Archives of Medical Research 30 (1999) 212–215

ORIGINAL ARTICLE
Bioavailability of Etoposide after Oral Administration of the Solution
Marketed for Intravenous Use:
Therapeutic and Pharmacoeconomic Perspectives
José Luis Aguilar Ponce,* Yolanda Flores-Picazo,** José Pérez-Urizar,**
Gilberto Castañeda-Hernández,** Juan W. Zinser-Sierra,* Alfonso Dueñas-González,*
Ernesto Calderón-Flores,* Blanca Angélica Segura-Pacheco* and Jaime de la Garza-Salazar*
*Instituto Nacional de Cancerología, México, D.F., Mexico
**Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, México, D.F., Mexico

Received for publication August 24, 1998; accepted March 1, 1999 (98/101).

Background. Oral etoposide administration is a suitable alternative to the intravenous

route; therefore, commercial capsules have been developed. Before these capsules were
available in Mexico, we studied drug bioavailability after oral administration of the intra-
venous etoposide solution (IVES).
Methods. Eight adult cancer patients received a 50-mg oral etoposide dose as IVES and
blood samples were collected over a period of 24 h. Plasma etoposide concentration was
determined by high-performance liquid chromatography, plasma concentration against
time curves were constructed, and bioavailability parameters were calculated.
Results. Oral IVES yielded an adequate bioavailability profile because Cmax was 2.38 6
0.30 mg/mL, AUC was 12.87 6 2.02 mg/mL and half-life was 6.72 6 0.97 h.
Conclusions. Considering that the pharmacokinetic aim is to maintain plasma concentra-
tions between 0.5 and 1.0 mg/mL for several hours while avoiding high concentrations,
i.e., of 10 mg/mL or higher, oral administration of 50-mg etoposide as IVES appears to be
a suitable dosing option. In addition, oral IVES is considerably less expensive than intra-
venous administration in terms of both drug presentation and administration. © 1999
IMSS. Published by Elsevier Science Inc.
Key Words: Etoposide, Oral administration, Bioavailability, Pharmacokinetics,
Pharmacoeconomics.

Introduction In most situations, etoposide is used as a high-dose intra-

Etoposide, a semi-synthetic derivative of epipodophyllo-
toxin, has been used as an effective anticancer agent for
more than two decades (1). Because its antitumor activity is
heavily dependent on the schedule of administration (2), a
suitable formulation to be administered by oral route was
introduced several years ago.
Address reprint requests to: Dr. José Luis Aguilar-Ponce, Instituto
Nacional de Cancerología, División de Enseñanza, San Fernando #22, Tlal-
pan, 14000, México, D.F., México. Tel.: (1525) 628-0435; FAX: (1525)
573-4651.
venous infusion (3–5); however, because of its dosage
schedule-dependent activity, the response rate is signifi-
cantly increased if the etoposide dose is fractionated and de-
livered as several short daily infusions (6–8). Although a
clear therapeutic plasma concentration window has not yet
been established, there is evidence suggesting that antitu-
mor activity can be achieved at etoposide plasma concentra-
tions of approximately 0.5–1 mg/mL (6,9). It is also widely
accepted that plasma levels of approximately 10 mg/mL are
associated with side effects (10,11).
Relatively constant plasma levels (i.e., avoiding large
peak-to-trough variations) can be achieved by short fre-
quent low-dose i.v. infusions for several days (6,9). This al-

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 Aguilar Ponce et al. / Archives of Medical Research 30 (1999) 212–215 213

ternative does not appear to be the most adequate, as it re-
quires 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 (1,2,11).
Several studies have demonstrated that treatment with
commercially available low-dose etoposide capsules is ef-
fective in several malignancies (12–15), because such for-
mulations have been specifically developed for oral admin-
istration.
Commercial etoposide formulations for oral administra-
tion were only recently introduced in Mexico. These cap-
sules are expensive and not widely available because their
development requires sophisticated pharmaceutical technol-
ogy. Attempts to develop oral etoposide capsules at the hos-
pital-pharmacy level have resulted in formulations with un-
acceptably low bioavailability (16).
Pharmacokinetic studies have shown that etoposide can
be absorbed when given orally as a solution (17). 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 administra-
tion as IVES.
Patients and Methods
Eight adult cancer patients, whose characteristics are shown
in Table 1, participated in the study after giving informed
consent. The protocol was approved by the ethical and sci-
entific board of the Instituto Nacional de Cancerología. Pa-
tients 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 ad-
ministration 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 medica-
tion. Plasma was obtained by centrifugation and kept frozen
until analysis.
Etoposide concentration in plasma samples was deter-
mined by high-performance liquid chromatography by
means of amperometric detection. The analytical method is
described in detail elsewhere (18). Bioavailability parame-
ters were obtained by non-compartmental analysis. Plasma
concentration against time curves were constructed for each
patient and maximal plasma concentration (Cmax) and the
time to reach this maximum (Tmax) were obtained directly
from these plots. Half-life (t1/2) 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-logarith-
mic coordinates. The area under the curve (AUC) was cal-
culated by the trapezoidal rule and extrapolation to infinity
was achieved by multiplying the last detectable concentra-
tion by the terminal slope (19).
Results
The clinical characteristics of the studied patients are shown
in Table 1. The majority of the patients were male, and the
lung carcinoma was the most frequent tumor type. All pa-
tients had normal levels of creatinine and normal hepatic
function as defined by serum levels of total bilirubin, aspar-
tate aminotransferase and alanine aminotransferase less
than 1.53 the upper limit of normal (ULN).
The oral administration of etoposide as IVES resulted in
adequate drug absorption, as noted in Figure 1. Individual
bioavailability parameters are shown in Table 2. Plasma
concentrations reached levels higher than 0.5 mg/mL in all
patients, and reached levels above 1.0 mg/mL in all but one
patient. In all cases, etoposide plasma concentrations were
much below 10 mg/mL, the highest concentration observed
being 3.31 mg/mL. Half-life values were in the range of
3.07–14.99 h.

Table 1. Demographic and clinical characteristics of the eight cancer patients who participated in the study

Patient Sex/age Primary Hb (g/dL) Creat (g/dL) Alb (g/dL) Bil (mg/dL) AST (U/L) ALT (U/L)

1 M/67 SCLC 12.3 1.0 3.3 0.1 53 19

2 M/70 NSCLC 10.9 1.1 3.4 0.2 20 11
3 F/54 NSCLC 11.2 1.4 2.7 0.3 41 29
4 M/76 NSCLC 10.4 0.6 4.2 0.4 22 10
5 M/58 NSCLC 13.6 1.1 3.9 0.2 26 28
6 F/47 CERVIX 14.7 1.4 4.1 0.2 20 31
7 M/74 NSCLC 13.5 1.4 4.0 0.1 22 21
8 F/49 PUO 9.5 1.5 4.0 0.3 27 41

Hb: hemoglobin; Creatinine: plasma creatinine; Alb: plasma albumin; Bil: total bilirubin; AST: aspartate aminotransferase (normal, 8–46 U/L); ALT: alanine
aminotransferase (normal, 3–69 U/L); SCLC: small-cell lung cancer; NSCLC: non-small-cell lung cancer; PUO: primary of unknown origin.
214 Aguilar Ponce et al./ Archives of Medical Research 30 (1999) 212–215

Table 2. Bioavailability parameters of etoposide observed in eight cancer

patients who received an oral 50-mg dose of the solution marketed for
intravenous use

AUC
Patient Cmax (mg/mL) Tmax (h) t1/2 (h) (mg · h/mL) t.0.5 (h) t>1 (h)

1 1.73 0.50 4.16 12.10 6.75 4.50

2 3.07 0.50 11.12 10.36 4.25 3.50
3 1.78 0.50 9.30 12.66 6.75 2.75
4 3.31 1.00 4.64 11.73 6.75 2.50
5 2.32 1.00 3.07 6.69 2.75 1.00
6 2.89 0.50 6.56 19.31 9.75 5.75
7 0.87 4.00 14.99 6.94 5.50 0.00
8 3.05 1.50 6.10 23.15 11.25 7.00
Mean 2.38 1.19 7.50 12.83 6.72 3.69
SEM 0.30 0.42 1.43 2.02 0.97 0.85

Cmax: maximal plasma concentration; Tmax: time to reach the maximal

plasma concentration; t1/2: half-life; AUC: area under the curve; t.0.5: time
that etoposide concentration was higher than 0.5 mg/mL; t.1: time that eto-
poside concentration was higher than 1 mg/mL.

Figure 1. Plasma etoposide concentrations observed in eight cancer

patients who received an oral 50-mg dose as the solution marketed for
intravenous use. Data are presented as mean 6 SEM.
Discussion
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 mg/mL (6,9). There is also evidence that high
plasma concentrations, i.e., around 10 mg/mL, result in my-
elosuppression and other side effects (9,11). Therefore, the
aim of an etoposide dosing scheme is to achieve plasma
concentrations of 0.5–1 mg/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 ob-
tained with intravenous infusions when the plasma concen-
trations achieved via both routes are within comparable
range (14,15).
Therefore, the oral route has been indicated as a new ap-
proach for the administration of this drug (2). Commercial
capsules specifically developed for the oral route have been
successfully introduced in the U. S., Europe and Japan (11–
15). 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 re-
sults show that oral IVES administration yields an adequate
bioavailability. Jonkman-de Vries et al. (11) reported that
after oral administration of a 50-mg commercial etoposide
capsule to cancer patients, the AUC was 11.4 6 1.55 mg · h/
mL and half-life was 7.76 6 0.06 h. These values are almost
identical to those observed after oral IVES administration
(Table 2), suggesting that the extent of drug absorption after
oral administration of either commercial capsules or IVES
is comparable. Jonkman-de Vries et al. (11) observed a Cmax
of 1.25 6 0.16 mg after the 50 mg capsule, a value which is
lower than the one we observed with 50-mg oral IVES (2.38 6
0.30 mg).
The fact that Cmax was higher while AUC was similar
suggests that the rate of etoposide absorption is faster with
IVES than with the commercial capsule (20). This bioavail-
ability 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 mg range
is longer. There is evidence that oral etoposide pharmacoki-
netics are linear at doses lower than 250 mg (21). Therefore,
drug accumulation after repetitive dosing depends on the
terminal half-life and the dosing interval (22). 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.
There is evidence that oral IVES administration results in
antitumor activity in children with refractory tumors while
being well tolerated (17). Moreover, preliminary evidence
from our group at the National Institute of Cancerology in
Mexico City in adult cancer patients also suggests that ade-
quate clinical response can be achieved with oral IVES.
These data are consistent with the pharmacokinetic results
obtained in the present study.
Etoposide is frequently administered as short daily i.v.
IVES infusions for several days. It should be noted, how-
ever, that the i.v. route is expensive because infusions can
only be performed by trained personnel. Oral administration
of IVES can be performed at home requiring only dilution
in a glass of water; hence, considerable savings can be
achieved, given that a hospital stay is not required, and
therefore, indirect costs are also importantly reduced in
comparison to the i.v. route. Moreover, additional savings
 Aguilar Ponce et al. / Archives of Medical Research 30 (1999) 212–215
in the cost of medication can be achieved. For oral adminis-
tration of a 50-mg etoposide dose, an IVES containing 100
mg of the drug can be used twice if medication is given fol-
lowing the procedure described here. It has been shown that
available undiluted commercial IVES can be stored for at
least 48 h in a refrigerator and still be suitable for oral ad-
ministration (23). However, an opened vial cannot be used
for i.v. administration even if it is refrigerated due to the
risk of pyrogen contamination (24). Moreover, it is impor-
tant to mention that oral administration results in consider-
ably less discomfort for the patient than i.v. infusions.
In summary, oral administration of the etoposide solu-
tion presently marketed for the i.v. route (IVES) yields ade-
quate bioavailability and appears to be a suitable dosing op-
tion from the pharmacokinetic point of view. Moreover,
savings for the patient and/or public health system can be
achieved by the substitution of i.v. etoposide infusions for
oral IVES administration. It is necessary, however, to per-
form additional clinical and pharmacokinetic studies in or-
der to clearly establish the role of oral IVES as a routine an-
titumor chemotherapy, given that the optimal schedule for
its administration is not yet clearly defined. In fact, a recent
study comparing the standard 3-day i.v. administration of
etoposide vs. the prolonged 21-day oral etoposide treat-
ment, each in combination with cisplatin in extensive-stage,
small-cell lung carcinoma patients revealed similar re-
sponses and survival. There was, however, a significantly
greater rate of severe or life-threatening hematologic toxic-
ity in the oral etoposide arm (25).
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