14 research outputs found
Clinical pharmacokinetics and metabolism of irinotecan (CPT-11)
CPT-11 belongs to the class of topoisomerase I inhibitors, and it acts as
a prodrug of SN-38, which is approximately 100-1000-fold more cytotoxic
than the parent drug. CPT-11 has shown a broad spectrum of antitumor
activity in preclinical models as well as clinically, with responses
observed in various disease types including colorectal, lung, cervical,
and ovarian cancer. The pharmacokinetics and metabolism of CPT-11 are
extremely complex and have been the subject of intensive investigation in
recent years. Both CPT-11 and SN-38 are known in an active lactone form
and an inactive carboxylate form, between which an equilibrium exists that
depends on the pH and the presence of binding proteins. CPT-11 is subject
to extensive metabolic conversion by various enzyme systems, including
esterases to form SN-38, UGT1A1 mediating glucuronidation of SN-38, as
well as CYP3A4, which forms several pharmacologically inactive oxidation
products. Elimination routes of CPT-11 also depend on the presence of
drug-transporting proteins, notably P-glycoprotein and canalicular
multispecific organic anion transporter, present on the bile canalicular
membrane. The various processes mediating drug elimination, either through
metabolic breakdown or excretion, likely impact substantially on
interindividual variability in drug handling. Strategies to individualize
CPT-11 administration schedules based on patient differences in enzyme or
protein expression or by coadministration of specific agents modulating
side effects are under way and may ultimately lead to more selective
chemotherapeutic use of this agent
Augmentation of Endoxifen Exposure in Tamoxifen-Treated Women Following SSRI Switch
Background and Objective: The anti-oestrogen tamoxifen requires metabolic activation to endoxifen by cytochr
Well being of obstetric patients on minimal blood transfusions (WOMB trial)
Background: Primary postpartum haemorrhage is an obstetrical emergency often causing acute anaemia that may require immediate red blood cell (RBC) transfusion. This anaemia results in symptoms such as fatigue, whic
Pharmacokinetic, Metabolic, and Pharmacodynamic Profiles in a Dose-Escalating Study of Irinotecan and Cisplatin
Dextromethorphan as a phenotyping test to predict endoxifen exposure in patients on tamoxifen treatment
Purpose: Tamoxifen, a widely used agent for the prevention and treatment of breast cancer, is mainly metabolized by CYP2D6 and CYP3A to form its most abundant active metabolite, endoxifen. Interpatient variability in toxicity and efficacy of tamoxifen is substantial. Contradictory results on the value of CYP2D6 genotyping to reduce the variable efficacy have been reported. In this pharmacokinetic study, we investigated the value of dextromethorphan, a known probe drug for both CYP2D6 and CYP3A enzymatic activity, as a potential phenotyping probe for tamoxifen pharmacokinetics. Methods: In this prospective study, 40 women using tamoxifen for invasive breast cancer received a single dose of dextromethorphan 2 hours after tamoxifen intake. Dextromethorphan, tamoxifen, and their respective metabolites were quantified. Exposure parameters of all compounds were estimated, log transformed, and subsequently correlated. Results: A strong and highly significant correlation (r=-0.72; P < .001) was found between the exposures of dextromethorphan (0 to 6 hours) and endoxifen (0 to 24 hours). Also, the area under the plasma concentration-time curve of dextromethorphan (0 to 6 hours) and daily trough endoxifen concentration was strongly correlated (r = -0.70; P < .001). In a single patient using the potent CYP2D6 inhibitor paroxetine, the low endoxifen concentration was accurately predicted by dextromethorphan exposure. Conclusion: Dextromethorphan exposure after a single administration adequately predicted endoxifen exposure in individual patients with breast cancer taking tamoxifen. This test could contribute to the personalization and optimization of tamoxifen treatment, but it needs additional validation and simplification before being applicable in future dosing strategies
Updated Survival Analysis of the Randomized Phase III Trial of S-1 Versus Capecitabine in the First-Line Treatment of Metastatic Colorectal Cancer by the Dutch Colorectal Cancer Group
A randomized phase II multicenter trial on the effects of budesonide on cabazitaxel-induced diarrhea: CABARESC.
Dextromethorphan as a phenotyping test to predict endoxifen exposure in patients on tamoxifen treatment
Item does not contain fulltextPURPOSE: Tamoxifen, a widely used agent for the prevention and treatment of breast cancer, is mainly metabolized by CYP2D6 and CYP3A to form its most abundant active metabolite, endoxifen. Interpatient variability in toxicity and efficacy of tamoxifen is substantial. Contradictory results on the value of CYP2D6 genotyping to reduce the variable efficacy have been reported. In this pharmacokinetic study, we investigated the value of dextromethorphan, a known probe drug for both CYP2D6 and CYP3A enzymatic activity, as a potential phenotyping probe for tamoxifen pharmacokinetics. METHODS: In this prospective study, 40 women using tamoxifen for invasive breast cancer received a single dose of dextromethorphan 2 hours after tamoxifen intake. Dextromethorphan, tamoxifen, and their respective metabolites were quantified. Exposure parameters of all compounds were estimated, log transformed, and subsequently correlated. RESULTS: A strong and highly significant correlation (r = -0.72; P < .001) was found between the exposures of dextromethorphan (0 to 6 hours) and endoxifen (0 to 24 hours). Also, the area under the plasma concentration-time curve of dextromethorphan (0 to 6 hours) and daily trough endoxifen concentration was strongly correlated (r = -0.70; P < .001). In a single patient using the potent CYP2D6 inhibitor paroxetine, the low endoxifen concentration was accurately predicted by dextromethorphan exposure. CONCLUSION: Dextromethorphan exposure after a single administration adequately predicted endoxifen exposure in individual patients with breast cancer taking tamoxifen. This test could contribute to the personalization and optimization of tamoxifen treatment, but it needs additional validation and simplification before being applicable in future dosing strategies
Therapeutic Drug Monitoring of Endoxifen for Tamoxifen Precision Dosing: Feasible in Patients with Hormone-Sensitive Breast Cancer
Background: Endoxifen is the most important active metabolite of tamoxifen. Several retrospective studies have suggested a minimal or threshold endoxifen systemic concentration of 14–16 nM is required for a lower recurrence rate. The aim of this study was to investigate the feasibility of reaching a predefined endoxifen level of ≥ 16 nM (5.97 ng/mL) over time using therapeutic drug monitoring (TDM). Methods: This prospective open-label intervention study enrolled patients who started treatment with a standard dose of tamoxifen 20 mg once daily for early breast cancer. An outpatient visit was combined with a TDM sample at 3, 4.5, and 6 months after initiation of the tamoxifen treatment. The tamoxifen dose was escalated to a maximum of 40 mg if patients had an endoxifen concentration < 16 nM. The primary endpoint of the study was the percentage of patients with an endoxifen level ≥ 16 nM at 6 months after the start of therapy compared with historical data, in other words, 80% of patients with endoxifen levels ≥ 16 nM with standard therapy. Results: In total, 145 patients were included. After 6 months, 89% of the patients had endoxifen levels ≥ 16 nM, compared with a literature-based 80% of patients with endoxifen levels ≥ 16 nM at baseline (95% confidence interval 82–94; P = 0.007). In patients with an affected CYP2D6 allele, it was not always feasible to reach the predefined endoxifen level of ≥ 16 nM. No increase in tamoxifen-related adverse events was reported after dose escalation. Conclusion: This study demonstrated that it is feasible to increase the percentage of patients with endoxifen levels ≥ 16 nM using TDM. TDM is a safe strategy that offers the possibility of nearly halving the number of patients with endoxifen levels < 16 nM