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BACKGROUND: In 2003, the Dutch government legalized the production and distribution of a standardized cannabis-product for medical treatment purposes (MC). Although there is no role up front for MC in the treatment of pain, anorexia, and nausea in cancer patients, its use is frequent. Due to the broad spectrum of cannabinoids present in cannabis, undesirable PK interactions with concomitantly prescribed anti-cancer drugs cannot be excluded. As CYP3A is involved in the metabolism of about 50-70% of prescribed drugs, we have set up a study to investigate the effects of MC on the pharmacokinetics of DOC and CPT-11, both frequently prescribed drugs metabolized by CYP3A isozymes.
METHODS: Patients were treated with one course of DOC (180 mg i.v.; 60 min) or CPT-11 (600 mg i.v.; 90 min) followed 3 weeks later by a second course with a, for safety reasons 25% reduced dose (135 mg, resp. 450 mg), with concomitant MC once daily (0.2g/200ml tea), starting 2 weeks prior to infusion. Use of co-medication known to induce or inhibit CYP3A was not allowed, as was use of herbals and dietary supplements. Interim analysis was planned after three patients per study arm to evaluate further necessity of dose reduction. Serial plasma samples were obtained up to 500 hours after infusion for PK analysis by HPLC.
RESULTS: At time of planned interim-analysis, 6 patients equally divided over both treatment arms were evaluable for analysis. For docetaxel no changes in dose normalized disposition and elimination profiles were seen between courses with and without MC co-administration. Mean maximal concentration (Cmax) in the absence or presence of MC were 3,117 vs 3,498 ng/mL (P=.25). For CPT-11 mean clearances (16.4 vs 16.7 L/h) and mean exposure to its active metabolite SN-38 (705 vs 693 ng*h/mL) were equal as well (P>.82). For CPT-11, the mean relative extent of conversion of CPT-11 into SN-38 (REC; 1.92% vs 1.89%) and mean relative extent of glucuronidation of SN-38 into SN-38G (REG; 11.6 vs 11.6) did not differ as well (P>.83). Patients tolerated MC tea very well, although one patient complained about dysphoric mood. In addition, incidence and severity of nausea and vomiting were not altered.
DISCUSSION: These preliminary data suggest that concomitant use of MC by cancer patients does not lead to significantly altered PK of DOC and CPT-11. As MC tea also does not seem to affect or alter the side-effect profile seen in these patients, the combination of MC with anti-cancer drugs predominantly metabolized by CYP3A seems to be safe. As the REG of SN-38 into its glucuronide by UGT1A did not differ between both courses, MC tea does not seem to affect UGT1A functional expression as well. Nonetheless, until more clinical evidence becomes available, we advise to combine these anti-cancer drugs with MC tea only in a palliative setting when other medications have proven not to be effective.
Source: Influence of medicinal cannabis (MC) on the pharmacokinetics (PK) of docetaxel (DOC) and irinotecan (CPT-11) -- De Jong et al. 2005 (1): 938 -- AACR Meeting Abstracts
METHODS: Patients were treated with one course of DOC (180 mg i.v.; 60 min) or CPT-11 (600 mg i.v.; 90 min) followed 3 weeks later by a second course with a, for safety reasons 25% reduced dose (135 mg, resp. 450 mg), with concomitant MC once daily (0.2g/200ml tea), starting 2 weeks prior to infusion. Use of co-medication known to induce or inhibit CYP3A was not allowed, as was use of herbals and dietary supplements. Interim analysis was planned after three patients per study arm to evaluate further necessity of dose reduction. Serial plasma samples were obtained up to 500 hours after infusion for PK analysis by HPLC.
RESULTS: At time of planned interim-analysis, 6 patients equally divided over both treatment arms were evaluable for analysis. For docetaxel no changes in dose normalized disposition and elimination profiles were seen between courses with and without MC co-administration. Mean maximal concentration (Cmax) in the absence or presence of MC were 3,117 vs 3,498 ng/mL (P=.25). For CPT-11 mean clearances (16.4 vs 16.7 L/h) and mean exposure to its active metabolite SN-38 (705 vs 693 ng*h/mL) were equal as well (P>.82). For CPT-11, the mean relative extent of conversion of CPT-11 into SN-38 (REC; 1.92% vs 1.89%) and mean relative extent of glucuronidation of SN-38 into SN-38G (REG; 11.6 vs 11.6) did not differ as well (P>.83). Patients tolerated MC tea very well, although one patient complained about dysphoric mood. In addition, incidence and severity of nausea and vomiting were not altered.
DISCUSSION: These preliminary data suggest that concomitant use of MC by cancer patients does not lead to significantly altered PK of DOC and CPT-11. As MC tea also does not seem to affect or alter the side-effect profile seen in these patients, the combination of MC with anti-cancer drugs predominantly metabolized by CYP3A seems to be safe. As the REG of SN-38 into its glucuronide by UGT1A did not differ between both courses, MC tea does not seem to affect UGT1A functional expression as well. Nonetheless, until more clinical evidence becomes available, we advise to combine these anti-cancer drugs with MC tea only in a palliative setting when other medications have proven not to be effective.
Source: Influence of medicinal cannabis (MC) on the pharmacokinetics (PK) of docetaxel (DOC) and irinotecan (CPT-11) -- De Jong et al. 2005 (1): 938 -- AACR Meeting Abstracts
