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  • 1
    Electronic Resource
    Electronic Resource
    Clinical pharmacology of UCN-01: initial observations and comparison to preclinical models (1998)
    Springer
    Cancer chemotherapy and pharmacology 42 (1998), S. S54 
    Details
    ISSN: 1432-0843
    Keywords: Key words Staurosporine ; 7-hydroxy ; Protein kinase antagonist ; α1-Acidic glycoprotein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  UCN-01 (7-hydroxystaurosporine; NSC 638850) is a protein kinase antagonist selected for clinical trial based in part on evidence of efficacy in a preclinical renal carcinoma xenograft model. Schedule studies and in vitro studies suggested that a 72-h continuous infusion would be appropriate. In rats and dogs, maximum tolerated doses produced peak plasma concentrations of approximately 0.2–0.3 μM. However, concentrations 10-fold greater are well tolerated in humans, and the compound has a markedly prolonged T1/2. Specific binding to human α1-acidic glycoprotein has been demonstrated. These findings reinforce the need to consider actual clinical pharmacology data in “real time” with phase I studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800051080
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  • 2
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of a novel protein kinase inhibitor, UCN-01 (1999)
    Springer
    Cancer chemotherapy and pharmacology 44 (1999), S. 12-18 
    Details
    ISSN: 1432-0843
    Keywords: Key words 7-Hydroxystaurosporine (UCN-01) ; Pharmacokinetics ; Pharmacodynamics ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: 7-Hydroxystaurosporine (UCN-01) is a potent protein kinase inhibitor and is being developed as a novel anticancer agent. We describe here its pharmacokinetics and pharmacodynamics in experimental animals. Methods: The pharmacokinetics of UCN-01 were studied following intravenous (i.v.) administration to mice, rats and dogs at doses of 1–9, 0.35–3.5 and 0.5 mg/kg, respectively. We also studied the pharmacodynamics of UCN-01 (9 mg/kg per day) during and after five consecutive i.v. administrations to nude mice bearing xenografted human pancreatic tumor cells (PSN-1). The concentrations of UCN-01 in plasma and tumor were measured by HPLC using a fluorescence detector. Results: UCN-01 in plasma after i.v. administration was eliminated biphasically in mice and rats, and triphasically in dogs. The elimination half-lives in mice, rats and dogs were 3.00–3.98, 4.02–4.46 and 11.6 h, respectively. The total clearance (Cltotal) values in mice, rats and dogs were high (1.93–2.64, 2.82–3.86 and 0.616 l/h per kg, respectively). The hepatic clearance (Clhepatic) in rats represented 54.0–81.3% of Cltotal. The volumes of distribution at steady-state in mice, rats and dogs were large (7.89–8.42, 13.0–16.9 and 6.09 l/kg, respectively). These pharmacokinetic parameters were dose-independent in mice and rats. UCN-01 produced significant inhibition of tumor growth during five consecutive i.v. administrations in mice bearing the xenografted PSN-1 cells, and the inhibitory effect continued for 3 days after the final administration. UCN-01 concentrations in tumor tissue were much higher than those in the plasma, and the ratio of tumor to plasma concentrations was about 500 at 24 h after five consecutive doses. Conclusions: The pharmacokinetic studies showed that UCN-01 has a high clearance and large distribution volume in various experimental animals, and its disposition is linear over the range of doses tested. The pharmacodynamic study showed that UCN-01 is distributed at much higher concentrations in tumor than those in plasma and that it significantly inhibits tumor growth. The high distribution of UCN-01 into tumor cells may contribute to the potent inhibition of tumor growth in vivo.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002800050939
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  • 3
    Electronic Resource
    Electronic Resource
    Phase I and pharmacologic study of oral (E)-2′-deoxy-2′-(fluoromethylene) cytidine: on a daily × 5-day schedule (1998)
    Springer
    Investigational new drugs 16 (1998), S. 245-254 
    Details
    ISSN: 1573-0646
    Keywords: phase I trial ; ribonucleoside diphosphate reductase inhibitor ; deoxytidine analog ; FMdC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract (E)-2′-deoxy-2′-(fluoromethylene)cytidine (FMdC), one of the most potent inhibitors of ribonucleoside diphosphate reductase, was selected for clinical development because of its novel mechanisms of action, and strong antitumor activity against experimental tumor models. This study was designed to determine the toxicities, maximum-tolerated dose (MTD), and pharmacokinetic profile of FMdC. FMdC was given orally for 5 consecutive days every 3 or 4 weeks in patients with advanced solid tumors. The starting dose was 8 mg/m2/day. Pharmacokinetic studies were carried out on days 1 through 5 of the first cycle. Ten patients with non-small cell lung cancer received 15 courses of FMdC at doses which were de-escalated from 8 mg/m2/day to 2 mg/m2/day because of unexpected severe toxicities at the starting dose level. Neutropenia was the dose-limiting toxicity. Thrombocytopenia and anemia were mild. Flu-like symptoms and fever were the common non-hematologic toxicities. The MTD was 4 mg/m2/day, since four of six patients developed grade 3–4 neutropenia. At the 4 mg/m2/day dose level, the mean terminal half-life, maximum plasma concentration (Cmax), plasma clearance, and mean residence time on day 1 were 3.20 h, 15.8 ng/ml, 2.91 l/h/kg, and 4.03 h, respectively. The recommended dose for phase II studies with this schedule is also 4 mg/m2/day for 5 days. Further investigations are necessary to establish optimal dosing schedules and routes for the administration of FMdC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006126212481
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  • 4
    Electronic Resource
    Electronic Resource
    Renal Clearance of a Recombinant Granulocyte Colony-Stimulating Factor, Nartograstim, in Rats (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1466-1469 
    Details
    ISSN: 1573-904X
    Keywords: granulocyte colony-stimulating factor ; nonlinear pharmacokinetics ; renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To clarify the role of the kidney in the elimination of a recombinant human granulocyte colony-stimulating factor, nartograstim, we have investigated its pharmacokinetics in rats with renal failure. Methods. The steady-state clearance (CLss) were determined by the intravenous infusion for 4 hr to unilateral renally-ligated and cisplatin-treated rats, whose renal functions were about 50 and 10 % of controls, respectively. Results. CLss of nartograstim (27 ml/hr/kg) in the renally-ligated rats at a high infusion rate was significantly lower (25%) than in control rats (p〈0.05). CLss in these rats, at a low infusion rate was 95 ml/hr/kg, 14 % lower than in control rats. The saturable CLss in these rats, 68 ml/hr/kg, was not significantly different from control rats (75 ml/hr/kg, p〉0.05). Also, CLss in cisplatin-treated rats with extensive renal failure, at a high infusion rate, decreased to 57 % of controls. Furthermore, the total body clearances (CLtot) of nartograstim after bolus intravenous administration to renally-ligated and cisplatin-treated rats were reduced to 33–49 % of controls. Conclusions. These results suggest that the kidney may be responsible for 40– 50 % of the nonsaturable clearance of nartograstim. Thus, the kidney should make a major contribution to the elimination of nartograstim when rats are given a high dose of nartograstim, which saturates the receptor-mediated clearance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016227202781
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  • 5
    Electronic Resource
    Electronic Resource
    Physiological Modeling of Altered Pharmacokinetics of a Novel Anticancer Drug, UCN-01 (7-Hydroxystaurosporine), Caused by Slow Dissociation of UCN-01 from Human α1-Acid Glycoprotein (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 553-564 
    Details
    ISSN: 1573-904X
    Keywords: α1-acid glycoprotein ; protein binding ; dissociation rate ; species difference ; physiological model ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The extremely low clearance and small distribution volumeof UCN-01 in humans could be partly due to the high degree of bindingto hAGP (1,2). The quantitative effects of hAGP on the pharmacokineticsof UCN-01 at several levels of hAGP and UCN-01 were estimatedin rats given an infusion of hAGP to mimic the clinical situation anda physiological model for analysis was developed. Methods. The plasma concentrations of UCN-01 (72.5–7250 nmol/kgiv) in rats given an infusion of hAGP, 15 or 150 nmol/h/kg, weremeasured by HPLC. Pharmacokinetic analysis under conditionsassuming rapid equilibrium of protein binding and incorporating thedissociation rate was conducted. Results. The Vdss and CLtot of UCN-01 (725 nmol/kg iv) in ratsgiven an infusion of hAGP, 150 nmol/h/kg, fell to about 1/250 and 1/700that in control rats. The Vdss and CLtot following 72.5–7250nmol/kg UCN-01 to rats given 150 nmol/h/kg hAGP were 63.9–688ml/kg and 3.18–32.9 ml/h/kg, respectively, indicating non-linearitydue to saturation of UCN-01 binding. The CLtot estimated by thephysiological model assuming rapid equilibrium of UCN-01 bindingto hAGP, was six times higher than the observed value while the CLtotestimated by the model incorporating koff, measured using DCC, wascomparable with the observed value. Conclusions. These results suggest that the slow dissociation ofUCN-01 from hAGP limits its disposition and elimination.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007512832006
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