scholarly journals Population Pharmacokinetics of Tafenoquine, a Novel Antimalarial

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Nilay Thakkar ◽  
Justin A. Green ◽  
Gavin C. K. W. Koh ◽  
Stephan Duparc ◽  
David Tenero ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Studies ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Radical Cure ◽  
Phase 3 ◽  
Content Type ◽  
Clinical Trial Simulations ◽  
Apparent Volume Of Distribution

ABSTRACTTafenoquine is a novel 8-aminoquinoline antimalarial drug recently approved by the U.S. Food and Drug Administration (FDA) for the radical cure of acutePlasmodium vivaxmalaria, which is the first new treatment in almost 60 years. A population pharmacokinetic (POP PK) analysis was conducted with tafenoquine exposure data obtained following oral administration from 6 clinical studies in phase 1 through phase 3 with a nonlinear mixed effects modeling approach. The impacts of patient demographics, baseline characteristics, and extrinsic factors, such as formulation, were evaluated. Model performance was assessed using techniques such as bootstrapping, visual predictive checks, and external data validation from a phase 3 study not used in model fitting and parameter estimation. Based on the analysis, the systemic pharmacokinetics of tafenoquine were adequately described using a two-compartment model. The final POP PK model included body weight (allometric scaling) on apparent oral and intercompartmental clearance (CL/FandQ/F, respectively), apparent volume of distribution for central and peripheral compartments (V2/FandV3/F, respectively), formulation on systemic bioavailability (F1) and absorption rate constant (Ka), and health status on apparent volume of distribution. The key tafenoquine population parameter estimates were 2.96 liters/h for CL/Fand 915 liters forV2/FinP. vivax-infected subjects. Additionally, the analyses demonstrated no clinically relevant difference in relative bioavailability across the capsule and tablet formulations administered in these clinical studies. In conclusion, a POP PK model for tafenoquine was developed. Clinical trial simulations based on this model supported bridging the exposures across two different formulations. This POP PK model can be applied to aid and perform clinical trial simulations in other scenarios and populations, such as pediatric populations.

scholarly journals Population Pharmacokinetics of Bedaquiline (TMC207), a Novel Antituberculosis Drug

2014 ◽  
Vol 58 (9) ◽  
pp. 5315-5324 ◽  
Author(s):  
Sarah C. McLeay ◽  
Peter Vis ◽  
Rolf P. G. van Heeswijk ◽  
Bruce Green
Keyword(s):  
Apparent Volume ◽  
Multidrug Resistant ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Time Data ◽  
Content Type ◽  
Mixed Effects Modeling ◽  
Phase Ii Studies ◽  
Apparent Clearance ◽  
Residual Unexplained Variability

ABSTRACTBedaquiline is a novel agent for the treatment of pulmonary multidrug-resistantMycobacterium tuberculosisinfections, in combination with other agents. The objective of this study was to develop a population pharmacokinetic (PK) model for bedaquiline to describe the concentration-time data from phase I and II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant tuberculosis (TB). A total of 5,222 PK observations from 480 subjects were used in a nonlinear mixed-effects modeling approach. The PK was described with a 4-compartment disposition model with dual zero-order input (to capture dual peaks observed during absorption) and long terminal half-life (t1/2). The model included between-subject variability on apparent clearance (CL/F), apparent central volume of distribution (Vc/F), the fraction of dose via the first input, and bioavailability (F). Bedaquiline was widely distributed, with apparent volume at steady state of >10,000 liters and low clearance. The long terminalt1/2was likely due to redistribution from the tissue compartments. The final covariate model adequately described the data and had good simulation characteristics. The CL/F was found to be 52.0% higher for subjects of black race than that for subjects of other races, andVc/F was 15.7% lower for females than that for males, although their effects on bedaquiline exposure were not considered to be clinically relevant. Small differences in F and CL/F were observed between the studies. The residual unexplained variability was 20.6% and was higher (27.7%) for long-term phase II studies.

Pharmacokinetics and Tissue Distribution of Norfloxacin in Eel Following Oral Gavage

2012 ◽  
Vol 452-453 ◽  
pp. 1069-1073
Author(s):  
Yun Hua Hui ◽  
You Qiong Cai ◽  
Bing Feng ◽  
Wen Ruan ◽  
Hui Juan Yu
Keyword(s):  
Apparent Volume ◽  
Volume Of Distribution ◽  
European Eel ◽  
Half Time ◽  
Oral Gavage ◽  
Concentration Time ◽  
Liver And Kidney ◽  
Apparent Volume Of Distribution ◽  
Different Tissues ◽  
Body Clearance

The pharmacokinetics of norfloxacin were investigated in the European eel after a single oral gavage of 10 mg norfloxacin per kg body weight. The concentrations of norfloxacin in the main tissues (kidney, muscle, hepatopancreas and blood) were simultaneously detected by HPLC. All of the concentration-time curves of norfloxacin in the plasma, muscle and liver were consistent with absorption of a two-compartment open kinetic model. Norfloxacin was widely distributed in different tissues in the European eel. Apparent volume of distribution (Vd) was 52.025 L/kg, 34.589 L/kg, 2.795 L/kg, and 0.969 L/kg, in plasma, muscle, liver and kidney, respectively. Norfloxacin in the eel was proved to eliminate slowly, and half-time (tβ1/2) in plasma, muscle, liver and kidney, was 201.222 h, 123.789 h, 120.634 h and 627473.495 h, respectively. Body clearance was 0.689 L / ( kg•h ), 1.793 L/( kg•h ), 0.097 L/( kg•h ) and 0.028 L /( kg•h ), in plasma, muscle, liver and kidney, respectively.

Ketamine kinetics: decerebrate vs. intact cats

1979 ◽  
Vol 57 (8) ◽  
pp. 878-881 ◽  
Author(s):  
James E. Heavner ◽  
Duane C. Bloedow
Keyword(s):  
Apparent Volume ◽  
Volume Of Distribution ◽  
Drug Dose ◽  
The Body ◽  
Pharmacokinetic Parameters ◽  
Peripheral Compartment ◽  
Blood Concentrations ◽  
Open Model ◽  
Apparent Volume Of Distribution ◽  
Compartment Open Model

Pharmacokinetic parameters of a ketamine (10 mg/kg, iv) bolus in decerebrate and intact cats were compared. A two-compartment open model best described the data in both groups. The apparent volume of distribution of the peripheral compartment, the apparent volume of distribution of the drug in the body, and the half-life of the postdistributive phase were significantly less (p < 0.05) in the decerebrate animals. These results emphasize the importance of correlating behavior and neuronal activity with plasma or blood concentrations of drug in animals rather than assuming that, for a given drug dose, blood (and thus tissue) levels of the agent will be similar regardless of how the animal is prepared for study.

Letters to the Editor

PEDIATRICS ◽  
1981 ◽  
Vol 68 (4) ◽  
pp. 601-602
Author(s):  
M. Spino ◽  
J. J. Thiessen ◽  
A. Isles ◽  
H. Levison ◽  
S. M. MacLeod
Keyword(s):  
Clinical Application ◽  
Drug Concentration ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Intravenous Dose ◽  
Single Intravenous Dose ◽  
Letters To The Editor ◽  
Potential Clinical Application ◽  
Apparent Volume Of Distribution

We found the report by Feldman et al1 interesting with potential clinical application. However, we would like to point out an error in their determination of the apparent volume of distribution (V) and comment on both their methodology and results. They state that V was calculated by dividing the dose of the drug by the extrapolated y intercept for drug concentration at time 0. This method is correct for a drug which exhibits monoexponential elimination following a single intravenous dose.

scholarly journals Tacrolimus Pharmacokinetics in Living-Donor and Deceased-Donor Liver Transplant in Saudi Patients

2019 ◽  
pp. 288-294
Author(s):  
Hisham S. Abou-Auda ◽  
Eqbal Qaddour ◽  
Hussein Alsisi ◽  
Azizah Ajlan ◽  
Mohammad Alsebayel
Keyword(s):  
Liver Transplant ◽  
Deceased Donor ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Transplant Recipients ◽  
Donor Liver ◽  
Apparent Clearance ◽  
Donor Liver Transplant ◽  
Liver Transplant Recipients ◽  
Apparent Volume Of Distribution

Introduction: Tacrolimus is a macrolide immunosuppressant. It has a narrow therapeutic index and serious side effects which necessitate monitoring of tacrolimus blood concentration. The trough concentration of the drug may also differ based on the type of liver transplant. This study was conducted to investigate differences in pharmacokinetics between transplant types and to determine tacrolimus population pharmacokinetic in liver transplant recipients in Saudi Arabia. Method: Patients on tacrolimus, as the main immunosuppressant, who underwent liver transplant throughout2012-2014 were retrospectively studied. Demographic characteristic, tacrolimus blood trough concentrations, liver, renal, biochemistry, and hematology lab results were all collected. The pharmacokinetic parameters were estimated assuming one compartment model. Results: Tacrolimus pharmacokinetic parameters were found to be as following; elimination rate constant () 0.094 ±  0.0123, apparent volume of distribution () 112.48±63.033 L/hr, elimination half-life () 7.46± 1.01 hr and apparent total body clearance () 10.27± 5.69 L/hr (mean ± SD). Statistically significant difference was found between living-donor and deceased-donor liver transplant with respect to apparent clearance and apparent volume of distribution. Living-donor liver transplant recipients have apparent volume of distribution of 97.39±47.00 L (mean ± SD) and an apparent clearance of 8.89±4.24L/hr (mean± SD). On the other hand, deceased-donor liver transplant has an apparent clearance of 12.97±7.09L/hr (mean ± SD) and an apparent volume of distribution of 142.17± 78.65 L (mean ± SD). Conclusions: Tacrolimus pharmacokinetics parameters were accurately determined in liver transplant recipients in Saudi Arabia. The results of the present study can be clinically used in the therapeutic drug monitoring of tacrolimus in the individualization of drug dosage and taking the appropriate clinical decisions to prevent allograft rejection.

Letters to the Editor

PEDIATRICS ◽  
1981 ◽  
Vol 68 (4) ◽  
pp. 602-603
Author(s):  
Charles H. Feldman ◽  
Vincent E. Hutchinson ◽  
Charles E. Pippenger ◽  
Thomas A. Blumenfeld ◽  
Bernard R. Feldman ◽  
...  
Keyword(s):  
Elimination Rate ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Apparent Volume ◽  
Systemic Circulation ◽  
Volume Of Distribution ◽  
Letters To The Editor ◽  
Correct Formula ◽  
Original Report ◽  
Apparent Volume Of Distribution

We appreciate the comments of Weinberger et al and Spino et al. The equation utilized in our original report to calculate the apparent volume of distribution (V) was in error, as it was based on determinations for drugs that exhibit monoexponential elimination following a single intravenous dose. The correct formula for oral dosing at steady state with a drug obeying one-compartment model kinetics is: V = F.X0/AUCτ. K, where F is the total fraction of dose reaching systemic circulation, X0, is the dose, AUCτ is the area under the curve during a dosing interval; K is the elimination rate constant.1

Relationship Between Dose and Apparent Volume of Distribution of Salicylate in Children

PEDIATRICS ◽  
1974 ◽  
Vol 54 (6) ◽  
pp. 713-717
Author(s):  
Gerhard Levy ◽  
Sumner J. Yaffe
Keyword(s):  
Salicylic Acid ◽  
Time Course ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
The Body ◽  
Method Of Calculation ◽  
Salicylate Concentration ◽  
Peritoneal Dialysis Fluid ◽  
Salicylate Intoxication ◽  
Apparent Volume Of Distribution

The apparent volume of distribution (Vd) of salicylate was determined in 11 children, 4 months to 16 years old, who had ingested from about 36 to over 340 mg of salicylic acid (mainly as aspirin) per kilogram of body weight. Vd was calculated from the amount of salicylate in the body at a given time (as determined by the amount of total salicylates excreted in the urine and, where applicable, removed in peritoneal dialysis fluid after that time) and the concentration of salicylate in the plasma at the same time. This method of calculation is ideal for the nonlinearly eliminated salicylic acid and does not require any assumptions with respect to the nature of the pharmacokinetic model for salicylate distribution. The Vd for salicylate in the children ranged from 162 to 345 ml/kg and was larger at the higher doses. Plots of salicylate concentration in plasma versus amount of drug in the body were usually linear for a given patient, showing that Vd remained relatively constant over the time course of elimination of the drug in the patients studied. This indicates that a given plasma salicylate concentration in children who have ingested large doses reflects a larger amount of salicylate in the body than the same plasma concentration in children who ingested smaller doses of the drug. These observations help to rationalize and emphasize the usefulness of the Done nomogram (which involves estimation of the theoretical zero time plasma salicylate concentration by back extrapolation) for assessing the severity of salicylate intoxication.

Pharmacokinetics and organ metabolism of carboxyamidated and glycine-extended gastrins in pigs

1996 ◽  
Vol 271 (1) ◽  
pp. G156-G163 ◽  
Author(s):  
C. P. Hansen ◽  
F. Stadil ◽  
L. Yucun ◽  
J. F. Rehfeld
Keyword(s):  
Clearance Rate ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Constant Rate Infusion ◽  
Constant Rate ◽  
Vascular Beds ◽  
Apparent Volume Of Distribution ◽  
Rate Infusion

The elimination of carboxyamidated gastrin-17 and its glycine-extended precursor was studied in anesthetized pigs during constant-rate infusion. Extraction of amidated gastrin-17 was recorded in the hindlimb (42%), kidney (40%), head (32%, P < 0.001), and the gut (13%, P < 0.01). Elimination was not recorded in the liver, lungs, or heart. Extraction of glycine-extended gastrin-17 was measured in the kidney (36%), hindlimb (31%, P < 0.001), head (26%), and the gut (16%, P < 0.01), but not in the liver or the lungs. Glycine-extended gastrin-17 was not processed to amidated gastrin during infusion. The half-life, metabolic clearance rate, and apparent volume of distribution for amidated gastrin-17 were 3.5 +/- 0.4 min, 15.5 +/- 1.1 ml.kg-1.min-1, and 76.5 +/- 9.9 ml/kg, respectively, and for glycine-extended gastrin-17 were 4.3 +/- 0.6 min, 17.4 +/- 0.9 ml.kg-1.min-1, and 104.7 +/- 11.9 ml/kg, respectively. We conclude that extraction of amidated and glycine-extended gastrin-17 varies in the vascular beds, with elimination mainly confined to nonorgan tissues and the kidneys.

scholarly journals Effects of Xuesaitong on the Pharmacokinetics of Losartan: An In Vivo UPLC-MS/MS Study

2019 ◽  
Vol 2019 ◽  
pp. 1-8
Author(s):  
Weina Ma ◽  
Lei Lv ◽  
Jungang Guo ◽  
Yongjun Meng ◽  
Yinghua Wang ◽  
...  
Keyword(s):  
Apparent Volume ◽  
Volume Of Distribution ◽  
Sprague Dawley ◽  
Oral Gavage ◽  
Sprague Dawley Rats ◽  
Liquid Chromatography Tandem Mass ◽  
Multiple Blood ◽  
Apparent Volume Of Distribution ◽  
Noncompartmental Model

The aim of this study was to examine whether Xuesaitong, a multiherbal formulation for coronary heart disease, alters the pharmacokinetics of losartan. Adult male Sprague Dawley rats randomly received losartan (10 mg/kg) or losartan plus Xuesaitong (10 mg/kg) through an oral gavage (n = 6). Multiple blood samples were obtained for up to 36 h to determine the concentrations of losartan and its active metabolite, EXP3174, through ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Pharmacokinetics were estimated using a noncompartmental model. The half-life (t1/2) of losartan was decreased by Xuesaitong (4.26 ± 1.51 vs. 6.35 ± 2.10 h; P<0.05). The apparent volume of distribution (Vd) of losartan was also decreased by the combination of losartan and Xuesaitong (4.41 ± 1.61 vs. 7.20 ± 2.41 mL; P<0.05). The time to maximum concentration (Tmax) of losartan was increased by Xuesaitong (1.06 ± 1.04 vs. 0.13 ± 0.05 h; P<0.05). Xuesaitong also decreased the t1/2 of EXP3174 (8.22 ± 1.41 vs. 6.29 ± 1.38 h; P<0.05). These results suggest that there is a complex interaction between losartan and Xuesaitong. In addition to enhanced elimination of losartan and EXP3174, Xuesaitong may also decrease the absorption rate and Vd of losartan.

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