Successful Use of Higher-Than-Recommended Dosage of Imipenem in Pseudomonas Aeruginosa Endocarditis

1992 ◽  
Vol 26 (5) ◽  
pp. 639-641 ◽  
Author(s):  
Jeffrey H. King ◽  
Elizabeth J. Kailath ◽  
Daniel B. Hrdy
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Clinical Decision ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
High Dose ◽  
Serum Concentrations ◽  
Case Summary ◽  
Apparent Volume Of Distribution

OBJECTIVE: To report a case of Pseudomonas aeruginosa endocarditis that was successfully treated with high-dose imipenem/cilastatin and to discuss dosage modification based on individual pharmacokinetic parameters. DATA SOURCES: Clinical studies, review articles, and relevant laboratory and pharmacokinetic information. CASE SUMMARY: A 27-year-old man with right-sided P. aeruginosa endocarditis was successfully treated with long-term imipenem/cilastatin and tobramycin. The imipenem dose required to achieve therapeutic serum concentrations and cidal activity was 6 g/d. The manufacturer's recommended maximum dose is 4.0 g/d or 50 mg/kg/d. Because of the patient's large apparent volume of distribution, low serum imipenem concentrations, and lack of serum cidal activity, the clinical decision was made to increase the dose to 6 g/d or 54 mg/kg/d. Treatment was tolerated for seven weeks without any adverse effects. The patient remains free of symptoms 24 months after the diagnosis. CONCLUSIONS: Careful and discriminate use of larger-than-recommended doses of imipenem may be indicated in certain clinical situations. Dosage may need to be adjusted to body size in order to obtain optimal serum concentrations and activity.

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.

The Pharmacokinetics of Buserelin after Intramuscular Administration in Pigs and Cows

2021 ◽  
Author(s):  
Zhengrong Gao ◽  
Yu Liu ◽  
Yuxin Yang ◽  
Yuying Cao ◽  
Jicheng Qiu ◽  
...  
Keyword(s):  
Area Under The Curve ◽  
Apparent Volume ◽  
Ultra Performance Liquid Chromatography ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Elimination Half ◽  
Liquid Chromatography Tandem Mass ◽  
Stability Method ◽  
Apparent Volume Of Distribution

Abstract Background: Buserelin is a LHRH agonist used for the treatment of hormone-dependent diseases in males and females. However, the pharmacokinetics of buserelin in pigs and cows are not clearly understood. This study was designed to develop a sensitive method to determine the concentration of buserelin and to investigate the pharmacokinetic parameters after intramuscular (i.m.) administration in pigs and cows. Results: A sensitive and rapid stability method based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed. The pharmacokinetic parameters of buserelin after i.m. administration were studies in five pigs and five cows at a single dose of 1 mg per pig and 3 mg per cow. The plasma kinetics were analyzed by WinNonlin 8.1.0 software using a non-compartmental model. The mean concentration area under the curve (AUC0-t) was 25.02 ± 6.93 h·ng/mL for pigs and 5.63 ±1.86 h·ng/mL for cows. The maximum plasma concentration (Cmax) and time to reach the maximum concentration (tmax) were 10.99 ± 2.04 ng/mL and 0.57 ± 0.18 h for pigs and 2.68 ± 0.36 ng/mL and 1.05 ±0.27 h for cows, respectively. The apparent volume of distribution (Vz) in pigs and cows was 80.49 ± 43.88 L and 839.88 ± 174.77 L, respectively. The elimination half-time (t1/2λz), and clearance (CL) were 1.29 ± 0.40 h and 41.15 ± 11.18 L/h for pigs and 1.13 ± 0.3 h and 545.04 ± 166.40 L/h for cows, respectively. No adverse effects were observed in any of the animals. Conclusion: This study extends previous studies describing the pharmacokinetics of buserelin following i.m. administration in pigs and cows. Further studies investigating other factors were needed to establish therapeutic protocol in pigs and cows and to extrapolate these parameters to others economic animals.

scholarly journals Indinavir, Efavirenz, and Abacavir Pharmacokinetics in Human Immunodeficiency Virus-Infected Subjects

2003 ◽  
Vol 47 (6) ◽  
pp. 1929-1935 ◽  
Author(s):  
Robert DiCenzo ◽  
Alan Forrest ◽  
Kathleen E. Squires ◽  
Scott M. Hammer ◽  
Margaret A. Fischl ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Wild Type Virus ◽  
Pharmacokinetic Parameters ◽  
Minimum Concentration ◽  
Immunodeficiency Virus ◽  
Aids Clinical Trials ◽  
Apparent Volume Of Distribution ◽  
Median Maximum

ABSTRACT Adult AIDS Clinical Trials Group (AACTG) Protocol 886 examined the dispositions of indinavir, efavirenz, and abacavir in human immunodeficiency virus-infected subjects who received indinavir at 1,000 mg every 8 h (q8h) and efavirenz at 600 mg q24h or indinavir at 1,200 mg and efavirenz at 300 mg q12h with or without abacavir 300 at mg q12h. Thirty-six subjects participated. The median minimum concentration in plasma (C min) for indinavir administered at 1,200 mg q12h was 88.1 nM (interquartile range [IR], 61.7 to 116.5 nM), whereas the median C min for indinavir administered at 1,000 mg q8h was 139.3 nM (IR, 68.8 to 308.7 nM) (P = 0.19). Compared to the minimum C min range for wild-type virus (80 to 120 ng/ml) estimated by the AACTG Adult Pharmacology Committee, the C min for indinavir administered at 1,200 mg q12h (54 ng/ml) is inadequate. The apparent oral clearance (CL/F) (P = 0.28), apparent volume of distribution at steady state (V ss/F) (P = 0.25), and half-life (t 1/2) (P = 0.80) of indinavir did not differ between regimens. The levels of efavirenz exposure were similar between regimens. For efavirenz administered at 600 mg q24h and 300 mg q12h, the median maximum concentrations in plasma (C maxs) were 8,968 nM (IR, 5,784 to 11,768 nM) and 8,317 nM (6,587 to 10,239 nM), respectively (P = 0.66), and the C mins were 4,289 nM (IR, 2,462 to 5,904 nM) and 4,757 nM (IR, 3,088 to 6,644 nM), respectively (P = 0.29). Efavirenz pharmacokinetic parameters such as CL/F (P = 0.62), V ss/F (P = 0.33), and t 1/2 (P = 0.37) were similar regardless of the dosing regimen. The median C max, C min, CL/F, V ss/F, and t 1/2 for abacavir were 6,852 nM (IR, 5,702 to 7,532), 21.0 nM (IR, 21.0 to 87.5), 43.7 liters/h (IR, 37.9 to 55.2), 153.9 liters (IR, 79.6 to 164.4), and 2.0 h (IR, 1.8 to 2.8), respectively. In summary, when indinavir was given with efavirenz, the trough concentration of indinavir after administration of 1,200 mg q12h was inadequate. Abacavir did not influence the pharmacokinetics or exposure parameters of either indinavir or efavirenz. The levels of efavirenz exposure were similar in subjects receiving efavirenz q12h or q24h.

Estimation of Pharmacokinetic Parameters at Steady-State in Patients

1978 ◽  
Vol 12 (10) ◽  
pp. 612-616 ◽  
Author(s):  
James W. Crow ◽  
Milo Gibaldi
Keyword(s):  
Steady State ◽  
Rate Constant ◽  
Elimination Rate ◽  
Simulated Data ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Total Clearance ◽  
Dosing Intervals ◽  
Apparent Volume Of Distribution

A method to characterize the pharmacokinetics of a drug in a patient receiving it chronically is proposed. In principle, such characterization may be carried out by obtaining one or more drug concentration in plasma-time values from several different dosing intervals, combining the data to create a composite dosing interval representative of the steady-state situation and fitting the data to an appropriate equation. The method was evaluated using simulated data based on the average pharmacokinetic parameters of theophylline in children. Reasonable estimates of the elimination rate constant and apparent volume of distribution may be obtained, but the estimation of the absorption rate constant presents formidable problems. The method appears to be most useful for obtaining very accurate estimates of total clearance.

Safety of a Higher Loading Dose of Phenobarbital in the Term Newborn

PEDIATRICS ◽  
1985 ◽  
Vol 75 (6) ◽  
pp. 1061-1064 ◽  
Author(s):  
Steven M. Donn ◽  
Thaddeus H. Grasela ◽  
Gary W. Goldstein
Keyword(s):  
Newborn Infants ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Loading Dose ◽  
Cardiorespiratory Function ◽  
Term Newborns ◽  
The Mean ◽  
Spontaneously Breathing ◽  
Apparent Volume Of Distribution

The conventional loading dose of phenobarbital for newborn infants with hypoxic-ischemic seizures, 20 mg/kg, often fails to control convulsive activity. To determine the safety of a higher loading dose and to establish the pharmacokinetic parameters of a higher loading dose, ten severely asphyxiated term newborns were given 30 mg/kg of phenobarbital intravenously over 15 minutes. The mean serum concentration of phenobarbital two hours after loading was 30.0 ± 3.2 µg/mL, the apparent volume of distribution was 0.97 ± 0.18 L/kg, total clearance was 0.08 ± 0.03 mL/min/kg, and mean serum half-life was 148 ± 55 hours. The higher loading dose was not associated with any short-term adverse effects on cardiorespiratory function, even in spontaneously breathing infants.

Metabolism and acid secretory effect of sulfated and nonsulfated gastrin-6 in humans

2000 ◽  
Vol 279 (5) ◽  
pp. G903-G909 ◽  
Author(s):  
C. Palnæs Hansen ◽  
F. Stadil ◽  
J. F. Rehfeld
Keyword(s):  
Clearance Rate ◽  
Main Product ◽  
Acid Output ◽  
Normal Subjects ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Metabolic Clearance ◽  
Metabolic Clearance Rate ◽  
Apparent Volume Of Distribution

The antral hormone gastrin is synthesized by processing progastrin into different peptides that stimulate gastric secretion. The effect on acid secretion depends mainly on the metabolic clearance rate of the peptides, but some of them may differ in potency and maximum acid output at similar concentrations in plasma. Sulfated and nonsulfated gastrin-6 are the smallest circulating bioactive gastrins in humans. Their effect and metabolism have now been investigated in nine normal subjects and compared with nonsulfated gastrin-17, a main product of progastrin. Maximum acid output after stimulation with gastrin-17, sulfated gastrin-6, and nonsulfated gastrin-6 were 28.3 ± 2.0, 24.5 ± 2.0 ( P < 0.02), and 19.3 ± 2.3 ( P < 0.05) mmol H+/50 min, respectively, and the corresponding EC50values were 43 ± 6, 24 ± 2 ( P < 0.01), and 25 ± 2 (not significant) pmol/l. The half-life of gastrin-17 was 5.3 ± 0.3 min, the metabolic clearance rate (MCR) was 16.5 ± 1.3 ml · kg−1· min−1, and the apparent volume of distribution (Vd) was 124.3 ± 9.6 ml/kg. The half-lives of sulfated and nonsulfated gastrin-6 were 2.1 ± 0.3 and 1.9 ± 0.3 min, the MCRs were 42.8 ± 3.7 and 139.4 ± 9.6 ml kg−1min−1( P < 0.01), and the Vdwere 139.0 ± 30.5 and 392.0 ± 81.6 ( P < 0.01) ml kg−1. All pharmacokinetic parameters differed significantly from gastrin-17 ( P < 0.01). We conclude that gastrin 6 has a higher potency but a lower efficacy than gastrin-17. The efficacy of gastrin-6 is increased by tyrosine O-sulfation, which also enhances the protection against elimination.

Pharmacokinetics of Factor VII

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2259-2259
Author(s):  
Massimo Morfini ◽  
Uriel Martinowitz ◽  
Angelika Batorova ◽  
Alberto Dolce ◽  
Mariasanta Napolitano ◽  
...  
Keyword(s):  
Half Life ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Factor Vii ◽  
Clotting Factor ◽  
Pharmacokinetic Parameters ◽  
Compound Heterozygous ◽  
Clotting Factors ◽  
Fvii Deficiency ◽  
Apparent Volume Of Distribution

Abstract Abstract 2259 Introduction: In Congenital Bleeding Disorders (CBD), efficacy of Replacement Therapy (RT) can be indirectly measured on the basis of pharmacokinetic (PK) methods. Therapeutic concentrations of clotting factors in the blood-stream at a given time depend on the dose and frequency of RT and the fall off patterns specific for each clotting factor (i.e. PK properties). The issue of the frequency of RT administration is particularly relevant in Factor VII (FVII) deficiency, a CBD characterized by the lack of a rare protein with a very short half-life. Recombinant FVIIa (rFVIIa), plasma-derived FVII (pdFVII) concentrates and Fresh Frozen Plasma (FFP) are used for on-demand or prophylaxis replacement despite reported half-lives in the range of 2–5 hours. Very limited information is available with reference to the pharmacokinetic parameters of infused FVII in FVII deficiency. The same holds for the In Vivo Recovery (IVR). In this study, we evaluated the PK of rFVIIa in 11 severe (FVIIc <2%) FVII deficient patients. Further, evaluation of “incremental” IVR was performed in 116 patients with a FVII deficiency (90 for rFVIIa, 19 for pdFVII concentrates and 7 for FFP). Methods & Results: Eleven severe FVII-deficient individuals in the non-bleeding state were given rFVIIa doses ranging from 16 to 24 μg/Kg/bw (mean 19.7, median 20). Pharmacokinetic parameters of rFVIIa were analyzed with reference to FVIIc post-infusion levels. Analyses of the PK parameters are detailed in Tab. 1. In Tab. 2 results regarding the IVR analyses of rFVIIa, pdFVII and FFP are reported, on the basis of FVIIc 15' after replacement. IVR data were also evaluated with reference to the baseline FVIIc, age and FVII mutation zygosity. Conclusions: PK data are characterized by an optimal correspondence between FVIIc levels and time; data variability is ample considering that all individuals were adults or teen-agers. Terminal half-life appeared longer than the Mean Residence Time (MRT) or T1/2, a data that can be interpreted as a reduction of the factor flow from the plasma pool to the extravascular space at the end of the fall off curve; this is confirmed by the Apparent volume of distribution based on the terminal phase (Vz) that is higher than the Apparent Volume of distribution at equilibrium (Vss). MRT and T1/2 are in keeping with previous studies and appear lower than those already reported for the pdFVII concentrates. Quite variable is also the Clearance (CL) showing that metabolic degradation and/or FVIIa vascular uptake greatly differ among patients. The latter aspect points towards the need for a CL individualized evaluation for patients who are eligible for continuous infusion protocols. Incremental IVRs of rFVIIa and FFP were lower (p< 0.001) than those calculated for the pdFVII concentrates. The difference between the recoveries of rFVIIa and pdFVII can either be ascribed to the FVIIc assay (only FVIIa assayed in the case of rFVIIa administration, FVII zymogen and FVIIa assayed in the case of pdFVII concentrates), to a more rapid disappearance rate of FVIIa from the vascular compartment or, finally, to a more rapid uptake by the FVIIa receptors (TF on the pericytes and the PC receptor on the endothelial cells). No difference was found between IVRs in children and adults nor between individuals with baseline FVIIc <2% or ≥ 2%. Also, no differences were found between patients homozygous or compound heterozygous for FVII gene lesions. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Changes in Vancomycin Pharmacokinetics in Critically Ill Infants

1995 ◽  
Vol 23 (6) ◽  
pp. 678-682 ◽  
Author(s):  
A. G. S. Gous ◽  
M. D. Dance ◽  
J. Lipman ◽  
D. K. Luyt ◽  
R. Mathivha ◽  
...  
Keyword(s):  
Critically Ill ◽  
Serum Levels ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Serum Concentrations ◽  
Serum Samples ◽  
Routine Monitoring ◽  
Elimination Half ◽  
Change In Mean

We aimed to assess the pharmacokinetics of vancomycin in critically ill infants, and to evaluate the standard recommended dose of 10 mg/kg 6 hourly. All infants admitted to the Baragwanath Hospital ICU who had arterial lines in situ, and for whom vancomycin 10 mg/kg 6 hourly was prescribed for an infective insult and who had parental consent, were included in the study. Vancomycin was infused over 60 minutes. Serum samples were taken immediately before the dose and at 30, 60, 120 and 300 minutes after the end of the vancomycin infusion, on days 2 and 8 of therapy. Extrapolated peak concentration (Cmax), trough concentration (Cmin), apparent volume of distribution (Vd), elimination half-life (t½el) and clearance (CL) were determined for each patient. Day 2 values were compared with those of day 8. Day 2 serum concentrations were assayed on 20 patients and day 8 concentrations in 15. The mean vancomycin Vd on day 2 (0.81 l/kg) was significantly (P=0.007) larger than that on day 8 (0.44 l/kg). The change in Vd resulted in a significant change in mean Cmax (29.1 vs 35.5 μg/ml) (P=0.02) and mean t½el (5.3 vs 3.4h) (P=0.01) over the treatment period. Critically ill infants displayed a large initial volume of distribution which probably resulted from aggressive fluid resuscitation. This also results in a large variation in other pharmacokinetic parameters, namely Cmax and t½el. Although the routine monitoring of vancomycin serum concentrations remain controversial, we feel that in view of these large pharmacokinetic variations, the critically ill infant is a specific group where monitoring of vancomycin serum levels is indicated.

scholarly journals Pharmacokinetics of (-)-2'-3'-dideoxy-3'-thiacytidine in woodchucks.

1996 ◽  
Vol 40 (3) ◽  
pp. 642-645 ◽  
Author(s):  
P Rajagopalan ◽  
F D Boudinot ◽  
C K Chu ◽  
B C Tennant ◽  
B H Baldwin ◽  
...  
Keyword(s):  
Animal Model ◽  
Body Weight ◽  
Steady State ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Nucleoside Analog ◽  
Pharmacokinetic Parameters ◽  
Allometric Relationships ◽  
Intravenous And Oral Administration ◽  
Apparent Volume Of Distribution

The woodchuck (Marmota monax) has proven to be a suitable animal model for studying hepatitis B virus (HBV) infection owing to similarities in the course of infection between woodchuck hepatitis virus (WHV) in woodchucks and HBV in humans. (-)-beta-L-2',3'-Dideoxy-3'-thiacytidine (3TC; lamivudine) is a nucleoside analog which has demonstrated antiviral activity against HBV as well as human immunodeficiency virus (HIV). The purpose of the present investigation was to characterize the pharmacokinetics of 3TC following intravenous and oral administration of 20 mg of 3TC per kg of body weight to woodchucks. Following intravenous administration, the concentrations of 3TC in plasma declined, with a terminal half-life of 2.84 +/- 0.85 h (mean +/- standard deviation). The systemic clearance and steady-state volume of distribution of 3TC were 0.22 +/- 0.078 liters/h/kg and 0.75 +/- 0.13 liters/kg, respectively. The renal clearance of the nucleoside analog was 0.063 +/- 0.016 liters/h/kg. The oral bioavailability of 3TC ranged from 18 to 54%. Allometric relationships between pharmacokinetic parameters and body weight developed by Hussey et al. (E.K. Hussey, K.H. Donn, M.J. Daniel, S.T. Hall, A.J. Harker, and G.L. Evans, J. Clin. Pharmacol. 34:975-977, 1994) were augmented by including data from woodchucks, monkeys (S.M. Blaney, M.J. Daniel, A.J. Harker, K. Godwin, and F.M. Balis, Antimicrob. Agents Chemother. 39:2779-2782, 1995), and additional data from rats (P. Rajagopalan, L. Moore, C.K. Chu, R.F. Schinazi, and F.D. Boudinot, submitted for publication). Interspecies scaling of the pharmacokinetic parameters of 3TC demonstrated a good correlation between clearance (0.74 . W0.76 [where W is body weight]; r = 0.93; P < 0.025), apparent volume of distribution (1.62 . W0.81; r = 0.98; P < 0.005), and steady-state volume of distribution (1.09 . W0.94; r = 0.99; P < 0.05) and species body weight. The allometric relationships for clearance and volume of distribution at steady state predicted the observed pharmacokinetic parameters in humans quite well; however, the apparent volume of distribution was underestimated in humans. Thus, the pharmacokinetic data obtained with the woodchuck HBV animal model should be useful for designing clinical trials.

Direct Determination of Tobramycin Clearance in Patients with Mild-to-Moderate Cystic Fibrosis

1987 ◽  
Vol 21 (7-8) ◽  
pp. 639-641 ◽  
Author(s):  
Carl W. Kildoo ◽  
Arthur F. Harralson ◽  
Hugo L. Folli ◽  
P. Colin Kelly ◽  
Eliezer Nussbaum
Keyword(s):  
Cystic Fibrosis ◽  
Serum Concentration ◽  
Direct Determination ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Concentration Data ◽  
Altered Pharmacokinetic ◽  
Apparent Volume Of Distribution

Studies performed in patients with cystic fibrosis (CF) have suggested altered pharmacokinetic parameters for aminoglycosides. Specifically, increased plasma clearance (CI) of aminoglycosides and increased apparent volume of distribution have been noted. In the present study, tobramycin CI is determined by both serum concentration data and direct renal clearance (Clren). Tobramycin Clren appeared to be directly correlated to the measured creatinine clearance (Clcr) (r = 0.93, p <0.01 ). The tobramycin Cl, by both methods of determination, was not elevated in comparison to the Clcr or expected values for patients without the disease. These results appear to corroborate a recent study in which the renal and plasma Cl of gentamicin was measured in patients with mild-to-moderate CF and were not noted to be elevated. It is suggested that standard doses of tobramycin be used initially in patients with mild-to-moderate CF with dosage adjustment based on serum concentration data to achieve the desired goals.

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