Randomized comparison of etoposide pharmacokinetics after oral etoposide phosphate and oral etoposide

Abstract

Summary Etoposide phosphate is a water-soluble prodrug of etoposide. The plasma pharmacokinetics of etoposide following oral administration of etoposide phosphate or oral etoposide were compared. Seventeen patients with solid tumours were enrolled to receive oral etoposide phosphate 125 mg m-2 on days 1-5 every 3 weeks, with escalation to 175 mg m-2 from course 3 when possible. Patients were randomized to receive oral etoposide phosphate or oral etoposide on day 1 of course 1 and the alternative compound on day 1 of course 2.Fifteen patients received two or more courses and were evaluable for pharmacokinetic comparisons. The median AUCinf (area under the concentration vs time curve from zero to infinity) of etoposide was 77.7 mg 1-1 h after etoposide phosphate (95% Cl 61.3-100.5) and 62.0 mg 1-1 h after oral etoposide (95% Cl 52.2-76.9). The difference in favour of etoposide phosphate was borderline significant: median 9.9 mg 1-1 h (95% Cl 0.1-32.8 mg 1-1 h; P = 0.05). However, the inter-patient variability of etoposide AUCinf was not improved (coefficients of variation 42.3% and 48.4%). Etoposide phosphate was undetectable in plasma after oral administration. Toxicities of oral etoposide phosphate were not different from those known for etoposide. In conclusion, oral etoposide phosphate does not offer a clinically relevant benefit over oral etoposide.Keywords: etoposide; etoposide phosphate; oral; pharmacokinetics; toxicity Etoposide, a podophyllotoxin derivative, is incorporated in standard chemotherapy for treatment of small-cell lung cancer (SCLC) and germ cell tumours, as well as in second-line treatment for haematological and many other malignancies . Activity is improved considerably when the dose is divided over several days, and therefore oral administration is attractive (Slevin et al, 1989a). It has been shown that oral etoposide monotherapy, usually with the dose divided over 5 days or longer periods, is an effective treatment in patients with SCLC and refractory malignant lymphomas . In small studies, prolonged oral etoposide treatment showed remarkable activity in relapsed or refractory breast and ovarian cancers (response rates up to 35% and 25% respectively) (Hoskins and Swenerton, 1994;Martin et al, 1994). Patient convenience is an important additional reason for choosing the oral route. However, pharmacokinetic studies have shown that oral etoposide also has disadvantages. Bioavailability is incomplete, probably decreasing with dose, and is reported to be below 50% for doses above 200 mg. Bioavailability shows wide inter-and intra-patient variability (Hande et al, 1993;Harvey et al, 1985;Slevin et al, 1989b). The consequences are considerable risks of underdosing and unpredictable toxicity.The water-soluble prodrug etoposide phosphate was synthesized because use of intravenous etoposide administration is Received 30 September 1996 Revised 19 December 1996 Accepted 20 December 1996 Correspondence to: EGE de Vries, Division of Medical Oncology, Department of Internal Medicine, University Hos...

Evaluation of in Vitro Models for Screening Alkaline Phosphatase-Mediated Bioconversion of Phosphate Ester Prodrugs

“…Most importantly, phosphate prodrugs are readily cleaved by alkaline phosphatase (ALP), an enzyme widely distributed in plasma and a variety of tissues, to their parent drugs (Fleisher et al, 1985(Fleisher et al, , 1996. This approach has been successfully used for a number of oral and parenterally administered drug candidates on the market (de Jong et al, 1997).…”

Conversion of the prodrug etoposide phosphate to etoposide in gastric juice and bile

“…However, in a comparative pharmacokinetic study, we found only minor improvement of bioavailability and wide variation in etoposide plasma concentrations (de Jong et al, 1997). In addition, the prodrug was never detectable in plasma after oral administration (de Jong et al, 1997;Sessa et al, 1995). These observations suggested that the prodrug was possibly converted to etoposide within the gastrointestinal lumen.…”

“…Because this prodrug is considerably more water-soluble, oral administration was expected to result in improved etoposide plasma pharmacokinetics compared with orally administered etoposide. However, in a comparative pharmacokinetic study, we found only minor improvement of bioavailability and wide variation in etoposide plasma concentrations (de Jong et al, 1997). In addition, the prodrug was never detectable in plasma after oral administration (de Jong et al, 1997;Sessa et al, 1995).…”

Characterization of Recombinantly Expressed Rat and Monkey Intestinal Alkaline Phosphatases: In Vitro Studies and In Vivo Correlations

“…Importantly, phosphate prodrugs are cleaved in the intestine and generate a super-saturated parent solution that enhances the absorption flux (Heimbach et al, 2003a). On the other hand, poor phosphate cleavage can give rise to an unacceptable oral profile, low parent drug exposure, and a lack of improvement in clinical efficacy (de Jong et al, 1997;Heimbach et al, 2003a;Stella, 2010). Poorly soluble parents with sufficient solubility in the formulation vehicle, and dissolution times less than their gastrointestinal transit times will exhibit slow yet complete absorption and in these cases a phosphate prodrug may not be beneficial (Heimbach et al, 2003a).…”

“…Therefore, a soluble prodrug approach is generally considered for the purpose of enhancing exposures. Phosphate prodrugs are an effective and commonly used approach to overcome solubility issues in drug delivery and have successfully been used for a number of oral and parenterally administered marketed drugs (Fleisher et al, 1996;de Jong et al, 1997;Heimbach et al, 2003a;Rautio et al, 2008;Jana et al, 2010;Stella, 2010;Huttunen et al, 2011). The advantages of phosphate prodrugs include their chemical stability, several orders of magnitude of improved solubility as compared with parent, and relative ease of synthesis in the presence of a suitable handle (Heimbach et al, 2003a).…”