Clinical pharmacodynamics of continuous infusion teniposide: Systemic exposure as a determinant of response in a Phase I trial

J. H. Rodman, M. Abromowitch, J. A. Sinkule, F. A. Hayes, G. K. Rivera, W. E. Evans

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Abstract

Teniposide (VM-26) is an effective anticancer drug usually administered as a short infusion in doses of 150 to 165 mg/m2. The objectives of the trial reported here were to evaluate clinical responses and assess pharmacokinetic parameters as a determinant of outcome when VM-26 was administered as a 72-hour continuous infusion (Cl) with doses escalated from 300 to 750 mg/m2 per course. Twenty-eight patients with recurrent leukemia, lymphoma, or neuroblastoma received 53 courses of Cl VM-26 and 16 had measurable responses. There were two partial remissions and one stable disease among seven neuroblastoma patients and 13 of 21 leukemia/lymphoma patients had oncolytic responses (≥ 75% decrease in circulating blasts). Toxicity included moderate to severe mucositis and myelosuppression. Pharmacokinetic parameters determined during 35 courses administered to 23 patients were highly variable. Clearance (Cl) ranged between 3.7 and 43.8 ml/min/m2, resulting in VM-26 plasma concentrations from 2.8 to 30.6 mg/L across all dose levels. The interpatient pharmacokinetic variability reflected in Cl and VM-26 steady state concentrations (Css), obscured any dose-response relationship. However, when pharmacokinetic parameters for responding and nonresponding patients were compared, statistically significant relationships were observed. For responders, the mean Css was 15.2 mg/L and mean Cl was 12.1 mL/min/m2; for nonresponders, mean Css was 6.2 mg/L (P < .01) and mean Cl was 21.3 mL/min/m2 (P < .05). Thus, patients with higher Cl and lower Css were less likely to respond. Clinical responses occurred in ten of ten patients with Css > 12 mg/L, and only five of 13 patients with Css < 12 mg/L (P < .01). In this study, interpatient pharmacokinetic variability yielded a four- to sixfold difference in intensity of systemic exposure (Css) within the same dose level, which was an important determinant of clinical response. These data indicate that achieving a VM-26 target concentration for individual patients could ensure an increased intensity of systemic exposure in patients with a high Cl and improve the likelihood of effective therapy.

Original languageEnglish (US)
Pages (from-to)1007-1014
Number of pages8
JournalJournal of Clinical Oncology
Volume5
Issue number7
DOIs
StatePublished - Jan 1 1987

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Teniposide
Pharmacokinetics
Neuroblastoma
Lymphoma
Leukemia
Mucositis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Clinical pharmacodynamics of continuous infusion teniposide : Systemic exposure as a determinant of response in a Phase I trial. / Rodman, J. H.; Abromowitch, M.; Sinkule, J. A.; Hayes, F. A.; Rivera, G. K.; Evans, W. E.

In: Journal of Clinical Oncology, Vol. 5, No. 7, 01.01.1987, p. 1007-1014.

Research output: Contribution to journalArticle

Rodman, J. H. ; Abromowitch, M. ; Sinkule, J. A. ; Hayes, F. A. ; Rivera, G. K. ; Evans, W. E. / Clinical pharmacodynamics of continuous infusion teniposide : Systemic exposure as a determinant of response in a Phase I trial. In: Journal of Clinical Oncology. 1987 ; Vol. 5, No. 7. pp. 1007-1014.
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abstract = "Teniposide (VM-26) is an effective anticancer drug usually administered as a short infusion in doses of 150 to 165 mg/m2. The objectives of the trial reported here were to evaluate clinical responses and assess pharmacokinetic parameters as a determinant of outcome when VM-26 was administered as a 72-hour continuous infusion (Cl) with doses escalated from 300 to 750 mg/m2 per course. Twenty-eight patients with recurrent leukemia, lymphoma, or neuroblastoma received 53 courses of Cl VM-26 and 16 had measurable responses. There were two partial remissions and one stable disease among seven neuroblastoma patients and 13 of 21 leukemia/lymphoma patients had oncolytic responses (≥ 75{\%} decrease in circulating blasts). Toxicity included moderate to severe mucositis and myelosuppression. Pharmacokinetic parameters determined during 35 courses administered to 23 patients were highly variable. Clearance (Cl) ranged between 3.7 and 43.8 ml/min/m2, resulting in VM-26 plasma concentrations from 2.8 to 30.6 mg/L across all dose levels. The interpatient pharmacokinetic variability reflected in Cl and VM-26 steady state concentrations (Css), obscured any dose-response relationship. However, when pharmacokinetic parameters for responding and nonresponding patients were compared, statistically significant relationships were observed. For responders, the mean Css was 15.2 mg/L and mean Cl was 12.1 mL/min/m2; for nonresponders, mean Css was 6.2 mg/L (P < .01) and mean Cl was 21.3 mL/min/m2 (P < .05). Thus, patients with higher Cl and lower Css were less likely to respond. Clinical responses occurred in ten of ten patients with Css > 12 mg/L, and only five of 13 patients with Css < 12 mg/L (P < .01). In this study, interpatient pharmacokinetic variability yielded a four- to sixfold difference in intensity of systemic exposure (Css) within the same dose level, which was an important determinant of clinical response. These data indicate that achieving a VM-26 target concentration for individual patients could ensure an increased intensity of systemic exposure in patients with a high Cl and improve the likelihood of effective therapy.",
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