scholarly journals Population Pharmacokinetics of Linezolid in Adults with Pulmonary Tuberculosis

2009 ◽  
Vol 53 (9) ◽  
pp. 3981-3984 ◽  
Author(s):  
Bryan McGee ◽  
Reynaldo Dietze ◽  
David Jamil Hadad ◽  
Lucilia Pereira Dutra Molino ◽  
Ethel Leonor Noia Maciel ◽  
...  
Keyword(s):  
Pulmonary Tuberculosis ◽  
Rate Constant ◽  
Population Model ◽  
Absorption Rate ◽  
Elimination Rate ◽  
Volume Of Distribution ◽  
Free Drug ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time

ABSTRACT Nineteen adults with pulmonary tuberculosis received linezolid (600 mg) once or twice daily in an early bactericidal activity trial. A one-compartment population model produced median values for the absorption rate constant, volume of distribution, and elimination rate constant of 1.5 h−1, 29.6 liters, and 0.25 h−1 (once daily) and 2.7 h−1, 32.1 liters, and 0.15 h−1 (twice daily). Linezolid administered twice daily produced higher values for free drug area under the concentration-time curve (AUC)/MIC and time above MIC. Both regimens achieved free AUC/MIC ratios > 100. Median times above the MIC for free drug were 100% (twice daily) and 63% (once daily).

Limited Sampling Strategies to Estimate the Area under the Concentration-time Curve

2012 ◽  
Vol 51 (05) ◽  
pp. 383-394 ◽  
Author(s):  
M. Fukumoto ◽  
L. Bax ◽  
A. Kohno ◽  
Y. Morishita ◽  
H. Tsuruta
Keyword(s):  
Rate Constant ◽  
Elimination Rate ◽  
Estimation Method ◽  
Pharmacokinetic Parameters ◽  
Good Precision ◽  
Sampling Strategies ◽  
Time Curve ◽  
New Methods ◽  
Limited Sampling ◽  
Concentration Time

SummaryBackground: Over 100 limited sampling strategies (LSSs) have been proposed to reduce the number of blood samples necessary to estimate the area under the concentration-time curve (AUC). The conditions under which these strategies succeed or fail remain to be clarified.Objectives: We investigated the accuracy of existing LSSs both theoretically and numerically by Monte Carlo simulation. We also proposed two new methods for more accurate AUC estimations.Methods: We evaluated the following existing methods theoretically: i) nonlinear curve fitting algorithm (NLF), ii) the trapezium rule with exponential curve approximation (TZE), and iii) multiple linear regression (MLR). Taking busulfan (BU) as a test drug, we generated a set of theoretical concentration-time curves based on the identified distribution of pharmacokinetic parameters of BU and re-evaluated the existing LSSs using these virtual validation profiles. Based on the evaluation results, we improved the TZE so that unrealistic parameter values were not used. We also proposed a new estimation method in which the most likely curve was selected from a set of pre-generated theoretical concentration-time curves.Results: Our evaluation, based on clinical profiles and a virtual validation set, revealed: i) NLF sometimes overestimated the absorption rate constant Ka, ii) TZE overestimated AUC over 280% when Ka is small, and iii) MLR underestimated AUC over 30% when the elimination rate constant Ke is small. These results were consistent with our mathematical evaluations for these methods. In contrast, our two new methods had little bias and good precision.Conclusions: Our investigation revealed that existing LSSs induce different but specific biases in the estimation of AUC. Our two new LSSs, a modified TZE and one using model concentration-time curves, provided accurate and precise estimations of AUC.

scholarly journals Pharmacokinetics of Tedizolid in Adults with Cystic Fibrosis

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S293-S293
Author(s):  
Joshua Wang ◽  
Jenny Park ◽  
Jordanna Jayne ◽  
Timothy Bensman ◽  
David D’Argenio ◽  
...  
Keyword(s):  
Rate Constant ◽  
Clinical Care ◽  
Elimination Rate ◽  
Study Drug ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Lung Function Decline ◽  
Once Daily ◽  
Linear Trapezoidal Rule ◽  
Laboratory Changes

Abstract Background The presence of MRSA in the airways of patients with CF is associated with more rapid lung function decline and a higher mortality. Tedizolid (TDZ) is an oxazolidinone antibiotic with potent activity against MRSA; however, the pharmacokinetics (PK) in CF have not been described. The purpose of this study was to determine the PK of IV/PO tedizolid in plasma in patients being treated for acute pulmonary exacerbations. Methods We conducted a prospective, multiple dose, randomized, crossover study. TDZ phosphate was administered as 200 mg IV over 1h or PO once daily x 3 under fed conditions, with a 2-day washout, followed by crossover. Laboratory studies were performed throughout the study as routine clinical care. Blood samples were obtained prior to the Third dose of IV and PO and at 8 additional timepoints over 48 hours. TDZ concentrations in plasma were determined by LC-MS/MS. The maximum concentration (Cmax) and time to maximum (Tmax) were obtained from the measured data. Area-under-the concentration curve (AUC24) was determined using the linear trapezoidal rule. Compartmental PK was performed using ADAPT 5 software. Data are described by mean ± SD. Results The patients (4M, 2F) had a mean age of 27 years (22–32), BMI 22.0 ± 4.2 kg/m2, and predicted creatinine clearance of 128 ± 44 mL/minute. There was one report of diarrhea and hoarseness of voice that was unlikely related to the study drug. There were no clinically relevant laboratory changes. The Cmax, Tmax, and AUC24 following IV and PO administration were 2.87 ± 0.64 mg/L / 2.26 ± 0.70 mg/L, 1.32 ± 0.49 hours /2.06 ± 1.29 hours, and 27.1 ± 4.74 mg/L x hours / 25.8 ± 6.03 mg/L x hours respectively. The PK parameters for TDZ were described by a 1-compartment model: Elimination rate constant (Kel) = 0.088 ± 0.014 hour-1, Volume of distribution (V) = 96.4 ± 27.4 L, absorption rate constant (Ka) = 0.869 ± 0.978 hours−1, and bioavailability (F) = 1.00 ± 0.101. Conclusion The oral bioavailability of TDZ in patients with CF is complete and the pharmacokinetics are similar to that reported for healthy volunteers indicating no dose adjustments are needed in future studies evaluating the efficacy and safety in patients with CF. Disclosures All authors: No reported disclosures.

scholarly journals Pharmacokinetic-Pharmacodynamic Modeling of Unboosted Atazanavir in a Cohort of Stable HIV-Infected Patients

2012 ◽  
Vol 57 (1) ◽  
pp. 517-523 ◽  
Author(s):  
Sylvain Goutelle ◽  
Thomas Baudry ◽  
Marie-Claude Gagnieu ◽  
André Boibieux ◽  
Jean-Michel Livrozet ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Rate Constant ◽  
Virological Failure ◽  
Absorption Rate ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Pharmacodynamic Modeling ◽  
Absorption Rate Constant ◽  
Time Curve ◽  
The Relationship

ABSTRACTLimited data on the pharmacokinetics and pharmacodynamics (PK/PD) of unboosted atazanavir (uATV) in treatment-experienced patients are available. The aim of this work was to study the PK/PD of unboosted atazanavir in a cohort of HIV-infected patients. Data were available for 58 HIV-infected patients (69 uATV-based regimens). Atazanavir concentrations were analyzed by using a population approach, and the relationship between atazanavir PK and clinical outcome was examined using logistic regression. The final PK model was a linear one-compartment model with a mixture absorption model to account for two subgroups of absorbers. The mean (interindividual variability) of population PK parameters were as follows: clearance, 13.4 liters/h (40.7%), volume of distribution, 71.1 liters (29.7%), and fraction of regular absorbers, 0.49. Seven subjects experienced virological failure after switch to uATV. All of them were identified as low absorbers in the PK modeling. The absorption rate constant (0.38 ± 0.20 versus 0.75 ± 0.28 h−1;P= 0.002) and ATV exposure (area under the concentration-time curve from 0 to 24 h [AUC0–24], 10.3 ± 2.1 versus 22.4 ± 11.2 mg · h · liter−1;P= 0.001) were significantly lower in patients with virological failure than in patients without failure. In the logistic regression analysis, both the absorption rate constant and ATV trough concentration significantly influenced the probability of virological failure. A significant relationship between ATV pharmacokinetics and virological response was observed in a cohort of HIV patients who were administered unboosted atazanavir. This study also suggests that twice-daily administration of uATV may optimize drug therapy.

scholarly journals Designing Fluoroquinolone Breakpoints for Streptococcus pneumoniae by Using Genetics instead of Pharmacokinetics-Pharmacodynamics

2004 ◽  
Vol 48 (9) ◽  
pp. 3630-3635 ◽  
Author(s):  
H. J. Smith ◽  
A. M. Noreddin ◽  
C. G. Siemens ◽  
K. N. Schurek ◽  
J. Greisman ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Streptococcus Pneumoniae ◽  
Monte Carlo Simulations ◽  
Free Drug ◽  
Target Attainment ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Bacteriological Eradication ◽  
High Level

ABSTRACT We determined fluoroquinolone microbiological resistance breakpoints for Streptococcus pneumoniae by using genetic instead of pharmacokinetic-pharmacodynamic parameters. The proposed microbiological breakpoints define resistance as the MIC at which >50% of the isolates carry quinolone resistance-determining region mutations and/or, if data are available, when Monte Carlo simulations demonstrate a <90% chance of bacteriological eradication. The proposed microbiological resistant breakpoints are as follows (in micrograms per milliliter): gatifloxacin, >0.25; gemifloxacin, >0.03; levofloxacin, >1; and moxifloxacin, >0.12. Monte Carlo simulations of the once daily 400-mg doses of gatifloxacin and 750-mg doses levofloxacin demonstrated a high level of target attainment (free-drug area under the concentration-time curve from 0 to 24 h/MIC ratio of 30) by using these new genetically derived breakpoints.

scholarly journals Ginsenoside Absorption Rate and Extent Enhancement of Black Ginseng (CJ EnerG) over Red Ginseng in Healthy Adults

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 487
Author(s):  
Saebyul Yoo ◽  
Bom-I Park ◽  
Do-hyun Kim ◽  
Sooyoung Lee ◽  
Seung-hoon Lee ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Molecular Weight ◽  
Absorption Rate ◽  
Systemic Exposure ◽  
Red Ginseng ◽  
Double Blind ◽  
Time Curve ◽  
Concentration Time ◽  
Black Ginseng ◽  
Clinically Significant

Red ginseng (RG) and black ginseng (BG, CJ EnerG) were prepared from fresh ginseng using one and nine cycles of steaming and drying, respectively. This process reduces the molecular weight (MW) of ginsenoside-active compounds in ginseng by removing sugar moieties from their dammaranes. We compared the pharmacokinetic characteristics of ginsenosides between BG comprising mainly low-MW ginsenosides (Rg3, Rg5, Rk1, and Rh1) and RG that predominantly contains high-MW ginsenosides (Rb1, Rb2, Rc, Rd, Re, and Rg1). The safety profiles and tolerability were also studied using a randomized, double-blind, single-dose, crossover clinical trial. A combination of Rb1, Rg1, and Rg3, well-known representative and functional RG components, exhibited a 1-h faster absorption rate (Tmax) and 58% higher exposure (24-h area under the concentration–time curve, AUC24) in BG than in RG. Furthermore, the combination of Rg3, Rg5, and Rk1, the major and most efficient components in BG, displayed 824% higher absorption (AUC24) in BG than in RG. The total ginsenoside showed a 5-h rapid intestinal absorption (Tmax) and 79% greater systemic exposure (AUC24) in BG than in RG. No clinically significant findings were observed in terms of safety or tolerability. Thus, BG extract was more effective than RG extract.

scholarly journals Praziquantel in a Clay Nanoformulation Shows More Bioavailability and Higher Efficacy against Murine Schistosoma mansoni Infection

2015 ◽  
Vol 59 (6) ◽  
pp. 3501-3508 ◽  
Author(s):  
Gina S. El-Feky ◽  
Wael S. Mohamed ◽  
Hanaa E. Nasr ◽  
Naglaa M. El-Lakkany ◽  
Sayed H. Seif el-Din ◽  
...  
Keyword(s):  
Schistosoma Mansoni ◽  
Rate Constant ◽  
Elimination Rate ◽  
New Drugs ◽  
Egg Load ◽  
Potential Cost ◽  
Time Curve ◽  
Content Type ◽  
Mmt Clay

ABSTRACTConsideration of existing compounds always simplifies and shortens the long and difficult process of discovering new drugs specifically for diseases of developing countries, an approach that may add to the significant potential cost savings. This study focused on improving the biological characteristics of the already-existing antischistosomal praziquantel (PZQ) by incorporating it into montmorillonite (MMT) clay as a delivery carrier to overcome its known bioavailability drawbacks. The oral bioavailability of a PZQ-MMT clay nanoformulation and itsin vivoefficacy againstSchistosoma mansoniwere investigated. The PZQ-MMT clay nanoformulation provided a preparation with a controlled release rate, a decrease in crystallinity, and an appreciable reduction in particle size. Uninfected and infected mice treated with PZQ-MMT clay showed 3.61- and 1.96-fold and 2.16- and 1.94-fold increases, respectively, in area under the concentration-time curve from 0 to 8 h (AUC0–8) and maximum concentration of drug in serum (Cmax), with a decrease in elimination rate constant (kel) by 2.84- and 1.35-fold and increases in the absorption rate constant (ka) and half-life (t1/2e) by 2.11- and 1.51-fold and 2.86- and 1.34-fold, respectively, versus the corresponding conventional PZQ-treated groups. This improved bioavailability has been expressed in higher efficacy of the drug, where the dose necessary to kill 50% of the worms was reduced by >3-fold (PZQ 50% effective dose [ED50] was 20.25 mg/kg of body weight for PZQ-MMT clay compared to 74.07 mg/kg for conventional PZQ), with significant reduction in total tissue egg load and increase in total immature, mature, and dead eggs in most of the drug-treated groups. This formulation showed better bioavailability, enhanced antischistosomal efficacy, and a safer profile despite the longer period of residence in the systemic circulation. Although the conventional drug's toxicity was not examined, animal mortality rates were not different between groups receiving the test PZQ-clay nanoformulation and conventional PZQ.

scholarly journals Pharmacokinetics of human chorionic gonadotropin after i.m. administration in goats (Capra hircus)

Reproduction ◽  
2012 ◽  
Vol 144 (1) ◽  
pp. 77-81 ◽  
Author(s):  
M Saleh ◽  
M Shahin ◽  
W Wuttke ◽  
M Gauly ◽  
W Holtz
Keyword(s):  
Rate Constant ◽  
Chorionic Gonadotropin ◽  
Human Chorionic Gonadotropin ◽  
Half Life ◽  
Absorption Rate ◽  
Elimination Rate ◽  
Elimination Rate Constant ◽  
Capra Hircus ◽  
Absorption Rate Constant ◽  
Biological Half Life

The present investigation addresses the pharmacokinetics of human chorionic gonadotropin (hCG), intramuscularly (i.m.) administered to goats. Nine pluriparous does of the Boer goat breed, 2–6 years of age and weighing 45–60 kg, were administered 500 IU hCG (2 ml Chorulon) deep into the thigh musculature 18 h after superovulatory FSH treatment. Blood samples were drawn from the jugular vein at 2 h intervals for the first 24 h, at 6 h intervals until 42 h, and at 12 h intervals until 114 h after administration. After centrifugation, plasma hCG concentrations were determined by electrochemiluminescence immunoassay. Pharmacokinetical parameters were as follows: lag time, 0.4 (s.e.m. 0.1) h; absorption rate constant, 0.34 (s.e.m. 0.002) h; absorption half-life, 2.7 (s.e.m. 0.5) h; elimination rate constant, 0.02 (s.e.m. 0.002) h; biological half-life, 39.4 (s.e.m. 5.1) h; and apparent volume of distribution, 16.9 (s.e.m. 4.3) l. The plasma hCG profile was characterized by an absorption phase of 11.6 (s.e.m. 1.8) h and an elimination phase of 70.0 (s.e.m. 9.8) h, with considerable individual variation in bioavailability and pharmacokinetical parameters. Biological half-life was negatively correlated (P<0.05) with peak concentration (r=−0.76), absorption rate constant (r=−0.78), and elimination rate constant (r=−0.87). The results indicate that after rapid absorption, hCG remains in the circulation for an extended period. This has to be taken into account when assessing the stimulatory response to hCG treatment on an ovarian level.

scholarly journals Fosamprenavir plus Ritonavir Increases Plasma Ketoconazole and Ritonavir Exposure, while Amprenavir Exposure Remains Unchanged

2007 ◽  
Vol 51 (8) ◽  
pp. 2982-2984 ◽  
Author(s):  
Mary B. Wire ◽  
Charles H. Ballow ◽  
Julie Borland ◽  
Mark J. Shelton ◽  
Yu Lou ◽  
...  
Keyword(s):  
Steady State ◽  
Healthy Subjects ◽  
Open Label ◽  
Time Curve ◽  
Once Daily ◽  
Open Label Study ◽  
Label Study ◽  
Concentration Time

ABSTRACT Plasma ketoconazole (KETO), amprenavir (APV), and ritonavir (RTV) pharmacokinetics were evaluated in 15 healthy subjects after being treated with KETO at 200 mg once daily (QD), fosamprenavir (FPV)/RTV at 700/100 mg twice daily (BID), and then KETO at 200 mg QD plus FPV/RTV at 700/100 mg BID in this open-label study. The KETO area under the concentration-time curve at steady state was increased 2.69-fold with FPV/RTV. APV exposure was unchanged, and RTV exposure was slightly increased.

scholarly journals Multidose Pharmacokinetics of Ritonavir and Zidovudine in Human Immunodeficiency Virus-Infected Patients

1998 ◽  
Vol 42 (7) ◽  
pp. 1788-1793 ◽  
Author(s):  
Allen Cato ◽  
Jiang Qian ◽  
Ann Hsu ◽  
Benjamin Levy ◽  
John Leonard ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Adverse Event ◽  
Dosage Adjustment ◽  
Elimination Rate ◽  
Time Curve ◽  
Safety And Efficacy ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
Asymptomatic Human Immunodeficiency Virus

ABSTRACT The effect of coadministration of ritonavir and zidovudine (ZDV) on the pharmacokinetics of these drugs was investigated in a three-period, multidose, crossover study. Eighteen asymptomatic, human immunodeficiency virus-positive men were assigned randomly to six different sequences of the following three regimens: ZDV (200 mg every 8 h [q8h]) alone for 4 days, ritonavir (300 mg q6h) alone for 4 days, and ZDV with ritonavir for 4 days. Ritonavir pharmacokinetics were unaffected by coadministration with ZDV. However, ZDV exposure was reduced by about 26% (P < 0.05) in the presence of ritonavir. The maximum concentration in (C max) of ZDV plasma decreased from 748 ± 375 (mean ± standard deviation) to 546 ± 296, and area under the concentration-time curve from 0 to 24 h (AUC0–24) decreased from 3,052 ± 1,007 to 2,261 ± 715 when coadministered with ritonavir. In contrast, the ZDV elimination rate constant was unaffected by ritonavir, suggesting that there was no change in ZDV systemic metabolism. Correspondingly, differences in ZDV-glucuronide C max and AUC were not statistically significantly different between regimens (P > 0.31). Also, there were no apparent differences in the formation of 3′-amino-3′-deoxythymidine or in the adverse event profiles between the regimens. The lack of change in ritonavir pharmacokinetics suggests that dosage adjustment of ritonavir is unnecessary when it is administered concurrently with ZDV. The clinical relevance of a 26% reduction in ZDV exposure when ZDV is administered with ritonavir is unknown. In addition to other multidrug regimens, the long-term safety and efficacy of coadministration of ritonavir and ZDV is being investigated.

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