Clinical Trial: CYP2D6 Related Dose Escalation of Tamoxifen in Breast Cancer Patients With Iranian Ethnic Background Resulted in Increased Concentrations of Tamoxifen and Its Metabolites

Abstract

Introduction: The polymorphic enzyme cytochrome P450 2D6 (CYP2D6) catalyzes a major step in the bioactivation of tamoxifen. Genotyping of clinically relevant CYP2D6 alleles and subsequent dose adjustment is a promising approach to individualize breast cancer therapy. The aim of this study was to investigate the relationship between the plasma levels of tamoxifen and its metabolites and different CYP2D6 genotypes under standard (20 mg/day) and dose-adjusted therapy (Registration ID in Iranian Registry of Clinical Trials: IRCT2015082323734N1). Materials and Methods: Using TaqMan ® assays common alleles of CYP2D6 ( ∗ 1, ∗ 2, ∗ 4, ∗ 5, ∗ 6, ∗ 10, ∗ 17, and ∗ 41) and gene duplication were identified in 134 breast cancer patients. Based on CYP2D6 genotypes patients with an activity score 1 ( n = 15) and 0–0.5 ( n = 2) were treated with tamoxifen adjusted dosage of 30 and 40 mg/day, respectively. The concentration of tamoxifen and its metabolites before and after 4 and 8 months of dose adjustment were measured using LC-MS/MS technology. Results: At baseline, (Z)-endoxifen plasma concentrations (33 ± 15.5, 28.1 ± 14, 26.6 ± 23.4, 14.3 ± 8.6, and 10.7 ± 5.5 nmol/l for EM/EM, EM/IM, EM/PM, IM/IM and PM/PM, respectively) and the metabolic ratio (Z)-Endoxifen/N-desmethyltamoxifen (0.0558 ± 0.02, 0.0396 ± 0.0111, 0.0332 ± 0.0222, 0.0149 ± 0.0026, and 0.0169 ± 0.0177 for EM/EM, EM/IM, EM/PM, IM/IM, and PM/PM, respectively) correlated with CYP2D6 genotype (Kruskal–Wallis p = 0.013 and p < 0.0001, respectively). Dose escalation to 30 and 40 mg/day in patients with a CYP2D6 activity score of 1 ( n = 15) and 0–0.5 ( n = 2) resulted in a significant increase in (Z)-endoxifen plasma levels (22.17 ± 24.42, 34.43 ± 26.54, and 35.77 ± 28.89 nmol/l at baseline, after 4 and 8 months, respectively, Friedman p = 0.0388) along with the plasma concentrations of tamoxifen and its other metabolites. No severe side effects were recorded during dose escalation. Conclusion: For the first time, we show the feasibility of dose escalation of tamoxifen in breast cancer patients with compromised CYP2D6 activity and Iranian ethnic background to increase the plasma concentrations of (Z)-endoxifen.

Therapeutic drug monitoring of oral targeted antineoplastic drugs

“…Considering this, TDM of endoxifen might be promising to identify patients with sub-optimal target concentrations [87]. Because no toxic tamoxifen dose has been identified, dose increases up until 120 mg QD for patients with endoxifen C SS < 5.97 ng/ mL have been investigated and TDM has proven feasible [20, [88][89][90][91][92]. As it takes about 3 months to attain endoxifen steady state, we propose to use MIPD for early endoxifen target attainment [93].…”

Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

“…Breast cancer patients with lower endoxifen levels than the published efficacy threshold of 5.9 ng/mL might benefit from a higher dose tamoxifen than the standard 20 mg/day. Khalaj et al [ 72 ] performed a prospective clinical trial with a total of 134 Iranian ER-positive breast cancer patients. Patients with AS = 1 ( n = 15) and AS = 0–0.5 ( n = 2) received dose-adjusted therapy of 30 and 40 mg/day, respectively.…”

Simulation-Based Assessment of the Impact of Non-Adherence on Endoxifen Target Attainment in Different Tamoxifen Dosing Strategies

“…This results in many individual concentrations being significantly above the target concentration in adherent patients and lower, but not yet subtarget, concentrations in non-adherent patients. Yet, as some individuals experience very high C SS , min ENDX , which can lead to increased frequencies of adverse events [ 31 , 32 , 33 ], CYP2D6 -guided dosing should not be the dosing strategy of choice.…”

“…Two additional dosing strategies were explored regarding their potential to increase the forgiveness of MIPD to non-adherence: (iv) MIPD targeting the proposed C SS,min ENDX therapeutic threshold concentration of 5.97 ng/mL while adding a fixed increment (here: 10 mg) to each individual dose, as it is common in current clinical practice [ 33 , 37 , 38 , 44 ] and (v) MIPD targeting the lowest reported mean endoxifen C SS , min ENDX in gNM (9 ng/mL) [ 29 ]. As it is common procedure to increase the dose in fixed increments, i.e., in 10 mg steps due to available tablet strengths, the dosing strategy (iv) aimed to represent the status-quo of dose adjustments to increase drug concentrations in clinical practice [ 33 , 37 , 38 , 44 ]. Representing the common clinical practice to measure minimum concentrations [ 45 ], we chose to collect our virtual TDM samples at the end of a dosing interval.…”