A phase 1 trial of XK469: Toxicity profile of a selective topoisomerase IIβ inhibitor

Alousi, Amin M.; Boinpally, Ramesh; Wiegand, Richard; Parchment, Ralph E.; Gadgeel, Shirish M.; Heilbrun, Lance K.; Wozniak, Antionette J.; DeLuca, Pamela; LoRusso, Patricia

doi:10.1007/s10637-006-9024-5

Cited by 23 publications

(13 citation statements)

References 14 publications

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“…However, upon dosing in humans, low clearance was observed (Alousi et al, 2007). Results from our studies using cryopreserved hepatocytes were consistent with these reports.…”

supporting

confidence: 91%

Characterization of Aldehyde Oxidase Enzyme Activity in Cryopreserved Human Hepatocytes

Hutzler

Yang²,

Albaugh³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Substrates of aldehyde oxidase (AO), for which human clinical pharmacokinetics are reported, were selected and evaluated in pooled mixed-gender cryopreserved human hepatocytes in an effort to quantitatively characterize AO activity. confirmed that the predominant oxidative metabolite was generated by AO, as expected isotope patterns in mass spectra were observed after analysis by high-resolution mass spectrometry. Second, clearance values were efficiently attenuated upon coincubation with hydralazine, an inhibitor of AO. The low exposure after oral doses of BIBX1382 and carbazeran (ϳ5% F) would have been fairly well predicted using simple hepatic extraction (f h ) values derived from cryopreserved hepatocytes. In addition, the estimated hepatic clearance value for O 6 -benzylguanine was within ϳ80% of the observed total clearance in humans after intravenous administration (15 ml ⅐ min ؊1 ⅐ kg ؊1 ), indicating a reasonable level of quantitative activity from this in vitro system. However, a 3.5-fold underprediction of total clearance was observed for zaleplon, despite the 5-oxo metabolite being clearly observed. These data taken together suggest that the use of cryopreserved hepatocytes may be a practical approach for assessing AO-mediated metabolism in discovery and potentially useful for predicting hepatic clearance of AO substrates.

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“…However, upon dosing in humans, low clearance was observed (Alousi et al, 2007). Results from our studies using cryopreserved hepatocytes were consistent with these reports.…”

supporting

confidence: 91%

Characterization of Aldehyde Oxidase Enzyme Activity in Cryopreserved Human Hepatocytes

Hutzler

Yang²,

Albaugh³

et al. 2011

Drug Metab Dispos

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“…The relative MFI FAM-siRNA and relative MFI Cy3-MB after 4 h transfection were plotted against the siRNA concentration (Figure 5). 24 Figure 5, A and C demonstrated that the MFI FAM-siRNA for both formulations was proportional to siRNA concentration, indicating that both formulations exhibited linear pharmacokinetics for cellular exposure. However, the MFI Cy3-MB plateaued for both NCs with increasing siRNA concentrations.…”

Section: Resultsmentioning

confidence: 93%

Comparative cellular pharmacokinetics and pharmacodynamics of siRNA delivery by SPANosomes and by cationic liposomes

Zhou

Zhang

et al. 2013

Nanomedicine: Nanotechnology, Biology and Medicine

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Mechanistic understanding of intracellular trafficking is important for the development of small interfering RNA (siRNA) delivery vehicles. Here, we describe a novel methodology to quantitatively analyze nanocarrier-mediated disposition of siRNA. Cellular uptake and cytoplasmic release of siRNA over time were quantified by measuring the fluorescence intensities of fluorescently-labeled siRNAs and molecular beacons using flow cytometry. This method was used to investigate the cellular pharmacokinetics (PK) of siRNA delivery by SPANosomes (SP) and by cationic liposomes (CL). The results showed that the superior pharmacodynamic (PD) response of SP was because it enhanced transport of siRNA into the cytoplasm compared to the CL. The divergent cellular pharmacokinetic profiles of the two formulations were associated with different cellular entry pathways. These findings can facilitate the rational design of more efficient siRNA delivery vehicles in the future.

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“…However, pharmacokinetic analysis revealed a much longer half-life in humans than expected and it has been hypothesised that the drug is sequestered (i.e. in bile) and recirculated resulting in an apparent long terminal phase 18. It was the long half-life that prompted the modification of the schedule to infusion on days 1, 3 and 5 of a 21-d cycle.…”

Section: Discussionmentioning

confidence: 99%

A phase I and pharmacokinetic study of the quinoxaline antitumour Agent R(+)XK469 in patients with advanced solid tumours

Undevia

Innocenti

Ramı́rez

et al. 2008

European Journal of Cancer

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Purpose To investigate the safety and pharmacokinetics of R(+)XK469, a quinoxaline analogue, in patients with advanced refractory solid tumours. Preclinical studies suggested that efficacy was independent of schedule but that toxicity was decreased by dividing the dose. Methods R(+)XK469 was initially administered as a 30 min intravenous infusion on days 1–5 of a 21-d cycle. Based on the demonstration of a long half-life, the dosing schedule was subsequently amended to infusion on days 1, 3 and 5 of a 21-d cycle. An alternate single-dose schedule of once every 21 d was also explored. Blood samples were collected for pharmaco-kinetic studies. Results Dose-limiting toxicity (DLT) was neutropaenia. There was significant interindividual variability in clearance as evidenced by a coefficient of variation of 46%. A flat-dosing scheme (not based on body surface area) was justified by the absence of correlation between clearance and body surface area. A partial response was observed in a patient with nasopharyngeal carcinoma. Conclusions The recommended phase II doses are 850–1100 mg/d on days 1, 3 and 5 of a 21-d cycle and 2500 mg on day 1 of a 21-d cycle. The observed interpatient pharmacokinetic variability should prompt investigation into the presence of genetic polymorphism in relevant metabolizing enzymes.

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A phase 1 trial of XK469: Toxicity profile of a selective topoisomerase IIβ inhibitor

Abstract: Traditional PK sampling designs were inadequate to describe XK469 disposition. XK469 and related structures work through a unique mechanism of action. A further understanding of the specific mechanism of these compounds might uncover a unique avenue for future drug development.

Cited by 23 publications

References 14 publications

Characterization of Aldehyde Oxidase Enzyme Activity in Cryopreserved Human Hepatocytes

Characterization of Aldehyde Oxidase Enzyme Activity in Cryopreserved Human Hepatocytes

Comparative cellular pharmacokinetics and pharmacodynamics of siRNA delivery by SPANosomes and by cationic liposomes

A phase I and pharmacokinetic study of the quinoxaline antitumour Agent R(+)XK469 in patients with advanced solid tumours

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