Search

The aim of the present study was to assess the pharmacokinetics (PK) of metronomic capecitabine and its metabolites in a population of refractory metastatic colorectal cancer (mCRC) patients. Thirty-four patients (M/F, 22/12) with a diagnosis of mCRC received capecitabine 800 mg p.o. twice a day and cyclophosphamide 50 mg/day p.o. Blood samples were collected at baseline, 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h and 5 h at day 1 after capecitabine administration. Plasma concentrations of capecitabine and its metabolites were measured by high performance liquid chromatography and the main PK parameters were calculated. Maximum plasma concentrations (Cmax) of capecitabine (11.51 ± 9.73 μg/ml) occurred at 0.5 h, whereas the Cmax of 5′-deoxy-5-fluorocytidine (5’-DFCR; 2.45 ± 2.93 μg/ml), 5′-deoxy-5-fluorouridine (5’-DFUR; 6.43 ± 8.2 μg/ml), and 5-fluorouracil (5-FU; 0.24 ± 0.16 μg/ml) were found at 1 h, 1.5 h and 1 h, respectively. Capecitabine, 5’-DFCR, 5’-DFUR and 5-FU AUCs at day 1 were 21.30 ± 10.78, 5.2 ± 4.6, 19.59 ± 3.83 and 0.66 ± 0.77 hxμg/ml, respectively. In conclusion, low doses of capecitabine were rapidly absorbed and extensively metabolized, achieving measurable plasma concentrations in a heavily pretreated population of patients. [ABSTRACT FROM AUTHOR]

Background and Objectives: Dihydropyrimidine dehydrogenase (DPD) plays a key role in the catabolism of 5-fluorouracil (5-FU) to 5-fluoro-5,6-dihydrouracil (5-FDHU), and as such, an impairment of DPD has been recognized as an important factor for altered 5-FU and 5-FDHU pharmacokinetics, predisposing patients to the development of severe 5-FU–associated toxicity. Our objectives were to avoid severe 5-FU toxicities in patients with greatly impaired 5-FU and 5-FDHU pharmacokinetics after the administration of a reduced test dose of 5-FU and to investigate possible 5-FU or 5-FDHU pharmacokinetic parameters of the test dose related to the most common drug toxicities that affect patients after the first cycle of 5-FU chemotherapy.Methods: Pharmacokinetics of 5-FU/5-FDHU and DPD activity in peripheral blood mononuclear cells (PBMCs) were examined in 188 gastrointestinal cancer patients given a test dose of 5-FU, 250 mg/m2, 2 weeks before starting the planned 5-FU treatment of 370 mg/m2 plus L-folinic acid, 100 mg/m2, for 5 days every 4 weeks. Drug levels were examined by HPLC, and toxicities were graded according to World Health Organization criteria.Results: The 5-FU test dose was well tolerated in all patients. Of 188 patients, 3 (1.6%) had marked alterations of 5-FU/5-FDHU pharmacokinetics (ie, 5-FU half-life [t½β] >5 hours, 5-FU total body clearance [CLTB] <1 L · h−1 · m−2, and 5-FDHU time to reach maximum plasma concentration [tmax] ≥45 minutes); they were excluded from 5-FU treatments and treated with irinotecan, which was well tolerated. The plasma disposition of 5-FU in the remaining 185 patients revealed an area under the curve (AUC) of 3.73 ± 2.18 h · μg/mL (mean ± SD), maximum plasma concentration (Cmax) of 16.78 ± 8.61 μg/mL, and t½β of 0.16 ± 0.15 hour, whereas the CLTB was 65.67 ± 31.86 L · h−1 · m−2. The 5-FDHU plasma profile showed a Cmax value of 3.64 ± 1.94 μg/mL, whereas the tmax value was 26.63 ± 10.06 minutes, with an AUC value of 3.71 ± 1.90 h · μg/mL. The PBMC DPD activity was 202.15 ± 141.14 pmol 5-FDHU · min−1 · mg−1 protein (95% confidence interval, 165-239.3 pmol 5-FDHU · min−1 · mg−1 protein). A significant correlation between 5-FU AUC and 5-FDHU AUC was found (r = 0.5492, P < .0001), whereas a weaker correlation between PBMC DPD activity and both 5-FDHU AUC (r = 0.328, P = .0121) and 5-FDHU Cmax (r = 0.369, P = .0044) was found. Interestingly, no relationships between PBMC DPD activity and common toxicities were found, whereas 5-FDHU tmax values greater than 30 minutes were associated with the risk of moderate to severe neutropenia and diarrhea (P = .0323 and P = .0138, respectively; chi-square test).Conclusions: This study suggests a successful approach for preventing severe or life-threatening toxicities in gastrointestinal cancer patients who are candidates for standard 5-FU treatment by analyzing the 5-FU and 5-FDHU pharmacokinetic parameters after the administration of a reduced 5-FU test dose.Clinical Pharmacology & Therapeutics (2006) 80, 384–395; doi: 10.1016/j.clpt.2006.06.007 [ABSTRACT FROM AUTHOR]

Aims To investigate the pharmacokinetics and pharmacodynamics of epirubicin and paclitaxel in combination, as well as the effects of paclitaxel and its vehicle Cremophor EL on epirubicin metabolism. Methods Twenty-seven female patients with metastatic breast cancer received epirubicin 90 mg m-2 i.v. followed 15 min or 30 h later by a 3 h i.v. infusion of paclitaxel 175, 200 and 225 mg m-2 . Plasma concentrations of paclitaxel, epirubicin and epirubicinol were measured and the relationship between neutropenia and drug pharmacokinetics was evaluated using a sigmoid maximum effect (Emax ) model. Finally, the influence of paclitaxel and Cremophor EL on epirubicin metabolism by whole blood was examined. Results An increase in epirubicinol plasma concentrations occurred after the start of the paclitaxel infusion, resulting in a significant increase in the area under the plasma concentration-time curve (AUC) of epirubicinol (+0.5 µmol l-1 h [95% CI for the difference: 0.29, 0.71],+0.66 µmol l-1 h [95% CI for the difference: 0.47, 0.85] and +0.82 µmol l-1 h [95% CI for the difference: 0.53, 1.11] at paclitaxel doses of 175, 200 and 225 mg m-2 , respectively), compared with epirubicin followed by paclitaxel 30 h later (0.61±0.1 µmol l-1 h). A significant increase in epirubicin AUC (+0.74 µmol l-1 h [95% CI for the difference: 0.14, 1.34] and +1.09 µmol l-1 h [95% CI for the difference: 0.44, 1.74]) and decrease in drug clearance (CLTB ) (-25.35 l h-1 m-2 [95% CI for the difference: -50.18, -0.52] and -35.9 l h-1 m-2 [95% CI for the difference -63,4,-8,36]) occurred in combination with paclitaxel 200 and 225 mg m-2 with respect to the AUC (3.16±0.6 µmol l-1 h) and CLTB (74.4±28.4 l h-1 m-2 ) of epirubicin... [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article about profiling dihydropyrimidine dehydrogenase deficiency in patients with cancer undergoing 5-fluorouracil/capecitabine therapy.

Abstract: This study investigated the effect of acute liver damage on the inactivation of 5-fluorouracil (5-FU) to its main catabolite 5-fluoro-5,6-dihydrouracil (5-FUH2) in mice. Plasma pharmacokinetics of 5-FU and 5-FUH2 in mice receiving 5-FU (10, 30, and 90 mg/kg) were compared to those in mice pretreated with carbon tetrachloride and receiving the same 5-FU doses. Carbon tetrachloride-induced hepatic damage was histopathologically examined under light microscopy and serum transaminases and dihydropyrimidine dehydrogenase activities were also measured. Liver histopathology and elevated aminotransferase activity levels confirmed the presence of liver damage. 5-FU Cmax and AUC both increased up to 71% in mice with liver damage. This was reflected by decreased 5-FUH2 production, since 5-FUH2 Cmax and AUC levels decreased up to 47% and 61%, respectively. Metabolic ratios between 5-FUH2 and 5-FU AUCs were considerably decreased as well, further suggesting that liver damage caused a reduction in 5-FU catabolism. DPD activity was not altered in damaged livers. The present results indicate that 5-FU disposition in mice could be profoundly altered in the presence of severe liver impairment, potentially leading to enhanced anabolic activation of 5-FU. This effect seems to be ascribed to a reduction of viable hepatocytes, rather than to an inactivation of DPD activity. [Copyright &y& Elsevier]

A population pharmacokinetic analysis of daptomycin was performed based on therapeutic drug monitoring (TDM) data from 58 patients receiving doses of 4–12mg/kg for the treatment of severe Gram-positive infections. At a daily dose of 8mg/kg, daptomycin plasma concentrations (mean±S.D.) were 76.9±9.8mg/L at the end of infusion and 52.7±15.4mg/L and 11.4±5.4mg/L at 0.5h and 23h after drug administration, respectively. The final model was a one-compartmental model with first-order elimination, with estimated clearance (CL) of 0.80±0.14L/h and a volume of distribution (V d) of 0.19±0.05L/kg. Creatinine clearance (CLCr) was identified as having a significant influence on daptomycin CL, and a decrease in CLCr of 30mL/min from the median value (80mL/min) was associated with a reduction of daptomycin CL from 0.80L/h to 0.73L/h. These results confirm that the presence of severe infection may be associated with an altered disposition of daptomycin, with an increased V d. MICs were available in 41 patients and results showed that 38 and 31 subjects achieved AUC/MIC values associated with bacteriostatic (>400) and bactericidal effects (>800), respectively. Of note, 31 of these 41 subjects experienced a clinical improvement or were cured. Although daptomycin pharmacokinetics may be influenced by infections, effective AUC/MIC values were achieved in the majority of patients. The present model may be applied in clinical settings for a TDM routine on the basis of a sparse blood sampling protocol. [ABSTRACT FROM AUTHOR]