Plasma Etoposide Concentration Research Articles

Pharmacokinetic Assessment of Absorptive Interaction of Oral Etoposide and Morphine in Rats

Etoposide and morphine are well known P-glycoprotein (P-gp) substrates. The pharmacokinetic effect of morphine on plasma etoposide concentration after the oral concomitant use of etoposide and morphine in rats was assessed using a population analysis approach. A P-gp substrate quinidine and the anticholinergic drug propantheline were also administered with etoposide to compare with the effects of morphine. Plasma etoposide concentration after oral administration was well described using a linear 2-compartment open model with first-order kinetic absorption from the intestine, although a flip-flop phenomenon was shown. After administration of etoposide with morphine, an increased concentration and extended time at maximum concentration were observed compared with the administration of etoposide alone. However, coadministered quinidine significantly increased the maximum concentration without changing the time of the peak concentration of etoposide. Coadministered propantheline significantly extended the time at maximum concentration, although no changes in the peak concentration of etoposide were observed. These coadministered drugs resulted in different pharmacokinetic parameters of etoposide and acted as a significant covariate. That is, morphine and quinidine significantly increased the bioavailability of etoposide believed to be due to competitive P-gp inhibition in the intestine. In contrast, morphine and propantheline decreased the absorption rate constant and were associated with the suppression of enterokinesis. These results indicate that it is necessary to understand the effects on P-gp as well as have information on other effects on the gastrointestinal tract, such as enterokinesis suppression, and to appropriately assess the pharmacokinetic interactions of the combined oral use of P-gp substrate drugs.

Oral bioavailability of etoposide after administration of a single dose to tumor-bearing dogs

To characterize oral bioavailability and pharmacokinetic disposition of etoposide when the IV formulation was administered orally to dogs. 8 tumor-bearing dogs. An open-label, single-dose, 2-way crossover study was conducted. Dogs were randomly assigned to initially receive a single dose of etoposide (50 mg/m2) IV or PO. A second dose was administered via the alternate route 3 to 7 days later. Medications were administered before IV administration of etoposide to prevent hypersensitivity reactions. Oral administration of etoposide was prepared by reconstituting the parenteral formulation with 0.9% NaCl solution and further diluting the reconstituted mixture 1:1 with a sweetening agent. Plasma samples were obtained after both treatments. Etoposide concentrations were measured with a high-performance liquid chromatography assay, and plasma etoposide concentration-time profiles were analyzed by use of noncompartmental methods. 4 dogs had hypersensitivity reactions during IV administration of etoposide. No adverse effects were detected after oral administration. Plasma etoposide concentrations were undetectable in 2 dogs after oral administration. Oral administration of etoposide resulted in significantly lower values for the maximum plasma concentration and the area under the plasma etoposide concentration-versus-time curve, compared with results for IV administration. Oral bioavailability of etoposide was low (median, 13.4%) and highly variable among dogs (range, 5.7% to 57.3%). CONCLUSIONS AND CLINICAL RELEVANCE-Vehicle-related toxicosis can limit the IV administration of etoposide in dogs. The parenteral formulation of etoposide can be safely administered orally to dogs, but routine use was not supported because of low and variable oral bioavailability in this study.

Oral Etoposide Is Equivalent to Intravenous Administration within the CHOEP-Regimen - Results of a Comparative Pharmacokinetic Study.

The addition of etoposide to the CHOP protocol (CHOEP) has been shown to improve outcome particularly in younger patients (<60 years) with aggressive non-Hodgkin's lymphoma [Pfreundschuh, Blood 2004]. In the previous trials a dose of 100 mg/m2 etoposide was given intravenously on three consecutive days representing a disadvantage of CHOEP compared to standard CHOP in terms of patients' convenience. Therefore we investigated the pharmacokinetic equivalency of etoposide as an oral preparation on days 2 and 3 compared to the intravenous route. Ten patients (male, n=7; female, n=3; median age 56 years) with aggressive B-cell- (n=9) or T-cell- (n=1) lymphoma were included. The CHOEP regimen consisted of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 2 mg/m2 and prednisone 100 mg orally days 1 to 5. Etoposide 100 mg/m2 was given intravenously on day 1, and 200 mg/m2 orally on days 3 and 4, respectively. EDTA blood for pharmacokinetic study were taken on days 1 (i.v. study) and 3 (p.o. study) before etoposide and after administration at 30, 60 and 90 min, every hour until 8 hours, followed by samplings at 16, 20, 24 and 48 hours. The samples were centrifuged immediately at 5°C for 15 min, and the plasma was aliquoted into cryo vials and stored at −20°C until assayed. Etoposide levels in plasma were determined by high-performance liquid chromatography (HPLC). The area under the plasma etoposide concentration versus time curve (AUC), plasma etoposide clearance (CL), volume of distribution in steady state (VDss) and terminal etoposide plasma half-life (t½) for the intravenous and oral administered drug were calculated based on the TOPFIT computer program. The median bioavailability after oral etoposide was 58 % with an interpatient variation (coefficient of variation, CV) of 26 %. AUC was very similar after 200 mg/m2 oral etoposide and intravenous administration of 100 mg/m2 of the drug, however the pharmacokinetic variation was higher after oral uptake compared to the parenteral route (35 % vs. 23 %). Data are presented in detail (medians and ranges) in Table #1. We conclude that, within the CHOEP regimen, the intravenous administration of 100 mg/m2 etoposide on days 2 and 3 can be replaced by 200 mg/m2 of the oral preparation, which simplifies the treatment in the outpatient setting.Table #1100 mg/m2 Etoposide i.v.200 mg/m2 Etoposide p.o.C max [μg/ml]16.7 (10.1 – 21.1)13.4 (5.8 – 16.8)V ss [L]14.4 (10.7 – 18.3)15.1 (10.6 – 25.4)CL total [ml/min]45.9 (29.6 – 62.8)82.5 (45.5 – 151.0)CL renal [ml/min]17.2 (9.4 – 52.6)16.3 (4.7 – 39.7)t 1/2 [h]4.1 (3.8 – 5.4)5.8 (3.2 – 8.3)AUC [μg × h/ml]72.5 (44.3 – 93.4)81.6 (44.0 – 147.0)

Bioavailability and Pharmacokinetic Features of Etoposide in Childhood Acute Lymphoblastic Leukemia Patients

The bioavailability and pharmacokinetic characteristics of etoposide were studied in 12 relapsed B-lineage acute lymphoblastic leukemia (ALL) patients after both intravenous (i.v.) infusion and oral administration. Following a 1 hour i.v. infusion of SO mg/m2 etoposide, the elimination half-life ranged from 49.8 min to 509.4 min (mean ± SD = 218.6 ± 134.7 min), the MRT ranged from 71.8 to 734.9 min (mean ± SD = 315.4 ± 194.3 min) and the systemic clearance of etoposide ranged from 15.7 to 38.0 ml/min/m2 (mean ± SD = 24.1 ± 7.0 ml/min/m2). The AUC ranged from 2234.9 to 5427.0 μM±min) (mean ± SD = 3827.8 ± 1069.5 μM±min) and Vc ranged from 2026.9 to 13505.2 rnl/m2 (mean ± SD = 6825.4 ± 3278.5 ml/m2). The maximum plasma etoposide levels ranged from 6.0 to 28.4 μM (mean ± SD = 13.6 ± 6.3 μM). The bioavailability of oral etoposide was determined by comparing the AUC following i.v. infusion to the AUC following oral administration in the same patient. The overall bioavailability (mean ± SD) was 60.6 ± 22.4% (ranged from 17.6% to 91.2%). The elimination half-life following oral administration (mean ± SD) was 209.8 ± 196.3 min (ranged from 51.0 to 794.2 min). The time required to reach the maximum plasma etoposide concentration was 145.4 ± 118.7 min (ranged from 23.7 to 396.9 min). To our knowledge, this is the first report concerning the bioavailability of etoposide in pediatric leukemia patients. All of the other pharmacokinetic properties of etoposide in pediatric B-lineage ALL leukemia patients reported here were similar to those described previously.

Bioavailability of Etoposide after Oral Administration of the Solution Marketed for Intravenous Use: Therapeutic and Pharmacoeconomic Perspectives

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 intravenous 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 C max was 2.38 ± 0.30 μg/mL, AUC was 12.87 ± 2.02 μg/mL and half-life was 6.72 ± 0.97 h. Conclusions Considering that the pharmacokinetic aim is to maintain plasma concentrations between 0.5 and 1.0 μg/mL for several hours while avoiding high concentrations, i.e., of 10 μg/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 intravenous administration in terms of both drug presentation and administration.

A randomised, concentration-controlled, comparison of standard (5-day) vs. prolonged (15-day) infusions of etoposide phosphate in small-cell lung cancer

This randomised trial was designed to investigate the activity and toxicity of continuous infusion etoposide phosphate (EP), targeting a plasma etoposide concentration of either 3 micrograms/ml for five days (5d) or 1 microgram/ml for 15 days (15d), in previously untreated SCLC patients with extensive disease. EP was used as a single agent. Plasma etoposide concentration was monitored on days 2 and 4 in patients receiving 5d EP and on days 2, 5, 8 and 11 in patients receiving 15d EP, with infusion modification to ensure target concentrations were achieved. Treatment was repeated every 21 days for up to six cycles, with a 25% reduction in target concentration in patients with toxicity. The study has closed early after entry of 29 patients (14 with 5d EP, 15 with 15d EP). Objective responses were seen in seven of 12 (58%, confidence interval (CI): 27%-85%) evaluable patients after 5d EP, and two of 14 (14%, CI: 4%-42%) evaluable patients after 15d EP (P = 0.038). Grade 3 or 4 neutropenia or leucopenia during the first cycle of treatment was observed in six of 12 patients after 5d EP and 0/14 patients after 15d EP (P = 0.004), with median nadir WBC count of 2.6 x 10(9)/1 after 5d and 5.0 x 10(9)/1 after 15d EP (P = 0.017). Only one of 49 cycles of 15d EP was associated with grade 3 or worse haematological toxicity, compared to 14 of 61 cycles of 5d EP. Although the number of patients entered into this trial was small, the low activity seen at 1 microgram/ml in the 15d arm suggests that this concentration is below the therapeutic window in this setting. Further concentration-controlled studies with prolonged EP infusions are required.

Etoposide dosage and pharmacodynamics

Etoposide is a schedule-dependent cytotoxic drug with high single agent activity in small-cell lung cancer and lymphoma. Despite its clear dose-dependent myelosuppressive activity, dose-dependent evidence of its anti-tumour activity is harder to demonstrate. A number of reports have correlated haematological toxicity with pharmacokinetic and physiological parameters, which explains some of the variability in dynamic effects that exists between patients. Recent reports have also suggested that anti-tumour response may be related to plasma etoposide concentration. In our own studies we have investigated factors that influence the pharmacodynamic effects of etoposide, principally with regard to haematological toxicity, and these studies have highlighted a number of patient groups who are at risk. Impaired renal function causes a reduction in clearance of etoposide, resulting in increased systemic exposure and more profound myelotoxicity. A 30% dose reduction in this group is recommended to normalise the area under the plasma concentration-time curve (AUC). Patients with low serum albumin concentrations (< 35 g/l) also showed significantly worse haematological toxicity, but with no apparent change in total drug pharmacokinetics. There was, however, an increase in the free drug fraction in this group due to decreased protein binding, such that the free drug AUC was similar to that found in patients with renal dysfunction. This would also indicate that a dose reduction of around 30%-40% is required in this patient group. Patients with normal albumin levels but liver enzyme values (aspartate transaminase or gamma-glutamyl transpeptidase) more than 3 times the upper limit of normal also had a less marked but significant increase in neutropenia. In patients with normal organ function, age was the only significant factor in predicting the degree of leukopenia/neutropenia, and increasing age was also associated with decreasing drug clearance and an increase in drug AUC. A small dose reduction and/or careful monitoring is required in this patient group. Further studies are required to elucidate further the relationship between the pharmacokinetics of etoposide and its pharmacodynamics, particularly with regard to anti-tumor activity, and to determine the role of individualised therapy, based on a pharmacokinetic parameter, in reducing the dynamic variability and optimising the use of this drug.

Ｅｔｏｐｏｓｉｄｅ経口連日投与時の薬物動態と至適投与法の検討

Eight patients with non-small cell lung cancer were given long-term oral therapy with lowdose etoposide (25mg to 5 patients and 50mg to 3), and the pharmacokinetics, efficacy, and safety were evaluated to determine the optimal administration method.Blood was collected 7-10 times on the day when treatment was initiated, and periodically thereafter for up to 60 days to measure the plasma etoposide concentration. The data obtained at each time on the initial day were analyzed and the pharmacokinetic parameters for each patient were calculated by the Bayesian method to estimate the plasma levels on day 2, 7, 14, 30, and 60 of treatment. The estimated levels conformed well to the actual measured data, and it was hence judged that no accumulation of the drug occurred during long-term therapy. No toxity (including hematological toxity) that required the discontinuation of treatment occurred, suggesting that the maximum tolerable dose (MTD) was not reached.Administration of a daily dose of 25mg did not maintain a sufficient plasma concentration, and not less than 50mg/day seemed to be needed. In view of the necessity for increasing the duration of a plasma level of ≥1μg/ml, treatment with a daily dose of 75 mg divided into 3 portions appears to be worth considering.

When is autologous bone marrow transplantation safe after high-dose treatment with etoposide?

Etoposide (VP16-213) is widely used in the treatment of malignant disease and increasingly high doses are now used in conjunction with autologous bone marrow transplantation. After treatment with etoposide, bone marrow should be reinfused as soon as the plasma etoposide concentration has fallen to a level which will not prove toxic to the small number of pluripotential stem cells present in the reinfused marrow, but this level has not been previously defined. Nine patients were studied of whom five received 1400 mg etoposide/m2 and four received 2400 mg etoposide/m2 intravenously over 3 days. Bone marrow was reinfused 64-136 h after finishing chemotherapy. Haemopoietic recovery occurred in all patients within 16 days of autologous bone marrow reinfusion performed at a time when plasma etoposide concentrations ranged from 0-2.42 micrograms/ml. However the clinical and in vitro data presented suggest that bone marrow reinfusion after treatment with high-dose etoposide should be delayed until the plasma etoposide concentrations have fallen to less than 0.4 microgram/ml although haemopoietic recovery may occur after bone marrow reinfusion at higher concentrations.