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, 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.

Model-Based Exposure-Response Assessment for Spectinamide 1810 in a Mouse Model of Tuberculosis

2021 ◽  
Author(s):  
Santosh Wagh ◽  
Chetan Rathi ◽  
Pradeep B. Lukka ◽  
Keyur Parmar ◽  
Zaid Temrikar ◽  
...  
Keyword(s):  
Mouse Model ◽  
Plasma Concentrations ◽  
Dose Fractionation ◽  
Population Pharmacokinetic ◽  
Response Relationship ◽  
Postantibiotic Effect ◽  
Bacterial Killing ◽  
Exposure Response

Despite decades of research, tuberculosis remains a leading cause of death from a single infectious agent. Spectinamides are a promising novel class of anti-tuberculosis agents, and lead spectinamide 1810 has demonstrated excellent efficacy, safety and drug-like properties in numerous in vitro and in vivo assessments in mouse models of tuberculosis. In the current dose ranging and dose fractionation study, we used 29 different combinations of dose level and dosing frequency to characterize the exposure-response relationship for spectinamide 1810 in a mouse model of M. tuberculosis infection and in healthy animals. The obtained data on 1810 plasma concentrations and counts of colony-forming units in lungs were analyzed using a population pharmacokinetic/pharmacodynamic (PK/PD) approach as well as classical anti-infective PK/PD indices. The analysis results indicate that there was no difference in the PK of 1810 in infected compared to healthy, uninfected animals. The PK/PD index analysis showed that bacterial killing of 1810 in mice was best predicted by fC max /MIC and fAUC/MIC rather than f%T MIC . A novel PK/PD model with consideration of postantibiotic effect could adequately describe the exposure-response relationship for 1810 and supports the notion that the in vitro observed postantibiotic effect of this spectinamide also translates to the in vivo situation in mice. The obtained results and pharmacometric model for the exposure-response relationship of 1810 provide a rational basis for dose selection in future efficacy studies of this compound against M. tuberculosis .

scholarly journals Acceleration of hematopoietic reconstitution with a synthetic cytokine (SC-55494) after radiation-induced bone marrow aplasia

Blood ◽  
1996 ◽  
Vol 87 (2) ◽  
pp. 581-591 ◽  
Author(s):  
AM Farese ◽  
F Herodin ◽  
JP McKearn ◽  
C Baum ◽  
E Burton ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Platelet Recovery ◽  
Hematopoietic Reconstitution ◽  
Radiation Induced ◽  
Complete Blood Counts ◽  
60Co Gamma Radiation

The synthetic cytokine (Synthokine) SC-55494 is a high-affinity interleukin-3 (IL-3) receptor ligand that stimulates greater in vitro multilineage hematopoietic activity than native IL-3, while inducing no significant increase in inflammatory activity relative to native IL-3. The aim of this study was to investigate the in vivo hematopoietic response of rhesus monkeys receiving Synthokine after radiation-induced marrow aplasia. Administration schedule and dose of Synthokine were evaluated. All animals were total-body irradiated (TBI) with 700 cGy 60Co gamma radiation on day 0. Beginning on day 1, cohorts of animals (n = 5) received Synthokine subcutaneously (SC) twice daily with 25 micrograms/kg/d or 100 micrograms/kg/d for 23 days or 100 micrograms/kg/d for 14 days. Control animals (n = 9) received human serum albumin SC once daily at 15 micrograms/kg/d for 23 days. Complete blood counts were monitored for 60 days postirradiation and the durations of neutropenia (NEUT; absolute neutrophil count [ANC] 500/microL) and thrombocytopenia (THROM; platelet count 20,000/microL) were assessed. Synthokine significantly (P .05) reduced the duration of THROM versus the HSA-treated animals regardless of dose or protocol length. The most striking reduction was obtained in the animals receiving 100 micrograms/kg/d for 23 days (THROM = 3.5 v 12.5 days in HSA control animals). Although the duration of NEUT was not significantly altered, the depth of the nadir was significantly lessened in all animal cohorts treated with Synthokine regardless of dose versus schedule length. Bone marrow progenitor cell cultures indicated a beneficial effect of Synthokine on the recovery of granulocyte-macrophage colony-forming units that was significantly higher at day 24 post-TBI in both cohorts treated at 25 and 100 micrograms/kg/d for 23 days relative to the control animals. Plasma pharmacokinetic parameters were evaluated in both normal and irradiated animals. Pharmacokinetic analysis performed in irradiated animals after 1 week of treatment suggests an effect of repetitive Synthokine schedule and/or TBI on distribution and/or elimination of Synthokine. These data show that the Synthokine, SC55 94, administered therapeutically post-TBI, significantly enhanced platelet recovery and modulated neutrophil nadir and may be clinically useful in the treatment of the myeloablated host.

scholarly journals Population Pharmacokinetic Analysis of Cefaclor in Healthy Korean Subjects

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 754
Author(s):  
Seung-Hyun Jeong ◽  
Ji-Hun Jang ◽  
Hea-Young Cho ◽  
Yong-Bok Lee
Keyword(s):  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Factors Affecting ◽  
Population Pharmacokinetic Study ◽  
Final Population ◽  
Subject Variability

The aims of this study were: (1) to perform population pharmacokinetic analysis of cefaclor in healthy Korean subjects, and (2) to investigate possible effects of various covariates on pharmacokinetic parameters of cefaclor. Although cefaclor belongs to the cephalosporin family antibiotic that has been used in various indications, there have been very few population studies on factors affecting its pharmacokinetics. Therefore, this study is very important in that effective therapy could be possible through a population pharmacokinetic study that explores effective covariates related to cefaclor pharmacokinetic diversity between individuals. Pharmacokinetic results of 48 subjects with physical and biochemical parameters were used for the population pharmacokinetic analysis of cefaclor. A one-compartment with lag-time and first-order absorption/elimination was constructed as a base model and extended to include covariates that could influence between-subject variability. Creatinine clearance and body weight significantly influenced systemic clearance and distribution volume of cefaclor. Cefaclor’s final population pharmacokinetic model was validated and some of the population’s pharmacokinetic diversity could be explained. Herein, we first describe the establishment of a population pharmacokinetic model of cefaclor for healthy Koreans that might be useful for customizing cefaclor or exploring additional covariates in patients.

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 Exposure Response Supports Therapeutic Drug Monitoring for Dabigatran Etexilate in Patients with Atrial Fibrillation

TH Open ◽  
2019 ◽  
Vol 03 (03) ◽  
pp. e210-e215 ◽  
Author(s):  
Bryan H. Simpson ◽  
David M. Reith ◽  
Natalie J. Medlicott ◽  
Alesha J. Smith
Keyword(s):  
Atrial Fibrillation ◽  
Dabigatran Etexilate ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Response Relationship ◽  
Effective Response ◽  
Exposure Response ◽  
Quartile Range ◽  
Increased Risk ◽  
Risk Of Hemorrhage

Background Dabigatran etexilate has become widely used for the prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF). Currently, there is limited information in real-world patients relating to dabigatran etexilate exposure and response. Methods This retrospective cohort study used administrative health data for NVAF patients dispensed dabigatran etexilate between July 1, 2011 and December 31, 2015. Outcomes of cerebrovascular accident (CVA), systemic embolism, and hemorrhage were extracted. Simulated pharmacokinetic parameters were obtained using a published population pharmacokinetic model of dabigatran etexilate. Area under the curve calculated for a 24-hour period at steady state (AUCss), the exposure parameter, was derived using these simulations and the dosing data and the exposure–response relationship were investigated. The risk of adverse outcomes at AUCss quartiles was compared using Poisson regression and expressed using incidence rate ratios (95% confidence interval) adjusted for known potential confounders. Results In total, 2,660 NVAF patients had been dispensed dabigatran etexilate. For these patients there was a decreased risk of hemorrhage (0.51, 0.32–0.79) when dabigatran AUCss was in the second quartile range of 1.70 to 1.96 mg h/L and thromboembolism/CVA (0.34, 0.16–0.76) when in the third quartile range of 1.97 to 2.26 mg h/L. An increased risk of hemorrhage (1.68, 1.18–2.38) was observed when AUCss was in the fourth quartile range of 2.27 to 12.76 mg h/L. Conclusion An exposure–response relationship for dabigatran etexilate was described, where the most effective response was observed when AUCss was in the range of 1.70 to 2.26 mg h/L. Hence, it is feasible to develop guidance for optimal dosing to improve outcomes for patients with NVAF.

Cytotoxicity of Dimethylacetamide and Pharmacokinetics in Children Receiving Intravenous Busulfan

2007 ◽  
Vol 25 (13) ◽  
pp. 1772-1778 ◽  
Author(s):  
Georg Hempel ◽  
Doris Oechtering ◽  
Claudia Lanvers-Kaminsky ◽  
Thomas Klingebiel ◽  
Josef Vormoor ◽  
...  
Keyword(s):  
Safety Concern ◽  
Plasma Concentrations ◽  
Leukemic Cell ◽  
Population Pharmacokinetic Analysis ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
High Dose ◽  
Leukemic Cell Lines

PurposeTo assess the cytotoxicity and the exposure of N,N-dimethylacetamide (DMA) in children during high-dose therapy with an intravenous (IV) formulation of busulfan containing the potentially hepatotoxic and neurotoxic DMA as a solvent.Patients and MethodsEighteen children aged 0.9 to 17.3 years (median age, 4.0 years) received IV busulfan in 15 doses of 0.7 to 1.0 mg/kg busulfan containing overall DMA amounts of between 5 mmol (437 mg) and 70.5 mmol (6,142 mg) per dose. Plasma concentrations of DMA and busulfan were quantified and analyzed using nonlinear mixed-effects modeling. Four different leukemic cell lines were incubated with DMA, and cytotoxicity was assessed in comparison with busulfan as well as in a combination reflecting the ratio in the formulation.ResultsMaximal plasma concentrations of DMA up to 3.09 mmol/L were observed. No accumulation of the solvent occurred. Instead, the trough levels decreased over the 4 treatment days. The population pharmacokinetic analysis revealed a clearance of 86.9 mL h−1kg−1± 27% that increased to 298 mL h−1kg−1on the fourth day and a volume of distribution of 469 mL kg ± 22% (population mean ± interindividual variability). DMA volume of distribution correlated with the volume of distribution of busulfan. The cytotoxicity of DMA in vitro was 3 orders of magnitude lower than that of busulfan. No synergism was observed.ConclusionThe lack of accumulation of DMA confirms that there is no safety concern related to the DMA content in this IV busulfan formulation. The contribution of DMA to the antileukemic effect of the formulation seems to be limited.

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