Assessment of toxicokinetics and toxicodynamics following intravenous administration of etoposide phosphate in beagle dogs.
The toxicokinetics and toxicodynamics of etoposide phosphate (BMY-40481), a water soluble phosphate ester derivative of etoposide, were investigated in beagle dogs (N = 4) following 5 min i.v. infusion doses equivalent to 57, 114 and 461 mg/m2 of etoposide. The doses were administered in sequence starting with the low dose. There was a 28 day wash-out period between the doses. Serial blood samples were collected over 32 hr and the levels of intact BMY-40481 and etoposide in plasma were measured using validated HPLC assays. Hematology profiles were obtained at pre-dose, and twice a week post-dose for 28 days to correlate systemic exposure to etoposide and hematologic toxicity. Following i.v. administration, plasma concentrations of BMY-40481 declined rapidly. For the 3 doses, mean t 1/2 of BMY-40481 ranged from 0.11-0.17 hr (6.6-11 min). The mean Cmax and AUC values of BMY-40481 ranged from 1.72-40.5 micrograms/ml and 0.16-4.14 hr.micrograms/ml, respectively. Both systemic clearance and steady state volume of distribution of BMY-40481 decreased significantly at the high dose. In contrast, the mean Cmax and AUC values of etoposide ranged from 5.46-39.4 micrograms/ml and 2.28-22.6 hr.micrograms/ml, respectively. Cmax occurred at the end of infusion (5 min) at all dose levels, indicating that etoposide was rapidly formed from BMY-40481. The apparent systemic clearance (range: 342-435 ml/min/m2) and apparent steady state volume of distribution (range: 21.5-26.6 l/m2) of etoposide were dose-independent. The AUC of etoposide was significantly correlated with hematologic toxicity, i.e., percent decreases in white blood count (WBC), absolute neutrophil count (ANC) and platelets.(ABSTRACT TRUNCATED AT 250 WORDS)
Igwemezie
L N
LN
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb, Princeton, New Jersey 08543-4000, USA.
Kaul
S
S
Barbhaiya
R H
RH
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D004285:Dogs; D004355:Drug Stability; D004492:Edetic Acid / Q000494:pharmacology; D005047:Etoposide / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D007262:Infusions, Intravenous; D008297:Male; D009943:Organophosphorus Compounds / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*
D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; C061400:etoposide phosphate; D005047:Etoposide; D004492:Edetic Acid