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.

The psychometric properties of the Italian version of PFS-r, as evaluated in cancer patients ongoing chemotherapy, were satisfactory. We suggest the possible implementation of the Italian PFS-r in the assessment of fatigue particularly when it has been more fully validated on a wider range of cancer patients.

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Purpose: Irinotecan (CPT11) is a prodrug activated in humans mainly by carboxylesterase 2 (CES2) generating the SN38 metabolite responsible for the drug efficacy and toxicity. The interpatients variability in CPT11 activation step could cause unpredictable toxicity. To identify a predictive molecular marker for CPT11 activation in cancer patients, we investigated the CES2 mRNA expression in peripheral blood mononuclear cells (PBMC) and correlated it to CPT11 activation rate, toxic effects, and response. Experimental Design: Forty-five colorectal cancer patients were treated with a CPT11-including regimen (FOLFIRI). CES2 mRNA expression in PBMC was quantified by reverse transcription-PCR in real time. Plasma concentrations of CPT11, SN38, and SN38-glucuronide were determined by high-performance liquid chromatography and the pharmacokinetic variables calculated adopting the noncompartmental model. ]. Patients with CES2 mRNA expression above the median cutoff value presented an activation ratio higher (median, 0.25; range, 0.15-0.42) than those with CES2 mRNA below the median (median, 0.20; range, 0.10-0.40; P = 0.013). This was associated with a nonsignificant trend of 1.34-fold increase of SN38 AUC in the group of patients with high CES2 mRNA expression (mean, 1.03 F 0.62 versus 0.77 F 0.32 Amol/L hour). Eight of 23 high CES2 mRNA^expressing patients (34.8%) developed grade 3 to 4 neutropenia or diarrhea compared with 2 of 22 (9.1%) in the low CES2-expressing group (P = 0.071). Conclusion: Our data support a predictive power of CES2 mRNA expression in PBMC for the activation rate of CPT11.