Pharmacokinetic comparison of oral and intravenous etoposide in patients treated with the CHOEP-regimen for malignant lymphomas

The addition of etoposide to the CHOP protocol (CHOEP) has been shown to improve outcome in patients with aggressive non-Hodgkin’s lymphoma. The intravenous administration of etoposide on three consecutive days represents a logistic problem and needs resources particular in the outpatient setting. This could be avoided by using etoposide capsules on days 2 and 3. However, the oral administration of cytotoxic agents is often affected by variable absorption and drug interactions.

We investigated the pharmacokinetic equivalency of oral and intravenous etoposide in ten patients (male, n = 7; female, n = 3; median age 56 years) with aggressive lymphomas. Treatment consisted of standard CHOP plus etoposide 100 mg/m² given intravenously on day 1, and 200 mg/m² orally on days 3 and 4. Samples from blood and urine were taken on days 1 (i.v. study) and 3 (p.o. study) before and after etoposide administration. Etoposide levels were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were calculated with the TOPFIT computer program.

Mean peak plasma level after intravenous etoposide was significantly higher compared to oral administration (16.3 ± 3.7 vs. 12.0 ± 4.2 μg/ml; P = 0.015). The mean bioavailability of oral etoposide was 58 ± 15% with an interpatient variability of 26%. Significant differences of bioavailability of oral etoposide between the used dose levels (350, 400 and 450 mg) were not observed. Mean AUC after a 100 mg/m² intravenous and a 200 mg/m² oral dose of etoposide were 74.0 ± 18.3 and 84.9 ± 29.6 μg h/ml (P = 0.481). Interpatient variability of AUC was 25% for the intravenous route and 35% after oral intake. Urinary etoposide excretion as percentage of administered dose was 39.4 ± 10.6% after intravenous infusion versus 35.4 ± 9.4% after oral intake (P = 0.422). Renal clearance was also very similar with intravenous and oral route (18.5 ± 7.4 vs. 16.7 ± 6.6 ml/min; P = 0.546).

The equivalency of AUC after 200 mg/m² of oral and 100 mg/m² of intravenous etoposide support the use of the oral preparation in patients treated with the CHOEP regimen, which makes the chemotherapy more convenient for the patients and help to reduce costs.