevecchi ◽  
Bethany Shoulders ◽  
Veena Venugopalan ◽  
...  
Keyword(s):  
Compartment Model ◽  
Volume Of Distribution ◽  
Target Range ◽  
Population Pharmacokinetic ◽  
Support Points ◽  
Two Compartment Model ◽  
Central Volume ◽  
Model Support ◽  
Median Rate ◽  
Concentration Prediction

Cefepime is the second most common cephalosporin used in U.S. hospitals. We aim to develop and validate cefepime population pharmacokinetic (PK) model and integrate into precision dosing tool for implementation. Two datasets (680 patients) were used to build cefepime PK model in Pmetrics, and three datasets (34 patients) were used for the validation. A separate application dataset (115 patients) was used for the implementation and validation of a precision dosing tool. The model support points and covariates were used to generate the optimal initial dose (OID). Cefepime PK was described by a two-compartment model including weight and creatinine clearance (CrCl) as covariates. The median rate of elimination was 0.30 hr −1 (adults) and 0.96 hr −1 (pediatrics), central volume of distribution 13.85 L, and rate of transfer from the central to the peripheral compartments 1.22 hr −1 and from the peripheral to the central compartments 1.38 hr −1 . After integration in BestDose, the observed vs. predicted cefepime concentration fit using the application dataset was excellent (R 2 >0.98) and the median difference between observed and what BestDose predicted in a second occasion was 4%. For OID, cefepime 0.5-1g 4-hour infusion q8-24hr with CrCl<70 mL/min was needed to achieve a target range of free trough:MIC 1-4 at MIC 8 mg/L, while continuous infusion was needed for higher CrCl and weight values. In conclusion, we developed and validated a cefepime model for clinical application. The model was integrated in a precision dosing tool for implementation and the median concentration prediction bias was 4%. OID algorithm was provided.

Population Pharmacokinetics of Recombinant Factor VIIa in Volunteers Anticoagulated with Acenocoumarol

1998 ◽  
Vol 80 (07) ◽  
pp. 109-113 ◽  
Author(s):  
Patrice Nony ◽  
Elisabeth Erhardtsen ◽  
Sylvie Delair ◽  
Patrick Ffrench ◽  
Marc Dechavanne ◽  
...  
Keyword(s):  
Factor Viia ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Individual Variability ◽  
Factor Vii ◽  
Recombinant Activated Factor Vii ◽  
Activated Factor Vii ◽  
Dose Ranging ◽  
Endogenous Activity ◽  
Dose Dependent

SummaryThis study establishes a population PK model for FVII clotting activity (FVII:C) after injection of recombinant activated factor VII (rFVIIa) to healthy volunteers. Twenty eight volunteers, anticoagulated with acenocoumarol, received one or two rFVIIa injections, with dose ranging from 5 to 320 μg/kg. The FVII:C kinetic was fitted to a 2 compartment model, with continuous “endogenous perfusion” mimicking endogenous activity. Estimated clearance was 2.4 l/h (20% inter-individual variability and 9% inter-period variability). The volume of distribution at steady-state appeared to be significantly dose dependent: 78 ml/kg for doses ≤20 μg/kg and 88 ml/kg for doses >20 μg/kg respectively, with 16% inter-individual variability. The dose producing 50% of the maximum drop of INR was estimated to be 2.2 μg/kg. The model will be used to better define the dosage regimen for future clinical developments.

Population pharmacokinetic modeling and dosing simulations of tobramycin in pediatric patients with cystic fibrosis

2021 ◽  
Author(s):  
Antonin Praet ◽  
Laurent Bourguignon ◽  
Florence Vetele ◽  
Valentine Breant ◽  
Charlotte Genestet ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dose Adjustment ◽  
Total Body Weight ◽  
Compartment Model ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Population Pharmacokinetic Modeling ◽  
Two Compartment Model ◽  
Total Body

Initial dosing and dose adjustment of intravenous tobramycin in cystic fibrosis children is challenging. The objectives of this study were to develop nonparametric population pharmacokinetic (PK) models of tobramycin in children with CF to be used for dosage design and model-guided therapeutic drug monitoring. We performed a retrospective analysis of tobramycin PK data in our CF children center. The Pmetrics package was used for nonparametric population PK analysis and dosing simulations. Both the maximal concentration over the MIC (Cmax/MIC) and daily area under the concentration-time curve to the MIC (AUC 24 /MIC) ratios were considered as efficacy target. Trough concentration (Cmin) was considered as the safety target. A total of 2884 tobramycin concentrations collected in 195 patients over 9 years were analyzed. A two-compartment model including total body weight, body surface area and creatinine clearance as covariates best described the data. A simpler model was also derived for implementation into the BestDose software to perform Bayesian dose adjustment. Both models were externally validated. PK/PD simulations with the final model suggest that an initial dose of tobramycin of 15 to 17.5 mg/kg/day was necessary to achieve Cmax/MIC ≥ 10 values for MIC values up to 2 mg/L in most patients. The AUC 24 /MIC target was associated with larger dosage requirements and higher Cmin. A daily dose of 12.5 mg/kg would optimize both efficacy and safety target attainment. We recommend to perform tobramycin TDM, model-based dose adjustment, and MIC determination to individualize intravenous tobramycin therapy in children with CF.

scholarly journals 1573. Population Pharmacokinetic Analyses for Cefepime in Adult and Pediatric Patients

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S574-S575
Author(s):  
Jiajun Liu ◽  
Michael Neely ◽  
Jeffrey Lipman ◽  
Fekade B Sime ◽  
Jason Roberts ◽  
...  
Keyword(s):  
Rate Constant ◽  
Pediatric Patients ◽  
Validation Cohort ◽  
External Validation ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Information Criteria ◽  
Population Pharmacokinetic ◽  
Final Model ◽  
Two Compartment Model

Abstract Background Cefepime (CEF) is commonly used for adult and pediatric infections. Several studies have examined CEF’s pharmacokinetics (PK) in various populations; however, a unifying PK model for adult and pediatric subjects does not yet exist. We developed a combined population model for adult and pediatric patients and validated the model. Methods The initial model includes adult and pediatric patients with a rich cefepime sampling design. All adults received 2 g CEF while pediatric subjects received a mean of 49 (SD 5) mg/kg. One- and two-compartment models were considered as base models and were fit using a non-parametric adaptive grid algorithm within the Pmetrics package 1.5.2 (Los Angeles, CA) for R 3.5.1. Compartmental model selection was based on Akaike information criteria (AIC). Covariate relationships with PK parameters were visually inspected and mathematically assessed. Predictive performance was evaluated using bias and imprecision of the population and individual prediction models. External validation was conducted using a separate adult cohort. Results A total of 45 subjects (n = 9 adults; n = 36 pediatrics) were included in the initial PK model build and 12 subjects in the external validation cohort. Overall, the data were best described using a two-compartment model with volume of distribution (V) normalized to total body weight (TBW/70 kg) and an allometric scaled elimination rate constant (Ke) for pediatric subjects (AIC = 4,138.36). Final model observed vs. predicted plots demonstrated good fit (population R2 = 0.87, individual R2 = 0.97, Figure 1a and b). For the final model, the population median parameter values (95% credibility interval) were V0 (total volume of distribution), 11.7 L (10.2–14.6); Ke for adult, 0.66 hour−1 (0.38–0.78), Ke for pediatrics, 0.82 hour−1 (0.64–0.85), KCP (rate constant from central to peripheral compartment), 1.4 hour−1 (1.3–1.8), KPC (rate constant from peripheral to central compartment), 1.6 hour−1 (1.2–1.8). The validation cohort has 12 subjects, and the final model fit the data well (individual R2 = 0.75). Conclusion In this diverse group of adult and pediatrics, a two-compartment model described CEF PK well and was externally validated with a unique cohort. This model can serve as a population prior for real-time PK software algorithms. Disclosures All authors: No reported disclosures.

scholarly journals Population Pharmacokinetics of Liposomal Amphotericin B and Caspofungin in Allogeneic Hematopoietic Stem Cell Recipients

2011 ◽  
Vol 56 (1) ◽  
pp. 536-543 ◽  
Author(s):  
Gudrun Würthwein ◽  
Charlotte Young ◽  
Claudia Lanvers-Kaminsky ◽  
Georg Hempel ◽  
Mirjam N. Trame ◽  
...  
Keyword(s):  
Stem Cell ◽  
Amphotericin B ◽  
Hematopoietic Stem Cell ◽  
Liposomal Amphotericin ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Concentration Data ◽  
Hematopoietic Stem ◽  
Two Compartment Model ◽  
Proportional Error Model

ABSTRACTLiposomal amphotericin B (LAMB) and caspofungin (CAS) are important antifungal agents in allogeneic hematopoietic stem cell transplant (aHSCT) recipients. Little is known, however, about the pharmacokinetics (PK) of both agents and their combination in this population. The PK of LAMB and CAS and the potential for PK interactions between both agents were investigated within a risk-stratified, randomized phase II clinical trial in 53 adult aHSCT recipients with granulocytopenia and refractory fever. Patients received either LAMB (n= 17; 3 mg/kg once a day [QD]), CAS (n= 19; 50 mg QD; day 1, 70 mg), or the combination of both (CAS-LAMB;n= 17) for a median duration of 10 to 13 days (range, 4 to 28 days) until defervescence and granulocyte recovery. PK sampling was performed on days 1 and 4. Drug concentrations in plasma (LAMB, 405 samples; CAS, 458 samples) were quantified by high-pressure liquid chromatography and were analyzed using population pharmacokinetic modeling. CAS concentration data best fitted a two-compartment model with a proportional error model and interindividual variability (IIV) for clearance (CL) and central volume of distribution (V1) (CL, 0.462 liter/h ± 25%;V1, 8.33 liters ± 29%; intercompartmental clearance [Q], 1.25 liters/h; peripheral volume of distribution [V2], 3.59 liters). Concentration data for LAMB best fitted a two-compartment model with a proportional error model and IIV for all parameters (CL, 1.22 liters/h ± 64%;V1, 19.2 liters ± 38%;Q, 2.18 liters/h ± 47%;V2, 52.8 liters ± 84%). Internal model validation showed predictability and robustness of both models. None of the covariates tested (LAMB or CAS comedication, gender, body weight, age, body surface area, serum bilirubin, and creatinine clearance) further improved the models. In summary, the disposition of LAMB and CAS was best described by two-compartment models. Drug exposures in aHSCT patients were comparable to those in other populations, and no PK interactions were observed between the two compounds.

scholarly journals Phenobarbital pharmacokinetics in neonates and infants during extracorporeal membrane oxygenation

Perfusion ◽  
2018 ◽  
Vol 33 (1_suppl) ◽  
pp. 80-86 ◽  
Author(s):  
Pavla Pokorná ◽  
Martin Šíma ◽  
Václav Vobruba ◽  
Dick Tibboel ◽  
Ondřej Slanař
Keyword(s):  
Body Weight ◽  
Extracorporeal Membrane Oxygenation ◽  
Volume Of Distribution ◽  
Individual Variability ◽  
Therapeutic Drug ◽  
Pharmacokinetic Data ◽  
Serum Concentrations ◽  
Linear Regression Models ◽  
Membrane Oxygenation ◽  
Neonates And Infants

Introduction: The disposition of drugs is potentially changed due to extracorporeal membrane oxygenation (ECMO) in neonates and infants. Methods: The aim of the study was to evaluate the individual pharmacokinetics (PK) of phenobarbital and the effect of PK covariates in neonates and infants undergoing ECMO. Sixteen patients (7 neonates, 9 infants) treated with phenobarbital during ECMO (centrifugal-flow pump circuits) were enrolled in the PK study. Phenobarbital serum concentrations were measured using a fluorescence polarization immunoassay. Individual PK parameters - volume of distribution (Vd) and clearance (CL) were calculated in a one-compartmental pharmacokinetic model. Results: The mean (SD) Vd and CL values in neonates were 0.46 (0.24) L/kg and 8.0 (4.5) mL/h/kg, respectively. Respective values in infants were 0.56 (0.23) L/kg and 8.5 (3.1) mL/h/kg. PK parameters in neonates and infants were not significantly different. We observed high inter-individual variability in PK parameters (coefficients of variation [CV] were 52% and 53% for CL and Vd, respectively). Doses were adjusted based on therapeutic drug monitoring (TDM) in 87.5% patients. Only 50% of the first measured phenobarbital serum concentrations in each patient were within the therapeutic range of 10-40 mg/L, in comparison with 88.6% concentration measured after TDM implementation. Linear regression models showed that both Vd and CL are significantly related with body weight (BW) and length. Median optimal phenobarbital loading dose (LD) and maintenance dose (MD), calculated from pharmacokinetic data, were 15 mg/kg and 4 mg/kg/day, respectively. Conclusions: Body weight was shown to be the main PK covariate of phenobarbital disposition. Subsequent dosing nomograms are provided for phenobarbital dosing during ECMO.

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