scholarly journals Reversible Crystallization of Argatroban after Subcutaneous Application in Pigs

Thrombosis ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-6
Author(s):  
Mercedes Lopez ◽  
Goetz Nowak
Keyword(s):  
Half Life ◽  
Subcutaneous Tissue ◽  
Subcutaneous Administration ◽  
Extended Period ◽  
Thrombin Inhibitor ◽  
Elimination Half Life ◽  
Chromogenic Assay ◽  
Elimination Half ◽  
Absorption Phase ◽  
Dose Dependent

Argatroban is a thrombin inhibitor used as anticoagulant in patients with heparin-induced thrombocytopenia. It is usually administered as an intravenous bolus followed by infusion. Nevertheless, its pharmacokinetics after subcutaneous administration is unknown. The aim of this study was to assess the pharmacokinetics of two different formulations of argatroban in pigs after subcutaneous administration. Antithrombotic activity in plasma was determined by ecarin chromogenic assay. To visualize the formation of crystals, argatroban was administered to rats into the subcutaneous tissue exposed after removing the skin, and the injection site was photographed at different times. After subcutaneous administration of a sorbitol/ethanol formulation of argatroban in pigs was observed a slow absorption phase was followed by long-lasting levels of this inhibitor. Cmax and AUC(0-24) showed dose-dependent increases, while elimination half-life and tmax value did not change significantly with dose. In contrast, saline-dissolved argatroban showed a faster absorption phase followed by a shorter elimination half-life. Argatroban dissolved in sorbitol/ethanol leads to long-lasting plasma levels due to the formation and permanent dissolution of a crystalline depot at the injection place. This represents a simple way to deliver argatroban continuously over an extended period which can be beneficial for prophylaxis or treatment of chronic coagulations disorders.

scholarly journals In Vivo Pharmacodynamic Activity of the Glycopeptide Dalbavancin

2007 ◽  
Vol 51 (5) ◽  
pp. 1633-1642 ◽  
Author(s):  
David Andes ◽  
William A. Craig
Keyword(s):  
Half Life ◽  
Dose Range ◽  
Lung Infection ◽  
Free Drug ◽  
Infection Model ◽  
Gram Positive ◽  
Elimination Half Life ◽  
Elimination Half ◽  
Dose Dependent

ABSTRACT Dalbavancin is a lipoglycopeptide antibiotic with broad-spectrum activity against gram-positive cocci and a markedly prolonged serum elimination half-life. We used the neutropenic murine thigh and lung infection models to characterize the pharmacodynamics of dalbavancin. Single-dose pharmacokinetic studies demonstrated linear kinetics and a prolonged elimination half-life which ranged from 7.6 to 13.1 h over the dose range of 2.5 to 80 mg/kg of body weight. The level of protein binding in mouse serum was 98.4%. The time course of in vivo activity of dalbavancin over the same dose range was examined in neutropenic ICR Swiss mice infected with a strain of either Streptococcus pneumoniae or Staphylococcus aureus by using the thigh infection model. The burden of organisms for S. pneumoniae was markedly reduced over the initial 24 h of study, and organism regrowth was suppressed in a dose-dependent fashion for up to the entire 96 h of study following dalbavancin doses of 2.5 mg/kg or greater. Dalbavancin doses of 20 mg/kg or greater resulted in less killing of S. aureus but were still followed by a prolonged suppression of regrowth. Multiple-dosing-regimen studies with the same organisms were used to determined which of the pharmacodynamic indices (maximum concentration in serum [C max]/MIC, area under the concentration-versus-time curve [AUC]/MIC, or the duration of time that levels in serum exceed the MIC) best correlated with treatment efficacy. These studies used a dose range of 3.8 to 480 mg/kg/6 days fractionated into 2, 4, 6, or 12 doses over the 144-h dosing period. Nonlinear regression analysis was used to examine the data fit with each pharmacodynamic index. Dalbavancin administration by the use of large, widely spaced doses was the most efficacious for both organisms. Both the 24-h AUC/MIC and the C max/MIC parameters correlated well with the in vivo efficacy of treatment against S. pneumoniae and S. aureus (for 24-h AUC/MIC, R 2 = 78 and 77%, respectively; for C max/MIC, R 2 = 90 and 57%, respectively). The free-drug 24-h AUC/MICs required for a bacteriostatic effect were 17 ± 7 for five S. pneumoniae isolates. A similar treatment endpoint for the treatment against five strains of S. aureus required a larger dalbavancin exposure, with a mean free-drug 24-h AUC/MIC of 265 ± 143. Beta-lactam resistance did not affect the pharmacodynamic target. The dose-response curves were relatively steep for both species; thus, the pharmacodynamic target needed to achieve organism reductions of 1 or 2 log10 in the mice were not appreciably larger (1.3- to 1.6-fold). Treatment was similarly efficacious in neutropenic mice and in the lung infection model. The dose-dependent efficacy and prolonged elimination half-life of dalbavancin support the widely spaced regimens used in clinical trials. The free-drug 24-h AUC/MIC targets identified in these studies should be helpful for discerning rational susceptibility breakpoints. The current MIC90 for the target gram-positive organisms would fall within this value.

Phase I Evaluation of ISIS 3521, an Antisense Oligodeoxynucleotide to Protein Kinase C-Alpha, in Patients With Advanced Cancer

1999 ◽  
Vol 17 (11) ◽  
pp. 3586-3595 ◽  
Author(s):  
J. Nemunaitis ◽  
J. T. Holmlund ◽  
M. Kraynak ◽  
D. Richards ◽  
J. Bruce ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Advanced Cancer ◽  
Half Life ◽  
Elimination Half Life ◽  
Kinase C ◽  
Elimination Half ◽  
Protein Kinase C Alpha ◽  
Moderate Nausea ◽  
Dose Dependent

PURPOSE: To determine the maximum-tolerated dose (MTD) and pharmacologic behavior of ISIS 3521 (ISI 641A), an antisense phosphorothioate oligonucleotide to protein kinase C-alpha. PATIENTS AND METHODS: Thirty-six patients with advanced cancer received 99 cycles of ISIS 3521 (0.15 to 6.0 mg/kg/d) as a 2-hour intravenous infusion administered three times per week for 3 consecutive weeks and repeated every 4 weeks. Plasma and urine sampling was performed during the first week of treatment and subjected to capillary gel electrophoresis to determine full-length antisense oligonucleotide in addition to chain-shortened metabolites. RESULTS: Drug-related toxicities included mild to moderate nausea, vomiting, fever, chills, and fatigue. Hematologic toxicity was limited to thrombocytopenia (grade 1, four patients; grade 2, one patient; grade 3, one patient). There was no relationship between dose, maximum concentration of the drug (Cmax), or area under the plasma concentration versus time curve (AUC) and coagulation times or complement levels. Dose escalation was discontinued because of the attainment of peak plasma concentrations, which approached that associated with complement activation in primates. Two patients with non-Hodgkin's lymphoma who completed 17 and nine cycles of therapy achieved complete responses. The pharmacokinetic profile of ISIS 3521 revealed a short elimination half-life (18 to 92 minutes), as well as a dose-dependent decrease in clearance and dose-dependent increases in Cmax, AUC, and elimination half-life. CONCLUSION: No dose-limiting toxicity of ISIS 3521 was identified, and clinical activity was observed. A short elimination half-life was identified, which suggests that alternate schedules with prolonged administration may be necessary for further clinical development.

Outcome of elderly DLBCL patients with 6xCHOP-14 and 8 rituximab (R) applications given over an extended period (SMARTE-R-CHOP-14 trial of the DSHNHL).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8025-8025
Author(s):  
Niels Murawski ◽  
Gerhard Held ◽  
Samira Zeynalova ◽  
Carsten Mueller ◽  
Viola Poeschel ◽  
...  
Keyword(s):  
Half Life ◽  
Poor Prognosis ◽  
Therapeutic Potential ◽  
Extended Period ◽  
Primary Treatment ◽  
Elderly Male ◽  
Elimination Half Life ◽  
Female Patients ◽  
Elimination Half ◽  
Male Patients

8025 Background: 6xCHOP-14 with 8xR given over an extended period improved 3-year EFS (67% vs. 54%; p=0.030) and OS (80% vs. 67%, p=0.034) of poor-prognosis patients (IPI=3-5) in the SMARTE-R trial compared to the RICOVER-60 trial where patients received 8xR every 2 weeks. Because we had recently shown (Mueller et al., Blood 2012) that elderly male patients have a faster R clearance (12.68 ml/h vs. 8.21 ml/h; p=0.003) and shorter serum elimination half life (t1/2ß=24.7 vs. t1/2ß=30.7 days; p=0.003) than females, we analyzed whether these differences translated into different outcomes by comparing the results achieved by elderly female and male patients in the RICOVER-60 and SMARTE-R trials. Methods: In SMARTE-R, 189 evaluable elderly (61-80 y) pts. with DLBCL received 6 cycles of 2-weekly CHOP-14 combined with 8xR on days -4, -1, 10, 29, 57, 99, 155, and 239. The primary endpoint was event-free survival (EFS). 306 pts treated within the RICOVER-60 trial with 6xCHOP-14 + 8 R given on days 1, 15, 29, 43, 57, 71, 85 and 99 served as controls. Results: The 3-year EFS of 51 poor-prognosis male patients in SMARTE-R was 67% compared to 47% of 66 poor-prognosis male patients treated in RICOVER-60 (p=0.037); the respective figures were 71% vs. 53% (p=0.051) for PFS and 80% vs. 60% (p=0.027) for OS. In contrast, female poor-risk patients had only a small benefit from the extended rituximab exposure in SMARTE-R (n=48) compared to RICOVER-60 (n=57): 67% vs. 61% (p=0.354) for EFS; 71% vs. 67% (p=0.489) for PFS; and 80% vs. 76% (p=0.528) for OS. Conclusions: Elderly male patients with poor-prognosis DLBCL who have a faster R clearance and shorter R serum elimination half life than female patients, benefit significantly from the longer R exposure in SMARTE-R with a gain of 20% in 3-year OS, while the outcome of female patients was only slightly improved. Even though R maintenance has failed to demonstrate any benefit in the primary treatment of DLBCL to date, these results underline the importance of a minimum exposure time of R in order to exploit its full therapeutic potential in DLBCL. Supported by Deutsche Krebshilfe.

scholarly journals Pharmacokinetics of KRM-1648, a new benzoxazinorifamycin, in rats and dogs.

1996 ◽  
Vol 40 (12) ◽  
pp. 2749-2755 ◽  
Author(s):  
K Hosoe ◽  
T Mae ◽  
E Konishi ◽  
K Fujii ◽  
K Yamashita ◽  
...  
Keyword(s):  
Whole Blood ◽  
Half Life ◽  
Volume Of Distribution ◽  
Late Time ◽  
Nonlinear Kinetics ◽  
Elimination Half Life ◽  
Elimination Half ◽  
Dose Dependent Decrease ◽  
High Degree ◽  
Dose Dependent

The pharmacokinetics of 3'-hydroxy-5'-(4-isobutyl-1-piperazinyl) benzoxazinorifamycin (KRM-1648) in rats and dogs given a single oral dose of 3, 30, or 100 mg/kg of body weight were studied. In the rats, the concentrations of KRM-1648 in plasma, whole blood, and tissues peaked between 2.0 and 24.0 h, with elimination half-lives ranging from 6.2 to 19.5 h. The peak concentrations and the areas under the concentration-versus-time curves (AUC) for whole blood and tissues were 2 to 277 times higher than those for plasma. The high levels of KRM-1648 in tissues were consistent with its large volume of distribution (in excess of 10 liters/kg). A nonlinear increase in peak concentrations and AUCs for plasma, whole blood, and tissues occurred as the dose was increased and was consistent with the dose-dependent decrease in bioavailability. In the dogs, KRM-1648 levels in plasma and whole blood also exhibited a late time to the peak concentration (ranging from 4.0 to 11.2 h), a long elimination half-life (ranging from 15.2 to 24.0 h), and nonlinear kinetics. KRM-1648 exhibited high levels of plasma protein binding (more than 99%) and a high degree of affinity for lipoproteins in the plasma of both animals. After administration of KRM-1648, measurable levels of its metabolites, 25-deacetyl KRM-1648 in rats and 25-deacetyl KRM-1648 and 30-hydroxy KRM-1648 in dogs, were found in the biological samples tested. Thus, KRM-1648 is characterized by a high tissue affinity, a long elimination half-life, and nonlinear pharmacokinetics.

Anticoagulant Activity of Hirulog™, a Direct Thrombin Inhibitor, in Humans

1993 ◽  
Vol 69 (02) ◽  
pp. 157-163 ◽  
Author(s):  
Irving Fox ◽  
Adrian Dawson ◽  
Peter Loynds ◽  
Jane Eisner ◽  
Kathleen Findlen ◽  
...  
Keyword(s):  
Rational Design ◽  
Therapeutic Potential ◽  
Anticoagulant Activity ◽  
Subcutaneous Administration ◽  
Direct Thrombin Inhibitor ◽  
Controlled Study ◽  
Thrombin Inhibitor ◽  
Thrombin Time ◽  
Thrombotic Disease ◽  
Dose Dependent

SummaryHirulog™ (BG8967) is a direct thrombin inhibitor built by rational design using the protein hirudin as a model (Maraganore et al. [1990]; Biochemistry 29: 7095–101). In order to evaluate the therapeutic potential for hirulog in the management of thrombotic disease, the tolerability and anticoagulant activity of the agent were examined in a study of human volunteers.In a randomized, placebo-controlled study (n = 54), the intravenous infusion of hirulog over 15 min showed a rapid, dose-dependent prolongation of activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). There was a corresponding dose-dependent increase in plasma hirulog levels. The peptide was rapidly cleared with a half-life of 36 min and a total body clearance rate for the peptide of 0.43 1 kg−1 h−1. Similar activity was observed following subcutaneous injection but with sustained pharmacodynamic and pharmacokinetic behavior. There was a significant correlation between pharmacokinetic and pharmacodynamic variables for both intravenous (r = 0.8, p <0.001) and subcutaneous administration (r = 0.7, p = 0.002).To evaluate the possible interactions of aspirin on the tolerability and anticoagulant activity of intravenous hirulog, a cross-over design was employed in eight subjects. Aspirin administration did not modify the peptide’s activity. At the administered dose of 0.6 mg kg−1 h−1 for 2 h, hirulog infusion prolonged APTT from 230 to 260% baseline. The infusion of hirulog in subjects who had received aspirin was not associated with any significant changes in the template bleeding time.The final phase of the study examined the activity and tolerability of hirulog in ten subjects during prolonged intravenous infusions for up to 24 h. The peptide (0.3 mg kg−1 h−1) exhibited sustained anticoagulant activity with no evidence for a cumulative effect. During hirulog infusion, APTT was prolonged from 210 to 250% baseline.In all phases of the study, hirulog administration was generally well-tolerated.Our observations show that hirulog is an active antithrombin agent with excellent tolerability in humans. As a direct thrombin inhibitor, hirulog provides a novel approach for the management of thrombotic disease.

Influence of concomitant drugs on methadone elimination half-life in patients under a maintenance treatment

2001 ◽  
Vol 6 (2) ◽  
pp. 171-176 ◽  
Author(s):  
A. C. S. Lucas ◽  
A. M. Bermejo ◽  
M. J. Tabernero ◽  
P. FernÁNdez ◽  
P. CÁMpora
Keyword(s):  
Half Life ◽  
Maintenance Treatment ◽  
Elimination Half Life ◽  
Elimination Half

Lactic Acidosis, Hyperglycaemia and Convulsions following Nalidixic Acid Overdosage

1984 ◽  
Vol 3 (3) ◽  
pp. 239-243 ◽  
Author(s):  
P.J.A. Leslie ◽  
R.J. Cregeen ◽  
A.T. Proudfoot
Keyword(s):  
Plasma Concentration ◽  
Lactic Acidosis ◽  
Nalidixic Acid ◽  
Half Life ◽  
Abnormal Behaviour ◽  
Elimination Half Life ◽  
Elimination Half

1 A woman survived ingestion of 32 g nalidixic acid despite developing lactic acidosis, hyperglycaemia, convulsions and abnormal behaviour. 2 The maximum recorded plasma concentration of nalidixic acid was 185 mg/l and the elimination half-life was 3.2 h. 3 Carboxy-nalidixic acid was demonstrated in the plasma. 4 Previously reported cases of nalidixic acid overdosage are reviewed.

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