A phase I study of 9-aminocamptothecin as a colloidal dispersion formulation given as a fortnightly 72-h infusion

Leguizamo, Jorge; Quinn, Mary; Takimoto, Chris H.; Liang, Michael D.; Ismail, Abdel Salam Attia; Pang, Janet; Dahut, William L.; Grem, Jean L.

doi:10.1007/s00280-003-0657-1

Cited by 7 publications

(4 citation statements)

References 20 publications

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“…Various types of drug delivery systems tested in phases I and II clinical studies were developed aiming to improve the pharmacokinetics of 9AC and unleash its therapeutic potential (10)(11)(12)(13)(14). Like other CPT analogs, 9AC also suffers from drawbacks of low solubility and hydrolytic instability at physiological pH but, to our knowledge, no comprehensive thermodynamic studies have ever been published in the literature.…”

Section: Introductionmentioning

confidence: 99%

Physicochemical Characterization of 9-Aminocamptothecin in Aqueous Solutions

2013

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Abstract. The present manuscript provides a detailed physicochemical and thermodynamic characterization of 9-aminocamptothecin (9AC) which can be used as a tool to develop novel formulation strategies for optimum pharmacological activity. The pK a of 9AC was determined to be 2.43 at 37°C, while the basicity of quinoline nitrogen of 9AC was found to decrease with increasing temperature due to a positive enthalpy of deprotonation of 10.36 kJ mol −1. The equilibrium solubility as well as the intrinsic solubility of the drug was found to increase with increasing temperature and decreasing pH. The enthalpies of solution of unionized and ionized forms of 9AC obtained from isothermal and iso-pH equilibrium solubility measurements were found to be 36.01 and 24.72 kJ mol −1 , respectively.Equilibrium hydrolysis studies revealed the hydrolytic susceptibility of 9AC with only 14% of active lactone species remaining at physiological pH 7.4. The intrinsic partition coefficient log P of the free base, 9AC-lactone, was estimated to be 1.28 (a characteristic of molecules suitable for oral absorption). The estimated pK a and log P values of 9AC, combined with its increased solubility at lower pH, are features that can be utilized to develop novel drug delivery systems to optimize the antitumor activity of 9AC.

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Section: Introductionmentioning

confidence: 99%

Physicochemical Characterization of 9-Aminocamptothecin in Aqueous Solutions

2013

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“…The solubility of 9‐AC is greatly enhanced in a DMA vehicle. A lyophilized colloidal dispersion of 9‐AC revealed not only enhanced water solubility, but also a slightly improved toxicity profile with regard to neutropenia, compared with the original DMA formulation 28. At first, 9‐AC was administered in DMA solvent at a maximum tolerated dose (MTD) of 0.85 mg · m −2 per day (total dose 2.55 mg · m −2 ) as a continuous intravenous infusion on days 1–3 and repeated every 2 weeks.…”

Section: Discussionmentioning

confidence: 97%

Antitumor Efficacy of Colon‐Specific HPMA Copolymer/9‐Aminocamptothecin Conjugates in Mice Bearing Human‐Colon Carcinoma Xenografts

Gao

Sun

Kopečková

et al. 2009

Macromolecular Bioscience

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The antitumor activity of a colon-specific N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer – 9-aminocamptothecin (9-AC) conjugate (P-9-AC) was assessed in orthotopic and subcutaneous animal (HT29 xenograft) tumor models. P-9-AC treatment of mice bearing orthotopic colon tumors, with a dose of 3 mg/kg of 9-AC equivalent every other day for 6 weeks, resulted in regression of tumors in 9 of 10 mice. A lower dose of P-9-AC (1.25 mg/kg of 9-AC equivalent) every other day for 8 weeks inhibited subcutaneous tumor growth in all mice. No liver metastases were observed. Colon-specific release of 9-AC from polymer conjugates enhanced antitumor activity and minimized the systemic toxicity.

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“…The solubility of 9-AC is greatly enhanced in a dime thylacetamide (DMA) vehicle. An alternative formulation of 9-AC, a lyophilized colloidal dispersion (CD), revealed enhanced water solubility, a similar growth inhibition pattern, and slightly improved toxicity profile, with regard to neutropenia, compared with the original DMA formulation [9]. Because phase I studies of 9-AC/CD were completed after activation of CALGB 9551, the study was amended to include this new formulation.…”

Section: Introductionmentioning

confidence: 99%

“…The dose-limiting toxicity (DLT) in both phase I studies was neutropenia without granulocyte colony-stimulating factor (G-CSF), and neutropenia and thrombocytopenia with G-CSF. Dosing recommendations for 9-AC/CD were 1.1 mg/m 2 per day for 3 days for the 2-week schedule and 1.3 mg/m 2 per day for 3 days for the 3 week schedule [9, 12]. Similar to the DMA formulation, neutropenia was the DLT and little non-hematologic toxicity was demonstrated with 9-AC/CD.…”

Section: Introductionmentioning

confidence: 99%

Phase II study of 9-aminocamptothecin in previously treated lymphomas: results of Cancer and Leukemia Group B 9551

Bartlett

Johnson

Wagner‐Johnston

et al. 2008

Cancer Chemother Pharmacol

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Purpose To evaluate the efficacy and toxicity of the topoisomerase I inhibitor, 9-aminocamptothecin (9-AC), in patients with relapsed lymphoma and to correlate 9-AC plasma concentrations with response and toxicity. Methods Eligible patients had relapsed Hodgkin lymphoma (HL) treated with one or two prior regimens, low grade non-Hodgkin’s lymphoma (NHL) treated with one or two prior regimens, or aggressive NHL treated with one prior regimen. The first nine patients received 9-AC dimethylacetamide 0.85 mg/m2 per day intravenously over 72 h every 2 weeks and the remaining 27 patients received 9-AC/colloidal dispersion 1.1 mg/m2 per day. Patients received a minimum of three cycles unless progression or intolerable toxicity occurred. Responding patients received two cycles past best response with a minimum of six cycles. Results CALGB 9551 accrued 37 patients from April 1996 through October 2000; one patient with HD, 18 patients with indolent lymphoma, and 17 patients with aggressive lymphoma. The overall response rate was 17%, with response rates of 11% (2 partial responses) in patients with indolent histologies and 23% (1 complete response, 3 partial responses) in patients with aggressive histologies. The patient with HD did not respond. Response rates were similar for both drug formulations. The median remission duration for the six responders was 6.5 months, with one remission lasting longer than 12 months. Significant grade 3 and 4 toxicities included neutropenia (66%), anemia (31%), and thrombocytopenia (36%), with 20% of patients experiencing grade 3 or 4 infection. No treatment related deaths occurred. Steady state serum concentrations did not correlate with patient response or toxicity. Conclusion Single agent 9-AC has modest activity in aggressive non-Hodgkin’s lymphoma

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A phase I study of 9-aminocamptothecin as a colloidal dispersion formulation given as a fortnightly 72-h infusion

Abstract: The recommended phase II dose of 9-AC colloidal dispersion as a 72-h infusion every 14 days is 47 microg/m2 per hour (1.13 mg/m2 per day). The Cpss of 9-AC lactone at this dose exceeded the 10 nM threshold level for preclinical activity.

Cited by 7 publications

References 20 publications

Physicochemical Characterization of 9-Aminocamptothecin in Aqueous Solutions

Physicochemical Characterization of 9-Aminocamptothecin in Aqueous Solutions

Antitumor Efficacy of Colon‐Specific HPMA Copolymer/9‐Aminocamptothecin Conjugates in Mice Bearing Human‐Colon Carcinoma Xenografts

Phase II study of 9-aminocamptothecin in previously treated lymphomas: results of Cancer and Leukemia Group B 9551

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