scholarly journals Combined Recirculatory-compartmental Population Pharmacokinetic Modeling of Arterial and Venous Plasma S(+) and R(–) Ketamine Concentrations

2018 ◽  
Vol 129 (2) ◽  
pp. 260-270 ◽  
Author(s):  
Thomas K. Henthorn ◽  
Michael J. Avram ◽  
Albert Dahan ◽  
Lars L. Gustafsson ◽  
Jan Persson ◽  
...  
Keyword(s):  
Pharmacokinetic Model ◽  
Venous Blood ◽  
Population Pharmacokinetic ◽  
Drug Infusion ◽  
Population Pharmacokinetic Modeling ◽  
Front End ◽  
Drug Concentrations ◽  
Link Rate ◽  
Recirculatory Model ◽  
Venous Plasma

Abstract What We Already Know about This Topic What This Article Tells Us That Is New Background The pharmacokinetics of infused drugs have been modeled without regard for recirculatory or mixing kinetics. We used a unique ketamine dataset with simultaneous arterial and venous blood sampling, during and after separate S(+) and R(–) ketamine infusions, to develop a simplified recirculatory model of arterial and venous plasma drug concentrations. Methods S(+) or R(–) ketamine was infused over 30 min on two occasions to 10 healthy male volunteers. Frequent, simultaneous arterial and forearm venous blood samples were obtained for up to 11 h. A multicompartmental pharmacokinetic model with front-end arterial mixing and venous blood components was developed using nonlinear mixed effects analyses. Results A three-compartment base pharmacokinetic model with additional arterial mixing and arm venous compartments and with shared S(+)/R(–) distribution kinetics proved superior to standard compartmental modeling approaches. Total pharmacokinetic flow was estimated to be 7.59 ± 0.36 l/min (mean ± standard error of the estimate), and S(+) and R(–) elimination clearances were 1.23 ± 0.04 and 1.06 ± 0.03 l/min, respectively. The arm-tissue link rate constant was 0.18 ± 0.01 min–1, and the fraction of arm blood flow estimated to exchange with arm tissue was 0.04 ± 0.01. Conclusions Arterial drug concentrations measured during drug infusion have two kinetically distinct components: partially or lung-mixed drug and fully mixed-recirculated drug. Front-end kinetics suggest the partially mixed concentration is proportional to the ratio of infusion rate and total pharmacokinetic flow. This simplified modeling approach could lead to more generalizable models for target-controlled infusions and improved methods for analyzing pharmacokinetic-pharmacodynamic data.

Using Front-end Kinetics to Optimize Target-controlled Drug Infusions

2003 ◽  
Vol 99 (5) ◽  
pp. 1078-1086 ◽  
Author(s):  
Michael J. Avram ◽  
Tom C. Krejcie
Keyword(s):  
Intravenous Administration ◽  
Pharmacokinetic Model ◽  
Sampling Site ◽  
Model Parameters ◽  
Drug Infusion ◽  
Concentration Data ◽  
Blood Concentrations ◽  
Compartment Models ◽  
Drug Concentrations ◽  
Recirculatory Model

Background The mode of drug administration, blood sampling schedule, and sampling site affect the pharmacokinetic model derived. The present study tested the hypothesis that three-compartment pharmacokinetic model parameters derived from arterial drug concentrations obtained after rapid intravenous administration can be used to design a target-controlled drug infusion (TCI) that deviates minimally from the target. Methods Arterial thiopental concentration data obtained from the moment of injection in a previous study of five dogs were used. Three three-compartment models were constructed, one based on early concentrations classically obtained at 1, 2, and 3 min; another using all concentrations obtained beginning with the thiopental recirculation peak; and the last with the initial distribution volume (VC) fixed to the sum of VC and the nondistributive volume of the recirculatory model from the earlier study. Using these models, TCIs were designed that would maintain 20 mug/ml thiopental concentrations in VC for 60 min if simulated with the models used in their design. Drug concentrations resulting from these TCIs were then simulated using recirculatory model kinetics, and prediction errors were evaluated. Results Models with VCs estimated from intermittent or frequent early blood concentrations overestimated not only VC but also the volume and clearance of the rapidly equilibrating tissues, and their TCIs significantly overshot the target. With VC fixed to recirculatory model parameters, drug distribution was described in a manner consistent with that of the recirculatory model, and the TCI deviated minimally from the target. A similar three-compartment model was derived from data obtained from a simulation of a 2-min infusion using recirculatory kinetic parameters. Conclusions Because three-compartment models based on drug concentration histories obtained after rapid intravenous administration do not characterize VC accurately, TCIs based on them produce concentrations exceeding the target. A model capable of producing TCIs deviating minimally from the target can be derived from data obtained during and after a brief drug infusion.

Modeling Population Pharmacokinetics of Lidocaine

2001 ◽  
Vol 94 (4) ◽  
pp. 566-573 ◽  
Author(s):  
Jette A. Kuipers ◽  
Fred Boer ◽  
Annemiek de Roode ◽  
Erik Olofsen ◽  
James G. Bovill ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Ratio Test ◽  
Pharmacokinetic Models ◽  
Population Pharmacokinetic Modeling ◽  
Population Pharmacokinetic Study ◽  
Electrical Bioimpedance ◽  
Demographic Covariates ◽  
The Individual

Background Inclusion of cardiac output and other physiologic parameters, in addition to or instead of, demographic variables might improve the population pharmacokinetic modeling of lidocaine. Methods Thirty-one patients were included in a population pharmacokinetic study of lidocaine. After bolus injection of lidocaine (1 mg/kg), 22 or 10 blood samples per patient were taken from a radial artery. During the experiment, cardiac output was measured using a thoracic electrical bioimpedance method. The following four population pharmacokinetic models were constructed and their performances investigated: a model with no covariates, a model with cardiac output as covariate, a model with demographic covariates, and a model with both cardiac output and demographic characteristics as covariates. Model discrimination was performed with the likelihood ratio test. Results Inclusion of cardiac output resulted in a significant improvement of the pharmacokinetic model, but inclusion of demographic covariates was even better. However, the best model was obtained by inclusion of both demographic covariates and cardiac output in the pharmacokinetic model. Conclusions When population pharmacokinetic models are used for individualization of dosing schedules, physiologic covariates, e.g., cardiac output, can improve their ability to predict the individual kinetics.

scholarly journals Probability of Target Attainment for Ceftobiprole as Derived from a Population Pharmacokinetic Analysis of 150 Subjects

2007 ◽  
Vol 51 (7) ◽  
pp. 2378-2387 ◽  
Author(s):  
Thomas P. Lodise ◽  
Rienk Pypstra ◽  
James B. Kahn ◽  
Bindu P. Murthy ◽  
Hui C. Kimko ◽  
...  
Keyword(s):  
Dose Adjustment ◽  
Bactericidal Effect ◽  
Phase Iii ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Gram Negative ◽  
Population Pharmacokinetic Modeling ◽  
Drug Concentrations ◽  
Complicated Skin

ABSTRACT Ceftobiprole is a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) that is undergoing phase III trials for the treatment of complicated skin and skin structure infections and nosocomial pneumonia. The objectives were to describe the pharmacodynamic profiles of ceftobiprole given at 500 mg intravenously (i.v.) every 8 h (q8h) (2-h infusion) and 500 mg i.v. every 12 h (q12h) (1-h infusion) to determine the overall probability of target attainment (PTA) by weighting for the expected distributions of renal function in the populations of interests, to determine the PTA against representative pathogens encountered in clinical trials, and to determine the optimal renal dose adjustment for ceftobiprole at 500 mg i.v. q8h (2-h infusion). Data for a total of 150 subjects in phase I/II trials were analyzed by using the population pharmacokinetic modeling program BigNPOD (nonparametric optimal design). Monte Carlo simulation was performed with the ADAPT II program to estimate the PTA at which the free drug concentrations exceed the MIC for 30 to 60% of the dosing interval (30 to 60% fT > MIC). For ceftobiprole at 500 mg i.v. q12h, the probabilities of achieving 30% and 50% fT > MIC exceeded 90% for MICs ≤2 mg/liter and ≤1 mg/liter, respectively, For ceftobiprole at 500 mg i.v. q8h, the probabilities of achieving 40 and 60% fT > MIC exceeded 90% for MICs ≤4 mg/liter and ≤2 mg/liter, respectively. For ceftobiprole at both 500 mg i.v. q12h and 500 mg i.v. q8h, the probability of achieving a nearly bactericidal effect (50% fT > MIC) exceeded 90% for methicillin-susceptible S. aureus and MRSA. For gram-negative pathogens, the PTA for achieving a nearly maximal bactericidal effect (60% fT > MIC) for ceftobiprole at 500 mg i.v. q8h exceeded 90% for non-AmpC-producing gram-negative organisms. Ceftobiprole at 500 mg i.v. q12h, for patients who had a creatinine clearance rate of ≤50 ml/min, was identified as the most appropriate treatment regimen for patients who require renal dose adjustment for mild to moderate renal impairment.

scholarly journals Pharmacokinetics of Dihydroartemisinin and Piperaquine in Pregnant and Nonpregnant Women with Uncomplicated Falciparum Malaria

2011 ◽  
Vol 55 (12) ◽  
pp. 5500-5506 ◽  
Author(s):  
Marcus J. Rijken ◽  
Rose McGready ◽  
Aung Phae Phyo ◽  
Niklas Lindegardh ◽  
Joel Tarning ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Falciparum Malaria ◽  
Half Life ◽  
Drug Exposure ◽  
Venous Blood ◽  
Uncomplicated Falciparum Malaria ◽  
Fixed Dose ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Population Pharmacokinetic Modeling

ABSTRACTDihydroartemisinin-piperaquine is a fixed-dose artemisinin-based combination treatment. Some antimalarials have altered pharmacokinetics in pregnancy. Pregnant women in the 2nd or 3rd trimester and matched nonpregnant women with uncomplicated falciparum malaria were treated with a total of 6.4 mg/kg of body weight dihydroartemisinin and 51.2 mg/kg piperaquine once daily for 3 days. Venous blood samples were drawn at prespecified time points over 9 weeks. Plasma dihydroartemisinin and piperaquine concentrations were analyzed by liquid chromatography-mass spectrometry. Piperaquine and dihydroartemisinin pharmacokinetics were well described. There were no significant differences in total piperaquine exposure (P= 0.80) or drug exposure during the terminal elimination phase (72 h to infinity) (P= 0.64) between the two groups. The apparent volume of distribution of piperaquine was significantly smaller (602 liters/kg versus 877 liters/kg) in pregnant women than in nonpregnant women (P= 0.0057), and the terminal elimination half-life was significantly shorter (17.8 days versus 25.6 days;P= 0.0023). Dihydroartemisinin exposure after the first dose was significantly lower (844 h × ng/ml versus 1,220 h × ng/ml,P= 0.0021) in pregnant women, but there were no significant differences in total dihydroartemisinin exposure or maximum concentrations between the two groups. There were no significant differences in any pharmacokinetic parameters between the second and third trimester. These results obtained through noncompartmental analysis suggest that in the treatment of falciparum malaria, there are no clinically important differences in the pharmacokinetics of dihydroartemisinin or piperaquine between pregnant and nonpregnant women. However, a more detailed analysis using population pharmacokinetic modeling is needed to fully investigate the differences found for some of the pharmacokinetic parameters, such as the terminal half-life.

scholarly journals Low Antituberculosis Drug Concentrations in HIV-Tuberculosis-Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines?

2019 ◽  
Vol 63 (6) ◽  
Author(s):  
Christine Sekaggya-Wiltshire ◽  
Maxwell Chirehwa ◽  
Joseph Musaazi ◽  
Amrei von Braun ◽  
Allan Buzibye ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Fixed Dose ◽  
Population Pharmacokinetic ◽  
Population Pharmacokinetic Modeling ◽  
Drug Concentrations ◽  
Optimal Drug ◽  
Lower Drug ◽  
Dose Combination ◽  
Current Weight

ABSTRACT Antituberculosis drugs display large pharmacokinetic variability, which may be influenced by several factors, including body size, genetic differences, and drug-drug interactions. We set out to determine these factors, quantify their effect, and determine the dose adjustments necessary for optimal drug concentrations. HIV-infected Ugandan adults with pulmonary tuberculosis treated according to international weight-based dosing guidelines underwent pharmacokinetic sampling (1, 2, and 4 h after drug intake) 2, 8, and 24 weeks after treatment initiation. Between May 2013 and November 2015, we enrolled 268 patients (148 males) with a median weight of 53.5 (interquartile range [IQR], 47.5 to 59.0) kg and a median age of 35 (IQR, 29 to 40) years. Population pharmacokinetic modeling was used to interpret the data and revealed that patients weighing <55 kg achieved lower concentrations than those in higher weight bands for all drugs in the regimen. The models predicted that this imbalance could be solved with a dose increment of one fixed-dose combination (FDC) tablet for the weight bands of 30 to 37 and 38 to 54 kg. Additionally, the concomitant use of efavirenz increased isoniazid clearance by 24.1%, while bioavailability and absorption of rifampin and isoniazid varied up to 30% in patients on different formulations. Current dosing guidelines lead to lower drug exposure in patients in the lower weight bands. Simply adding one FDC tablet to current weight band-based dosing would address these differences in exposure and possibly improve outcomes. Lower isoniazid exposures due to efavirenz deserve further attention, as does the quality of currently used drug formulations of anti-TB drugs. (This study has been registered at ClinicalTrials.gov under identifier NCT01782950.)

Pharmacodynamic Effect of Morphine-6-glucuronide versus  Morphine on Hypoxic and Hypercapnic Breathing in Healthy Volunteers

2003 ◽  
Vol 99 (4) ◽  
pp. 788-798 ◽  
Author(s):  
Raymonda Romberg ◽  
Erik Olofsen ◽  
Elise Sarton ◽  
Luc Teppema ◽  
Albert Dahan
Keyword(s):  
Carbon Dioxide ◽  
Input Function ◽  
Time Profile ◽  
Population Pharmacokinetic ◽  
Model Parameters ◽  
Drug Infusion ◽  
Potency Ratio ◽  
Effect Site ◽  
Drug Concentrations ◽  
End Tidal

Background Morphine-6-glucuronide (M6G) is an active metabolite of morphine that is generally associated with less respiratory depression than morphine. Because M6G will be on the market in the near future, the authors assessed the time profile and relative potency of M6G's effect versus morphine's effect on carbon dioxide-driven and hypoxic breathing. Methods In nine healthy female volunteers, the effects of 0.2 mg/kg intravenous M6G, 0.13 mg/kg intravenous morphine, and intravenous placebo were tested on ventilation at a fixed end-tidal pressure of carbon dioxide (Petco2) of 45 mmHg (Vi45) and on the acute hypoxic ventilatory response (AHR). All subjects participated in all three arms of the study. Respiratory studies were performed at 1-h intervals for 7 h after drug infusion. The data were analyzed using a population dose-driven approach, which uses a dose rate in function of time as input function driving the pharmacodynamics, and a population pharmacokinetic-pharmacodynamic (PK/PD) approach in which fixed pharmacokinetic parameter values from the literature were used as input function to the respiratory model. From the latter analysis, the authors obtained the blood effect-site equilibration half-life (t1/2ke0) and the effect-site concentration producing 25% depression of Vi45 and AHR (C25). Values reported are mean +/- SE. Results Placebo had no effect on Vi45 or AHR over time. Both analysis approaches yielded good descriptions of the data with comparable model parameters. M6G PK/PD model parameters for Vi45 were t1/2ke0 2.1 +/- 0.2 h and C25 528 +/- 88 nm and for AHR were t1/2ke0 1.0 +/- 0.1 h and C25 873 +/- 81 nm. Morphine PK/PD model parameters for Vi45 were t1/2ke0 3.8 +/- 0.9 h and C25 28 +/- 6 nm and for AHR were t1/2ke0 4.3 +/- 0.6 h and C25 16 +/- 2 nm. Conclusions Morphine is more potent in affecting hypoxic ventilatory control than M6G, with a potency ratio ranging from 1:19 for Vi45 to 1:50 for AHR. At drug concentrations causing 25% depression of Vi45, M6G caused only 15% depression of AHR, whereas morphine caused greater than 50% depression of AHR. Furthermore, the speed of onset/offset of M6G is faster than morphine by a factor of approximately 2. The authors discuss some of the possible mechanisms for the observed differences in opioid behavior.

scholarly journals An Evaluation of Using Population Pharmacokinetic Models to Estimate Pharmacodynamic Parameters for Propofol and Bispectral Index in Children

2011 ◽  
Vol 115 (1) ◽  
pp. 83-93 ◽  
Author(s):  
Marc J. Coppens ◽  
Douglas J. Eleveld ◽  
Johannes H. Proost ◽  
Luc A. M. Marks ◽  
Jan F. P. Van Bocxlaer ◽  
...  
Keyword(s):  
Objective Function ◽  
Bispectral Index ◽  
Pharmacokinetic Model ◽  
Dental Treatment ◽  
Venous Blood ◽  
Plasma Concentrations ◽  
Accurate Estimation ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Models ◽  
Objective Function Values

Background To study propofol pharmacodynamics in a clinical setting a pharmacokinetic model must be used to predict drug plasma concentrations. Some investigators use a population pharmacokinetic model from existing literature and minimize the pharmacodynamic objective function. The purpose of the study was to determine whether this method selects the best-performing pharmacokinetic model in a set and provides accurate estimates of pharmacodynamic parameters in models for bispectral index in children after propofol administration. Methods Twenty-eight children classified as American Society of Anesthesiologists physical status 1 who were given general anesthesia for dental treatment were studied. Anesthesia was given using target-controlled infusion of propofol based on the Kataria model. Propofol target plasma concentration was 7 μg/ml for 15 min, followed by 1 μg/ml for 15 min or until signs of awakening, followed by 5 μg/ml for 15 min. Venous blood samples were taken 1, 2, 5, 10, and 15 min after each change in target. A classic pharmacokinetic-pharmacodynamic model was estimated, and the methodology of other studies was duplicated using pharmacokinetic models from the literature and (re-)estimating the pharmacodynamic models. Results There is no clear relationship between pharmacokinetic precision and the pharmacodynamic objective function. Low pharmacodynamic objective function values are not associated with accurate estimation of the pharmacodynamic parameters when the pharmacokinetic model is taken from other sources. Conclusion Minimization of the pharmacodynamic objective function does not select the most accurate pharmacokinetic model. Using population pharmacokinetic models from the literature instead of the 'true' pharmacokinetic model can lead to better predictions of bispectral index while incorrectly estimating the pharmacodynamic parameters.

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

2019 ◽  
Vol 64 (1) ◽  
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.

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

2015 ◽  
Vol 59 (4) ◽  
pp. 2398-2404 ◽  
Author(s):  
Kristina Öbrink-Hansen ◽  
Tore Forsingdal Hardlei ◽  
Birgitte Brock ◽  
Søren Jensen-Fangel ◽  
Marianne Kragh Thomsen ◽  
...  
Keyword(s):  
Legionella Pneumophila ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Plasma Concentrations ◽  
Community Acquired Pneumonia ◽  
Population Pharmacokinetic ◽  
Efficacy Evaluation ◽  
Therapeutic Success ◽  
Content Type ◽  
Drug Concentrations

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.)

scholarly journals Population Pharmacokinetics and Significant Under-Dosing of Anti-Tuberculosis Medications in People with HIV and Critical Illness

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 739
Author(s):  
Prakruti S. Rao ◽  
Christopher C. Moore ◽  
Amir A. Mbonde ◽  
Edwin Nuwagira ◽  
Patrick Orikiriza ◽  
...  
Keyword(s):  
Critical Illness ◽  
Drug Exposure ◽  
Case Fatality ◽  
Population Pharmacokinetic ◽  
Post Dose ◽  
Population Pharmacokinetic Modeling ◽  
Drug Concentrations ◽  
Immunodeficiency Virus ◽  
Living With Hiv ◽  
Lost To Follow Up

Critical illness from tuberculosis (TB) bloodstream infection results in a high case fatality rate for people living with human immunodeficiency virus (HIV). Critical illness can lead to altered pharmacokinetics and suboptimal drug exposures. We enrolled adults living with HIV and hospitalized with sepsis, with and without meningitis, in Mbarara, Uganda that were starting first-line anti-TB therapy. Serum was collected two weeks after enrollment at 1-, 2-, 4-, and 6-h post-dose and drug concentrations quantified by validated LC-MS/MS methods. Non-compartmental analyses were used to determine total drug exposure, and population pharmacokinetic modeling and simulations were performed to determine optimal dosages. Eighty-one participants were enrolled. Forty-nine completed pharmacokinetic testing: 18 (22%) died prior to testing, 13 (16%) were lost to follow-up and one had incomplete testing. Isoniazid had the lowest serum attainment, with only 4.1% achieving a target exposure over 24 h (AUC0–24) of 52 mg·h/L despite appropriate weight-based dosing. Simulations to reach target AUC0–24 found necessary doses of rifampin of 1800 mg, pyrazinamide of 2500–3000 mg, and for isoniazid 900 mg or higher. Given the high case fatality ratio of TB-related critical illness in this population, an early higher dose anti-TB therapy should be trialed.

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