Phase I/pharmacokinetic study of high-dose progesterone and doxorubicin.
OBJECTIVE
We  developed a new formulation of progesterone that permits administration of up to 10 g of progesterone as a continuous intravenous infusion over 24 hours and conducted a phase I clinical trial to determine whether progesterone could modulate the in vivo cytotoxicity of the P-glycoprotein substrate doxorubicin.


METHODS
Thirty-four patients with advanced malignancies were treated with increasing doses of progesterone and a fixed dose of 60 mg/m2 of doxorubicin given as an intravenous bolus 2 hours after starting a 24-hour intravenous infusion of progesterone.


RESULTS
Progesterone enhanced doxorubicin-induced myelotoxicity in a dose-dependent fashion without altering the pharmacokinetics of doxorubicin. The steady-state plasma concentration of progesterone at a dose level of 4 g was 4.1 +/- 0.9 mumol/L, which was higher than the minimal concentration required to reverse multidrug resistance (MDR) in vitro.


CONCLUSIONS
Progesterone enhanced the hematologic toxicity of doxorubicin without altering its pharmacokinetics, suggesting that progesterone could modulate P-glycoprotein at the level of pluripotent hematopoietic stem cells. Adequate tissue concentrations of progesterone could be achieved in vivo to modulate doxorubicin toxicity in the bone marrow and thus potentially in tumor tissue as well. Selectivity may potentially be gained by using hematopoietic growth factors to offset the enhanced hematologic toxicity of doxorubicin while leaving the enhancement of toxicity to tumor cells unchanged.
Christen
R D
RD
Department of Medicine, University of California at Diego, La Jolla 92093-0812.
McClay
E F
EF
Plaxe
S C
SC
Yen
S S
SS
Kim
S
S
Kirmani
S
S
Wilgus
L L
LL
Heath
D D
DD
Shalinsky
D R
DR
Freddo
J L
JL
D000328:Adult; D000368:Aged; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004351:Drug Resistance; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D009503:Neutropenia / Q000139:chemically induced; D011374:Progesterone / Q000008:administration & dosage / Q000009:adverse effects*
D011374:Progesterone; D004317:Doxorubicin