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

PD CORRELATES OF PK MEASUREMENTS.
Because of the wide PK variability of BCNU, and the known pulmonary
toxicity of BCNU when low chronic doses are given, we hypothesized that
BCNU PK might correlate with the risk of acute pulmonary injury. We evaluated
44 consecutive patients treated with CPA/cDDP/BCNU for the development
of acute pulmonary injury and covariates of this injury. Six patients in this
group had either incomplete PK data, short followup, or comorbid pulmonary
conditions making interpretation of their pulmonary function impossible.
Of the 38 évaluable patients, 20 (53%) developed acute pulmonary injury.
Twelve of the 20 patients had an elevated exposure to BCNU (>600 ug-min/ml
AUC). Only two of the 18 unaffected patients had a similar elevated BCNU exposure,
a difference which was statistically significant. There was no association
between CPA or cDDP PK and the acute pulmonary injury. Other known pretreatment
covariates of the risk of pulmonary injury (PFT's with DLCO, smoking,
cardiac, hepatic or renal function, chest irradiation) were not different between
the two groups. We thus concluded that elevated BCNU AUC is a
covariate of acute pulmonary injury following CPA/cDDP/BCNU, and might
be of causative importance in the development of this injury.
After a further followup of a larger cohort of breast cancer patients, we will
assess the association between CPA and cDDP PK and the risk of toxicities such
as cardiac injury or renal insufficiency, and evaluate all PK for relationship to 2year
relapse-free survival.
FUTURE DIRECTIONS
Given the growing body of observations which show correlations between
antineoplastic agent PK and patient outcome, we plan to develop mechanisms
to perform PK-directed drug dosing for CPA/cDDP/BCNU, and compare the
outcome of patients treated on the basis of therapeutic drug monitoring with
patients treated with standard doses of the regimen. Measurable outcomes will
include the effectiveness of the PK-directed method itself to reduce the variability
of CPA/cDDP/BCNU PK and whether or not clinical outcomes are affected
by this maneuver. If clinical outcomes were favorably affected by therapeutic
drug monitoring, this investigation would suggest an important role for the
clinical laboratory in monitoring and directing high-dose chemotherapy regimens.
REFERENCES
1. Jones RB, and Matthes S. Pharmacokinetics, in: High Dose Cancer Therapy. Pharmacology,
Hematopoietins, and Stem Cells. Armitage JO, and Antman KH, ed. pp. 43-
60. Williams and Wilkins, Baltimore, 1992.
2. Ayash LS, Wright, JE, Tretyakov O, et al. Cyclophosphamide pharmacokinetics:
correlation with cardiac toxicity and antitumor response. J Clin Oncol 10:995-1000,
1992.
3. Jones RB, Matthes SM, Shpall EJ, etal. Acute lung injury following high-dose
cyclophosphamide, cisplatin, and BCNU: pharmacodynamic evaluation of BCNU. J
Nat Cancer Inst, accepted for publication, 1/93.
4. Groshow LB, Jones RJ, Brundrett RB, et al. Pharmacokinetics of busulfan: correlation
with veno-occlusive disease in patients undergoing bone marrow transplantation.
Cancer Chemother Pharmacol 25:55-61,1989.
SIXTH INTERNATIONAL SYMPOSIUM ON AUTOLOGOUS BONE MARROW TRANSPLANTATION 127