Pharmacokinetics of etoposide: correlation of pharmacokinetic parameters with clinical conditions

Abstract

The pharmacokinetic parameters of etoposide were established in 35 patients receiving the drug parenterally within the framework of different polychemotherapy protocols. A total of 62 data for 24-h kinetics were analysed. After sample extraction and high-performance liquid chromatography (HPLC) or thin-layer chromatographic (TLC) separation, etoposide was measured by means of [252Cf]-plasma desorption mass spectrometry (PDMS). This highly specific detection system proved to be very practicable and reproducible. The present study comprised two parts that were absolutely comparable in terms of clinical and pharmacokinetic parameters. In part II of the study, sensitivity was improved by modifying the analytical technique. After the exclusion of patients who had previously been given cisplatin or who exhibited renal impairment and of one patient who showed extremely high levels of alkaline phosphatase, gamma-GT and SGPT, the mean values calculated for the pharmacokinetic parameters evaluated were: beta-elimination half-life (t 1/2 beta), 4.9 +/- 1.2 h; mean residence time (MRT), 6.7 +/- 1.4 h; area under the concentration-time curve (AUC), 5.43 +/- 1.74 mg min ml-1; volume of distribution at steady state (Vdss), 6.8 +/- 2.7 l/m2; and clearance (Cl), 18.8 +/- 5.3 ml min-1 m-2. The pharmacokinetic parameters were correlated with 12 different demographic or biochemical conditions. Impaired renal function, previous application of cisplatin and the age of patients were found to influence etoposide disposition to a statistically significant extent. We suggest that the dose of etoposide should be reduced in elderly patients and/or in individuals with impaired renal function, especially in those exhibiting general risk factors such as reduced liver function with regard to the polychemotherapy.

Etoposide and antimetabolite pharmacology in patients who develop secondary acute myeloid leukemia

“…This clearance is higher than that reported in seven previous studies in children 1,6,9,12,28 and 14 previous studies in adults. 1,2,7,11,13 One possible explanation for the very high clearance we observed is that the previous 4 week course of prednisone may have induced CYP3A4 43 metabolism of etoposide, 40 a finding consistent with our previous observations of enhanced P450 metabolism following remission induction. 44 In summary, although our data should be interpreted with caution due to their retrospective nature and the small number of patients, they represent the only pharmacokinetic data available in identically treated patients who did and did not go on to develop epipodophyllotoxin-associated AML, and may provide insights into variables that deserve further study.…”

“…2,4-8 However, defining the optimal dosages and schedules of the epipodophyllotoxins has proven challenging, in part due to a 10-fold interpatient variability in systemic clearance [9][10][11][12][13][14] and because we do not understand the risk factors for their most devastating delayed toxicity: the development of secondary acute myeloid leukemia (AML) in as many as 10-20% of adult and pediatric patients. [15][16][17][18][19] The epipodophyllotoxins are often incorporated into treatment regimens for the most common childhood malignancy, acute lymphoblastic leukemia (ALL).…”

Recombinant human epidermal growth factor on oral mucositis induced by intensive chemotherapy with stem cell transplantation

“…In contrast, one can speculate that rhEGF performed its full epidermal regeneration activity when it was administered during the recovery period following high-dose chemotherapy. Chemotherapeutic agents administered as part of the conditioning regimen in this study have different elimination half-lives that range from 60 min to 75 hr [23][24][25][26]. In most cases, accordingly to firstorder kinetics, it takes approximately three to five half-lives for a drug to be essentially eliminated from the body [27].…”

A study of the feasibility and accuracy of pharmacokinetically guided etoposide dosing in children

“…This patient had a [5LCr]EDTA clearance, which was at the bottom of the normal range (59 ml min-' m-2) and the longest [5'Cr]EDTA elimination half-life (114 min vs 77±23 min), although no overt signs of renal impairment. It seems likely that the reduced interpatient pharmacokinetic variability seen in this group of patients was due to the fact that only one child had previously received cisplatin, as cisplatin therapy has previously been shown to predict for reduced etoposide clearance (Pfluger et al, 1987(Pfluger et al, , 1993Relling et al, 1994 Previous studies involving targeted dosing with etoposide using limited sampling methods have involved the administration of etoposide as a continuous infusion over 3 or 5 days (Ratain et al, 1989(Ratain et al, , 1991Joel et al, 1996). In addition, English et al (1996) reported two anephric paediatric patients in whom targeted dosing with both etoposide and carboplatin was possible using detailed pharmacokinetic sampling over three doses.…”