Pharmacodynamics and pharmacokinetics of a 72-hour infusion of 9-aminocamptothecin in adult cancer patients.

Takimoto, Chris H.; Dahut, William L.; Marino, Mark T.; Nakashima, Hiroshi; Liang, Michael D.; Harold, Nancy; Lieberman, Ronald; Arbuck, Susan G.; Band, Roger A.; Chen, A P; Hamilton, J. Michael; Cantilena, Louis R.; Allegra, Carmen J.; Grem, Jean L.

doi:10.1200/jco.1997.15.4.1492

Cited by 33 publications

(18 citation statements)

References 9 publications

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“…The proposed mechanism of action for camptothecins is inhibition of the DNA topological enzyme topoisomerase I through direct binding. This drug‐DNA‐enzyme binding results in a stabilized, cleavable complex along the DNA replication fork, resulting in an accumulation of single‐ and double‐strand DNA breaks and ultimately cell death 1–3 …”

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confidence: 99%

“…This drug-DNA-enzyme binding results in a stabilized, cleavable complex along the DNA replication fork, resulting in an accumulation of single-and double-strand DNA breaks and ultimately cell death. [1][2][3] Clinical trials in the early 1970s of the plant product camptothecin, formulated in sodium hydroxide to enhance solubility, were terminated due to a lack of clinical antitumor activity and a significant incidence of 1008 •…”

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confidence: 99%

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Evaluation of In Vitro Drug Interactions with Karenitecin, a Novel, Highly Lipophilic Camptothecin Derivative in Phase II Clinical Development

Smith

Newman

Hausheer

et al. 2003

The Journal of Clinical Pharma

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The objective of this study was to describe the potential metabolism and protein-binding interactions with karenitecin, a novel computer-engineered, highly lipophilic camptothecin. Individual cloned cytochrome P450 (CYP450) isoenzymes were used to determine, in vitro, the metabolism of karenitecin. Known substrates and inhibitors of each isoenzyme were employed to evaluate CYP450 drug interactions with karenitecin. To assess the extent, variability, and role of various drug-binding proteins, the authors examined, in vitro, the effects of both albumin (Alb) and alpha-acidic glycoprotein (AAG) on karenitecin plasma protein binding (PPB). Equilibrium dialysis techniques were used to measure the free fraction of karenitecin in the presence of varying ratios of Alb and AAG. Artificial plasma, spiked with karenitecin, was dialyzed for 72 hours at 37 degrees C against a Sorensen's buffer solution using regenerated cellulose membranes having a molecular weight cutoff of 12 to 14 kDa. Additional protein-binding experiments were conducted to assess the potential PPB drug interactions between karentiecin and other highly protein-bound drugs commonly used in the treatment of cancer patients. In vitro experiments suggested that karenitecin is metabolized by CYP450 3A4, 2C8, and 2D6 isoenzymes and is an inhibitor of the CYP450 3A4 and 2C8 isoenzymes. The mean (+/- SD) percentage of karenitecin bound to plasma proteins was 99.1% +/- 0.27%. The extent of karenitecin protein binding was directly proportional to the plasma concentration of AAG. Protein-binding displacement interactions were observed in the in vitro experiments with phenobarbital, phenytoin, mitoxantrone, and salicylic acid. It was concluded that karenitecin has the potential to alter CYP450 3A4 and 2C8 drug-metabolizing activity. In addition, in vitro PPB evaluations have demonstrated that karenitecin may displace other highly PPB drugs and that slight variations in plasma AAG concentration may result in large variations in free drug exposure. Each of these interactions could potentially result in increasing the toxicity or alter the efficacy of combination anticancer drug therapy if they are significant in patients. Future karenitecin clinical trials should include studies to monitor or evaluate the effects of these potential drug interactions on the overall toxicity of karenitecin when used in combination with other drugs.

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confidence: 99%

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confidence: 99%

Evaluation of In Vitro Drug Interactions with Karenitecin, a Novel, Highly Lipophilic Camptothecin Derivative in Phase II Clinical Development

Smith

Newman

Hausheer

et al. 2003

The Journal of Clinical Pharma

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“…is effective in the treatment of experimental colon and lung cancer. However, clinical trials of 9-AC did not demonstrate a substantial anticancer activity against colon and rectal cancers [4,5,[12][13][14][15]. Nonetheless, Rothenberg and Blanke proposed additional clinical trials to explore a dose-response effect [5]; their conclusion were based on the observation by Saltz et al who detected a high proportion of patients achieving prolonged stabilization [4].…”

Section: Discussionmentioning

confidence: 98%

“…In clinical trials, however, 9-AC did not demonstrate substantial activity against colon and rectal cancers. This may be because insufficient doses and/or inadequate administration schedule did not provide an effective drug concentration in the tumor tissue and cells [4,5,[12][13][14][15]. The activity of 9-AC toward a spectrum of tumor models and in clinical trials [16] indicates that a delivery system may be needed to fully exploit the potential of 9-AC for tumor treatment.…”

Section: Introductionmentioning

confidence: 99%

N-(2-Hydroxypropyl)methacrylamide Copolymer-9-Aminocamptothecin Conjugate: Colon-Specific Drug Delivery in Rats

Sakuma¹,

Lü²,

Pecharová³

et al. 2002

Journal of Bioactive and Compatible Polymers

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An N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugate containing 9-aminocamptothecin (9-AC) bound via a spacer containing an aromatic azo bond and leucylalanine (P-Azo-Leu-Ala-9-AC) was synthesized. The in vivo pharmacokinetic profile after oral administration was examined in rats and compared to free 9-AC. The aromatic azo bond of P-Azo-Leu-Ala-9-AC was stable in stomach and small intestine; the delivery of a large amount of intact conjugate to the colon was achieved. In the colon, the azoreductase activity first cleaved the azo bond followed by peptidase catalyzed cleavage of the leucylalanyl drug derivative resulting in the release of free 9-AC. However, the release rate from the conjugate was not fast enough to achieve high colon concentrations of free 9-AC. The results of the study suggest design features for the second generation of conjugates, including the use of a side-chain with a higher cleavage rate in the colon, combined with the incorporation of bioadhesion technology, to increase colon transit time.

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“…administration may determine the antitumor effectiveness of the drug. [30][31][32][33][34][35][36][37] We have previously studied 9-AC in a Phase-I trial (CTEP T92-0163, NYU 92-37) using 21-day and 14-day i.v. continuous infusions (CI), 38,39 paralleling our experience with a low-dose 21-day CI of topotecan.…”

Section: Development Of 9-amino-20(s)-camptothecinmentioning

confidence: 99%

Intraperitoneal Topoisomerase‐I Inhibitors: Preliminary Findings with 9‐Aminocamptothecin

Muggia

Liebes

Potměšil

et al. 2000

Annals of the New York Academy of Sciences

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The i.p. administration of topoisomerase I (Topo I) inhibitors has a pharmacologic advantage over intravenous application, including preservation of the biologically active lactone form. In our ongoing study, patients have received 9-amino-20(S)-camptothecin (9-AC) i.p. on days 1, 3, 5, 8, 10, and 12, repeated every 4 weeks. The daily dose has been escalated to level IV of 1.5 mg/m 2 (9.0 mg/m 2 per course), median of 3 cycles, range 1-4, with a reversible Grade 3 neutropenia in one patient. Responses included one CR (resolution of a pleural effusion), two patients without progressive disease (PD), two not evaluable, and two patients too early for evaluation. The area under the curve (AUC)ip/ AUCpl ratio (pharmacologic advantage) ranged from 7.6 to 16.5 on average, and, using nonlinear modeling, the pharmacologic decay data were fit to oneor two-compartmental models. Overall, a 9-AC i.p. application is well tolerated and anticipated to be an active regimen against i.p. malignancies, particularly those known to be sensitive to systemic Topo-I inhibitors.

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Pharmacodynamics and pharmacokinetics of a 72-hour infusion of 9-aminocamptothecin in adult cancer patients.

Cited by 33 publications

References 9 publications

Evaluation of In Vitro Drug Interactions with Karenitecin, a Novel, Highly Lipophilic Camptothecin Derivative in Phase II Clinical Development

Evaluation of In Vitro Drug Interactions with Karenitecin, a Novel, Highly Lipophilic Camptothecin Derivative in Phase II Clinical Development

N-(2-Hydroxypropyl)methacrylamide Copolymer-9-Aminocamptothecin Conjugate: Colon-Specific Drug Delivery in Rats

Intraperitoneal Topoisomerase‐I Inhibitors: Preliminary Findings with 9‐Aminocamptothecin

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