Etoposide, a semi-synthetic derivative of epipodophyllotoxin, has been used as an effective anticancer agent for more than two decades. Because its antitumor activity is heavily dependent on the schedule of administration, a suitable formulation to be administered by oral route was introduced several years ago.

In most situations, etoposide is used as a high-dose intravenous infusion; however, because of its dosage schedule-dependent activity, the response rate is significantly increased if the etoposide dose is fractionated and delivered as several short daily infusions. Although a clear therapeutic plasma concentration window has not yet been established, there is evidence suggesting that antitumor activity can be achieved at etoposide plasma concentrations of approximately 0.5–1 ?g/mL.It is also widely accepted that plasma levels of approximately 10 ?g/mL are associated with side effects.

Relatively constant plasma levels (i.e., avoiding large peak-to-trough variations) can be achieved by short frequent low-dose i.v. infusions for several days. This alternative does not appear to be the most adequate, as it requires hospitalization and represents significant discomfort for the patient. However, oral administration can also yield relatively constant plasma concentrations; it has been shown that etoposide can be absorbed when administered via this route.

Several studies have demonstrated that treatment with commercially available low-dose etoposide capsules is effective in several malignancies, because such formulations have been specifically developed for oral administration.

Commercial etoposide formulations for oral administration were only recently introduced in Mexico. These capsules are expensive and not widely available because their development requires sophisticated pharmaceutical technology. Attempts to develop oral etoposide capsules at the hospital-pharmacy level have resulted in formulations with unacceptably low bioavailability.

Pharmacokinetic studies have shown that etoposide can be absorbed when given orally as a solution. If this is so, oral administration of intravenous etoposide solution (IVES) may represent an adequate, cheaper and convenient dose option. Therefore, the purpose of the present study was to examine etoposide bioavailability after oral administration as IVES.

Eight adult cancer patients, participated in the study after giving informed consent. The protocol was approved by the ethical and scientific board of the Instituto Nacional de Cancerología. Patients received a daily 50-mg oral etoposide dose as IVES as follows: vials containing 100 mg of etoposide dissolved in 5 ml of vehicle (Vepesid™) were provided by Bristol-Myers-Squibb de México (Mexico City, Mexico); 2.5 mL of this solution was extracted from the vial with a syringe, diluted in 100 mL of water and given to the patient, and drug administration was performed after an overnight fast 30 min before breakfast in the morning. Blood samples were drawn from a suitable forearm vein at 0, 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 6.0, 8.0, 12.0, 16.0, and 24 h after medication. Plasma was obtained by centrifugation and kept frozen until analysis.

Etoposide concentration in plasma samples was determined by high-performance liquid chromatography by means of amperometric detection. The analytical method is described in detail elsewhere. Bioavailability parameters were obtained by non-compartmental analysis. Plasma concentration against time curves were constructed for each patient and maximal plasma concentration (C_max) and the time to reach this maximum (T_max) were obtained directly from these plots. Half-life (t_1/2) was estimated from the slope obtained by means of linear regression of the points corresponding to the terminal decay phase of the plasma concentration against a time curve plotted in semi-logarithmic coordinates. The area under the curve (AUC) was calculated by the trapezoidal rule and extrapolation to infinity was achieved by multiplying the last detectable concentration by the terminal slope.

The majority of the patients were male, and the lung carcinoma was the most frequent tumor type. All patients had normal levels of creatinine and normal hepatic function as defined by serum levels of total bilirubin, aspartate aminotransferase and alanine aminotransferase less than 1.5× the upper limit of normal (ULN).

The oral administration of etoposide as IVES resulted in adequate drug absorption. Plasma concentrations reached levels higher than 0.5 ?g/mL in all patients, and reached levels above 1.0 ?g/mL in all but one patient. In all cases, etoposide plasma concentrations were much below 10 ?g/mL, the highest concentration observed being 3.31 ?g/mL. Half-life values were in the range of 3.07–14.99 h.

Etoposide is an effective antitumor agent used worldwide. There is evidence that partial therapeutic responses can be achieved with mean plasma etoposide concentrations of 0.5–1.0 ?g/mL. There is also evidence that high plasma concentrations, i.e., around 10 ?g/mL, result in myelosuppression and other side effects11. J.D. Jonkman-de Vries, H. Rosing, O. van Tellingen, C. Neef, A.C. Dubbelman, A. Bult, W.W. ten Bokkel-Huinink, B.G. Taal and J.H. Beijnen, Pharmacokinetics of etoposide after oral and intravenous administration in patients with gastric carcinoma. Clin Drug Invest 10 (1995), p. 86. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus (5). Therefore, the aim of an etoposide dosing scheme is to achieve plasma concentrations of 0.5–1 ?g/mL for several hours while avoiding high-peak levels.

It has been shown that repeated daily oral administration of etoposide yields clinical responses similar to those obtained with intravenous infusions when the plasma concentrations achieved via both routes are within comparable range.

Therefore, the oral route has been indicated as a new approach for the administration of this drug. Commercial capsules specifically developed for the oral route have been successfully introduced in the U. S., Europe and Japan. At the time of this study, etoposide was marketed in Mexico only as IVES. We therefore examined whether oral administration of IVES results in drug absorption. Our results show that oral IVES administration yields an adequate bioavailability. Jonkman-de Vries et al. reported that after oral administration of a 50-mg commercial etoposide capsule to cancer patients, the AUC was 11.4 ± 1.55 ?g · h/mL and half-life was 7.76 ± 0.06 h. These values are almost identical to those observed after oral IVES administration, suggesting that the extent of drug absorption after oral administration of either commercial capsules or IVES is comparable. Jonkman-de Vries et al. observed a C_max of 1.25 ± 0.16 ?g after the 50 mg capsule, a value which is lower than the one we observed with 50-mg oral IVES (2.38 ± 0.30 ?g).

The fact that C_max was higher while AUC was similar suggests that the rate of etoposide absorption is faster with IVES than with the commercial capsule. This bioavailability profile of oral IVES appears to be more favorable than that of the commercially available capsule because the time that plasma concentrations are in the 0.5–1.0 ?g range is longer. There is evidence that oral etoposide pharmacokinetics are linear at doses lower than 250 mg. Therefore, drug accumulation after repetitive dosing depends on the terminal half-life and the dosing interval. Under such conditions, oral administration of 50-mg etoposide as IVES once or twice daily should be an adequate dosing regimen and negligible drug accumulation would be expected, avoiding high etoposide plasma levels which reduce the probability of the occurrence of side effects.