Journal of Clinical Oncology, Vol 10, 1897-1906, Copyright © 1992 by American Society of Clinical Oncology
Plasma pharmacokinetics and pharmacodynamics of a new prodrug N-l- leucyldoxorubicin and its metabolites in a phase I clinical trial
J de Jong, GJ Geijssen, CN Munniksma, JB Vermorken and WJ van der Vijgh
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
PURPOSE: N-l-leucyldoxorubicin (Leu-Dox) was developed as a prodrug of
doxorubicin (Dox) to circumvent the cardiotoxicity associated with repeated
administration of Dox. Our purpose was to assess the pharmacokinetics of
Leu-Dox, Dox, doxorubicinol (Dol) and four other metabolites for
pharmacokinetically guided dose-escalation and to verify the prodrug
character of Leu-Dox. PATIENTS AND METHODS: Blood and urine of 14 patients
were sampled during the phase I clinical trial and analyzed by
high-performance liquid chromatography. Dose levels of Leu-Dox ranged from
18 mg/m2 to 225 mg/m2, the maximum-tolerated dose (MTD). Hematologic
parameters were monitored regularly in each patient. RESULTS: Leu-Dox was
rapidly distributed (half-life at alpha phase [t1/2 alpha] = 2.5 +/- 0.6
minutes) followed by a biphasic elimination (half-life at beta phase [t1/2
beta] = 17.4 +/- 7.3 minutes; half-life at gamma phase [t1/2 gamma] = 1.5
+/- 0.5 hours), as measured over the first 12 hours after administration.
In three patients, in whom Leu-Dox was found in the plasma for up to 48
hours after injection, a final elimination half-life (t1/2,elim) of 16
hours was observed. The t1/2,elim of Leu-Dox was short (0.6 to 16.5 hours)
compared with the t1/2,elim of Dox (38 +/- 11 hours). The mean residence
time and apparent volume of distribution were 23 +/- 5 minutes and 19 +/- 6
L/m2, respectively. Only 1.5% to 5% of the dose was excreted in the urine
over 48 hours, with Dox as major constituent. Dox was rapidly formed,
reaching its maximum concentration within 10 minutes after the end of
Leu-Dox infusion. Areas under the plasma concentration versus time curve
(AUC infinity, mean +/- SD, n = 16) of Leu-Dox, Dox, and Dol were 115 +/-
27 mumol.min/L, 41 +/- 12 mumol.min/L, and 33 +/- 14 mumol.min/L after a
dose of 60 mg/m2 Leu-Dox (= 86 mumol/m2). After the same molar dose of Dox
(50 mg/m2 = 86 mumol/m2), the AUC infinity of Dox was 179 mumol.min/L,
indicating that Leu-Dox was converted into Dox for 23% in the plasma
compartment. The AUCs infinity of Leu-Dox, Dox, and Dol increased linearly
with the dose. Negligible AUCs were observed for the other four
metabolites. The AUCs infinity of Leu-Dox and Dox at the MTD (517 and 145
mumol.min/L, respectively) were lower than those in mice at the LD10 (1,930
and 798 mumol.min/L, respectively), which means that the MTD could not be
predicted from the preclinical pharmacokinetics in mice. Hematologic
toxicity, especially the WBC count, appeared to correlate much better with
the AUC of Dox (r = .91) than with the AUC of Leu-Dox (r = .74), thus
confirming the prodrug character of Leu-Dox. CONCLUSIONS: Dox is rapidly
formed from Leu-Dox, and seems causative in the observed myelotoxicity. The
MTD could not be predicted from the AUC at the LD10 in mice.
