INTRODUCTION: Plasma protein binding is an important factor for many drugs that can influence the tissue distribution and pharmacokinetics. alpha(1)-acid glycoprotein (AGP) is an acute-phase protein that can increase in plasma of patients with several pathological conditions including cancer. Studies performed in cultured cells indicate that paclitaxel cytotoxicity is reduced by adding AGP and the sensitivity to paclitaxel is restored by displacing its binding to AGP with clindamycin, resulting in an increased paclitaxel cell uptake. The purpose of this study was to evaluate whether clindamycin modifies paclitaxel pharmacokinetics also in cancer patients. PATIENTS AND METHODS: Sixteen patients with advanced ovarian cancer, previously treated with surgery and chemotherapy were enrolled in this study. A pharmacokinetic study of paclitaxel was performed in the first three cycles of the consolidation therapy (paclitaxel and carboplatin) in each patient. In these cycles paclitaxel was administered alone and with two different doses (600 and 1,200 mg) of concurrent clindamycin. The sequence of the three treatments was randomly assigned in each patient in order to avoid the same order of treatments. RESULTS: Paclitaxel pharmacokinetics were partly modified by the concurrent administration of clindamycin. C (max) and AUC(0-last) of paclitaxel were significantly higher when the drug was given alone than when it was coadministered with 1,200 mg clindamycin. Moreover, AGP concentrations seem to have a small but statistically significant influence on paclitaxel pharmacokinetic, since AUC(0-last) showed a positive significant correlation with AGP plasma concentration when paclitaxel was given alone. The linear relation was lost when paclitaxel was coadministered with 1,200 mg clindamycin. Toxicity was not influenced by the coadministration of clindamycin. CONCLUSION: The hypothesis that clindamycin could affect paclitaxel pharmacokinetics seems to be verified with this study. Nevertheless, changes induced by giving the combination of the two drugs are minimal and thus of questionable clinical relevance.
Fruscio, R., Lissoni, A., Frapolli, R., Corso, S., Mangioni, C., D'Incalci, M., et al. (2006). Clindamycin-paclitaxel pharmacokinetic interaction in ovarian cancer patients. CANCER CHEMOTHERAPY AND PHARMACOLOGY, 58(3), 319-325 [10.1007/s00280-005-0160-y].
Clindamycin-paclitaxel pharmacokinetic interaction in ovarian cancer patients
FRUSCIO, ROBERT;LISSONI, ANDREA ALBERTO;CORSO, SILVIA;
2006
Abstract
INTRODUCTION: Plasma protein binding is an important factor for many drugs that can influence the tissue distribution and pharmacokinetics. alpha(1)-acid glycoprotein (AGP) is an acute-phase protein that can increase in plasma of patients with several pathological conditions including cancer. Studies performed in cultured cells indicate that paclitaxel cytotoxicity is reduced by adding AGP and the sensitivity to paclitaxel is restored by displacing its binding to AGP with clindamycin, resulting in an increased paclitaxel cell uptake. The purpose of this study was to evaluate whether clindamycin modifies paclitaxel pharmacokinetics also in cancer patients. PATIENTS AND METHODS: Sixteen patients with advanced ovarian cancer, previously treated with surgery and chemotherapy were enrolled in this study. A pharmacokinetic study of paclitaxel was performed in the first three cycles of the consolidation therapy (paclitaxel and carboplatin) in each patient. In these cycles paclitaxel was administered alone and with two different doses (600 and 1,200 mg) of concurrent clindamycin. The sequence of the three treatments was randomly assigned in each patient in order to avoid the same order of treatments. RESULTS: Paclitaxel pharmacokinetics were partly modified by the concurrent administration of clindamycin. C (max) and AUC(0-last) of paclitaxel were significantly higher when the drug was given alone than when it was coadministered with 1,200 mg clindamycin. Moreover, AGP concentrations seem to have a small but statistically significant influence on paclitaxel pharmacokinetic, since AUC(0-last) showed a positive significant correlation with AGP plasma concentration when paclitaxel was given alone. The linear relation was lost when paclitaxel was coadministered with 1,200 mg clindamycin. Toxicity was not influenced by the coadministration of clindamycin. CONCLUSION: The hypothesis that clindamycin could affect paclitaxel pharmacokinetics seems to be verified with this study. Nevertheless, changes induced by giving the combination of the two drugs are minimal and thus of questionable clinical relevance.
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