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Therapeutic drug monitoring of 21-day oral etoposide in patients with advanced non-small cell lung cancer.
Clin Cancer Res. 1998 Jul; 4(7):1705-10.CC

Abstract

The purpose of this study was to prospectively test a pharmacodynamic model for therapeutic drug monitoring of 21-day oral etoposide. In our previous studies, etoposide trough concentrations on this schedule were related to the hematological toxicity, expressed as WBC and neutrophil counts at the nadir. The following pharmacodynamic model estimated the absolute neutrophil count at the nadir (ANCn) based on the etoposide concentration (Ec) and the pretreatment count (ANCp): ANCn=0.32(1 + ANCp x e(-2.47 x Ec)). Patients were treated with 40 mg/m2/day etoposide p.o. x 21 days and 100 mg/m2 cisplatin i.v. on day 1. All patients had non-small cell lung cancer stage IIIB or IV, had a performance status of 0-2, and had a median age of 66 (range, 42-80). Etoposide was measured in the plasma on day 8 by high-performance liquid chromatography, and dosage adjustments were made for the remainder of the course. We targeted for grade 3 neutropenia (ANCn, 500 to 999/microl) and attempted to avoid grade 4 neutropenia (ANCn, <500/microl). Of 25 patients entered, 22 were evaluable for therapeutic drug monitoring in the first course. Three patients developed grade 3 neutropenia, and seven patients developed grade 4 neutropenia. Etoposide concentrations were significantly correlated with ANCn in the first course (r=-0.50, P < 0.02). For those patients whose dosages were not changed, the estimated correlation between predicted and actual ANCn was 0.77 (P < 0.01). No evidence of significant bias of the pharmacodynamic model was detected. The etoposide dosages were increased in 12 patients and were not changed in the remaining patients. The precision of the model was good in patients whose dosages were not changed but poor in patients whose dosages were increased. The actual observed ANCn was compared with the predicted ANCn based on the pharmacodynamic model. The prediction was considered accurate if the predicted and actual ANCn values were within 500/microl of each other. Using this margin, the ANCn was accurately predicted in 10 of 22 patients. Etoposide concentrations >0.3 microg/ml on this schedule were significantly correlated with combined grades 3 and 4 neutropenia (P < 0.0001). In conclusion, the pharmacodynamic model is statistically sound when applied to a population of patients. However, when applied to individual patients for therapeutic drug monitoring, the model lacks precision and accuracy.

Authors+Show Affiliations

Department of Veteran Affairs Medical Center, University of Tennessee, Memphis 38163, USA. amiller@utmem1.utmem.eduNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

9676845

Citation

Miller, A A., et al. "Therapeutic Drug Monitoring of 21-day Oral Etoposide in Patients With Advanced Non-small Cell Lung Cancer." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 4, no. 7, 1998, pp. 1705-10.
Miller AA, Tolley EA, Niell HB. Therapeutic drug monitoring of 21-day oral etoposide in patients with advanced non-small cell lung cancer. Clin Cancer Res. 1998;4(7):1705-10.
Miller, A. A., Tolley, E. A., & Niell, H. B. (1998). Therapeutic drug monitoring of 21-day oral etoposide in patients with advanced non-small cell lung cancer. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 4(7), 1705-10.
Miller AA, Tolley EA, Niell HB. Therapeutic Drug Monitoring of 21-day Oral Etoposide in Patients With Advanced Non-small Cell Lung Cancer. Clin Cancer Res. 1998;4(7):1705-10. PubMed PMID: 9676845.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Therapeutic drug monitoring of 21-day oral etoposide in patients with advanced non-small cell lung cancer. AU - Miller,A A, AU - Tolley,E A, AU - Niell,H B, PY - 1998/7/24/pubmed PY - 1998/7/24/medline PY - 1998/7/24/entrez SP - 1705 EP - 10 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 4 IS - 7 N2 - The purpose of this study was to prospectively test a pharmacodynamic model for therapeutic drug monitoring of 21-day oral etoposide. In our previous studies, etoposide trough concentrations on this schedule were related to the hematological toxicity, expressed as WBC and neutrophil counts at the nadir. The following pharmacodynamic model estimated the absolute neutrophil count at the nadir (ANCn) based on the etoposide concentration (Ec) and the pretreatment count (ANCp): ANCn=0.32(1 + ANCp x e(-2.47 x Ec)). Patients were treated with 40 mg/m2/day etoposide p.o. x 21 days and 100 mg/m2 cisplatin i.v. on day 1. All patients had non-small cell lung cancer stage IIIB or IV, had a performance status of 0-2, and had a median age of 66 (range, 42-80). Etoposide was measured in the plasma on day 8 by high-performance liquid chromatography, and dosage adjustments were made for the remainder of the course. We targeted for grade 3 neutropenia (ANCn, 500 to 999/microl) and attempted to avoid grade 4 neutropenia (ANCn, <500/microl). Of 25 patients entered, 22 were evaluable for therapeutic drug monitoring in the first course. Three patients developed grade 3 neutropenia, and seven patients developed grade 4 neutropenia. Etoposide concentrations were significantly correlated with ANCn in the first course (r=-0.50, P < 0.02). For those patients whose dosages were not changed, the estimated correlation between predicted and actual ANCn was 0.77 (P < 0.01). No evidence of significant bias of the pharmacodynamic model was detected. The etoposide dosages were increased in 12 patients and were not changed in the remaining patients. The precision of the model was good in patients whose dosages were not changed but poor in patients whose dosages were increased. The actual observed ANCn was compared with the predicted ANCn based on the pharmacodynamic model. The prediction was considered accurate if the predicted and actual ANCn values were within 500/microl of each other. Using this margin, the ANCn was accurately predicted in 10 of 22 patients. Etoposide concentrations >0.3 microg/ml on this schedule were significantly correlated with combined grades 3 and 4 neutropenia (P < 0.0001). In conclusion, the pharmacodynamic model is statistically sound when applied to a population of patients. However, when applied to individual patients for therapeutic drug monitoring, the model lacks precision and accuracy. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/9676845/Therapeutic_drug_monitoring_of_21_day_oral_etoposide_in_patients_with_advanced_non_small_cell_lung_cancer_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=9676845 DB - PRIME DP - Unbound Medicine ER -