Skip Navigation

This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (12)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Ghazal-Aswad, S.
Right arrow Articles by Newell, D. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ghazal-Aswad, S.
Right arrow Articles by Newell, D. R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Annals of Oncology 10:329-334, 1999
© 1999 European Society for Medical Oncology

research-article

Pharmacokinetically guided dose escalation of carboplatin in epithelial ovarian cancer: Effect on drug-plasma AUC and peripheral blood drug-DNA adduct levels

S. Ghazal-Aswad1, M.J. Tilby2,, M. Lind2, N. Baily2, D. P. Sinha2, A. H. Calvert2 and D. R. Newell2

1Gynaecology Department, United Arab Emirates University, Al-Ain, United Arab Emirates Newcastle General Hospital, Newcastle upon Tyne, UK
2Cancer Research Unit, Medical School, University of Newcastle upon Tyne and the Department of Oncology, Northern Centre for Cancer Treatment Newcastle General Hospital, Newcastle upon Tyne, UK

Dr M.J.Tilby, Paediatric Oncology Laboratory, Cancer Research Unit, Medical School, University of Newcastle upon, Tyne Newcastle upon Tyne NE2 4HH UK E-mail: M.J.Tilby{at}ncl.ac.uk

Background: Platinum based drugs are active agents in epithelial ovarian cancer and increased platinum drug dose intensity is thought to lead to improved survival, because of the largely untested assumption that increased dose intensity results in an increased interaction of the platinum drug with its target, DNA. In a previously reported phase I trial (Lind et al., J Clin Oncol 1996; 14: 800–5), carboplatin dose intensity was increased by the use of G-CSF to support the bone marrow and using pharmacokinetically-guided carboplatin dosing. The objectives of this study were to validate the carboplatin dosing formula during high dose intensity therapy and evaluate the relationship between systemic carboplatin exposure and Pt-DNA adduct levels in peripheral blood leucocytes.

Patients and methods: A total of 17 patients were studied over four levels of dose intensification. The carboplatin dose was calculated using the ‘Calvert formula’. Levels of drug-target interaction in peripheral blood leukocytes were measured using an immunoassay based on a monoclonal antibody that recognises DNA-platinum adducts. Pharmacokinetic measurements were carried out using a previously validated single sample method.

Results: The area under the curve of concentration of unbound carboplatin in plasma versus time (AUC) for target AUC values of 5, 7 and 9 mg/ml min were: 5.6 ± 1.0, 7.3 ± 0.7 and 9.8 ± 0.5 mg/ml min (mean ± S.D.). There was a good correlation between target and achieved dose intensities (r2 = 0.899) and the slope of the linear regression line was 0.95 (±0.09 SD) not significantly different to 1.0 (P > 0.6). The levels of immunoreactive DNA adducts were not detectable at a target AUC of 5 mg/ml.min but increased progressively at the higher AUC levels. Accumulation of adducts between courses was not detected.

Conclusions: Pharmacokinetically-based carboplatin dosing during high intensity therapy accurately predicted the dose required to achieve a target AUC and resulted in consistent patient exposure to active drug. During the dose escalation study, peripheral blood leucocyte DNA platinum-DNA adduct levels were positively related to drug dose and drug AUC.

carboplatin, drug-target interaction, ovarian cancer, pharmacokinetically based dosing, pharmacokinetics, platinum-DNA adducts


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Nucleic Acids ResHome page
E. E. Bosco, C. N. Mayhew, R. F. Hennigan, J. Sage, T. Jacks, and E. S. Knudsen
RB signaling prevents replication-dependent DNA double-strand breaks following genotoxic insult
Nucleic Acids Res., January 2, 2004; 32(1): 25 - 34.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
M. C. Etienne, F. Leger, X. Pivot, E. Chatelut, R. J. Bensadoun, E. Guardiola, N. Renee, N. Magne, P. Canal, and G. Milano
Pharmacokinetics of low-dose carboplatin and applicability of a method of calculation for estimating individual drug clearance
Ann. Onc., April 1, 2003; 14(4): 643 - 647.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
T. E. Murdter, J. Coller, A. Claviez, F. Schonberger, U. Hofmann, P. Dreger, and M. Schwab
Sensitive and Rapid Quantification of Busulfan in Small Plasma Volumes by Liquid Chromatography-Electrospray Mass Spectrometry
Clin. Chem., August 1, 2001; 47(8): 1437 - 1442.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
M. Mazumdar, A. Smith, W. P. Tong, and R. J. Motzer
Calvert's Formula for Dosing Carboplatin: Overview and Concerns of Applicability in High-Dose Setting
J Natl Cancer Inst, September 6, 2000; 92(17): 1434 - 1436.
[Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.