A comparative study on Capecitabine (Cape) pharmacokinetics (PK) in elderly or younger patients with metastatic breast (MBC) or colo-rectal cancer (CRC)

Background: Cape is an efficient oral prodrug of 5FU in MBC and CRC. Unexpected severe toxicity in older patients (pts) was reported after standard dose of 2500mg/sm/day. About 70% of drug and metabolites are excreted with the urine and a 25% reduction of the dose is recommended if the pt has a creatinine clearance (CrCl) <50ml/min. However no prospective study has been done on Cape PK in the elderly pts. Methods: Between Oct 2004 and Nov 2005, 21 pts with MBC or CRC and age >70yrs or <60yrs who received Cape (1000 mg/sm bid for 14 days every 21 days) entered the study after giving signed informed consent. CrCl was calculated according to the Cockcroft-Gault method. Patient characteristics: 15 elderly pts (median 78 range71-84yrs), 6 younger pts (median 50.5 range 43-57yrs); 9 (42.9%) males and 12 (57.1%) females; median KPS 90 (range 70-100); 8 MBC pts (38%), 13 CRC pts (62%). Blood samples were taken on the first day of treatment at time 0 and at 0.25,0.5,1,2,3,4,5,6,8 hrs after the first drug administration and on 4th, 8th, 12th and 14th days in the morning. Plasma levels of Cape, 5DFUR, 5DFCR and 5FU were determined by a validated HPLC method and UV detection. Results: At present PK data after the first administration of Cape are available for 13 pts (9 elderly; 4 younger). The mean Cape and 5DFCR AUC0-8hr are higher in older patients (Cape 6653±2564.8 vs. 4427±2714.5; P=0.09; 5DFCR 8635±5197.1 vs. 6292±3813.6; P=0.26), while no evident differences are present for 5DFUR and 5FU. The same results are obtained both in pts with CrCl 50 ml/min. The ratios of DFUR_AUC to Cape_AUC and 5FU_AUC to Cape_AUC are conversely higher in younger than in older pts (mean: 2.2 vs 1.62). A large interindividual variability in the concentration/time curves is present for Cape and metabolites. Cape dose reduction because of G3 toxicity (2 hand-foot syndrome, 1 stomatitis) was performed in 3 elderly pts. Drug systemic exposure was higher in 2 of these pts independently of CrCl. Conclusions: The preliminary results of this PK study suggest that elderly patients treated with Cape at 1000 mg/sm/bid are more drug-exposed than younger patients, independently of renal function. PK analysis is ongoing for the remaining patients