The effect of food and concurrent chemotherapy on the bioavailability of oral etoposide

Abstract

Summary There is no information on the effect of food or concurrent drug administration on the bioavailability of oral etoposide, despite the fact that treatment is frequently administered over several days and most often in combination with other cytotoxic agents. The influence of these factors has been studied in 11 Etoposide was introduced into clinical trials in the early 1970s (Issell, 1982) and is established in the treatment of several malignancies, including small cell lung cancer, germ cell tumours and lymphomas (Arnold, 1979; Issell & Crooke, 1979;Vogelzang et al., 1982).The demonstration of schedule dependency in both experimental systems (Dombernowsky & Nissen, 1973;Rozencweig et al., 1977;D'Incalci & Garattini, 1982) and possibly also in man (Cavalli et al., 1978;Pedersen & Hansen, 1983) has led to most schedules of therapy being given over several (usually 3-5) days (Arnold, 1979;Nissen et al., 1980;Issell, 1982).The bioavailability of the oral etoposide capsule has been shown to be approximately 50% but with large variation between patients Harvey et al., 1984a). Despite the widespread use of oral etoposide over 3-5 days and its predominant use as part of combination chemotherapy regimens (Arnold, 1979;Comis, 1982;Rivera et al., 1982;Williams & Einhorn, 1982), there are no data concerning the influence of food or other chemotherapy on etoposide bioavailability.The intestinal absorption of some drugs has been shown to be affected by both food (Melander, 1978;McLean et al., 1978;Pinkerton et al., 1980) and chemotherapy (Pinkerton et al., 1982). The effect of food and concomitant oral and intravenous chemotherapy on the bioavailability of etoposide has therefore been studied. Materials and methods PatientsEleven patients receiving chemotherapy for extensive small cell lung carcinoma were studied. All were ambulant (performance score > 60% Karnofsky et al., 1948) with normal bone marrow, hepatic and renal function. No patients had disturbance of the gastrointestinal tract. Eight patients receiving primary chemotherapy were studied on 3 separate occasions to assess the effect of food and concomitant oral chemotherapy on etoposide bioavailability (Study 1). Six patients (3 of whom had previously been part of the above study) were receiving therapy for relapsed extensive SCLC and were studied on 3 successive days to assess the effect of intravenous and oral chemotherapy on etoposide bioavailability (Study 2).

A quantitative approach to probe the dependence and correlation of food-effect with aqueous solubility, dose/solubility ratio, and partition coefficient (LogP) for orally active drugs administered as immediate-release formulations

“…Standard breakfast [Charman et al, 1993] [Gunnarsson et al, 1990] Etoposide 9.8 (B) 114.5 [Shah et al, 1999] 0.60 Capsules 0.877 Standard breakfast [Harvey et al, 1985] Etretinate -0.0012 [Li et al, 1996] 8.48 [Li et al, 1996] Standard meal [Blanchett et al, 1991] Fenretinide -0.005 [Li et al, 1996] 9.81 [Li et al, 1996] Standardized breakfast [Milton et al, 1989] Hydralazine. HCl [Doose et al, 1996] The equation describing the quantitative correlation of food-effect with aqueous solubility may be represented as below:…”

Pharmacokinetics of Anticancer Drugs in Children

“…One contains glycerin and is hydrophilic, while the other uses polyethylene glycol and is lipophilic (Smyth et al 1985). Both capsules have an absolute bioavailability of ""50% and may be administered with food; however, there is a great deal of both inter-and intrasubject variability (D'Incalci et al 1982a;Harvey et al 1984aHarvey et al , 1985aPfeffer et al 1984;Smyth et al 1985;Stewart et al 1985b). The drinkable ampoule provides a greater systemic bioavailability (D'Incalci et al 1982a); however, it may be unpalatable to many patients (Brunner et al 1976).…”

A phase I study on the reversal of multidrug resistance (MDR) in vivo: nifedipine plus etoposide

“…Plasma was immediately separated and stored at -20°C pending analysis. Etoposide levels were determined by reverse-phase high-performance liquid chromatography with UV detection (Harvey et al, 1985). Pharmacokinetic parameters were derived using STRIPE, an interactive computer programme (Johnson & Woollard, 1983).…”