scholarly journals Population Pharmacokinetic Analysis of Isoniazid, Acetylisoniazid, and Isonicotinic Acid in Healthy Volunteers

2015 ◽  
Vol 59 (11) ◽  
pp. 6791-6799 ◽  
Author(s):  
Kok-Yong Seng ◽  
Kim-Hor Hee ◽  
Gaik-Hong Soon ◽  
Nicholas Chew ◽  
Saye H. Khoo ◽  
...  
Keyword(s):  
Isonicotinic Acid ◽  
Compartment Model ◽  
Hepatic Function ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Mixed Effects Modeling ◽  
Two Compartment Model

ABSTRACTIn this study, we aimed to quantify the effects of theN-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolismin vivoand identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function. A two-compartment model with first-order absorption best described the INH pharmacokinetics. AcINH and INA data were best described by a two- and a one-compartment model, respectively, linked to the INH model. In the final model for INH, the derived metabolic phenotypes for NAT2 were identified as a significant covariate in the INH clearance, reducing its interindividual variability from 86% to 14%. The INH clearance in fast eliminators was 1.9- and 7.7-fold higher than in intermediate and slow eliminators, respectively (65 versus 35 and 8 liters/h). Creatinine clearance was confirmed as a significant covariate for AcINH clearance. Simulations suggested that the current dosing guidelines (200 mg for 30 to 45 kg and 300 mg for >45 kg) may be suboptimal (3 mg/liter ≤Cmax≤ 6 mg/liter) irrespective of the acetylator class. The analysis established a model that adequately characterizes INH, AcINH, and INA pharmacokinetics in healthy Asians. Our results refine the NAT2 phenotype-based predictions of the pharmacokinetics for INH.

scholarly journals Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis

2014 ◽  
Vol 58 (8) ◽  
pp. 4718-4726 ◽  
Author(s):  
Ping Liu ◽  
Diane R. Mould
Keyword(s):  
Invasive Aspergillosis ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Institutional Review Boards ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
First Order ◽  
Two Compartment Model

ABSTRACTTo assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC0–12] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479).

scholarly journals Joint Population Pharmacokinetic Analysis of Zidovudine, Lamivudine, and Their Active Intracellular Metabolites in HIV Patients

2011 ◽  
Vol 55 (7) ◽  
pp. 3423-3431 ◽  
Author(s):  
C. Bazzoli ◽  
H. Bénech ◽  
E. Rey ◽  
S. Retout ◽  
D. Salmon ◽  
...  
Keyword(s):  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Intracellular Metabolites ◽  
Drug Concentrations ◽  
The Mean ◽  
Intracellular Concentrations ◽  
Apparent Bioavailability

ABSTRACTThe population pharmacokinetic parameters of zidovudine (AZT), lamivudine (3TC), and their active intracellular metabolites in 75 naïve HIV-infected patients receiving an oral combination of AZT and 3TC twice daily as part of their multitherapy treatment in the COPHAR2-ANRS 111 trial are described. Four blood samples per patient were taken after 2 weeks of treatment to measure drug concentrations at steady state. Plasma AZT and 3TC concentrations were measured in 73 patients, and among those, 62 patients had measurable intracellular AZT-TP and 3TC-TP concentrations. For each drug, a joint population pharmacokinetic model was developed and we investigated the influence of different covariates. We then studied correlations between the mean plasma and intracellular concentrations of each drug. A one-compartment model with first-order absorption and elimination best described the plasma AZT concentration, with an additional compartment for intracellular AZT-TP. A similar model but with zero-order absorption was found to adequately described concentrations of 3TC and its metabolite 3TC-TP. The half-lives of AZT and 3TC were 0.81 h (94.8%) and 2.97 h (39.2%), respectively, whereas the intracellular half-lives of AZT-TP and 3TC-TP were 10.73 h (69%) and 21.16 h (44%), respectively. We found particularly a gender effect on the apparent bioavailability of AZT, as well as on the mean plasma and intracellular concentrations of AZT, which were significantly higher in females than in males. Relationships between mean plasma drug and intracellular metabolite concentrations were also highlighted both for AZT and for 3TC. Simulation with the model of plasma and intracellular concentrations for once- versus twice-daily regimens suggested that a daily dosing regimen with double doses could be appropriate.

scholarly journals Pyrimethamine pharmacokinetics in human immunodeficiency virus-positive patients seropositive for Toxoplasma gondii.

1996 ◽  
Vol 40 (6) ◽  
pp. 1360-1365 ◽  
Author(s):  
J M Jacobson ◽  
M Davidian ◽  
P M Rainey ◽  
R Hafner ◽  
R H Raasch ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Toxoplasma Gondii ◽  
Drug Users ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Immunodeficiency Virus

Pyrimethamine pharmacokinetics were studied in 11 human immunodeficiency virus (HIV)-positive patients who were seropositive for exposure to Toxoplasma gondii and were taking zidovudine (AIDS Clinical Trials Group Protocol 102). Pyrimethamine was administered at 50 mg daily for 3 weeks to achieve steady state, and pharmacokinetic profiles were determined after administration of the last dose. Noncompartmental and compartmental analyses were performed. Population pharmacokinetic analysis assuming a one-compartment model yielded the following estimates: area under the 24-h concentration-time curve, 42.7 +/- 12.3 micrograms.h/ml; halflife, 139 +/- 34 h; clearance, 1.28 +/- 0.41 liters/h; volume of distribution, 246 +/- 641; and absorption rate constant, 1.5 +/- 1.3 liters/h. These values are similar to those seen in subjects without HIV infection. Pyrimethamine pharmacokinetics did not differ significantly in those subjects who were intravenous drug users. Adverse effects were noted in 73% of those initially enrolled in this study, leading to discontinuation for 38%. No association was noted between pyrimethamine levels and the incidence of adverse events. No significant differences were seen in zidovudine pharmacokinetic parameters obtained from studies performed before and during treatment with pyrimethamine. In summary, pyrimethamine exhibited pharmacokinetics in HIV-infected patients that were similar to those in non-HIV-infected subjects and it did not alter the pharmacokinetics of zidovudine in these patients.

scholarly journals Population pharmacokinetic analysis of doripenem for Japanese patients in intensive care unit

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ko Nonoshita ◽  
Yosuke Suzuki ◽  
Ryota Tanaka ◽  
Tetsuya Kaneko ◽  
Yoshifumi Ohchi ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Population Analysis ◽  
Compartment Model ◽  
Japanese Patients ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Analysis Model ◽  
Mixed Effects Modeling

AbstractWe aimed to construct a novel population pharmacokinetics (PPK) model of doripenem (DRPM) for Japanese patients in intensive care unit, incorporating the clearance of DRPM by continuous renal replacement therapy (CRRT). Twenty-one patients treated with DRPM (0.25 or 0.5 g) by intravenous infusion over 1 h were included in the study. Nine of the 21 patients were receiving CRRT. Plasma samples were obtained before and 1, 2, 4, 6 and 8 h after the first DRPM administration. PPK analysis was conducted by nonlinear mixed effects modeling using a two-compartment model. Total clearance (CLtotal) in the model was divided into CRRT clearance (CLCRRT) and body clearance (CLbody). The final model was: CLtotal (L h−1) = CLbody(non-CRRT) = 3.65 × (Ccr/62.25)0.64 in the absence of CRRT, or = CLbody(CRRT) + CLCRRT = 2.49 × (Ccr/52.75)0.42 + CLCRRT in the presence of CRRT; CLCRRT = QE × 0.919 (0.919 represents non-protein binding rate of DRPM); V1 (L) = 10.04; V2 (L) = 8.13; and Q (L h−1) = 3.53. Using this model, CLtotal was lower and the distribution volumes (V1 and V2) tended to be higher compared to previous reports. Also, Ccr was selected as a significant covariate for CLbody. Furthermore, the contribution rate of CLCRRT to CLtotal was 30–40%, suggesting the importance of drug removal by CRRT. The population analysis model used in this study is a useful tool for planning DRPM regimen and administration. Our novel model may contribute greatly to proper use of DRPM in patients requiring intensive care.

Model-Based Dose-Exposure-Response Assessment for Lead and Backup Spectinamide in a Mouse Model of Tuberculosis

2020 ◽  
Author(s):  
◽  
Santosh Wagh ◽  
Keyword(s):  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Response Relationship ◽  
Exposure Response ◽  
Antibiotic Effect ◽  
Post Antibiotic Effect

Despite decades of research, tuberculosis remains the oldest pathogen-based disease that is the leading cause of death from a single infectious agent. Among many anti-tubercular therapies under investigation, the semisynthetic compounds spectinamides are a promising novel class of anti-tuberculosis agents. One such lead candidate, spectinamide 1810, and backup spectinamide 1599 have demonstrated excellent efficacy, safety, and drug-like properties in various in vitro and in vivo assessments. The dose-ranging and dose fractionation studies were designed to characterize the dose-exposure-response relationship for lead and backup spectinamide in a mouse model of Mycobacterium tuberculosis infection. In this current study, we used 26 and 23 combinations of dose level and dosing frequency for the lead and backup spectinamide, respectively. The dedicated pharmacokinetic studies with a collection of series of blood samples were conducted in healthy animals. Population pharmacokinetic analysis was performed using non-linear mixed effect modeling to estimate pharmacokinetic parameters in healthy animals. The Bayesian principles were applied for reliable pharmacokinetic estimation in infected animals by using informed priors obtained from healthy animals. The individual pharmacokinetic parameters were obtained for infected animals through post-hoc estimation and subsequently used for pharmacokinetic/-pharmacodynamic (PK/PD) indices and mechanism-based PK/PD modeling. The obtained data on spectinamides’ plasma concentrations and counts of colony-forming units were analyzed using a PK/PD approach as well as classical anti-infective PK/PD indices. The population pharmacokinetic analysis results suggest that there is no difference in the pharmacokinetic parameters of lead and backup spectinamide in infected animals as compared to healthy animals. The PK/PD index analysis showed that the efficacy of spectinamide 1810 is largely driven by concentration (Cmax/MIC) and exposure (AUC/MIC) rather than a threshold minimum inhibitory level (T>MIC). Although similar results were obtained for spectinamide 1599 in previously performed in vitro experiments, in the present in vivo studies, spectinamide 1599 did not demonstrate the expected correlation between efficacy and PK/PD indices. Therefore, we could not identify major drivers for the efficacy of this compound. Additionally, a novel mechanism-based PK/PD model with consideration to post-antibiotic effect could adequately describe the exposure-response relationship for lead and backup spectinamide. This supports the idea that the in vitro observed post-antibiotic effect of these spectinamides can translate to the in vivo situation, as well. Altogether we suggest, the obtained results and pharmacometric model for the exposure-response relationship of lead and backup spectinamides provide a rational basis for dose selection for future efficacy studies of these compounds against Mycobacterium tuberculosis in mice and other animal species.

scholarly journals Population Pharmacokinetic Analysis of Isoniazid among Pulmonary Tuberculosis Patients from China

2020 ◽  
Vol 64 (3) ◽  
Author(s):  
Wei Jing ◽  
Zhaojing Zong ◽  
Bohao Tang ◽  
Jing Wang ◽  
Tingting Zhang ◽  
...  
Keyword(s):  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Slow Acetylators ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Tuberculosis Patients ◽  
Two Compartment Model ◽  
Acetylator Status ◽  
Liquid Chromatography Tandem Mass

ABSTRACT The blood concentration of isoniazid (INH) is evidently affected by polymorphisms in N-acetyltransferase 2 (NAT2), an enzyme that is primarily responsible for the trimodal (i.e., fast, intermediate, and slow) INH elimination. The pharmacokinetic (PK) variability, driven largely by NAT2 activity, creates a challenge for the deployment of a uniform INH dosage in tuberculosis (TB) patients. Although acetylator-specific INH dosing has long been suggested, well-recognized dosages according to acetylator status remain elusive. In this study, 175 blood samples were collected from 89 pulmonary TB patients within 0.5 to 6 h after morning INH administration. According to their NAT2 genotypes, 32 (36.0%), 38 (42.7%), and 19 (21.3%) were fast, intermediate, and slow acetylators, respectively. The plasma INH concentration was detected by liquid chromatography-tandem mass spectrometry. Population pharmacokinetic (PPK) analysis was conducted using NONMEM and R software. A two-compartment model with first-order absorption and elimination well described the PK parameters of isoniazid. Body weight and acetylator status significantly affected the INH clearance rate. The dosage simulation targeting three indicators, including the well-recognized efficacy-safety indicator maximum concentration in serum (Cmax; 3 to 6 μg/ml), the reported area under the concentration-time curve from 0 h to infinity (AUC0–∞; ≥10.52 μg·h/ml), and the 2-h INH serum concentrations (≥2.19 μg/ml), was associated with the strongest early bactericidal activity. The optimal dosages targeting the different indicators varied from 700 to 900 mg/day, 500 to 600 mg/day, and 300 mg/day for the rapid, intermediate, and slow acetylators, respectively. Furthermore, a PPK model for isoniazid among Chinese tuberculosis patients was established for the first time and suggested doses of approximately 800 mg/day, 500 mg/day, and 300 mg/day for fast, intermediate, and slow acetylators, respectively, after a trade-off between efficacy and the occurrence of side effects.

scholarly journals Population Pharmacokinetic Analysis of Colistin Methanesulfonate and Colistin after Intravenous Administration in Critically Ill Patients with Infections Caused by Gram-Negative Bacteria

2009 ◽  
Vol 53 (8) ◽  
pp. 3430-3436 ◽  
Author(s):  
D. Plachouras ◽  
M. Karvanen ◽  
L. E. Friberg ◽  
E. Papadomichelakis ◽  
A. Antoniadou ◽  
...  
Keyword(s):  
Steady State ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Colistin Methanesulfonate

ABSTRACT Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.

scholarly journals A Population Pharmacokinetic Analysis Shows that Arylacetamide Deacetylase (AADAC) Gene Polymorphism and HIV Infection Affect the Exposure of Rifapentine

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Jose Francis ◽  
Simbarashe P. Zvada ◽  
Paolo Denti ◽  
Mark Hatherill ◽  
Salome Charalambous ◽  
...  
Keyword(s):  
Food Intake ◽  
Hiv Infection ◽  
Pregnane X Receptor ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Volume Of Distribution ◽  
Fat Free Mass ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Antituberculosis Treatment

ABSTRACT Rifapentine is a rifamycin used to treat tuberculosis. As is the case for rifampin, plasma exposures of rifapentine are associated with the treatment response. While concomitant food intake and HIV infection explain part of the pharmacokinetic variability associated with rifapentine, few studies have evaluated the contribution of genetic polymorphisms. We evaluated the effects of functionally significant polymorphisms of the genes encoding OATP1B1, the pregnane X receptor (PXR), constitutive androstane (CAR), and arylacetamide deacetylase (AADAC) on rifapentine exposure. Two studies evaluating novel regimens among southern African patients with drug-susceptible pulmonary tuberculosis were included in this analysis. In the RIFAQUIN study, rifapentine was administered in the continuation phase of antituberculosis treatment in 1,200-mg-once-weekly or 900-mg-twice-weekly doses. In the Daily RPE study, 450 or 600 mg was given daily during the intensive phase of treatment. Nonlinear mixed-effects modeling was used to describe the pharmacokinetics of rifapentine and to identify significant covariates. A total of 1,144 drug concentration measurements from 326 patients were included in the analysis. Pharmacogenetic information was available for 162 patients. A one-compartment model with first-order elimination and transit compartment absorption described the data well. In a typical patient (body weight, 56 kg; fat-free mass, 45 kg), the values of clearance and volume of distribution were 1.33 liters/h and 25 liters, respectively. Patients carrying the AA variant (65.4%) of AADAC rs1803155 were found to have a 10.4% lower clearance. HIV-infected patients had a 21.9% lower bioavailability. Once-weekly doses of 1,200 mg were associated with a reduced clearance (13.2%) compared to that achieved with more frequently administered doses. Bioavailability was 23.3% lower among patients participating in the Daily RPE study than in those participating in the RIFAQUIN study. This is the first study to report the effect of AADAC rs1803155AA on rifapentine clearance. The observed increase in exposure is modest and unlikely to be of clinical relevance. The difference in bioavailability between the two studies is probably related to the differences in food intake concomitant with the dose. HIV-coinfected patients had lower rifapentine exposures.

scholarly journals Population Pharmacokinetics of Ciprofloxacin in Neonates and Young Infants Less than Three Months of Age

2014 ◽  
Vol 58 (11) ◽  
pp. 6572-6580 ◽  
Author(s):  
Wei Zhao ◽  
Helen Hill ◽  
Chantal Le Guellec ◽  
Tim Neal ◽  
Sarah Mahoney ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Newborn Infants ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Dosing Regimen ◽  
Creatinine Concentration ◽  
Young Infants

ABSTRACTCiprofloxacin is used in neonates with suspected or documented Gram-negative serious infections. Currently, its use is off-label partly because of lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin in neonates and young infants <3 months of age and define the appropriate dose in order to optimize ciprofloxacin treatment in this vulnerable population. Blood samples were collected from neonates treated with ciprofloxacin and concentrations were quantified by high-pressure liquid chromatography–mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM software. The data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9 weeks) were available for population pharmacokinetic analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that gestational age, postnatal age, current weight, serum creatinine concentration, and use of inotropes had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with a PMA of <34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with a PMA ≥34 weeks and young infants receiving 12.5 mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associated risks of overdose for the proposed dosing regimen were <8%. The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants <3 months old, and a dosing regimen was established based on simulation.

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