Population Pharmacokinetic Parameter Estimates Research Articles

Exploring population pharmacokinetic models in patients treated with vancomycin during continuous venovenous haemodiafiltration (CVVHDF)

BackgroundTherapeutic antibiotic dose monitoring can be particularly challenging in septic patients requiring renal replacement therapy. Our aim was to conduct an exploratory population pharmacokinetic (PK) analysis on PK of vancomycin following intermittent infusion in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF); focussing on the influence of dialysis-related covariates.MethodsThis was a retrospective single-centre tertiary level intensive care unit (ICU) study, which included patients treated concurrently with vancomycin and CVVHDF between January 2015 and July 2016. We extracted clinical, laboratory and dialysis data from the electronic healthcare record (EHR), using strict inclusion criteria. A population PK analysis was conducted with a one-compartment model using the PMetrics population PK modelling package. A base structural model was developed, with further analyses including clinical and dialysis-related data to improve model prediction through covariate inclusion. The final selected model simulated patient concentrations using probability of target attainment (PTA) plots to investigate the probability of different dosing regimens achieving target therapeutic concentrations.ResultsA total of 106 vancomycin dosing intervals (155 levels) in 24 patients were examined. An acceptable 1-compartment base model was produced (Plots of observed vs. population predicted concentrations (Obs–Pred) R2 = 0.78). No continuous covariates explored resulted in a clear improvement over the base model. Inclusion of anticoagulation modality and vasopressor use as categorical covariates resulted in similar PK parameter estimates, with a trend towards lower parameter estimate variability when using regional citrate anti-coagulation or without vasopressor use. Simulations using PTA plots suggested that a 2 g loading dose followed by 750 mg 12 hourly as maintenance dose, commencing 12 h after loading, is required to achieve adequate early target trough concentrations of at least 15 mg/L.ConclusionsPTA simulations suggest that acceptable trough vancomycin concentrations can be achieved early in treatment with a 2 g loading dose and maintenance dose of 750 mg 12 hourly for critically ill patients on CVVHDF.

Pharmacokinetics of Hydroxyurea Therapy in African Children with Sickle Cell Anemia:Â Noharm Ancillary PK Study

▪Background. Hydroxyurea is an important disease-modifying therapy for sickle cell anemia (SCA). Through induction of fetal hemoglobin and other mechanisms, hydroxyurea reduces the number and severity of vaso-occlusive painful crises and episodes of acute chest syndrome, while also lowering the frequency of transfusions and hospitalizations, and even reducing mortality. In the US, hydroxyurea is recommended widely for both children and adults with SCA, although variation in treatment response is well-recognized. In sub-Saharan Africa, which has the greatest global burden of SCA, hydroxyurea is not used widely, due in part to a lack of data regarding its safety and efficacy. Pharmacokinetics (PK) analysis of hydroxyurea has also not been performed to date in Africa, but would provide important data regarding the variable responses to hydroxyurea treatment in low-resource settings.Objectives. There were three main goals of the NOHARM Ancillary PK Study: (1) to evaluate the feasibility of hydroxyurea sparse sampling PK collection and analysis in a low-resource clinical setting; (2) to determine the PK parameters for a cohort of young African children with SCA receiving hydroxyurea at an average oral daily dose of 20 mg/kg; and (3) to compare the PK parameters of African children collected and analyzed in the NOHARM trial with those of US children with SCA from the earlier HUSTLE study that included African-American children with SCA.Methods. NOHARM (NCT01976416) is a prospective, randomized, placebo-controlled, double-blinded phase 3 trial that is investigating the effects of hydroxyurea on the incidence and severity of malaria in very young children living in Uganda with SCA. After a year of blinded treatment, all participants were offered open-label hydroxyurea at an average oral daily dose of 20 ± 2.5 mg/kg, using either a 5-day or 7-day per week treatment regimen. After written informed consent for the ancillary PK study, hydroxyurea analysis was performed using a published sparse-sampling technique based on Bayesian estimation with collections pre-dose and then at T=15 minutes, 60 minutes, and 180 minutes. These four timed finger-prick sample collections over 3 hours used a volumetric absorptive microsampling device that collects exact 10 uL aliquots. All samples were stored at -80°C until analysis of hydroxyurea by LC-MS/MS (ug/mL) using a stable isotope internal standard, performed at Cincinnati Children's Hospital. Population PK analysis was performed using nonlinear mixed effect modeling (NONMEM 7.2). Allometric scaling was used to correct for differences in size.Results. A total of 100 children were enrolled in the NOHARM ancillary PK study (average age 3.8 ± 0.9 years; 55 males), and 98 of these children had three evaluable post-dose samples. Individual PK profiles were best described by a one-compartment model with first order absorption. The dose-normalized hydroxyurea concentrations in NOHARM were comparable between the 5-day and 7-day dosing regimens and similar to published HUSTLE data for 96 children, except for higher T=180 hydroxyurea concentrations and overall higher hydroxyurea exposure in the NOHARM cohort. The higher blood hydroxyurea concentrations were the result of reduced drug clearance in NOHARM, possibly influenced by younger age. Population PK parameter estimates of oral clearance in the NOHARM and HUSTLE cohorts were 9.8 L/h/70kg versus 12.9 L/h/70kg, respectively (p<0.01).Conclusions. The NOHARM PK study demonstrates the feasibility of collecting timed samples for analysis of hydroxyurea exposure, even in the low-resource setting of Uganda. Using a sparse sampling technique, young children with SCA had individual PK parameters calculated and a population PK model established. The oral drug clearance was lower in NOHARM than HUSTLE, with resulting higher hydroxyurea exposure, perhaps reflecting differences in age, nutrition, glomerular filtration, and genetic modifiers that warrant further investigation. DisclosuresWare:Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Effect of severe renal impairment on the pharmacokinetics of brigatinib

SummaryBackground Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, targets activated, mutant forms of ALK and overcomes mechanisms of resistance to the ALK inhibitors crizotinib, ceritinib, and alectinib. Brigatinib is approved in multiple countries for treatment of patients with ALK-positive non–small cell lung cancer. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is required for patients with mild or moderate renal impairment. Methods An open-label, single-dose study was conducted to evaluate the PK of brigatinib (90 mg) in patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m2; n = 8) and matched healthy volunteers with normal renal function (estimated glomerular filtration rate ≥ 90 mL/min/1.73 m2; n = 8). Plasma and urine were collected for the determination of plasma protein binding and estimation of plasma and urine PK parameters. Results Plasma protein binding of brigatinib was similar between patients with severe renal impairment (92 % bound) and matched healthy volunteers with normal renal function (91 % bound). Unbound brigatinib exposure (area under the plasma concentration-time curve from time zero to infinity) was approximately 92 % higher in patients with severe renal impairment compared with healthy volunteers with normal renal function. The renal clearance of brigatinib in patients with severe renal impairment was approximately 20 % of that observed in volunteers with normal renal function. Conclusions These findings support a brigatinib dosage reduction of approximately 50 % in patients with severe renal impairment.Trial registry: Not applicable.

Ethionamide population pharmacokinetics/pharmacodynamics and therapeutic implications in South African adult patients with drug-resistant tuberculosis.

Ethionamide is part of the drug-resistant tuberculosis regimen whose pharmacokinetic (PK) and pharmacodynamic (PD) information is limited. The aim of the study was to describe the PK and simulate doses to assess PD attainment. This was an observational population PK study of patients admitted for drug-resistant tuberculosis at a hospital in South Africa. Nonlinear mixed-effects modelling implemented in Monolix 2019R2 was used to estimate population pharmacokinetic parameters. We performed Monte Carlo simulations to assess and optimise the dose regimen. The target Cmax range was 2.5-5μg/mL, which is within the minimum inhibitory concentration (MIC) range. The target AUC0-24h was 140.5μg*h/mL, which corresponds to the PK/PD target ratio AUC0-24h /MIC of 56.2. A one-compartment pharmacokinetic model with a lag-time, first-order absorption and elimination best described the PK of ethionamide. The lag-time, absorption rate constant (ka), volume of distribution (V/F) and clearance (Cl/F) were 0.66 hours, 0.434 h-1 , 180 L and 99.5L/h, respectively, for a typical individual weighing 52.6kg. Between-subject variability in lag-time, ka, V/F and Cl/F were 38%, 92%, 168% and 120%, respectively. Simulation of the recommended doses of 15-20 mg/kg, 500 mg, 750 mg and 1000 mg for patients in the weight bands <33, 33-50, 51-70 and >70 kg resulted in <17% and 3% of the patients achieving the target Cmax and AUC0-24h , respectively. There is high variability in ethionamide PK and very few patients attain the desired target exposure at standard or optimised doses. We propose individualised dose regimen optimisation.

Abstract PS17-08: Population pharmacokinetic and exposure-response modeling of the oral selective estrogen receptor degrader, rintodestrant (G1T48), in patients with ER+/HER2- advanced breast cancer

Abstract Background: Rintodestrant is an orally bioavailable, potent and selective estrogen receptor degrader (SERD) that competitively binds to the estrogen receptor (ER) and blocks ER signaling in tumors resistant to other endocrine therapies. Clinical trials have been conducted to evaluate the safety and efficacy of rintodestrant in healthy volunteers and patients with ER+/HER2- locally advanced or metastatic breast cancer (ABC). Population pharmacokinetic (PK) and exposure-response (Ex/Re) analyses were performed to further characterize the PK profile of rintodestrant and identify potential Ex/Re relationships. Methods: The present analyses include data from two studies: (1) G1T48-01, a Phase 1 first-in-human study of rintodestrant monotherapy (200-1000 mg once daily [QD]) in women with ER+/HER2- ABC after progression on endocrine therapy (NCT03455270), and (2) G1T48-10, a study in healthy volunteers investigating potential drug-drug interactions between rintodestrant (200 mg QD) and palbociclib (125 mg QD). A PK model was developed using nonlinear mixed effects methodology to estimate PK parameters for individual patients. A tumor dynamic model was built to characterize the relationship between rintodestrant concentrations and the longitudinal tumor sizes according to RECIST v1.1. Ex/Re for key pharmacodynamic markers, including ER target engagement (18F-fluoroestradiol positron emission tomography [FES-PET]), dynamics of cell-free DNA mutational burden, ER degradation and proliferation (Ki67) in tumors, and enumeration of circulating tumor cells are being evaluated. Relationships between model-predicted exposures and study endpoints (objective response rate, clinical benefit rate) are also being evaluated. Results: Rintodestrant PK was best described using a linear two-compartment model with a mixed absorption model. The predicted population mean trough concentration of rintodestrant at the recommended Phase 2 dose (800 mg QD) exceeded the IC90 value for ER degradation established in vitro. A positive Ex/Re relationship was identified between total exposure and target ER engagement as measured by FES-PET. A clear Ex/Re relationship was not identified between any PK parameters and ER degradation or proliferation, potentially due to confounding effects from covariates in the model (eg, prior SERD treatment, ESR1 mutations, etc). Additional exploration of these covariates is ongoing. The final PK, Ex/Re and PK/tumor dynamics model results will be presented. Conclusions: A population PK model was developed and Ex/Re relationship analyses were performed to support the development of rintodestrant for the treatment of patients with ER+ breast cancer. Initial results identified an Ex/Re relationship with target ER engagement via FES-PET analysis. Citation Format: Andrew P Beelen, Chao Li, Praneeth Jarugula, Mathangi Gopalakrishnan, Jessica A Sorrentino, Curt D Wolfgang, Sarika Jain, Wenli Tao. Population pharmacokinetic and exposure-response modeling of the oral selective estrogen receptor degrader, rintodestrant (G1T48), in patients with ER+/HER2- advanced breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-08.

Population Pharmacokinetics Analysis of Amikacin Initial Dosing Regimen in Elderly Patients.

There are limited data of amikacin pharmacokinetics (PK) in the elderly population. Hence, we aimed to describe the population PK of amikacin in elderly patients (>70 years old) and to establish optimized initial dosing regimens. We simulated individual maximum concentrations in plasma (Cmax) and minimal concentrations (Cmin) for several dosing regimens (200–2000 mg every 24, 48, and 72 h) for patients with creatinine clearance (CCr) of 10–90 mL/min and analyzed efficacy (Cmax/minimal inhibitory concentration (MIC) ≥ 8) for MICs of 4, 8, and 16 mg/L and safety (Cmin < 4 mg/L). A one-compartment model best described the data. CCr was the only covariate associated with amikacin clearance. The population PK parameter estimates were 2.25 L/h for clearance and 18.0 L for volume of distribution. Dosing simulations recommended the dosing regimens (1800 mg) with dosing intervals ranging 48–72 h for patients with CCr of 40–90 mL/min based on achievement of both efficacy for the MIC of 8 mg/L and safety. None of the dosing regimens achieved the targets for an MIC of 16 mg/L. We recommend the initial dosing regimen using a nomogram based on CCr for an MIC of ≤8 mg/L in elderly patients with CCr of 40–90 mL/min.

Pharmacologic effects of oseltamivir in immunocompromised adult patients as assessed by population PK/PD analysis and drug-disease modelling for dosing regimen optimization.

AimPharmacologic effects were analysed to determine a dose recommendation for oseltamivir in immunocompromised (IC) adults with influenza.MethodsQuantitative clinical pharmacology methods were applied to data from 160 adult IC patients (aged 18‐78 years) from two studies (NV20234, 150 patients; NV25118, 10 patients) who received oseltamivir 75‐200 mg twice daily for up to 10 days. An established population‐pharmacokinetic (PK) model with additional effects on oseltamivir and oseltamivir carboxylate (OC) clearance described the PK characteristics of oseltamivir in IC patients versus otherwise healthy (OwH) patients from previous clinical trials. Estimated PK parameters were used to evaluate exposure‐response relationships for virologic endpoints (time to cessation of viral shedding, viral load measures and treatment‐emergent resistance). A drug‐disease model characterized the viral kinetics of influenza accounting for the effect of OC on viral production.ResultsOseltamivir clearance was 32.5% lower (95% confidence interval [CI], 26.1‐38.8) and OC clearance was 33.7% lower (95% CI, 23.2‐44.1) in IC versus OwH patients. No notable exposure‐response relationships were identified for exposures higher than those achieved after conventional dose oseltamivir 75 mg, which appeared to be close to the maximum effect of oseltamivir. Simulations of the drug‐disease model predicted that initiating treatment within 48 hours of symptom onset had maximum impact, and a treatment duration of 10 days was favourable over 3‐5 days to limit viral rebound.ConclusionsOur findings support the use of conventional‐dose oseltamivir 75 mg twice daily for 10 days in the treatment of IC adult patients with influenza.

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

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. 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. 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>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). Pharmacokinetic/pharmacodynamic goals for amoxicillin can be obtained in obese subjects.

Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.

An Update on Population Pharmacokinetic Analyses of Vancomycin, Part I: In Adults.

Despite the wide clinical use of vancomycin, controversy remains regarding its optimal dosage regimens. This can be attributed to the large between- and within-subject variability in the pharmacokinetics of vancomycin. This review aimed at providing a synthesis of population pharmacokinetic models of vancomycin in adults, determining the most reported pharmacokinetic models, and identifying various sources of variability in different special subpopulations to better inform vancomycin dosing. We searched PubMed and EMBASE for population pharmacokinetic studies of vancomycin published from January 2011 to May 2019. Inspection of the relevant lists of references was conducted, as well. This search resulted in a total of 30 eligible studies, which were included. One-, two-, and three-compartments models were reported to best describe vancomycin population pharmacokinetics in 13, 14, and 3 studies, respectively. Three-compartment models were implemented in three studies to account for an additional cerebrospinal fluid compartment. The most common predictors were creatinine clearance and bodyweight, in 20 and 13 studies, respectively. Estimated values of vancomycin clearance and total volume of distribution varied widely from 0.334 to 8.75 L/h (0.0054-0.1279 L/h/kg) and from 7.12 to 501.8 L (0.097-6.97 L/kg), respectively. Almost all studies implemented an exponential interindividual variability model, and the highest variability on clearance was 99.2%. In conclusion, this review highlights the wide ranges and the high variability of estimated population pharmacokinetic parameters. This information can help guide dosing in different subpopulations. Yet, additional analyses with pooled subpopulations might be needed to confirm the necessity of modified dosage regimens.

A Dried Blood Spot Analysis for Solithromycin in Adolescents, Children, and Infants: A Short Communication.

Solithromycin is a fourth-generation macrolide antibiotic with potential efficacy in pediatric community-acquired bacterial pneumonia. Pharmacokinetic (PK) studies of solithromycin in pediatric subjects are limited, therefore application of minimally invasive drug sampling techniques, such as dried blood spots (DBS), may enhance the enrollment of children in PK studies. The objectives of this study were to compare solithromycin concentrations in DBS with those in liquid plasma samples (LPS) and to quantify the effects of modeling DBS concentrations on the results of a population PK model. Comparability analysis was performed on matched DBS and LPS solithromycin concentrations collected from two different phase 1 clinical trials of solithromycin treatment in children (clinicaltrials.gov #NCT01966055 and #NCT02268279). Comparability of solithromycin concentrations was evaluated based on DBS:LPS ratio, median percentage prediction error, and median absolute percentage prediction error. The effect of correcting DBS concentrations for both hematocrit and protein binding was investigated. In addition, a previously published population PK model (NONMEM) was leveraged to compare parameter estimates resulting from either DBS or LPS concentrations. A total of 672 paired DBS-LPS concentrations were available from 95 subjects (age: 0-17 years of age). The median (range) LPS and DBS solithromycin concentrations were 0.3 (0.01-12) mcg/mL and 0.32 (0.01-14) mcg/mL, respectively. Median percentage prediction error and median absolute percentage prediction error of raw DBS to LPS solithromycin concentrations were 5.26% and 22.95%, respectively. In addition, the majority of population PK parameter estimates resulting from modeling DBS concentrations were within 15% of those obtained from modeling LPS concentrations. Solithromycin concentrations in DBS were similar to those measured in LPS and did not require correction for hematocrit or protein binding.

Population pharmacokinetics of ticarcillin in critically ill patients receiving extended daily diafiltration

The aim of this study was to describe the population pharmacokinetics of ticarcillin during extended daily diafiltration (EDDf) in critically ill patients with acute kidney injury. Blood samples were collected from critically ill patients prescribed ticarcillin during one to two dosing intervals during which EDDf was performed. Plasma samples were measured using a validated ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. Concentration-time data were analysed using a population pharmacokinetics approach with Pmetrics®. A total of 53 blood samples were collected from six critically ill patients (three male). The mean ± standard deviation patient age, weight and body mass index (BMI) was 43 ± 22 years, 88 ± 14 kg and 31 ± 5 kg/m2, respectively. A two-compartment linear model adequately described the data. Median population pharmacokinetic parameter estimates were as follows: clearance in the presence of EDDf (CLEDDf), 6.41 L/h; clearance of EDDf (CLnon-EDDf), 4.97 L/h; volume of distribution of the central compartment (Vc), 56.46 L; intercompartmental clearance from the central to peripheral compartment (kCP), 13.54 L/h; and intercompartmental clearance from the peripheral to central compartment (kPC), 21.93 L/h. This is the first population pharmacokinetic model of ticarcillin in patients receiving EDDf. Large pharmacokinetic variability was found, supporting further investigation of the pharmacokinetics of less-studied β-lactam antibiotics in prolonged intermittent renal replacement therapy.

Development of a dosing algorithm for meropenem in critically ill patients based on a population pharmacokinetic/pharmacodynamic analysis

Effective antibiotic dosing is vital for therapeutic success in critically ill patients. This work aimed to develop an algorithm to identify appropriate meropenem dosing in critically ill patients. Population pharmacokinetic (PK) modelling was performed in NONMEM®7.3 based on densely sampled meropenem serum samples (npatients = 48; nsamples = 1376) and included a systematic analysis of 27 pre-selected covariates to identify factors influencing meropenem exposure. Using Monte Carlo simulations newly considering the uncertainty of PK parameter estimates, standard meropenem dosing was evaluated with respect to attainment of the pharmacokinetic/pharmacodynamic (PK/PD) target and was compared with alternative infusion regimens (short-term, prolonged, continuous; daily dose, 2000-6000 mg). Subsequently, a dosing algorithm was developed to identify appropriate dosing regimens. The two-compartment population PK model included three factors influencing meropenem pharmacokinetics: the Cockcroft-Gault creatinine clearance (CLCRCG) on meropenem clearance; and body weight and albumin on the central and peripheral volume of distribution, respectively; of these, only CLCRCG was identified as a vital influencing factor on PK/PD target attainment. A three-level dosing algorithm was developed (considering PK parameter uncertainty), suggesting dosing regimens depending on renal function and the level (L) of knowledge about the infecting pathogen (L1, pathogen unknown; L2, pathogen known; L3(-MIC), pathogen and susceptibility known; L3(+MIC), MIC known). Whereas patients with higher CLCRCG and lower pathogen susceptibility required mainly intensified dosing regimens, lower than standard doses appeared sufficient for highly susceptible pathogens. In conclusion, a versatile meropenem dosing algorithm for critically ill patients is proposed, indicating appropriate dosing regimens based on patient- and pathogen-specific information.

Accuracy of predicting the vancomycin concentration in Japanese cancer patients by the Sawchuk-Zaske method or Bayesian method.

In cancer patients treated with vancomycin, therapeutic drug monitoring is currently performed by the Bayesian method that involves estimating individual pharmacokinetics from population pharmacokinetic parameters and trough concentrations rather than the Sawchuk-Zaske method using peak and trough concentrations. Although the presence of malignancy influences the pharmacokinetic parameters of vancomycin, it is unclear whether cancer patients were included in the Japanese patient populations employed to estimate population pharmacokinetic parameters for this drug. The difference of predictive accuracy between the Sawchuk-Zaske and Bayesian methods in Japanese cancer patients is not completely understood. To retrospectively compare the accuracy of predicting vancomycin concentrations between the Sawchuk-Zaske method and the Bayesian method in Japanese cancer patients. Using data from 48 patients with various malignancies, the predictive accuracy (bias) and precision of the two methods were assessed by calculating the mean prediction error, the mean absolute prediction error, and the root mean squared prediction error. Prediction of the trough and peak vancomycin concentrations by the Sawchuk-Zaske method and the peak concentration by the Bayesian method showed a bias toward low values according to the mean prediction error. However, there were no significant differences between the two methods with regard to the changes of the mean prediction error, mean absolute prediction error, and root mean squared prediction error. The Sawchuk-Zaske method and Bayesian method showed similar accuracy for predicting vancomycin concentrations in Japanese cancer patients.

Population Pharmacokinetic Modelling of Pyrazinamide and Pyrazinoic Acid in Patients with Multi-Drug Resistant Tuberculosis.

Pyrazinamide, a drug used in the regimen for the treatment of drug-sensitive tuberculosis, is also used for the treatment of multidrug-resistant tuberculosis (MDR-TB). We aimed to describe the population pharmacokinetics of pyrazinamide and its major metabolite, pyrazinoic acid, in patients with MDR-TB and characterise the effects of demographic variables. This was a non-randomised clinical study involving 51 adult patients admitted for the intensive phase of MDR-TB treatment. Blood samples were collected at pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 8, 16 and 24h after drug administration. Plasma concentrations of pyrazinamide and pyrazinoic acid were analysed using a validated LC-MS/MS method. Nonlinear mixed-effects modelling using Monolix 2018R1 software was employed to estimate population pharmacokinetic parameters. A one-compartment pharmacokinetic model with transit compartment absorption process and first-order elimination best described the pyrazinamide and pyrazinoic acid concentration-time data. The estimated population pharmacokinetic parameters were 0.7h, 3.38h-1, 57.1l, 4.37L/h and 10.5L/h for mean transit time, absorption rate constant, apparent distribution volume for pyrazinamide, and apparent clearance for pyrazinamide and pyrazinoic acid (CLm/F), respectively. These parameters were not affected by patient age, HIV status or sex. The parameter variability in CLm/F was the highest (83.5%), while the rest of the parameters ranged from 16.2 to 58%. The developed population pharmacokinetic model adequately described the disposition of pyrazinamide and pyrazinoic acid and can be useful for dose determination of pyrazinamide in patients with MDR-TB.

A Simple and Flexible Computational Framework for Inferring Sources of Heterogeneity from Single-Cell Dynamics.

Single-cell time-lapse data provide the means for disentangling sources of cell-to-cell and intra-cellular variability, a key step for understanding heterogeneity in cell populations. However, single-cell analysis with dynamic models is a challenging open problem: current inference methods address only single-gene expression or neglect parameter correlations. We report on a simple, flexible, and scalable method for estimating cell-specific and population-average parameters of non-linear mixed-effects models of cellular networks, demonstrating its accuracy with a published model and dataset. We also propose sensitivity analysis for identifying which biological sub-processes quantitatively and dynamically contribute to cell-to-cell variability. Our application to endocytosis in yeast demonstrates that dynamic models of realistic size can be developed for the analysis of single-cell data and that shifting the focus from single reactions or parameters to nuanced and time-dependent contributions of sub-processes helps biological interpretation. Generality and simplicity of the approach will facilitate customized extensions for analyzing single-cell dynamics.

PKconverter: R package to convert the pharmacokinetic parameters.

Population pharmacokinetic analysis and modeling procedures typically require estimates of both population and individual pharmacokinetic parameters. However, only some of these parameters are contained in models and only parameters in the model can be estimated. In this paper, we introduce a new R package, PKconverter, to calculate pharmacokinetic parameters using the relationships among them. After fitting the model, other parameters can be calculated from the functional relationship among the parameters. PKconverter provides the functions to calculate whole parameters along with a Shiny application for converting the parameters. With this package, it is also possible to calculate the standard errors of the other parameters that are not in the model and estimate individual parameters simultaneously.

An Evaluation of Vancomycin Area Under the Curve Estimation Methods for Children Treated for Acute Pulmonary Exacerbations of Cystic Fibrosis Due to Methicillin-Resistant Staphylococcus aureus.

The prevalence of pulmonary methicillin-resistant Staphylococcus aureus infections in patients with cystic fibrosis (CF) has increased over the last 2 decades. Two concentrations-a postdistributive and a trough-are currently used to estimate the area under the curve (AUC) of vancomycin, an antibiotic routinely used to treat these infections, to achieve the target AUC/minimum inhibitory concentration of ≥400mg·h/L in ensuring optimal dosing of this drug. This study evaluated precision and bias in estimating vancomycin AUCs obtained either from a population pharmacokinetic (PK) model by using a single trough concentration or from standard PK equation-based 2-point monitoring approach. AUCs were either obtained from a single trough concentration-fitted model or derived from a model fitted by 2 concentration points. Children ≥2 years of age with CF received intravenous vancomycin at 2 centers from June 2012 to December 2014. A population PK model was developed in Pmetrics to quantify the between-subject variability in vancomycin PK parameters, define the sources of PK variability, and leverage information from the population to improve individual AUC estimates. Twenty-three children with CF received 27 courses of vancomycin. The median age was 12.3 (interquartile range [IQR] 8.5-16.6) years. From the individual vancomycin PK parameter estimates from the population PK model, median AUC was 622 (IQR 529-680) mg·h/L. Values were not significantly different from the AUC calculated using the standard PK equation-based approach (median 616 [IQR 540-663] mg·h/L) (P = .89). A standard PK equation-based approach using 2 concentrations and a population PK model-based approach using a single trough concentration yielded unbiased and precise AUC estimates. Findings suggest that options exist to implement AUC-based pediatric vancomycin dosing in patients with CF. The findings of this study reveal that several excellent options exist for centers to implement AUC-based pediatric vancomycin dosing for patients with CF.

Pharmacokinetics of Doripenem in Healthy Koreans and Monte Carlo Simulations to Explore Optimal Dosage Regimens in Patients With Normal and Enhanced Renal Function.

Dose adjustment is often required in patients with normal or enhanced renal function. The aim of this study is to investigate the pharmacokinetic (PK) properties of doripenem and explore optimal dosing regimens in patients with normal or enhanced renal function according to various minimum inhibitory concentrations (MICs). The authors conducted a clinical trial and analyzed PK samples in 11 healthy Korean subjects applying noncompartmental analysis and a population approach. The population PK parameter estimates were used in Monte Carlo simulations to explore optimal dosing regimens for a probability of target attainment of 90% at 40% fTMIC (free drug concentrations above MIC). The time course of doripenem concentrations was well described by a 2-compartment model. The population typical values of clearance and steady-state volume were 22.9 L/h and 19.1 L, respectively, and were consistent with our noncompartmental analysis results. When the MIC was greater than 1 mcg/mL, at least increasing the dose or prolonging the infusion time was essential in patients with normal or enhanced renal function. These results suggest that dosage adjustment such as increasing the dose or lengthening the infusion time should be considered in patients with normal or enhanced renal function.

Population pharmacokinetics of vancomycin in critically ill patients receiving prolonged intermittent renal replacement therapy

The aim of this study was to describe the population pharmacokinetics of vancomycin during prolonged intermittent renal replacement therapy (PIRRT) in critically ill patients with acute kidney injury. Critically ill patients prescribed vancomycin across two sites had blood samples collected during one to three dosing intervals during which PIRRT was performed. Plasma samples were assayed with a validated immunoassay method. Population pharmacokinetic analysis and Monte Carlo simulations were performed using Pmetrics®. The target vancomycin exposures were the area under the concentration-time curve within a 24-h period (AUC0-24)/minimum inhibitory concentration (MIC) ratio of 400 for efficacy and AUC0-24 700 for toxicity. Eleven critically ill patients (seven male) were enrolled and contributed 192 plasma samples. The patient's mean ± standard deviation (SD) age, weight and body mass index (BMI) were 57 ± 13 years, 98 ± 43 kg and 31 ± 9 kg/m2, respectively. A two-compartment linear model adequately described the data. The mean ± SD population pharmacokinetic parameter estimates were PIRRT clearance (CL) 3.47 ± 1.99 L/h, non-PIRRT CL 2.15 ± 2.07 L/h, volume of distribution of the central compartment (Vc) 41.85 ± 24.33 L, distribution rate constant from central to peripheral compartment 5.97 ± 7.93 per h and from peripheral to central compartment 5.29 ± 6.65 per h. Assuming a MIC of 1 mg/L, vancomycin doses of 25 mg/kg per day are suggested to be efficacious, whilst minimising toxic, exposures. This is the first population pharmacokinetic study of vancomycin in patients receiving PIRRT and we observed large pharmacokinetic variability. Empirically, weight-based doses that are appropriate for the duration of PIRRT, should be selected and supplemented with therapeutic drug monitoring.