Phase I Clinical and Pharmacologic Trial of Intravenous Estramustine Phosphate

2002 ◽  
Vol 20 (4) ◽  
pp. 1115-1127 ◽  
Author(s):  
Gary Hudes ◽  
Naomi Haas ◽  
Gwen Yeslow ◽  
Thomas Gillon ◽  
Per Olov Gunnarsson ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
High Dose ◽  
Weekly Dose ◽  
Estramustine Phosphate ◽  
Active Metabolites ◽  
Elimination Half

PURPOSE: To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of intravenous estramustine phosphate (IV EMP). PATIENTS AND METHODS: A total of 31 patients with hormone-refractory prostate cancer received IV EMP as a 30- to 90-minute infusion weekly (n = 28) or for 3 consecutive days followed by a single weekly dose (n = 3). IV EMP dose was escalated from 500 to 3,000 mg/m2. Pharmacokinetics of EMP and the metabolites estramustine (EaM), estromustine (EoM), estradiol, and estrone were assessed after weeks 1 and 4 of treatment. RESULTS: The initial IV EMP infusion caused perineal discomfort that was ameliorated by lengthening the infusion time. Other common toxicities were grade 1 to 2 hepatotoxicity, nausea or vomiting, and fatigue or malaise. Lower-extremity thrombosis occurred in one patient, and two others developed upper-extremity thrombosis associated with venous infusion catheters. Dose-limiting fatigue and hypotension occurred at 3,000 mg/m2, and cumulative fatigue developed after multiple cycles at 2,500 mg/m2. Mean EMP clearance, estimated steady-state volume of distribution, and elimination half-life were 3.7 L/h, 10.6 L, and 3.7 hours, respectively. Variability of EMP clearance was 21%, and variation in area under the curve per dose for the metabolites was 28% to 36%. Elimination half-lives of EoM and EaM were 110 hours and 64 hours, and peak plasma concentrations of these active metabolites exceeded 10 μmol/L after IV EMP doses ≥ 2,000 mg/m2. CONCLUSION: High-dose IV EMP can be administered safely as a weekly short infusion to patients with HRPC. High peak concentrations of active metabolites after IV EMP may provide an advantage over oral EMP in antimicrotubule drug combinations.

Phase I evaluation of a water-soluble etoposide prodrug, etoposide phosphate, given as a 5-minute infusion on days 1, 3, and 5 in patients with solid tumors.

1994 ◽  
Vol 12 (9) ◽  
pp. 1902-1909 ◽  
Author(s):  
D R Budman ◽  
L N Igwemezie ◽  
S Kaul ◽  
J Behr ◽  
S Lichtman ◽  
...  
Keyword(s):  
High Performance ◽  
Peak Plasma ◽  
Performance Status ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Water Soluble ◽  
High Dose ◽  
Maximum Plasma ◽  
Rapid Infusion ◽  
Etoposide Phosphate

PURPOSE To determine the toxicities, maximum-tolerated dose (MTD), and pharmacology of etoposide phosphate, a water-soluble etoposide derivative, administered as a 5-minute intravenous infusion on a schedule of days 1, 3, and 5 repeated every 21 days. PATIENTS AND METHODS Thirty-six solid tumor patients with a mean age of 63 years, performance status of 0 to 1, WBC count > or = 4,000/microL, and platelet count > or = 100,000/microL, with normal hepatic and renal function were studied. Doses evaluated in etoposide equivalents were 50, 75, 100, 125, 150, 175, and 200 mg/m2/d. Etoposide in plasma and urine and etoposide phosphate in plasma were measured by high-performance liquid chromatography (HPLC). Eleven of 36 patients were treated with concentrated etoposide phosphate at 150 mg/m2/d. RESULTS Grade I/II nausea, vomiting, alopecia, and fatigue were common. Leukopenia (mainly neutropenia) occurred at doses greater than 75 mg/m2, with the nadir occurring between days 15 and 19 posttreatment. All effects were reversible. Hypotension, bronchospasm, and allergic reactions were not observed in the first 25 patients. The MTD due to leukopenia was determined to be between 175 and 200 mg/m2/d. In 11 patients treated with concentrated etoposide phosphate, no local phlebitis was noted, but two patients did develop allergic phenomena. The conversion of etoposide phosphate to etoposide was not saturated in the dosages studied. Etoposide phosphate had peak plasma concentrations at 5 minutes, with a terminal half-life (t1/2) of 7 minutes. Etoposide reached peak concentrations at 7 to 8 minutes, with a t1/2 of 6 to 9 hours. Both etoposide phosphate and etoposide demonstrated dose-related linear increases in maximum plasma concentration (Cmax) and area under the curve (AUC). CONCLUSION Etoposide phosphate displays excellent patient tolerance in conventional dosages when administered as a 5-minute intravenous bolus. The suggested phase II dose is 150 mg/m2 on days 1, 3, and 5. The ability to administer etoposide phosphate as a concentrated, rapid infusion may prove of value both in the outpatient clinic and in high-dose regimens.

Pharmacokinetic Evaluation of anti-HIV Drug Interactions: Effect of Zidovudine on 2′-3′-Dideoxyinosine Kinetics in Monkeys

1993 ◽  
Vol 4 (3) ◽  
pp. 155-159 ◽  
Author(s):  
M. Qian ◽  
A. R. Swagler ◽  
M. Mehta ◽  
C.T. Vishwanathan ◽  
J. M. Gallo
Keyword(s):  
Dose Group ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
High Dose ◽  
Combination Regimen ◽  
Time Profiles ◽  
Elimination Half ◽  
Constant Rate ◽  
Rate Infusion

The current investigation was conducted to determine if zidovudine (AZT) altered the pharmacokinetics of dideoxyinosine (ddl) in non-hurnan primates, an appropriate animal model for AZT and ddl pharmacokinetics in human. Each of nine animals received 20 mg kg−1 of ddl intravenously in the absence and presence of two different dosage regimens of AZT. For each combination regimen, AZT was administered as a combined i.v. bolus-constant rate infusion regimen for 30 min that produced AZT plasma concentrations of about 4 μg ml−1 in six animals (low dose group) and 11 μg ml−1 in three others (high dose group). Serial blood samples were collected, and pharmacokinetic parameters for ddl were calculated based on plasma ddl concentrations measured by HPLC techniques. The pharmacokinetics of ddl given alone in the first phase of the low ( n = 6) and high ( n = 6) dose AZT groups, resulted in a mean elimination half-life 1.54 and 1.9h, a mean total clearance of 0.62 and 0.731 h−1 kg−1, and a mean steady state volume of distribution of 1.02 and 0.891 kg−1, respectively. Following combined ddl and AZT administrations, in both the low and high dose AZT groups, plasma concentration-time profiles of ddl were similar for each monkey, and no statistical differences were observed in the pharmacokinetic parameters compared to those obtained when ddl was given alone. The fact that AZT does not alter the pharmacokinetics of ddl at the range of AZT dose studied provides a basis for rational dosage design for combined ddl and AZT treatments in HIV infection.

Pharmacokinetics of Thiopental Enantiomers during and following Prolonged High-dose Therapy 

1999 ◽  
Vol 91 (6) ◽  
pp. 1693-1693 ◽  
Author(s):  
Dennis J. Cordato ◽  
Laurence E. Mather ◽  
Annette S. Gross ◽  
Geoffrey K. Herkes
Keyword(s):  
Nonlinear Models ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
High Dose ◽  
Time Data ◽  
High Dose Therapy ◽  
Dose Therapy ◽  
Elimination Half ◽  
Dose Infusion

Background Thiopental is used as a racemate; however, this is not generally recognized. During conditions of prolonged high-dose therapy, the pharmacokinetics of thiopental may become nonlinear, but whether this derives from one or both enantiomers has not been evaluated. The authors determined the pharmacokinetics of R- and S-thiopental and serum concentrations of R- and S-pentobarbital from prolonged high-dose infusion of thiopental for neuroprotection. Methods Twenty patients received a mean thiopental dose of 41.2 g over a mean duration of 95 h. R- and S-thiopental enantiomer serum concentration-time data from 18 patients were fitted with two models: a linear one-compartment model with first-order output, and a nonlinear one-compartment model with Michaelis-Menten output. Results Nonlinear models were preferred in 16 of 18 patients. Paired analysis indicated that steady state clearance (Clss) and volume of distribution (Vd) were higher for R-thiopental (0.108 vs. 0.096 l/min, P < 0.0001; and 313 vs. 273 l, P < 0.0005, respectively); maximal rate of metabolism (Vm) was higher for S- than for R-thiopental (1.01 vs. 0.86 mg x l(-1) x h(-1), P = 0.02); elimination half-lives did not differ (14.6 vs. 14.7 h, P = 0.8); unbound fractions (f(u)) of R- and S-thiopental were 0.20 and 0.18, respectively, P < 0.0001). The differences in mean Clss, Vd and Vm were not significant when adjusted by f(u). Plasma concentrations of R- and S-pentobarbital were relatively small and unlikely to be of clinical significance. Conclusion The pharmacokinetics of R- and S-thiopental became nonlinear at these doses. The pharmacokinetic differences between R- and S-thiopental, although small, were statistically significant and were influenced by the higher f(u) of R-thiopental.

scholarly journals Phase II Dose Escalation Study of Caspofungin for Invasive Aspergillosis

2011 ◽  
Vol 55 (12) ◽  
pp. 5798-5803 ◽  
Author(s):  
O. A. Cornely ◽  
J. J. Vehreschild ◽  
M. J. G. T. Vehreschild ◽  
G. Würthwein ◽  
D. Arenz ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
Peak Plasma ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Dose Escalation Study ◽  
Time Curve ◽  
Dose Limiting Toxicity

ABSTRACTOur objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥4 in 2 of 8 patients or ≥3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution. Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500 mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response rates were similar to those previously reported for voriconazole and liposomal amphotericin.

scholarly journals Pharmacokinetic Behavior and Pharmacokinetic/Pharmacodynamic Integration of Danofloxacin Following Single or Co-Administration with Meloxicam in Healthy Lambs and Lambs with Respiratory Infections

Antibiotics ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1190
Author(s):  
Mehmet Nihat Ural ◽  
Kamil Uney
Keyword(s):  
High Performance ◽  
Respiratory Infections ◽  
Plasma Concentrations ◽  
Subcutaneous Administration ◽  
Area Under The Curve ◽  
Lavage Fluid ◽  
Volume Of Distribution ◽  
E Coli ◽  
Elimination Half ◽  
Pharmacokinetic Behavior

The aim of this study was to determine the pharmacokinetics and pharmacodynamics of danofloxacin (DAN; 6 mg/kg) following subcutaneous administration alone or co-administration with meloxicam (MLX; 1 mg/kg) in healthy lambs and lambs with respiratory infections. The study was carried out using a total of four groups: HD (healthy; n = 6) and ID (infected; n = 7) groups who were administered DAN only, and HDM (healthy; n = 6) and IDM (infected; n = 7) groups who were administered DAN and MLX simultaneously. The plasma concentrations of DAN were determined using high-performance liquid chromatography–UV and analyzed by the non-compartmental method. DAN exhibited a similar elimination half-life in all groups, including both the healthy and infected lambs. The total clearance in the HDM, ID and IDM groups and volume of distribution in the HDM and IDM groups were significantly reduced. MLX in the IDM group significantly increased the area under the curve (AUC) and peak concentration (Cmax) of DAN compared to the HD group. The Mannheimia haemolytica, Escherichia coli, and Streptococcus spp. strains were isolated from bronchoalveolar lavage fluid samples of the infected lambs. When co-administration with meloxicam, DAN at a 6 mg/kg dose can provide optimum values of ƒAUC0–24/MIC (>56 h) and ƒCmax/MIC (>8) for susceptible M. haemolytica isolates with an MIC90 value of 0.25 µg/mL and susceptible E. coli isolates with an MIC value of ≤0.125 µg/mL.

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.

scholarly journals Compartmental Pharmacokinetics and Tissue Drug Distribution of the Pradimicin Derivative BMS 181184 in Rabbits

1998 ◽  
Vol 42 (10) ◽  
pp. 2700-2705 ◽  
Author(s):  
Andreas H. Groll ◽  
Tin Sein ◽  
Vidas Petraitis ◽  
Ruta Petraitiene ◽  
Diana Callender ◽  
...  
Keyword(s):  
Single Dose ◽  
Half Life ◽  
Peak Plasma ◽  
Volume Of Distribution ◽  
Multiple Dosing ◽  
Time Curve ◽  
Dose Administration ◽  
Single Dose Administration ◽  
Elimination Half ◽  
Dose Dependent

ABSTRACT The pharmacokinetics of the antifungal pradimicin derivative BMS 181184 in plasma of normal, catheterized rabbits were characterized after single and multiple daily intravenous administrations of dosages of 10, 25, 50, or 150 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of BMS 181184 were determined by a validated high-performance liquid chromatography method, and plasma data were modeled into a two-compartment open model. Across the investigated dosage range, BMS 181184 demonstrated nonlinear, dose-dependent kinetics with enhanced clearance, reciprocal shortening of elimination half-life, and an apparently expanding volume of distribution with increasing dosage. After single-dose administration, the mean peak plasma BMS 181184 concentration (C max) ranged from 120 μg/ml at 10 mg/kg to 648 μg/ml at 150 mg/kg; the area under the concentration-time curve from 0 to 24 h (AUC0–24) ranged from 726 to 2,130 μg · h/ml, the volume of distribution ranged from 0.397 to 0.799 liter/kg, and the terminal half-life ranged from 4.99 to 2.31 h, respectively (P < 0.005 toP < 0.001). No drug accumulation in plasma occurred after multiple daily dosing at 10, 25, or 50 mg/kg over 15 days, although mean elimination half-lives were slightly longer. Multiple daily dosing at 150 mg/kg was associated with enhanced total clearance and a significant decrease in AUC0–24 below the values obtained at 50 mg/kg (P < 0.01) and after single-dose administration of the same dosage (P < 0.05). Assessment of tissue BMS 181184 concentrations after multiple dosing over 16 days revealed substantial uptake in the lungs, liver, and spleen and, most notably, dose-dependent accumulation of the drug within the kidneys. These findings are indicative of dose- and time-dependent elimination of BMS 181184 from plasma and renal accumulation of the compound after multiple dosing.

Pharmacokinetics of linezolid for methicillin-resistant Staphylococcus aureus pneumonia in an adult receiving extracorporeal membrane oxygenation

2020 ◽  
Vol 77 (11) ◽  
pp. 877-881 ◽  
Author(s):  
Peter Nikolos ◽  
Justin Osorio ◽  
Kerry Mohrien ◽  
Christina Rose
Keyword(s):  
Staphylococcus Aureus ◽  
Respiratory Failure ◽  
Extracorporeal Membrane Oxygenation ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Volume Of Distribution ◽  
Minimum Concentration ◽  
Methicillin Resistant ◽  
Membrane Oxygenation

Abstract Purpose We present a case of a 55-year-old man post right lung transplantation receiving ECMO for treatment of respiratory failure secondary to methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. Summary Extracorporeal membrane oxygenation (ECMO) is a frequently utilized support therapy for patients with cardiac and/or respiratory failure. Dosing of medications during ECMO can be challenging due to several factors, including sequestration of medications within ECMO circuits, alterations in volume of distribution, and changes in drug clearance. The patient was initiated on empiric antibiotics, then switched to linezolid at a dose of 600 mg every 8 hours. Linezolid plasma concentrations were collected 30 minutes prior to the sixth administered dose and 30 minutes following the 1-hour infusion of the sixth dose, which resulted in values of 0.4 and 1.7 μg/mL, respectively. The ratio of 24-hour area under the curve (AUC0-24) to minimum inhibitory concentration (MIC), assuming a MIC of 2 μg/mL, was calculated using the extrapolated maximum concentration (1.9 μg/mL) and minimum concentration (0.35 μg/mL), resulting in an AUC0-24/MIC value of 10.8. Due to subtherapeutic linezolid plasma concentrations, ceftaroline was initiated and continued for a total of 18 days. To our knowledge, this is the second report to describe inadequate plasma concentrations of linezolid during ECMO. Conclusion In the case described here, linezolid at a dose of 600 mg every 8 hours did not achieve target plasma concentrations in a patient receiving concomitant venovenous ECMO support.

scholarly journals Pharmacokinetics of Ceftaroline in Normal Body Weight and Obese (Classes I, II, and III) Healthy Adult Subjects

2015 ◽  
Vol 59 (7) ◽  
pp. 3956-3965 ◽  
Author(s):  
Julie Ann Justo ◽  
Stockton M. Mayer ◽  
Manjunath P. Pai ◽  
Melinda M. Soriano ◽  
Larry H. Danziger ◽  
...  
Keyword(s):  
Body Weight ◽  
Healthy Adult ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Total Body Weight ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Ceftaroline Fosamil ◽  
Plasma And Urine Samples

ABSTRACTThe pharmacokinetic profile of ceftaroline has not been well characterized in obese adults. The purpose of this study was to evaluate the pharmacokinetics of ceftaroline in 32 healthy adult volunteers aged 18 to 50 years in the normal, overweight, and obese body size ranges. Subjects were evenly assigned to 1 of 4 groups based on their body mass index (BMI) and total body weight (TBW) (ranges, 22.1 to 63.5 kg/m2and 50.1 to 179.5 kg, respectively). Subjects in the lower-TBW groups were matched by age, sex, race/ethnicity, and serum creatinine to the upper-BMI groups. Serial plasma and urine samples were collected over 12 h after the start of the infusion, and the concentrations of ceftaroline fosamil (prodrug), ceftaroline, and ceftaroline M-1 (inactive metabolite) were assayed. Noncompartmental and population pharmacokinetic analyses were used to evaluate the data. The mean plasma ceftaroline maximum concentration and area under the curve were ca. 30% lower in subjects with a BMI of ≥40 kg/m2compared to those <30 kg/m2. A five-compartment pharmacokinetic model with zero-order infusion and first-order elimination optimally described the plasma concentration-time profiles of the prodrug and ceftaroline. Estimated creatinine clearance (eCLCR) and TBW best explained ceftaroline clearance and volume of distribution, respectively. Although lower ceftaroline plasma concentrations were observed in obese subjects, Monte Carlo simulations suggest the probability of target attainment is ≥90% when the MIC is ≤1 μg/ml irrespective of TBW or eCLCR. No dosage adjustment for ceftaroline appears to be necessary based on TBW alone in adults with comparable eCLCR. Confirmation of these findings in infected obese patients is necessary to validate these findings in healthy volunteers. (This study has been registered at ClinicalTrials.gov under registration no. NCT01648127.)

Pharmacokinetics of L-arginine during chronic administration to patients with hypercholesterolaemia

1999 ◽  
Vol 96 (2) ◽  
pp. 199-207 ◽  
Author(s):  
Oranee TANGPHAO ◽  
Stephan CHALON ◽  
Heitor MORENO ◽  
Brian B. HOFFMAN ◽  
Terrence F. BLASCHKE
Keyword(s):  
Nitric Oxide ◽  
Animal Studies ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Chronic Administration ◽  
Pharmacokinetic Studies ◽  
Acute Administration ◽  
Term Administration ◽  
Endothelial Nitric Oxide

Acute administration of L-arginine, the precursor of endothelial nitric oxide, has been shown to improve endothelial function in hypercholesterolaemic rabbits and humans. Animal studies suggest that this beneficial effect, which is thought to be related to the increased availability of nitric oxide, may not be sustained during chronic oral administration. Pharmacokinetic alterations may contribute to this observation. The present study was designed to examine the disposition of L-arginine in hypercholesterolaemic subjects during long-term administration. Plasma L-arginine concentrations were determined by HPLC in 10 patients (eight women and two men; mean age 46±16 years) after an intravenous dose of 10 or 30 g and an oral dose of 5 or 7 g. Pharmacokinetic studies were performed at regular intervals (4 weeks) during a 12-week period of oral L-arginine administration (14–21 g/day). The average plasma L-arginine concentrations before (baseline) and during administration were 16.1±1.2 and 22.5±1.3 μg/ml respectively (P< 0.05). Plasma concentrations of L-arginine remained above baseline throughout weeks 2–12. The L-arginine exposure, expressed as a normalized area-under-the-curve for 8 h (AUC0–8) after oral or intravenous doses during the first visit, was 894.4±118.7 and 1837.8±157.0 units respectively. There were no significant changes in peak plasma L-arginine concentrations or in the AUC0–8 after oral and intravenous doses during subsequent visits (P> 0.05). The mean non-renal clearance of L-arginine during the four visits remained constant. Knowledge of the pharmacokinetics of L-arginine may be useful in the design of clinical trials involving this agent, as well as in the interpretation of the pharmacodynamics of this important precursor of nitric oxide.

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