Abstract

The addition of etoposide to the CHOP protocol (CHOEP) has been shown to improve outcome particularly in younger patients (<60 years) with aggressive non-Hodgkin’s lymphoma [Pfreundschuh, Blood 2004]. In the previous trials a dose of 100 mg/m2 etoposide was given intravenously on three consecutive days representing a disadvantage of CHOEP compared to standard CHOP in terms of patients’ convenience. Therefore we investigated the pharmacokinetic equivalency of etoposide as an oral preparation on days 2 and 3 compared to the intravenous route. Ten patients (male, n=7; female, n=3; median age 56 years) with aggressive B-cell- (n=9) or T-cell- (n=1) lymphoma were included. The CHOEP regimen consisted of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 2 mg/m2 and prednisone 100 mg orally days 1 to 5. Etoposide 100 mg/m2 was given intravenously on day 1, and 200 mg/m2 orally on days 3 and 4, respectively. EDTA blood for pharmacokinetic study were taken on days 1 (i.v. study) and 3 (p.o. study) before etoposide and after administration at 30, 60 and 90 min, every hour until 8 hours, followed by samplings at 16, 20, 24 and 48 hours. The samples were centrifuged immediately at 5°C for 15 min, and the plasma was aliquoted into cryo vials and stored at −20°C until assayed. Etoposide levels in plasma were determined by high-performance liquid chromatography (HPLC). The area under the plasma etoposide concentration versus time curve (AUC), plasma etoposide clearance (CL), volume of distribution in steady state (VDss) and terminal etoposide plasma half-life (t½) for the intravenous and oral administered drug were calculated based on the TOPFIT computer program. The median bioavailability after oral etoposide was 58 % with an interpatient variation (coefficient of variation, CV) of 26 %. AUC was very similar after 200 mg/m2 oral etoposide and intravenous administration of 100 mg/m2 of the drug, however the pharmacokinetic variation was higher after oral uptake compared to the parenteral route (35 % vs. 23 %). Data are presented in detail (medians and ranges) in Table #1. We conclude that, within the CHOEP regimen, the intravenous administration of 100 mg/m2 etoposide on days 2 and 3 can be replaced by 200 mg/m2 of the oral preparation, which simplifies the treatment in the outpatient setting.

Table #1
100 mg/m2 Etoposide i.v.200 mg/m2 Etoposide p.o.
C max [μg/ml] 16.7 (10.1 – 21.1) 13.4 (5.8 – 16.8) 
V ss [L] 14.4 (10.7 – 18.3) 15.1 (10.6 – 25.4) 
CL total [ml/min] 45.9 (29.6 – 62.8) 82.5 (45.5 – 151.0) 
CL renal [ml/min] 17.2 (9.4 – 52.6) 16.3 (4.7 – 39.7) 
t 1/2 [h] 4.1 (3.8 – 5.4) 5.8 (3.2 – 8.3) 
AUC [μg × h/ml] 72.5 (44.3 – 93.4) 81.6 (44.0 – 147.0) 
100 mg/m2 Etoposide i.v.200 mg/m2 Etoposide p.o.
C max [μg/ml] 16.7 (10.1 – 21.1) 13.4 (5.8 – 16.8) 
V ss [L] 14.4 (10.7 – 18.3) 15.1 (10.6 – 25.4) 
CL total [ml/min] 45.9 (29.6 – 62.8) 82.5 (45.5 – 151.0) 
CL renal [ml/min] 17.2 (9.4 – 52.6) 16.3 (4.7 – 39.7) 
t 1/2 [h] 4.1 (3.8 – 5.4) 5.8 (3.2 – 8.3) 
AUC [μg × h/ml] 72.5 (44.3 – 93.4) 81.6 (44.0 – 147.0) 

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