A novel pharmacodynamically based approach to dose optimization of carboplatin when used in combination with etoposide

Chandra Belani, M. J. Egorin, J. S. Abrams, D. Hiponia, M. Eisenberger, J. Aisner, D. A. Van Echo

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Thrombocytopenia, the dose-limiting toxicity of carboplatin, is manageable and predictable with the dosing equation: Dose (mg/m2) = (0.091) (creatinine clearance)/(body surface area) (desired percentage change in platelet count) + 86. We used this equation to dose patients receiving carboplatin (day 1) and etoposide (80 mg/m2 days 1 to 3). An initial cohort of 14 patients with non-small-cell lung cancer (NSCLC) were treated with 75% of the calculated dose of carboplatin (29 evaluable courses) as a precaution against added myelosuppression from combination chemotherapy. The observed reduction in platelets was essentially equal to the reduction in platelets predicted if patients had received carboplatin alone. Subsequently, a second cohort of 20 evaluable patients with NSCLC received the full calculated dose of carboplatin and etoposide (51 evaluable courses). There was a linear relationship between observed (o) and predicted (p) reductions in platelets. With full-dose carboplatin in combination with etoposide, there was a significantly greater reduction in platelets, and lower platelet nadir. Among 34 evaluable patients (80 courses) there was one complete response (CR) and four partial responses (PRs) for an overall response rate of 15% (90% confidence ± 9%). The median duration of survival for responders was 336+ days and for nonresponders was 204+ days. Therapy was well tolerated. This study, in addition, supports our concept of individualized dosing of carboplatin and the underlying pharmacokinetic/pharmacodynamic relationships and represents an interesting pharmacodynamic and quantitative approach to studying potential drug-drug interactions and defining appropriate dosages for combination chemotherapy.

Original languageEnglish (US)
Pages (from-to)1896-1902
Number of pages7
JournalJournal of Clinical Oncology
Volume7
Issue number12
DOIs
StatePublished - Jan 1 1989

Fingerprint

Carboplatin
Etoposide
Blood Platelets
Combination Drug Therapy
Non-Small Cell Lung Carcinoma
Body Surface Area
Platelet Count
Drug Interactions
Thrombocytopenia
Creatinine
Pharmacokinetics
Survival
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Belani, Chandra ; Egorin, M. J. ; Abrams, J. S. ; Hiponia, D. ; Eisenberger, M. ; Aisner, J. ; Van Echo, D. A. / A novel pharmacodynamically based approach to dose optimization of carboplatin when used in combination with etoposide. In: Journal of Clinical Oncology. 1989 ; Vol. 7, No. 12. pp. 1896-1902.
@article{17e8bafc8d514c25aa5e59b90e622960,
title = "A novel pharmacodynamically based approach to dose optimization of carboplatin when used in combination with etoposide",
abstract = "Thrombocytopenia, the dose-limiting toxicity of carboplatin, is manageable and predictable with the dosing equation: Dose (mg/m2) = (0.091) (creatinine clearance)/(body surface area) (desired percentage change in platelet count) + 86. We used this equation to dose patients receiving carboplatin (day 1) and etoposide (80 mg/m2 days 1 to 3). An initial cohort of 14 patients with non-small-cell lung cancer (NSCLC) were treated with 75{\%} of the calculated dose of carboplatin (29 evaluable courses) as a precaution against added myelosuppression from combination chemotherapy. The observed reduction in platelets was essentially equal to the reduction in platelets predicted if patients had received carboplatin alone. Subsequently, a second cohort of 20 evaluable patients with NSCLC received the full calculated dose of carboplatin and etoposide (51 evaluable courses). There was a linear relationship between observed (o) and predicted (p) reductions in platelets. With full-dose carboplatin in combination with etoposide, there was a significantly greater reduction in platelets, and lower platelet nadir. Among 34 evaluable patients (80 courses) there was one complete response (CR) and four partial responses (PRs) for an overall response rate of 15{\%} (90{\%} confidence ± 9{\%}). The median duration of survival for responders was 336+ days and for nonresponders was 204+ days. Therapy was well tolerated. This study, in addition, supports our concept of individualized dosing of carboplatin and the underlying pharmacokinetic/pharmacodynamic relationships and represents an interesting pharmacodynamic and quantitative approach to studying potential drug-drug interactions and defining appropriate dosages for combination chemotherapy.",
author = "Chandra Belani and Egorin, {M. J.} and Abrams, {J. S.} and D. Hiponia and M. Eisenberger and J. Aisner and {Van Echo}, {D. A.}",
year = "1989",
month = "1",
day = "1",
doi = "10.1200/JCO.1989.7.12.1896",
language = "English (US)",
volume = "7",
pages = "1896--1902",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "12",

}

A novel pharmacodynamically based approach to dose optimization of carboplatin when used in combination with etoposide. / Belani, Chandra; Egorin, M. J.; Abrams, J. S.; Hiponia, D.; Eisenberger, M.; Aisner, J.; Van Echo, D. A.

In: Journal of Clinical Oncology, Vol. 7, No. 12, 01.01.1989, p. 1896-1902.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A novel pharmacodynamically based approach to dose optimization of carboplatin when used in combination with etoposide

AU - Belani, Chandra

AU - Egorin, M. J.

AU - Abrams, J. S.

AU - Hiponia, D.

AU - Eisenberger, M.

AU - Aisner, J.

AU - Van Echo, D. A.

PY - 1989/1/1

Y1 - 1989/1/1

N2 - Thrombocytopenia, the dose-limiting toxicity of carboplatin, is manageable and predictable with the dosing equation: Dose (mg/m2) = (0.091) (creatinine clearance)/(body surface area) (desired percentage change in platelet count) + 86. We used this equation to dose patients receiving carboplatin (day 1) and etoposide (80 mg/m2 days 1 to 3). An initial cohort of 14 patients with non-small-cell lung cancer (NSCLC) were treated with 75% of the calculated dose of carboplatin (29 evaluable courses) as a precaution against added myelosuppression from combination chemotherapy. The observed reduction in platelets was essentially equal to the reduction in platelets predicted if patients had received carboplatin alone. Subsequently, a second cohort of 20 evaluable patients with NSCLC received the full calculated dose of carboplatin and etoposide (51 evaluable courses). There was a linear relationship between observed (o) and predicted (p) reductions in platelets. With full-dose carboplatin in combination with etoposide, there was a significantly greater reduction in platelets, and lower platelet nadir. Among 34 evaluable patients (80 courses) there was one complete response (CR) and four partial responses (PRs) for an overall response rate of 15% (90% confidence ± 9%). The median duration of survival for responders was 336+ days and for nonresponders was 204+ days. Therapy was well tolerated. This study, in addition, supports our concept of individualized dosing of carboplatin and the underlying pharmacokinetic/pharmacodynamic relationships and represents an interesting pharmacodynamic and quantitative approach to studying potential drug-drug interactions and defining appropriate dosages for combination chemotherapy.

AB - Thrombocytopenia, the dose-limiting toxicity of carboplatin, is manageable and predictable with the dosing equation: Dose (mg/m2) = (0.091) (creatinine clearance)/(body surface area) (desired percentage change in platelet count) + 86. We used this equation to dose patients receiving carboplatin (day 1) and etoposide (80 mg/m2 days 1 to 3). An initial cohort of 14 patients with non-small-cell lung cancer (NSCLC) were treated with 75% of the calculated dose of carboplatin (29 evaluable courses) as a precaution against added myelosuppression from combination chemotherapy. The observed reduction in platelets was essentially equal to the reduction in platelets predicted if patients had received carboplatin alone. Subsequently, a second cohort of 20 evaluable patients with NSCLC received the full calculated dose of carboplatin and etoposide (51 evaluable courses). There was a linear relationship between observed (o) and predicted (p) reductions in platelets. With full-dose carboplatin in combination with etoposide, there was a significantly greater reduction in platelets, and lower platelet nadir. Among 34 evaluable patients (80 courses) there was one complete response (CR) and four partial responses (PRs) for an overall response rate of 15% (90% confidence ± 9%). The median duration of survival for responders was 336+ days and for nonresponders was 204+ days. Therapy was well tolerated. This study, in addition, supports our concept of individualized dosing of carboplatin and the underlying pharmacokinetic/pharmacodynamic relationships and represents an interesting pharmacodynamic and quantitative approach to studying potential drug-drug interactions and defining appropriate dosages for combination chemotherapy.

UR - http://www.scopus.com/inward/record.url?scp=0024786735&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0024786735&partnerID=8YFLogxK

U2 - 10.1200/JCO.1989.7.12.1896

DO - 10.1200/JCO.1989.7.12.1896

M3 - Article

C2 - 2555452

AN - SCOPUS:0024786735

VL - 7

SP - 1896

EP - 1902

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 12

ER -