Moxifloxacin Pharmacokinetic Profile and Efficacy Evaluation in Empiric Treatment of Community-Acquired Pneumonia

ABSTRACTWhen antimicrobials are used empirically, pathogen MICs equal to clinical breakpoints or epidemiological cutoff values must be considered. This is to ensure that the most resistant pathogen subpopulation is appropriately targeted to prevent emergence of resistance. Accordingly, we determined the pharmacokinetic (PK) profile of moxifloxacin at 400 mg/day in 18 patients treated empirically for community-acquired pneumonia. We developed a population pharmacokinetic model to assess the potential efficacy of moxifloxacin and to simulate the maximal MICs for which recommended pharmacokinetic-pharmacodynamic (PK-PD) estimates are obtained. Moxifloxacin plasma concentrations were determined the day after therapy initiation using ultra-high-performance liquid chromatography. Peak drug concentrations (Cmax) and area under the free drug concentration-time curve from 0 to 24 h (fAUC0–24) values predicted for each patient were evaluated against epidemiological cutoff MIC values forStreptococcus pneumoniae,Haemophilus influenzae, andLegionella pneumophila. PK-PD targets adopted were aCmax/MIC of ≥12.2 for all pathogens, anfAUC0–24/MIC of >34 forS. pneumoniae, and anfAUC0–24/MIC of >75 forH. influenzaeandL. pneumophila. Individual predicted estimates forCmax/MIC andfAUC0–24/MIC as well as simulated maximal MICs resulting in target attainment for oral and intravenous administration of the drug were suitable forS. pneumoniaeandH. influenzaebut not forL. pneumophila. These results indicate that caution must be taken when moxifloxacin is used as monotherapy to treat community-acquired pneumonia caused byL. pneumophila. In conclusion, this report reveals key information relevant to the empirical treatment of community-acquired pneumonia while highlighting the robust and flexible nature of this population pharmacokinetic model to predict therapeutic success. (Clinical Trials Registration no. NCT01983839.)

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Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00756-15 ◽

2015 ◽

Vol 59 (8) ◽

pp. 4907-4913 ◽

Cited By ~ 21

Author(s):

Marieke G. G. Sturkenboom ◽

Leonie W. Mulder ◽

Arthur de Jager ◽

Richard van Altena ◽

Rob E. Aarnoutse ◽

...

Keyword(s):

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Mean Squared Error ◽

Geometric Mean ◽

Plasma Concentrations ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Optimal Sampling ◽

Sampling Strategies ◽

Wide Range

ABSTRACTRifampin, together with isoniazid, has been the backbone of the current first-line treatment of tuberculosis (TB). The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0–24) to the MIC is the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of efficacy. The objective of this study was to develop an optimal sampling procedure based on population pharmacokinetics to predict AUC0–24values. Patients received rifampin orally once daily as part of their anti-TB treatment. A one-compartmental pharmacokinetic population model with first-order absorption and lag time was developed using observed rifampin plasma concentrations from 55 patients. The population pharmacokinetic model was developed using an iterative two-stage Bayesian procedure and was cross-validated. Optimal sampling strategies were calculated using Monte Carlo simulation (n= 1,000). The geometric mean AUC0–24value was 41.5 (range, 13.5 to 117) mg · h/liter. The median time to maximum concentration of drug in serum (Tmax) was 2.2 h, ranging from 0.4 to 5.7 h. This wide range indicates that obtaining a concentration level at 2 h (C2) would not capture the peak concentration in a large proportion of the population. Optimal sampling using concentrations at 1, 3, and 8 h postdosing was considered clinically suitable with anr2value of 0.96, a root mean squared error value of 13.2%, and a prediction bias value of −0.4%. This study showed that the rifampin AUC0–24in TB patients can be predicted with acceptable accuracy and precision using the developed population pharmacokinetic model with optimal sampling at time points 1, 3, and 8 h.

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Vancomycin in neonatal sepsis: predictive performance of a Chinese neonatal population pharmacokinetic model and clinical efficacy evaluation

European Journal of Hospital Pharmacy ◽

10.1136/ejhpharm-2020-002479 ◽

2021 ◽

pp. ejhpharm-2020-002479

Author(s):

Xiao-Hong Weng ◽

Chen-Qi Zhu ◽

Lu-Fen Duan ◽

Lan Li ◽

Zu-Ming Yang ◽

...

Keyword(s):

Clinical Efficacy ◽

Neonatal Sepsis ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Predictive Performance ◽

Population Pharmacokinetic ◽

Efficacy Evaluation ◽

Neonatal Population

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Caspofungin Weight-Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00905-20 ◽

2020 ◽

Vol 64 (9) ◽

Author(s):

Anne-Grete Märtson ◽

Kim C. M. van der Elst ◽

Anette Veringa ◽

Jan G. Zijlstra ◽

Albertus Beishuizen ◽

...

Keyword(s):

Critically Ill ◽

Rate Constant ◽

Critically Ill Patients ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Central Compartment ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Content Type ◽

The Mean

ABSTRACT The objective of this study was to develop a population pharmacokinetic model and to determine a dosing regimen for caspofungin in critically ill patients. Nine blood samples were drawn per dosing occasion. Fifteen patients with (suspected) invasive candidiasis had one dosing occasion and five had two dosing occasions, measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modeling and probability of target attainment (PTA). A target 24-h area under the concentration-time curve (AUC) value of 98 mg·h/liter was used as an efficacy parameter. Secondarily, the AUC/MIC targets of 450, 865, and 1,185 were used to calculate PTAs for Candida glabrata, C. albicans, and C. parapsilosis, respectively. The final 2-compartment model included weight as a covariate on volume of distribution (V). The mean V of the central compartment was 7.71 (standard deviation [SD], 2.70) liters/kg of body weight, the mean elimination constant (Ke) was 0.09 (SD, 0.04) h−1, the rate constant for the caspofungin distribution from the central to the peripheral compartment was 0.44 (SD, 0.39) h−1, and the rate constant for the caspofungin distribution from the peripheral to the central compartment was 0.46 (SD, 0.35) h−1. A loading dose of 2 mg/kg on the first day, followed by 1.25 mg/kg as a maintenance dose, was chosen. With this dose, 98% of the patients were expected to reach the AUC target on the first day and 100% of the patients on the third day. The registered caspofungin dose might not be suitable for critically ill patients who were all overweight (≥120 kg), over 80% of median weight (78 kg), and around 25% of lower weight (≤50 kg). A weight-based dose regimen might be appropriate for achieving adequate exposure of caspofungin in intensive care unit patients.

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A Population Pharmacokinetic Model-Guided Evaluation of Ceftolozane-Tazobactam Dosing in Critically Ill Patients Undergoing Continuous Venovenous Hemodiafiltration

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01655-19 ◽

2019 ◽

Vol 64 (1) ◽

Cited By ~ 5

Author(s):

Fekade B. Sime ◽

Melissa Lassig-Smith ◽

Therese Starr ◽

Janine Stuart ◽

Saurabh Pandey ◽

...

Keyword(s):

Critically Ill ◽

Critically Ill Patients ◽

Pharmacokinetic Model ◽

Population Pharmacokinetic ◽

Clearance Rates ◽

Content Type ◽

Dialysate Flow ◽

Continuous Venovenous Hemodiafiltration ◽

Drug Concentrations ◽

The Mean

ABSTRACT The aim of this work was to describe optimized dosing regimens of ceftolozane-tazobactam for critically ill patients receiving continuous venovenous hemodiafiltration (CVVHDF). We conducted a prospective observational pharmacokinetic study in adult critically ill patients with clinical indications for ceftolozane-tazobactam and CVVHDF. Unbound drug concentrations were measured from serial prefilter blood, postfilter blood, and ultrafiltrate samples by a chromatographic assay. Population pharmacokinetic modeling and dosing simulations were performed using Pmetrics. A four-compartment pharmacokinetic model adequately described the data from six patients. The mean (± standard deviation [SD]) extraction ratios for ceftolozane and tazobactam were 0.76 ± 0.08 and 0.73 ± 0.1, respectively. The mean ± SD sieving coefficients were 0.94 ± 0.24 and 1.08 ± 0.30, respectively. Model-estimated CVVHDF clearance rates were 2.7 ± 0.8 and 3.0 ± 0.6 liters/h, respectively. Residual non-CVVHDF clearance rates were 0.6 ± 0.5 and 3.3 ± 0.9 liters/h, respectively. In the initial 24 h, doses as low as 0.75 g every 8 h enabled cumulative fractional response of ≥85% for empirical coverage against Pseudomonas aeruginosa, considering a 40% fT>MIC (percentage of time the free drug concentration was above the MIC) target. For 100% fT>MIC, doses of at least 1.5 g every 8 h were required. The median (interquartile range) steady-state trough ceftolozane concentrations for simulated regimens of 1.5 g and 3.0 g every 8 h were 28 (21 to 42) and 56 (42 to 84) mg/liter, respectively. The corresponding tazobactam concentrations were 6.1 (5.5 to 6.7) and 12.1 (11.0 to 13.4) mg/liter, respectively. We suggest a front-loaded regimen with a single 3.0-g loading dose followed by 0.75 g every 8 h for critically ill patients undergoing CVVHDF with study blood and dialysate flow rates.

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Population Pharmacokinetic Model for Topotecan Derived From Phase I Clinical Trials

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.12.2459 ◽

2000 ◽

Vol 18 (12) ◽

pp. 2459-2467 ◽

Cited By ~ 42

Author(s):

James M. Gallo ◽

Paul B. Laub ◽

Eric K. Rowinsky ◽

Louise B. Grochow ◽

Sharyn D. Baker

Keyword(s):

Phase I ◽

Population Model ◽

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Plasma Concentrations ◽

Pharmacokinetic Parameters ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Total Clearance ◽

Phase I Clinical Trials

PURPOSE: To characterize the pharmacokinetics of topotecan in a population model that would identify patient variables or covariates that appreciably impacted on its disposition. PATIENTS AND METHODS: All data were collected from 82 patients entered in four different phase I trials that were previously reported as separate studies from 1992 to 1996. All patients received topotecan as a 30-minute constant-rate infusion on a daily-times-five schedule and were selected for this study because their daily dose did not exceed 2.0 mg/m2. Among the 82 patients were 30 patients classified as having renal insufficiency and 13 patients with hepatic dysfunction. The population pharmacokinetic model was built in sequential manner, starting with a covariate-free model and progressing to a covariate model with the aid of generalized additive modeling. RESULTS: A linear two-compartment model characterized total topotecan plasma concentrations (n = 899). Four primary pharmacokinetic parameters (total clearance, volume of the central compartment, distributional clearance, and volume of the peripheral compartment) were related to various combinations of covariates. The relationship for total clearance (TVCL [L/h] = 32.0 + [0.356(WT − 71) + 0.308(HT − 168.5) − 8.42(SCR − 1.1)] × [1 + 0.671 sex]) was dependent on the patients’ weight (WT), height (HT), serum creatinine (SCR), and sex and had a moderate ability to predict (r2 = 0.64) each patient’s individual clearance value. The addition of covariates to the population model improved the prediction errors, particularly for clearance. Removal of 10 outlying patients from the analysis improved the ability of the model to predict individual clearance values (r2 = 0.77). CONCLUSION: A population pharmacokinetic model for total topotecan has been developed that incorporates measures of body size and renal function to predict total clearance. The model can be used prospectively to obtain a revised and validated model that can then be used to design individualized dosing regimens.

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Pharmacokinetics of Vancomycin in Elderly Patients Aged over 80 Years

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00303-16 ◽

2016 ◽

Vol 60 (8) ◽

pp. 4563-4567 ◽

Cited By ~ 5

Author(s):

Laurent Bourguignon ◽

Yoann Cazaubon ◽

Guillaume Debeurme ◽

Constance Loue ◽

Michel Ducher ◽

...

Keyword(s):

Pharmacokinetic Model ◽

External Validation ◽

Plasma Concentrations ◽

Volume Of Distribution ◽

Population Pharmacokinetic ◽

Very Elderly ◽

Content Type ◽

Gram Positive Bacteria ◽

Severe Infections ◽

People First

ABSTRACTSince the 1950s, vancomycin has remained a reference treatment for severe infections caused by Gram-positive bacteria, including methicillin-resistantStaphylococcus aureus. Vancomycin is a nephrotoxic and ototoxic drug mainly eliminated through the kidneys. It has a large interindividual pharmacokinetic variability, which justifies monitoring its plasma concentrations in patients. This is especially important in patients aged over 80 years, who frequently have renal impairment. However, the pharmacokinetics of vancomycin in this population is very poorly described in the literature. The objective of this work was to propose a model able to predict the pharmacokinetics of vancomycin in very elderly people. First, a population pharmacokinetic model was carried out using the algorithm NPAG (nonparametric adaptive grid) on a database of 70 hospitalized patients aged over 80 years and treated with vancomycin. An external validation then was performed on 41 patients, and the predictive capabilities of the model were assessed. The model had two compartments and six parameters. Body weight and creatinine clearance significantly influenced vancomycin volume of distribution and body clearance, respectively. The means (± standard deviations) of vancomycin volume of distribution and clearance were 36.3 ± 15.2 liter and 2.0 ± 0.9 liter/h, respectively. In the validation group, the bias and precision were −0.75 mg/liter and 8.76 mg/liter for population predictions and −0.39 mg/liter and 2.68 mg/liter for individual predictions. In conclusion, a pharmacokinetic model of vancomycin in a very elderly population has been created and validated for predicting plasma concentrations of vancomycin.

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Population Pharmacokinetic Model of Doxycycline Plasma Concentrations Using Pooled Study Data

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02401-16 ◽

2017 ◽

Vol 61 (3) ◽

Cited By ~ 4

Author(s):

Ashley M. Hopkins ◽

Jessica Wojciechowski ◽

Ahmad Y. Abuhelwa ◽

Stuart Mudge ◽

Richard N. Upton ◽

...

Keyword(s):

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Phase 1 ◽

Plasma Concentrations ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Pharmacokinetic Data ◽

Delayed Release

ABSTRACT The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion (P < 0.01) and then backward deletion (P < 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability (F), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decrease F by 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens.

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The relationship between simulated milrinone exposure and hypotension in children

Cardiology in the Young ◽

10.1017/s1047951121003103 ◽

2021 ◽

pp. 1-7

Author(s):

Sarah Jane Commander ◽

Daniel Gonzalez ◽

Karan R. Kumar ◽

Tracy Spears ◽

Michael Cohen-Wolkowiez ◽

...

Keyword(s):

Population Pharmacokinetic Model ◽

Pharmacokinetic Model ◽

Drug Exposure ◽

Plasma Concentrations ◽

Multivariable Analysis ◽

Population Pharmacokinetic ◽

Maximum Plasma ◽

Electronic Health Record Data ◽

Clinically Significant ◽

The Relationship

Abstract Introduction: Hypotension is an adverse event that may be related to systemic exposure of milrinone; however, the true exposure–safety relationship is unknown. Methods: Using the Pediatric Trials Network multicentre repository, we identified children ≤17 years treated with milrinone. Hypotension was defined according to age, using the Pediatric Advanced Life Support guidelines. Clinically significant hypotension was defined as hypotension with concomitant lactate >3 mg/dl. A prior population pharmacokinetic model was used to simulate milrinone exposures to evaluate exposure–safety relationships. Results: We included 399 children with a median (quarter 1, quarter 3) age of 1 year (0,5) who received 428 intravenous doses of milrinone (median infusion rate 0.31 mcg/kg/min [0.29,0.5]). Median maximum plasma milrinone concentration was 110.7 ng/ml (48.4,206.2). Median lowest systolic and diastolic blood pressures were 74 mmHg (60,85) and 35 mmHg (25,42), respectively. At least 1 episode of hypotension occurred in 178 (45%) subjects; clinically significant hypotension occurred in 10 (2%). The maximum simulated milrinone plasma concentrations were higher in subjects with clinically significant hypotension (251 ng/ml [129,329]) versus with hypotension alone (86 ng/ml [44, 173]) versus without hypotension (122 ng/ml [57, 208], p = 0.002); however, this relationship was not retained on multivariable analysis (odds ratio 1.01; 95% confidence interval 0.998, 1.01). Conclusions: We successfully leveraged a population pharmacokinetic model and electronic health record data to evaluate the relationship between simulated plasma concentration of milrinone and systemic hypotension occurrence, respectively, supporting the broader applicability of our novel, efficient, and cost-effective study design for examining drug exposure–response and –safety relationships.

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