Phase I pharmacological study of continuous chronomodulated capecitabine treatment.

PURPOSE: Capecitabine is an oral pre-pro-drug of the anti-cancer drug 5-fluorouracil (5-FU). The biological activity of the 5-FU degrading enzyme, dihydropyrimidine dehydrogenase (DPD), and the target enzyme thymidylate synthase (TS), are subject to circadian rhythmicity in healthy volunteers. The aim of this study was to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics (PK) and pharmacodynamics (PD) of capecitabine therapy adapted to this circadian rhythm (chronomodulated therapy). METHODS: Patients aged ≥18 years with advanced solid tumours potentially benefitting from capecitabine therapy were enrolled. A classical dose escalation 3 + 3 design was applied. Capecitabine was administered daily without interruptions. The daily dose was divided in morning and evening doses that were administered at 9:00 h and 24:00 h, respectively. The ratio of the morning to the evening dose was 3:5 (morning: evening). PK and PD were examined on treatment days 7 and 8. RESULTS: A total of 25 patients were enrolled. The MTD of continuous chronomodulated capecitabine therapy was established at 750/1250 mg/m2/day, and was generally well tolerated. Circadian rhythmicity in the plasma PK of capecitabine, dFCR, dFUR and 5-FU was not demonstrated. TS activity was induced and DPD activity demonstrated circadian rhythmicity during capecitabine treatment. CONCLUSION: The MTD of continuous chronomodulated capecitabine treatment allows for a 20% higher dose intensity compared to the approved regimen (1250 mg/m2 bi-daily on day 1-14 of every 21-day cycle). Chronomodulated treatment with capecitabine is promising and could lead to improved tolerability and efficacy of capecitabine.

Pronounced between-subject and circadian variability in thymidylate synthase and dihydropyrimidine dehydrogenase enzyme activity in human volunteers.

AIMS: The enzymatic activity of dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are important for the tolerability and efficacy of the fluoropyrimidine drugs. In the present study, we explored between-subject variability (BSV) and circadian rhythmicity in DPD and TS activity in human volunteers. METHODS: The BSVs in DPD activity (n = 20) in peripheral blood mononuclear cells (PBMCs) and in plasma, measured by means of the dihydrouracil (DHU) and uracil (U) plasma levels and DHU : U ratio (n = 40), and TS activity in PBMCs (n = 19), were examined. Samples were collected every 4 h throughout 1 day for assessment of circadian rhythmicity in DPD and TS activity in PBMCs (n = 12) and DHU : U plasma ratios (n = 23). In addition, the effects of genetic polymorphisms and gene expression on DPD and TS activity were explored. RESULTS: Population mean (± standard deviation) DPD activity in PBMCs and DHU : U plasma ratio were 9.2 (±2.1) nmol mg(-1) h(-1) and 10.6 (±2.4), respectively. Individual TS activity in PBMCs ranged from 0.024 nmol mg(-1) h(-1) to 0.596 nmol mg(-1) h(-1) . Circadian rhythmicity was demonstrated for all phenotype markers. Between 00:30 h and 02:00 h, DPD activity in PBMCs peaked, while the DHU : U plasma ratio and TS activity in PBMCs showed trough activity. Peak-to-trough ratios for DPD and TS activity in PBMCs were 1.69 and 1.62, respectively. For the DHU : U plasma ratio, the peak-to-trough ratio was 1.43. CONCLUSIONS: BSV and circadian variability in DPD and TS activity were demonstrated. Circadian rhythmicity in DPD might be tissue dependent. The results suggested an influence of circadian rhythms on phenotype-guided fluoropyrimidine dosing and supported implications for chronotherapy with high-dose fluoropyrimidine administration during the night.

Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) gene dosage on plasma pharmacokinetics and brain accumulation of dasatinib, sorafenib, and sunitinib.

Low brain accumulation of anticancer drugs due to efflux transporters may limit chemotherapeutic efficacy, necessitating a better understanding of the underlying mechanisms. P-glycoprotein (Abcb1a/1b) and breast cancer resistance protein (Abcg2) combination knockout mice often display disproportionately increased brain accumulation of shared drug substrates compared with single transporter knockout mice. Recently developed pharmacokinetic models could explain this phenomenon. To experimentally test these models and their wider relevance for tyrosine kinase inhibitors and other drugs, we selected dasatinib, sorafenib, and sunitinib because of their divergent oral availability and brain accumulation profiles: the brain accumulation of dasatinib is mainly restricted by Abcb1, that of sorafenib mainly by Abcg2, and that of sunitinib equally by Abcb1 and Abcg2. We analyzed the effect of halving the efflux activity of these transporters at the blood-brain barrier by generating heterozygous Abcb1a/1b;Abcg2 knockout mice and testing the plasma and brain levels of the drugs after oral administration at 10 mg/kg. Real-time reverse transcription-polymerase chain reaction analysis confirmed the ∼2-fold decreased expression of both transporters in brain. Interestingly, whereas complete knockout of the transporters caused 24- to 36-fold increases in brain accumulation of the drugs, the heterozygous mice only displayed 1.6- to 1.9-fold increases of brain accumulation relative to wild-type mice. These results are well in line with the predictions of the pharmacokinetic models and provide strong support for their validity for a wider range of drugs. Moreover, retrospective analysis of fetal accumulation of drugs across the placenta in Abcb1a/1b heterozygous knockout pups suggests that these models equally apply to the maternal-fetal barrier.