VI Autologous Bone Marrow Transplantation.pdf - Blog Science ...

THE PHARMACOLOGY OF INTENSIVE CYCLOPHOSPHAMIDE,
CISPLATIN AND BCNU (CPA/CDDP/BCNU) IN PATIENTS WITH
BREAST CANCER.
Roy B. Jones, Steven Matthes, Christopher Dufton, Scott I. Bearman,
Salomon M. Stemmer, Susan Meyers, and Elizabeth J. Shpall.
Combinations of alkylating agents in intensive doses with autologous bone
marrow support (ABMS) are commonly used to treat advanced adult solid tumors,
particularly breast and ovarian cancer. These drugs are usually administered
in the maximally tolerated doses adjusted for weight or body surface area.
The specific drug combinations and schedule of administration often lack firm
scientific or clinical rationale, and, with rare exception, no further individualization
of dose is ever done. In an attempt to lend further rationale to these treatments,
we embarked on a program of comprehensive pharmacokinetic (PK)
monitoring of the CPA/cDDP/BCNU regimen. The major goals of this program
were:
1) Description of the PK variability of the regimen
2) Definition of pharmacodynamic (PD) correlations of this PK variability
3) Development of predictive methods for the PK of each drug in each patient
to allow individualized drug dosing.
4) Testing the impact of individualized dosing on patient outcomes.
BACKGROUND AND SIGNIFICANCE
The use of PK measurements to direct drug dosing is common in medicine.
Antibiotics, neurotropic agents, and immunosuppressants exemplify classes of
drugs where therapeutic drug monitoring is routinely performed. The goal of
this activity is to optimize the therapeutic index of the drug by optimally balancing
toxicity and therapeutic effect through dosage individualization. Several hypotheses
underlie these programs:
1) Important variability in drug PK exists between patients in spite of standardized
drug dosing
2) This variability should correlate with toxic or therapeutic outcome, preferably
both.
3) Correction of this variability should be possible using therapeutic drug
monitoring, and should improve the therapeutic index of the drug (regimen).
It is ironic that therapeutic drug monitoring is almost never used in
anticancer therapy. Antineoplastic agents have the narrowest therapeutic index
of any class of drugs and are the most common class of drugs to produce fatal
toxicity in routine use. The only antineoplastic agent frequently monitored is
methotrexate, ironically a drug where a "rescue" compound (leucovorin) is
available.
There are important deterrents to antineoplastic drug monitoring. Most
124 SIXTH INTERNATIONAL SYMPOSIUM ON AUTOLOGOUS BONE MARROW TRANSPLANTATION