scholarly journals Treatment of gastrointestinal cytomegalovirus infection with twice-daily foscarnet: a pilot study of safety, efficacy, and pharmacokinetics in patients with AIDS.

1997 ◽  
Vol 41 (6) ◽  
pp. 1226-1230 ◽  
Author(s):  
D T Dieterich ◽  
M A Poles ◽  
E A Lew ◽  
S Martin-Munley ◽  
J Johnson ◽  
...  
Keyword(s):  
Body Weight ◽  
Steady State ◽  
Gastrointestinal Disease ◽  
Elimination Rate ◽  
Volume Of Distribution ◽  
Open Label ◽  
Laboratory Observation ◽  
Patient Reports ◽  
Elimination Half ◽  
Days Of Therapy

Ten patients with AIDS and cytomegalovirus (CMV) gastrointestinal infection were included in an open-label study to evaluate the safety, efficacy, and pharmacokinetics of 90 mg of intravenous foscarnet/kg of body weight twice daily accompanied by (pre)hydration of 500 to 750 ml. Efficacy was documented endoscopically, while safety was evaluated clinically by patient reports and physical and laboratory observation. The pharmacokinetics of foscarnet was evaluated after the first dose and following approximately 20 days of therapy. Nine patients (90%) responded histopathologically, nine (90%) responded endoscopically, and nine (90%) responded symptomatically to foscarnet therapy. Adverse events resulted in discontinuance of medication in the case of one patient. The mean maximal concentration was 621 microM following the first dose and 687 microM at steady state (P = 0.11). The apparent elimination rate constant and elimination half-life were not different between dose 1 and steady state. There were no significant changes in foscarnet excretion or renal clearance between dose 1 and steady state. The steady-state volume of distribution was 23.4 liters following the first dose and 19.0 liters at steady state (P < 0.002). Twice-daily foscarnet appeared to be safe and efficacious in the treatment of CMV gastrointestinal disease in this study, resulting in endoscopic or histologic improvement in 9 of the 10 (90%) patients. Minor changes in clearance and volume of distribution noted at steady state compared to single-dose administration are readily explained by study design, known information about foscarnet pharmacokinetics, and changes in body weight and creatinine clearance in the patients.

scholarly journals A Pharmacokinetic Study of Amphotericin B Lipid Complex Injection (Abelcet) in Patients with Definite or Probable Systemic Fungal Infections

2000 ◽  
Vol 44 (10) ◽  
pp. 2900-2902 ◽  
Author(s):  
Adedayo Adedoyin ◽  
Christine E. Swenson ◽  
Lois E. Bolcsak ◽  
Andrzej Hellmann ◽  
Danuta Radowska ◽  
...  
Keyword(s):  
Body Weight ◽  
Steady State ◽  
Amphotericin B ◽  
Fungal Infections ◽  
Volume Of Distribution ◽  
Lipid Complex ◽  
Systemic Fungal Infection ◽  
Elimination Half ◽  
Amphotericin B Lipid Complex ◽  
Pharmacokinetic Evaluation

ABSTRACT This study describes a pharmacokinetic evaluation of amphotericin B (AMB) lipid complex injection (ABLC or Abelcet) in 17 patients with systemic fungal infection administered 5 mg/kg of body weight/day by infusion for 10 to 17 days. The results showed that AMB exhibited multiexponential disposition with high clearance, large volume of distribution at steady state, and long apparent elimination half-life but no evidence of accumulation in the blood after multiple daily doses. The results confirm previous observations and further reinforce the suggestion that ABLC may exist as a depot in the tissues from which free AMB is slowly released to limit exposure.

scholarly journals The Role of Pharmacokinetics in Anaesthesia: Application to Intravenous Infusions

1987 ◽  
Vol 15 (1) ◽  
pp. 7-14 ◽  
Author(s):  
D. R. Stanski
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Drug Dose ◽  
Metabolic Clearance ◽  
Drug Infusion ◽  
Fixed Rate ◽  
Elimination Half

Pharmacokinetic concepts describe the relationship between drug dose and resulting plasma concentration. A drug's pharmacokinetic profile can be described by distribution and elimination half-lives, initial volume of distribution, steady-state distribution volume, and metabolic and distributional clearance. After initiating a fixed rate of drug infusion, four to five terminal elimination half-lives are required to reach a steady state of constant plasma concentration. If a loading dose is given, a steady state can be achieved more rapidly. The most rapid method of achieving a constant plasma concentration involves using a variable rate of drug infusion that adjusts for the metabolic clearance and distribution of the drug. Computer-driven infusion pumps can be used to rapidly achieve, then maintain, constant plasma concentrations of a drug.

Rationality of Administered Gentamicin Dose in Cerebral Coma Patients Treated in an Intensive Care Unit

Medicina ◽  
2011 ◽  
Vol 47 (2) ◽  
pp. 10
Author(s):  
Tomas Janušonis ◽  
Romaldas Mačiulaitis ◽  
Audrius Sveikata ◽  
Rima Kregždytė ◽  
Keyword(s):  
Intensive Care Unit ◽  
Body Weight ◽  
Intensive Care ◽  
Serum Concentration ◽  
Inverse Correlation ◽  
Volume Of Distribution ◽  
Icu Patients ◽  
Elimination Half ◽  
Dose Infusion ◽  
Gentamicin Concentration

Gentamicin is still widely used in the treatment of patients in an intensive care unit (ICU). The efficacy of aminoglycosides correlates with the peak serum concentration (Cmax), and the toxicity with the minimum serum concentration (Cmin). The aim of this study was to determine Cmax and Cmin in serum of cerebral coma ICU patients when a dosage of gentamicin of 5 mg/kg body weight was administered once daily; to evaluate the rationality of mentioned dose; and to identify factors associated with these concentrations. Material and Methods. A total of 24 ICU patients suffering from cerebral coma were included into this analysis. A dosage of gentamicin of 5 mg/kg body weight was administered once a day. Gentamicin concentrations were tested twice after the first dose infusion (immediately and 5 hours after 1-hour infusion). Cmax, Cmin, volume of distribution (Vd), and elimination half-life (T1/2) were obtained. Results. The mean Cmax was 17.96 (SD, 4.31) μg/mL (range, 10.30–27.87 μg/mL). The desirable Cmax (≥20 μg/mL) was reached only in 6 patients (25%). Cmin was calculated using a special pharmacokinetic program “Kinetica.” Cmin of 0.5 μg/mL was not exceeded in any patient. A correlative analysis indicated a significant inverse direct correlation between Cmax and Vd and between Cmax and treatment duration in the ICU. An inverse correlation was observed between Cmin and T1/2, evaluation of coma according to the Glasgow coma scale, and creatinine clearance. Conclusions. A dosage of 5 mg/kg body weight once a day was not sufficient in cerebral coma ICU patients. This dose was not associated with the nephrotoxic effect of gentamicin (additional risk factors were absent). It is recommended to obtain gentamicin concentration at two time points following administration of the first dose (e.g., immediately after 1-hour infusion and 5 hours later), and using a special pharmacokinetic software, to calculate a necessary dose and interval of administration.

scholarly journals Phase I Study To Evaluate the Pharmacokinetics, Safety, and Tolerability of Two Dosing Regimens of Oral Fosfomycin Tromethamine in Healthy Adult Participants

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Eric Wenzler ◽  
Susan C. Bleasdale ◽  
Monica Sikka ◽  
Kristen L. Bunnell ◽  
Matthew Finnemeyer ◽  
...  
Keyword(s):  
Phase I ◽  
Healthy Adult ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Open Label ◽  
Time Curve ◽  
Elimination Half ◽  
Apparent Clearance ◽  
Dosing Regimens ◽  
Repeated Dosing

ABSTRACTThe pharmacokinetics (PK), safety, and tolerability of two repeated dosing regimens of oral fosfomycin tromethamine were evaluated in 18 healthy adult subjects. Subjects received 3 g every other day (QOD) for 3 doses and then every day (QD) for 7 doses, or vice versa, in a phase I, randomized, open-label, two-period-crossover study. Serial blood (n= 11) and urine (n= 4 collection intervals) samples were collected before and up to 24 h after dosing on days 1 and 5, along with predose concentrations on days 3 and 7. PK parameters were similar between days 1 and 5 within and between dosing regimens. The mean (± standard deviation [SD]) PK parameters for fosfomycin in plasma on day 5 during the respective QOD and QD dosing regimens were as follows: maximum concentration of drug in serum (Cmax) = 24.4 ± 6.2 versus 23.8 ± 5.6 μg/ml, time toCmax(Tmax) = 2.2 ± 0.7 versus 2.0 ± 0.4 h, apparent volume of distribution (V/F) = 141 ± 67.9 versus 147 ± 67.6 liters, apparent clearance (CL/F) = 21.4 ± 8.0 versus 20.4 ± 5.3 liters/h, renal clearance (CLR) = 7.5 ± 4.1 versus 7.3 ± 3.5 liters/h, area under the concentration-time curve from 0 to 24 h (AUC0–24) = 151.6 ± 35.6 versus 156.6 ± 42.5 μg · h/ml, and elimination half-life (t1/2) = 4.5 ± 1.1 versus 5.0 ± 1.7 h. Urine concentrations peaked at approximately 600 μg/ml through the 0- to 8-h urine collection intervals but displayed significant interindividual variability. Roughly 35 to 40% of the 3-g dose was excreted in the urine by 24 h postdose. No new safety concerns were identified during this study. The proportion of diarrhea-free days during the study was significantly lower with the QD regimen than with the QOD regimen (61% versus 77%;P< 0.0001). Further studies to establish the clinical benefit/risk ratio for repeated dosing regimens of oral fosfomycin tromethamine are warranted. (This trial is registered at ClinicalTrials.gov under registration no. NCT02570074.)

Steady-State Pharmacokinetics of Cefoperazone and Sulbactam in Patients with Acute Appendicitis

1994 ◽  
Vol 28 (6) ◽  
pp. 703-707
Author(s):  
Larry H. Danziger ◽  
Stephen C. Piscitelli ◽  
Donna J. Occhipinti ◽  
Daniel J. Resnick ◽  
Keith A. Rodvold
Keyword(s):  
Steady State ◽  
Acute Appendicitis ◽  
Dosage Reduction ◽  
Area Under The Curve ◽  
Compartment Model ◽  
Hepatic Function ◽  
Volume Of Distribution ◽  
Two Compartment Model ◽  
Elimination Half ◽  
G Prior

OBJECTIVE: To determine the steady-state pharmacokinetics of intravenously administered cefoperazone and sulbactam when given in combination to patients with acute appendicitis. METHODS: Six patients with normal renal and hepatic function received cefoperazone 2 g with sulbactam 1 g prior to appendectomy and then every 12 hours. Serial blood samples were collected after each patient received at least three doses of cefoperazone/sulbactam. RESULTS: Cefoperazone and sulbactam could be best described by a two-compartment model. Mean ± SD values for cefoperazone steady-state volume of distribution (Vssd), elimination half-life (t1/2β), clearance (Cl), and area under the curve (AUC0-t) were 19.8 ± 8.0 L, 3.97 ± 1.06 h, 62.6 ± 16.3 mL/min, and 556.9 ± 122.0 mg·h/L, respectively. Sulbactam Vssd, t1/2β, Cl, and AUC0-t were 34.7 ± 13.9 L, 1.39 ± 0.4 h, 288.6 ± 68.2 mL/min, and 64.8 ± 24.5 mg·h/L, respectively. CONCLUSIONS: Compared with data from healthy volunteers, cefoperazone exhibited a decreased Cl and increased Vssd and t1/2β in patients with acute appendicitis. An increased Vssd also was observed for sulbactam. The disposition of cefoperazone/sulbactam is altered in this group of patients; however, these changes are not likely to warrant a dosage reduction.

Doxorubicin clearance in the obese.

1988 ◽  
Vol 6 (8) ◽  
pp. 1321-1327 ◽  
Author(s):  
K A Rodvold ◽  
D A Rushing ◽  
D A Tewksbury
Keyword(s):  
Body Weight ◽  
Half Life ◽  
High Performance ◽  
Area Under The Curve ◽  
Ideal Body Weight ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Obese Patients ◽  
Elimination Half Life ◽  
Elimination Half

A study was carried out to examine the effect, if any, of obesity on doxorubicin pharmacokinetics. Body weight was found to be significantly related to doxorubicin clearance (r = -.75; P less than .001) and elimination half-life (r = .62; P = .003). Thus, the contribution of obesity on pharmacokinetics of antineoplastic agents should be taken into consideration in the analysis of clinical data with respect to toxicity and tumor response. Twenty-one patients were studied with their first course of doxorubicin (50 to 70 mg/m2) administered as a 60-minute intravenous (IV) infusion. Patients were divided into three groups on the basis of percentage of ideal body weight (IBW): normal (less than 115% IBW), mildly obese (115% to 130% IBW), and obese (greater than 130% IBW). Blood samples were collected up to 48 hours after the infusion and analyzed for doxorubicin and its metabolite, doxorubicinol, by high performance liquid chromatography. Doxorubicin area under the curve (AUC) was greater in obese than in normal patients (2,209 v 1,190 ng h/mL; P less than .05), yielding correspondingly reduced systemic clearance of the agent in obese patients (891 v 1,569 mL/min; P less than .001). The mean elimination half-life (T1/2) was 20.4 hours in the obese patients and 13.0 hours in the normal patients. The apparent volume of distribution (Vss) was not significantly different among the three groups of patients, indicating that the prolonged T1/2 in the obese patients is due to the reduction in clearance. The AUC and T1/2 of doxorubicinol were similar among all patient groups.

scholarly journals Integration of Pharmacokinetic and Pharmacodynamic Indices of Orbifloxacin in Beagle Dogs after a Single Intravenous and Intramuscular Administration

2009 ◽  
Vol 53 (7) ◽  
pp. 3024-3029 ◽  
Author(s):  
Elias Gebru ◽  
Joong-Su Lee ◽  
Zhi-Qiang Chang ◽  
Mi-Hyun Hwang ◽  
Henrique Cheng ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Body Weight ◽  
Steady State ◽  
Bacterial Infections ◽  
Volume Of Distribution ◽  
Absolute Bioavailability ◽  
Beagle Dogs ◽  
Staphylococcus Intermedius ◽  
Terminal Half Life

ABSTRACT The pharmacokinetics (PK) and pharmacodynamics (PD) of orbifloxacin were studied in beagle dogs after intravenous (i.v.) and intramuscular (i.m.) administration at a dose of 2.5 mg/kg body weight. An absolute bioavailability of 100.1% ± 4.76%, a terminal half-life of 4.23 ± 0.2 h and 3.95 ± 0.15 h after i.v. and i.m. administration, a steady-state volume of distribution of 1.61 ± 0.13 liters/kg, and clearance of 0.31 ± 0.03 liters/h/kg were observed. Orbifloxacin showed rapid, concentration-dependent killing against the Escherichia coli, Staphylococcus aureus, Staphylococcus intermedius, and Proteus mirabilis clinical isolates. Computations based on PK-PD analysis indicated that the recommended dose is unlikely to be clinically effective against some strains like S. intermedius. Therefore, a higher dose of orbifloxacin would be worthy of consideration for treatment of certain bacterial infections in dogs.

Dose-Ranging Pharmacokinetic Study of Ciprofloxacin after 200-, 300-, and 400-mg Intravenous Doses

1992 ◽  
Vol 26 (1) ◽  
pp. 8-10 ◽  
Author(s):  
David E. Nix ◽  
J. Michael Spivey ◽  
Allyn Norman ◽  
Jerome J. Schentag
Keyword(s):  
Steady State ◽  
Half Life ◽  
Total Body Clearance ◽  
Volume Of Distribution ◽  
Elimination Half Life ◽  
Elimination Half ◽  
The Mean ◽  
Total Body ◽  
Venous Irritation ◽  
Body Clearance

OBJECTIVE: To assess the pharmacokinetics and tolerance of ciprofloxacin after the administration of single intravenous doses of 200, 300, and 400 mg. DESIGN: Double-blind, three-period, randomized, crossover trial. SETTING: Private, university-affiliated, hospital-based, clinical research center. PATIENTS: Normal healthy male volunteers, 18–40 years of age. INTERVENTIONS: Subjects received 200-, 300-, and 400-mg single intravenous doses of ciprofloxacin via 30-minute infusions in random sequence. MAIN OUTCOME MEASURES: Serum ciprofloxacin concentrations were determined by HPLC after each dose and the results were used to derive pharmacokinetic parameters. Tolerance was assessed by reported and observed adverse events, urine microscopic examinations for crystals, and examination of intravenous infusion sites. RESULTS: The mean area under the time curve (AUC) values displayed linearity with respect to the administered dose. No statistical differences were observed in total body clearance, steady-state volume of distribution, or elimination half-life with respect to dose administered. The mean total body clearance, steady-state volume of distribution, or elimination half-life ranged from 36 to 41 L/h, 146 to 169 L, and 3.5 to 3.7 h for the 200-, 300-, and 400-mg doses, respectively. Adverse effects, including venous irritation (four subjects) and crystalluria (two subjects), were mild and did not require withdrawal of any subject from the study. CONCLUSIONS: Intravenous ciprofloxacin in doses ranging from 200 to 400 mg demonstrated linear pharmacokinetics. These single doses were well tolerated, although cases of transient venous irritation and crystalluria were observed.

scholarly journals A Large Impact of Obesity on the Disposition of Ivermectin, Moxidectin and Eprinomectin in a Canine Model: Relevance for COVID-19 Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Alain Bousquet-Mélou ◽  
Anne Lespine ◽  
Jean-François Sutra ◽  
Isabelle Bargues ◽  
Pierre-Louis Toutain
Keyword(s):  
Body Weight ◽  
Steady State ◽  
Obese Subject ◽  
Control Period ◽  
Total Body Weight ◽  
Canine Model ◽  
Volume Of Distribution ◽  
Lean Body Weight ◽  
Total Body

Ivermectin (IVM) and moxidectin (MOX) are used extensively as parasiticides in veterinary medicine. Based on in vitro data, IVM has recently been proposed for the prevention and treatment of COVID-19 infection, a condition for which obesity is a major risk factor. In patients, IVM dosage is based on total body weight and there are no recommendations to adjust dosage in obese patients. The objective of this study was to establish, in a canine model, the influence of obesity on the clearance and steady-state volume of distribution of IVM, MOX, and a third analog, eprinomectin (EPR). An experimental model of obesity in dogs was based on a high calorie diet. IVM, MOX, and EPR were administered intravenously, in combination, to a single group of dogs in two circumstances, during a control period and when body weight had been increased by 50%. In obese dogs, clearance, expressed in absolute values (L/day), was not modified for MOX but was reduced for IVM and EPR, compared to the initial control state. However, when scaled by body weight (L/day/kg), plasma clearance was reduced by 55, 42, and 63%, for IVM, MOX and EPR, respectively. In contrast, the steady-state volume of distribution was markedly increased, in absolute values (L), by obesity. For IVM and MOX, this obese dog model suggests that the maintenance doses in the obese subject should be based on lean body weight rather than total weight. On the other hand, the loading dose, when required, should be based on the total body weight of the obese subject.

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.

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