The pharmacokinetics of azacitidine following subcutaneous treatment in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7087-7087
Author(s):  
E. Laille ◽  
R. Ward ◽  
A. Nasser ◽  
M. Stoltz ◽  
C. Cogle ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Plasma Concentrations ◽  
Hepatic Metabolism ◽  
Volume Of Distribution ◽  
Adverse Event Reporting ◽  
Myelogenous Leukemia ◽  
Minor Role ◽  
Renal Elimination ◽  
Drug Concentrations ◽  
A Minor

7087 Background: 5-azacitidine (AZA), through its effects on DNA metabolism, gene expression, and cell differentiation, has proven beneficial in treatment of MDS and AML and AZA therapy significantly increases survival in higher-risk MDS and AML compared to conventional care. Few studies have evaluated the pharmacokinetics (PK) of AZA and the renal elimination of AZA has not been previously published to our knowledge. Plasma PK of AZA are herein reported in patients receiving SC doses of 75 mg/m2. This study was designed to also assess the contribution of renal elimination to the overall clearance of AZA. Methods: Adult patients with MDS or AML and ECOG status 0–2 were treated with 7 consecutive daily SC doses of 75 mg/m2 AZA during their first treatment cycle. PK parameters of AZA were derived from drug concentrations in plasma and urine collected after the first and last dose (day 7) of AZA. Safety was evaluated by adverse event reporting (NCI-CTC). Results: Currently, 18 patients have been treated with SC AZA. AZA was rapidly absorbed and reached peak plasma concentrations (concs) within 0.5 hr post dosing. The AUCinf after SC doses was 1170 hr*ng/mL. The AZA concs declined in a pseudo bi-phasic manner with an elimination half-life of 1.25 hours. The plasma PK profiles after the first and last dose were superimposable. The apparent total clearance (CL/F) and volume of distribution (Vd/F) were 143 L/hr and 318 L, respectively. AZA recovery in urine was very small relative to dose (<2%). AZA was well tolerated and no unexpected toxicities were observed. Conclusions: The AZA AUCinf after SC doses is similar to the published AUC value (1044 hr*ng/mL) after 75 mg/m2 IV doses indicating approximating 100% systemic bioavailability. After SC dosing, CL/F exceeded hepatic blood flow indicating extra-hepatic metabolism. Vd/F was 4–5 fold greater than total body water suggesting extensive AZA tissue distribution. Renal elimination appears to play a minor role in the overall clearance of AZA. [Table: see text]

Pharmacokinetics of Ropivacaine in Patients with Chronic End-stage Liver Disease

2007 ◽  
Vol 106 (1) ◽  
pp. 43-55 ◽  
Author(s):  
Mika J. Jokinen ◽  
Pertti J. Neuvonen ◽  
Leena Lindgren ◽  
Krister Höckerstedt ◽  
Jan Sjövall ◽  
...  
Keyword(s):  
Liver Disease ◽  
Half Life ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Hepatic Metabolism ◽  
International Normalized Ratio ◽  
Volume Of Distribution ◽  
End Stage Liver Disease ◽  
Single Block ◽  
End Stage

Background Ropivacaine is mainly eliminated by hepatic metabolism. The authors studied the effect of chronic end-stage liver disease on the pharmacokinetics of ropivacaine. Methods Thirteen patients with chronic end-stage liver disease and eight healthy volunteers received a single dose of 0.6 mg/kg ropivacaine intravenously over 30 min. Ropivacaine, 3-hydroxyropivacaine, and 2',6'-pipecoloxylidide were measured in venous plasma and urine. Results Peak ropivacaine plasma concentrations were similar. Patients with chronic end-stage liver disease had, on average, 60% lower total (P=0.001) and 56% lower unbound plasma clearance (P=0.002), 59% higher steady state volume of distribution (P=0.03), and 4.2-fold longer half-life (P&lt;0.001) of ropivacaine. Of the variation in total ropivacaine clearance, 69% was accounted for by variation in albumin, 57% in prealbumin, 25% in international normalized ratio of plasma thromboplastin time, and 24% in galactose half-life. The patients excreted a larger fraction of the original dose as unchanged ropivacaine (2.1% vs. 0.3%; P&lt;0.001) and a smaller fraction as 3-hydroxyropivacaine (11% vs. 27%; P=0.001). The fraction excreted as 2',6'-pipecoloxylidide (4.7% vs. 5.0%) was similar. Conclusions Ropivacaine clearance is decreased in chronic end-stage liver disease. A normal dose can be considered for a single block in patients with liver impairment, because the peak plasma concentrations were essentially similar. When using a postoperative ropivacaine infusion in a patient with end-stage liver disease, the lowest effective dose should be used for the shortest possible time and the patient should be monitored closely, because systemic toxicity cannot be ruled out. Because of wide interindividual differences in pharmacokinetics in patients with liver disease, no definitive dosing instructions can be given.

Pseudoephedrine is without ergogenic effects during prolonged exercise

1996 ◽  
Vol 81 (6) ◽  
pp. 2611-2617 ◽  
Author(s):  
Hunter Gillies ◽  
Wayne E. Derman ◽  
Timothy D. Noakes ◽  
Peter Smith ◽  
Alicia Evans ◽  
...  
Keyword(s):  
Urinary Excretion ◽  
High Intensity ◽  
Muscle Function ◽  
Prolonged Exercise ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
High Intensity Exercise ◽  
Double Blind ◽  
Drug Concentrations ◽  
Ergogenic Effects

Gillies, Hunter, Wayne E. Derman, Timothy D. Noakes, Peter Smith, Alicia Evans, and Gary Gabriels.Pseudoephedrine is without ergogenic effects during prolonged exercise. J. Appl. Physiol. 81(6): 2611–2617, 1996.—This study was designed to measure whether a single dose of 120 mg pseudoephedrine ingested 120 min before exercise influences performance during 1 h of high-intensity exercise. The effects of exercise on urinary excretion of the drug were also studied. Ten healthy male cyclists were tested on two occasions, separated by at least 7 days, by using a randomly assigned, double-blind, placebo-controlled, crossover design. Exercise performance was tested during a 40-km trial on a laboratory cycle ergometer, and skeletal muscle function was measured during isometric contractions. On a third occasion, subjects ingested 120 mg pseudoephedrine but did not exercise [control (C)]. Pseudoephedrine did not influence either time trial performance [drug (D) vs. placebo: 58.1 ± 1.4 (SE) vs. 58.7 ± 1.5 min] or isometric muscle function. Urinary pseudoephedrine concentrations were significantly increased 1 h after exercise (D vs. C: 114.3 ± 27.2 vs. 35.4 ± 13.1 μg/ml; P < 0.05). Peak plasma pseudoephedrine concentrations ( P < 0.05) but not time taken to reach peak plasma concentrations or the area under the plasma pseudoephedrine concentration vs. time curve was significantly increased in the total group with exercise (D vs. C). In three subjects, plasma pseudoephedrine concentrations were not influenced by exercise. Only these subjects showed increased urinary pseudoephedrine excretion during exercise. We conclude that a single therapeutic dose of pseudoephedrine did not have a measurable ergogenic effect during high-intensity exercise of 1-h duration, but plasma drug concentrations and urinary excretion were altered by exercise. These findings have practical relevance to doping control regulations in international sporting competitions.

scholarly journals Bioavailability of butorphanol after intranasal administration to horses

2020 ◽  
Vol 23 (4) ◽  
pp. 443-447
Author(s):  
V. Ferreira ◽  
M. Velloso ◽  
M. Landoni
Keyword(s):  
Intranasal Administration ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Intravenous Route ◽  
Liquid Chromatography Mass Spectrometry ◽  
Intranasal Route ◽  
Predetermined Time ◽  
Mass Spectrometry Assay

The aim of the present study was to describe butorphanol pharmacokinetics and bioavailability following intranasal administration to horses. Six adult horses received 0.05 mg/kg butorphanol, in a randomised crossover design, by either intravenous or intranasal route. Plasma concentrations of butorphanol were measured at predetermined time points using liquid chromatography/mass spectrometry assay. After intravenous injection, mean ±SD butorphanol steady-state volume of distribution and clearance was 3.20 ± 1.77 l/kg and 3.18 ± 1.47 L/kg/h, respectively. Terminal half-lives for butorphanol after intravenous and intranasal administrations were 0.68 ± 0.17 h and 1.79 ± 1.43 h. For intranasal administration, absorption half-life and peak plasma concentration were 0.43 ± 0.33 h and 1.95 ± 1.7 ng/mL, respectively. Bioavailability was 54.45 ± 20.09%. Intranasal butorphanol administration in horses is practical, not stressful and well tolerated. Therefore, it might be a substitute to the intravenous route in adult horses

scholarly journals Pharmacokinetics of Tildipirosin in Ewes after Intravenous, Intramuscular and Subcutaneous Administration

Animals ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1332
Author(s):  
Juan Sebastián Galecio ◽  
Elisa Escudero ◽  
José Joaquín Cerón ◽  
Giuseppe Crescenzo ◽  
Pedro Marín
Keyword(s):  
Bacterial Infections ◽  
High Performance ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Subcutaneous Administration ◽  
Apparent Volume ◽  
Wide Distribution ◽  
Volume Of Distribution ◽  
Time Data ◽  
Administration Time

A single-dose disposition kinetics for tildipirosin was evaluated in clinically healthy ewes (n = 6) after intravenous (IV), intramuscular (IM), and subcutaneous (SC) administration of a commercial formulation. Tildipirosin concentrations were determined by high-performance liquid chromatography with ultraviolet detection. Plasma concentration-time data was calculated by non-compartmental pharmacokinetic methods. The apparent volume of distribution (Vz) of tildipirosin after IV administration was 5.36 ± 0.57 L/kg suggesting a wide distribution in tissues and inside the cells. The elimination half-life (t½λz) was 17.16 ± 2.25, 23.90 ± 6.99 and 43.19 ± 5.17 h after IV, IM and SC administration, respectively. Following IM administration, tildipirosin was rapidly absorbed (tmax = 0.62 ± 0.10 h) even to a greater extent than after SC administration. Time to reach peak concentration (tmax) and peak plasma concentrations (Cmax) differed significantly, but both parameters showed a more significant variability after SC than after IM administration. Bioavailabilities after extravascular administration were high (>70%). Therefore, given general adverse reactions that were not observed in any ewe and favourable pharmacokinetics, tildipirosin could be effective in treating bacterial infections in sheep.

scholarly journals Plasma Concentrations of Posaconazole Administered via Nasogastric Tube in Patients in a Surgical Intensive Care Unit

2012 ◽  
Vol 56 (8) ◽  
pp. 4468-4470 ◽  
Author(s):  
Dominic Störzinger ◽  
Stephan Borghorst ◽  
Stefan Hofer ◽  
Cornelius J. Busch ◽  
Christoph Lichtenstern ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Nasogastric Tube ◽  
High Performance ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Surgical Intensive Care Unit ◽  
Surgical Intensive Care ◽  
Drug Concentrations ◽  
Apparent Clearance

ABSTRACTAbdominal surgery may affect intestinal absorption and the resulting levels of posaconazole in the blood. We measured plasma posaconazole levels in surgical intensive care unit (SICU) patients and tried to develop a predictive population pharmacokinetics model. A total of 270 samples from 15 patients receiving posaconazole via nasogastric tube were measured by high-performance liquid chromatography (HPLC). SICU patients showed lower plasma drug concentrations, a higher apparent clearance, and a higher volume of distribution than those in hematology patients, possibly due to poor absorption.

scholarly journals Pharmacokinetics and Safety of Mitragynine in Beagle Dogs

Planta Medica ◽  
2020 ◽  
Vol 86 (17) ◽  
pp. 1278-1285 ◽  
Author(s):  
Elizabeth A. Maxwell ◽  
Tamara I. King ◽  
Shyam H. Kamble ◽  
Kanumuri Siva Rama Raju ◽  
Erin C. Berthold ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Plasma Concentrations ◽  
Compartmental Analysis ◽  
Ultra Performance Liquid Chromatography ◽  
Volume Of Distribution ◽  
Pharmacokinetic Studies ◽  
Beagle Dogs ◽  
Limit Of Quantification ◽  
Significant Information ◽  
Pharmacokinetic Properties

AbstractMitragynine is the most abundant psychoactive alkaloid derived from the leaves of Mitragyna speciosa (kratom), a tropical plant indigenous to regions of Southeast Asia. Mitragynine displays a moderate affinity to opioid receptors, and kratom is often self-prescribed to treat pain and/or opioid addiction. The purpose of this study was to investigate the safety and pharmacokinetic properties of mitragynine in the dog. Single dose oral (5 mg/kg) and intravenous (0.1 mg/kg) pharmacokinetic studies of mitragynine were performed in female beagle dogs. The plasma concentrations of mitragynine were measured using ultra-performance liquid chromatography coupled with a tandem mass spectrometer, and the pharmacokinetic properties were analyzed using non-compartmental analysis. Following intravenous administration, mitragynine showed a large volume of distribution (Vd, 6.3 ± 0.6 L/kg) and high clearance (Cl, 1.8 ± 0.4 L/h/kg). Following oral mitragynine dosing, first peak plasma (Cmax, 278.0 ± 47.4 ng/mL) concentrations were observed within 0.5 h. A potent mu-opioid receptor agonist and active metabolite of mitragynine, 7-hydroxymitragynine, was also observed with a Cmax of 31.5 ± 3.3 ng/mL and a Tmax of 1.7 ± 0.6 h in orally dosed dogs while its plasma concentrations were below the lower limit of quantification (1 ng/mL) for the intravenous study. The absolute oral bioavailability of mitragynine was 69.6%. Administration of mitragynine was well tolerated, although mild sedation and anxiolytic effects were observed. These results provide the first detailed pharmacokinetic information for mitragynine in a non-rodent species (the dog) and therefore also provide significant information for allometric scaling and dose predictions when designing clinical studies.

Contrasting plasma atrial natriuretic factor concentrations during comparable natriuresis with infusions of atrial natriuretic factor and saline in normal man

1988 ◽  
Vol 75 (5) ◽  
pp. 455-462 ◽  
Author(s):  
A. Mark Richards ◽  
Giancarlo Tonolo ◽  
Jorge Polonia ◽  
Piero Montorsi
Keyword(s):  
Atrial Natriuretic Factor ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Urine Volume ◽  
Normal Subjects ◽  
Renin Angiotensin ◽  
Natriuretic Factor ◽  
The Face ◽  
A Minor ◽  
Atrial Natriuretic

1. To explore the role of atrial natriuretic factor (ANF) in the response to an acute saline load, we compared plasma hormone and urinary electrolyte interrelationships during administration of ANF and saline. Plasma concentrations of ANF, renin, angiotensin II and aldosterone, together with urine volume and electrolytes, were measured during infusions of placebo, ANF [α-human ANF (99–126)] and 0.9% (w/v) NaCl solution in normal subjects under standardized conditions of diet and posture. 2. Saline loading and ANF infusions initially induced similar natriuresis and suppression of renin–angiotensin– aldosterone system activity in association with markedly disparate values of plasma ANF. Plasma ANF levels rose to two- and eight-fold placebo values with saline and ANF, respectively (P < 0.001). Conversely, in the period after infusion plasma ANF values were similar while natriuresis differed significantly. Peak natriuresis lagged behind peak plasma ANF values with both stimuli. 3. ANF, but not saline, enhanced urinary excretion of calcium and magnesium. Saline, but not ANF, caused increased kaliuresis. 4. The data suggest that ANF makes only a minor contribution to natriuresis induced by saline challenge, although full confirmation of this point requires quantification of end-organ responses to endogenous ANF in the face of changing arterial pressure and circulating volume.

Compound GW506U78 in refractory hematologic malignancies: relationship between cellular pharmacokinetics and clinical response.

1998 ◽  
Vol 16 (11) ◽  
pp. 3607-3615 ◽  
Author(s):  
V Gandhi ◽  
W Plunkett ◽  
C O Rodriguez ◽  
B J Nowak ◽  
M Du ◽  
...  
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
Peak Plasma ◽  
Lymphoblastic Leukemia ◽  
Plasma Concentrations ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Cancer Center ◽  
Pharmacokinetic Studies

PURPOSE In vitro investigations with arabinosylguanine (ara-G) demonstrated potent cytotoxicity to T-lymphoblastoid cell lines. The goals of the present study were to evaluate GW506U78, a prodrug of ara-G, against human hematologic malignancies and to determine its pharmacokinetics in plasma and cells. PATIENTS AND METHODS During a phase I multicenter trial of GW506U78, 26 patients were treated at M.D. Anderson Cancer Center (MDACC). Daily doses between 20 and 60 mg/kg were administered for 5 days. Parallel plasma and cellular pharmacokinetic studies were conducted. RESULTS Complete (n=5) or partial remission (n=5) was achieved in T-cell acute lymphoblastic leukemia (T-ALL), T-lymphoid blast crisis, T-lymphoma, and B-cell chronic lymphocytic leukemia (B-CLL) (n=13). In contrast, patients with B-ALL, B-lymphoma, acute myelogenous leukemia (AMI), or T-CLL did not respond. Peak plasma concentrations of GW506U78 and ara-G were dose-dependent. The elimination of GW506U78 (half-life [t1/2]=17 minutes) was faster than the elimination of ara-G (t1/2=3.7 hours). Median peak concentrations of ara-GTP were 23, 42, 85, and 93 micromol/L at 20, 30, 40, and 60 mg/kg, respectively. T-lymphoblasts accumulated significantly (P=.0008) higher peak arabinsylguanosine triphosphate (ara-GTP) (median, 140 micromol/L; n=7) compared with other diagnoses (median, 50 micromol/L; n=9) and normal mononuclear cells (n=3). The ara-GTP elimination was slow in all diagnoses (median, > 24 hours). Responders accumulated significantly (P=.0005) higher levels of ara-GTP (median, 157 micromol/L) compared with patients who failed to respond (median, 44 micromol/L). CONCLUSION GW506U78 is an effective prodrug and a potent agent for hematologic malignancies with major efficacy in T-cell diseases. The pharmacokinetics of ara-GTP in leukemia cells are strongly correlated with clinical responses to GW506U78.

A novel inhibitor of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) – Part I: Pharmacological characterization

2007 ◽  
Vol 97 (01) ◽  
pp. 45-53 ◽  
Author(s):  
Lei Zhao ◽  
Mariko Nagashima ◽  
Jon Vincelette ◽  
Drew Sukovich ◽  
Weiwei Li ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Mutagenic Activity ◽  
Plasma Concentrations ◽  
Clot Lysis ◽  
Significant Activity ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Pharmacological Characterization ◽  
Drug Concentrations ◽  
Fibrinolysis Inhibitor

SummaryWe have discovered a novel small-molecule (3-phosphinoylpropionic acid) inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa), BX 528, which had an IC50 of 2 nM in an enzymatic assay and 50 nM in an in-vitro clot lysis assay, with 3,500- to 35,000-fold selectivity against other carboxypeptidases, such as CPN, CPZ and CPD, and 5- and 12-fold selectivity against CPE (CPH) and CPB, respectively. At 10 µM, BX 528 had no significant activity (< 50% inhibition or antagonism) in a panel of 137 enzymes and receptors. It had no effects on blood coagulation and platelet aggregation up to 300 and 10 µM, respectively. The plasma half-life following intravenous administration was 0.85 hours in rats and 4.5 hours in dogs. No significant metabolism was detected in human, dog or rabbit hepatic microsomes, and no significant inhibition of cytochrome P450 3A4 and 2D6 up to 30 µM. No cytotoxic or cell proliferative effects were found in three hepatic and renal cell lines up to 300 µM and no mutagenic activity was seen in the Ames II screen. There were no significant hemodynamic effects in rats and dogs up to 100 and 30 mg/kg with peak plasma drug concentrations of ~1,000 and 300 µM, respectively. In an in-vivo complement activation model in guinea pigs, BX 528 showed minimal inhibition of plasma CPN activity up to 60 mg/kg with peak plasma concentrations up to 250 µM. Thus, these data demonstrate that BX 528 is a novel, potent, selective and safe TAFIa inhibitor.

scholarly journals Safety, Tolerability, and Pharmacokinetics of Single Oral Doses of BCH-10652 in Healthy Adult Males

2000 ◽  
Vol 44 (10) ◽  
pp. 2816-2823 ◽  
Author(s):  
Patrick F. Smith ◽  
Alan Forrest ◽  
Charles H. Ballow ◽  
David E. Martin ◽  
Louise Proulx
Keyword(s):  
Plasma Concentrations ◽  
Transcriptase Inhibitor ◽  
Volume Of Distribution ◽  
Statistical Hypothesis ◽  
Adult Males ◽  
Statistical Hypothesis Testing ◽  
Serious Adverse Events ◽  
Drug Concentrations ◽  
The Mean ◽  
Oral Doses

ABSTRACT Racemic dOTC (BCH-10652) is a novel nucleoside reverse transcriptase inhibitor consisting of two enantiomers of 2′-deoxy-3′-oxa-4′-thiocytidine, (−)dOTC and (+)dOTC, that have both shown activity against human immunodeficiency virus type 1. The objectives of this study were to characterize the safety, tolerability, and stereospecific pharmacokinetics of single oral doses of racemic dOTC in healthy, nonsmoking adult male volunteers. Subjects received single oral doses of 100, 200, 400, 800, and 1,600 mg of racemic dOTC in a placebo-controlled, dose-rising, incomplete crossover study design, and the pharmacokinetics of both (+)dOTC and (−)dOTC were determined. At least six subjects were studied at each dose level, with each subject studied in three of five periods, receiving two different doses of racemic dOTC and one placebo dose. Plasma and urine drug concentrations were measured for 24 to 48 h after each dose. Pharmacokinetic models were fitted to the plasma concentrations of (+)dOTC and (−)dOTC using maximum likelihood and maximum a posteriori Bayesian procedures. Statistical hypothesis testing was by nonparametric analysis of variance (where possible) and, when tests with dose as a covariate were performed, by linear mixed-effects modeling. The mean terminal elimination half-lives for (+)dOTC and (−)dOTC were 15.3 h (coefficient of variation [CV], 28%) and 11.3 h (CV, 43%), respectively (P < 0.05). The mean CV for total oral clearance (liter/h/65 kg) was 17.5 (25%) for (+)dOTC and 21.5 (24%) for (−)dOTC; for oral steady-state volume of distribution (liter/65 kg), values were 61.8 (24%) for (+)dOTC and 34.1 (33%) for (−)dOTC (P < 0.05). The mean CV for renal clearance (liter/h/65 kg) of (+)dOTC was 10.4 (19%) and for (−)dOTC was 13.6 (20%) (P < 0.05). There was no significant effect of dose size on the pharmacokinetics of racemic dOTC. All doses were well tolerated, and no serious adverse events or laboratory abnormalities were observed.

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