Population pharmacokinetics and pharmacodynamics of oral etoposide

Abstract

Aims To study the population pharmacokinetics and pharmacodynamics of oral etoposide in patients with solid tumours.Methods A prospective, open label, cross‐over, bioavailability study was performed in 50 adult patients with miscellaneous, advanced stage solid tumours, who were receiving oral (100 mg capsules) etoposide for 14 days and i.v. (50 mg) etoposide on day 1 or day 7 in randomised order during the first cycle treatment. Total and unbound etoposide concentration were assayed by h.p.l.c. Population PK parameters estimation was done by using the P‐Pharm software (Simed). Haematological toxicity and tumour response were the main pharmacodynamic endpoints.Results Mean clearance was 1.14 l h−1 (CV 25%). Creatinine clearance was the only covariable to significantly reduce clearance variability (residual CV 18%). (CL = 0.74 + 0.0057 CLCR; r2 = 0.32). Mean bioavailability was 45% (CV 22%) and mean protein binding 91.5% (CV 5%). Exposure to free, pharmacologically active etoposide (free AUC p.o.) was highly variable (mean value 2.8 mg l−1 h; CV 64%; range 0.4–9.5). It decreased with increased creatinine clearance and increased with age which accounted for 9% of the CV. Mean free AUC p.o. was the best predictor of neutropenia. Free AUC50 (exposure producing a 50% reduction in absolute neutrophil count) was 1.80 mg l−1 h. In patients with lung cancer, the free AUC p.o. was higher in the two patients with responsive tumour (5.9 mg l−1 h) than in patients with stable (2.1 mg l−1 h) or progressive disease (2.3 mg l−1 h) (P = 0.01).Conclusions Exposure to free etoposide during prolonged oral treatment is highly variable and is the main determinant of pharmacodynamic effects. The population PK model based on creatinine clearance is poorly predictive of exposure. Therapeutic drug monitoring would be necessary for dose individualization or to study the relationship between exposure and antitumour effect.

A Linear Approach to Multi-Panel Sensing in Personalized Therapy for Cancer Treatment

“…This means that for low concentration of Etoposide (< 50 μM) we can use the linear approximation proposed in this model. And in many clinical applications Etoposide is administered at concentration in the range 1-40 μM, as in [14] and in the more recent [15], [16].…”

Limited inter-occasion variability in relation to inter-individual variability in chemotherapy-induced myelosuppression

“…Th e individual concentration-timecourse of topotecan and etoposide were derived from observed plasma concentrations and PK models developed by Legér et al [20] and Toff oli et al [21], respectively. For etoposide two plasma concentration samples per patient and treatment course were sampled [14] and for topotecan 185 plasma concentration measurements of total topotecan were obtained in the fi rst treatment course [15,16].…”

Clinical pharmacology of cancer therapies in older adults

“…Studies evaluating the impact of age on the pharmacokinetics of etoposide have produced conflicting results. Toffoli et al (2001) studied 50 patients ranging in age from 50 to 83. They found no impact of age on the pharmacokinetics of etoposide when taking creatinine clearance into account.…”

“…The clearance of etoposide is slower in patients with impaired renal function (Toffoli et al, 2001). In contrast, there is no significant difference in the pharmacokinetics of etoposide in patients with impaired hepatic function (Aita et al, 1999;Toffoli et al, 2001). Studies evaluating the impact of age on the pharmacokinetics of etoposide have produced conflicting results.…”