Phase I and Pharmacokinetic Study of a Daily Times 5 Short Intravenous Infusion Schedule of 9-Aminocamptothecin in a Colloidal Dispersion Formulation in Patients With Advanced Solid Tumors

Herben, V. M. M.; Gijn, R. van; Schellens, Jan H.M.; Schot, Margaret; Lieverst, Jan A.; Hillebrand, M. J. X.; Schoemaker, Nadja E.; Porro, Maria Grazia; Beijnen, Jos H.; Huinink, W.W. ten Bokkel

doi:10.1200/jco.1999.17.6.1906

Cited by 8 publications

(7 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…17 For the daily times 5 schedule of 9-AC, the recommended phase II dose of 9-AC was 1.1 mg/m 2 per day infused over 15 min daily every 3 weeks. 19 Neutropenia and thrombocytopenia were dose limiting. Phase I trials in pediatric patients 20 and acute leukemia patients 21 have also been completed (TABLE 2).…”

Section: Phase I Studiesmentioning

confidence: 99%

“…18,20,24,28 This is consistent with earlier studies demonstrating greater instability of 9-AC lactone in human plasma compared with other camptothecin derivatives such as topotecan or irinotecan. 29 Other pharmacokinetic parameters for 9-AC lactone include a terminal elimination half-life commonly ranging from 4.5 to 10 hr, [18][19][20][21]28 a volume of distribution at steady state ranging from 58 to 325 l/m 2 , [18][19][20][21]28 and a systemic clearance ranging from 11.3 to 55 l/(hr ⋅ m 2 ). [18][19][20][21]28 Urinary clearance accounts for 8.6 to 32.1% of the total dose administered.…”

Section: Clinical Pharmacologymentioning

confidence: 99%

“…[18][19][20][21]28 Urinary clearance accounts for 8.6 to 32.1% of the total dose administered. 19,28 As with other camptothecin derivatives, interpatient variability in plasma pharmacokinetics is quite high (TABLE 2). Preliminary reports suggest that patients receiving anticonvulsant medications may have increased clearance and lower plasma drug levels of 9-AC.…”

Section: Clinical Pharmacologymentioning

confidence: 99%

“…31 An alternative explanation may be the induction of transport proteins by these same agents that could lead to increased 9-AC clearance and biliary secretion in these patients. 32 In pharmacodynamic studies, 9-AC steady-state plasma concentrations 28,32 and AUC 18,19,33 correlated with the dose-limiting toxicity of neutropenia.…”

Section: Clinical Pharmacologymentioning

confidence: 99%

“…More recently, other schedules of intravenous 9‐AC administration have been developed, including a prolonged 120‐hr infusion weekly,17 a 24‐hr infusion weekly for 4 of 5 weeks,18 or a short intravenous infusion daily for 5 days every 3 weeks (Table 2). 19 On all of these schedules, the principal dose‐limiting toxicity was myelosuppression, although gastrointestinal toxicities such as diarrhea were also observed in some of the prolonged infusion schedules 17. For the daily times 5 schedule of 9‐AC, the recommended phase II dose of 9‐AC was 1.1 mg/m 2 per day infused over 15 min daily every 3 weeks 19.…”

Section: Phase I Studiesmentioning

confidence: 99%

See 4 more Smart Citations

The Clinical Development of 9‐Aminocamptothecin

Takimoto

Thomas

2000

Annals of the New York Academy of Sciences

View full text Add to dashboard Cite

9-Aminocamptothecin (9-AC) is a topoisomerase I-targeting agent first synthesized by Wani and Wall in 1986. Because of its potent in vitro effects and promising preclinical activity in colorectal cancer animal models, it was designated a high-priority compound for further drug development by the NCI. In 1993, 9-AC first entered clinical trials as a 72-hour intravenous (i.v.) infusion. Predictable myelosuppression was the major dose-limiting toxicity, and pharmacokinetic studies showed a relatively short plasma half-life and unstable lactone ring. Unfortunately, phase II studies using this schedule showed minimal or no activity in tumors such as colorectal and lung cancer. Modest activity was observed in ovarian cancer and in refractory lymphomas. Efforts to improve systemic drug exposure by utilizing alternative schedules of administration of 9-AC such as prolonged, continuous intravenous infusions have also been tested. However, phase II studies of 120-hour weekly infusions of 9-AC have not shown improved activity against solid tumors such as colorectal cancer. More recently, a daily times 5 days i.v. administration schedule has been tested. Currently, further development of intravenously administered 9-AC for the treatment of colorectal cancer is not promising. Thus, topotecan and irinotecan remain the only two successfully developed topoisomerase I-targeting drugs in the United States. This experience with 9-AC raises important questions regarding how to best select new topoisomerase I-targeting drugs for future clinical development.

show abstract

Section: Phase I Studiesmentioning

confidence: 99%