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Simplified biotransformation scheme of tamoxifen in man. Tamoxifen is mainly N-demethylated to NDM-TAM and subsequently 4-hydroxylated to endoxifen. A minor pathway proceeds via 4-hydroxylation to 4OH-TAM followed by N-demethylation to endoxifen. The polymorphic CYP2D6 is involved in crucial steps of the endoxifen formation. Abbreviations used in diagram: cytochrome P450 (CYP), sulfonyltransferase (SULT), uridine-5′-diphosphoglucuronyltransferase (UGT), tamoxifen (TAM), N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen (4OH), endoxifen (END).
Source publication
Purpose
To overcome cytochrome P450 2D6 (CYP2D6) mediated tamoxifen resistance in postmenopausal early breast cancer, CYP2D6 phenotype-adjusted tamoxifen dosing in patients with impaired CYP2D6 metabolism and/or the application of endoxifen, the most potent tamoxifen metabolite, are alternative treatment options. To elucidate both strategies compre...
Citations
... Interestingly, simulations performed on 15,000 virtual European female patients with early breast cancer using a physiologically-based pharmacokinetic model for TAM based on in vitro and in vivo data, 39 led to similar dose recommendations as in our model, confirming the robustness of our analysis. ...
Variations in clinical response to tamoxifen (TAM) may be related to polymorphic cytochromes P450 (CYPs) involved in forming its active metabolite endoxifen (ENDO). We developed a population pharmacokinetic (PopPK) model for tamoxifen and six metabolites to determine clinically relevant factors of ENDO exposure. Concentration-time data for TAM and 6 metabolites come from a prospective, multicenter, 3-year follow-up study of adjuvant TAM (20 mg/day) in patients with breast cancer, with plasma samples drawn every 6 months, and genotypes for 63 genetic polymorphisms (PHACS study, NCT01127295). Concentration data for TAM and 6 metabolites from 928 patients (n = 27,433 concentrations) were analyzed simultaneously with a 7-compartment PopPK model. CYP2D6 phenotype (poor metabolizer (PM), intermediate metabolizer (IM), normal metabolizer (NM), and ultra-rapid metabolizer (UM)), CYP3A4*22, CYP2C19*2, and CYP2B6*6 genotypes, concomitant CYP2D6 inhibitors, age, and body weight had a significant impact on TAM metabolism. Formation of ENDO from N-desmethyltamoxifen was decreased by 84% (relative standard error (RSE) = 14%) in PM patients and by 47% (RSE = 9%) in IM patients and increased in UM patients by 27% (RSE = 12%) compared with NM patients. Dose-adjustment simulations support an increase from 20 mg/day to 40 and 80 mg/day in IM patients and PM patients, respectively, to reach ENDO levels similar to those in NM patients. However, when considering Antiestrogenic Activity Score (AAS), a dose increase to 60 mg/day in PM patients seems sufficient. This PopPK model can be used as a tool to predict ENDO levels or AAS according to the patient’s CYP2D6 phenotype for TAM dose adaptation. © 2020 The Authors Clinical Pharmacology & Therapeutics © 2020 American Society for Clinical Pharmacology and Therapeutics
... Since 2000, the model has been used to support decision-making [3] during the different phases of drug discovery to select potential candidate compounds [4] for clinical development [5]. The applications of PBPK modeling in oncology drug development include the prediction of drug concentration-time profiles in animals [6][7][8][9], first-in-human (FIH) dose extrapolation [10][11][12][13][14], phase II/III clinical trials [18][19][20][21][22][23], organ impairment [24][25][26], dose adjustment in pediatrics [27][28][29][30] and drug-drug interactions (DDIs) [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. In addition, through simulating blood concentration-time profiles in a virtual population as an individual model (together with patient information, called Bpersonalized medicine^ [17,46]) or population-based model, the model helps to reduce the number of animals and human participants enrolled in nonclinical studies and clinical trials. ...
... Fifteen articles reported the application of PBPK modeling in DDIs with various mechanisms, including reversible inhibition (RI), mechanism-based inhibition (MBI), time-dependent inhibition (TDI) or irreversible inhibition, and enzyme induction (EI) [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. Median AAFEs of the predicted AUC ratio for all 15 DDI studies was 1.08 (range 1.0-1.17). ...
... Two studies did not report the type of inhibition and/or induction [40,45]. In addition, PBPK modeling was applied to evaluate the DDI studies in phase II metabolizing enzymes [43], transporters [34,41], the effect of therapeutic proteins on CYP450 enzymes [37], the effect of phenotype polymorphism [40,44] and the effect of metabolites on parent drug [32,40]. Median AAFEs of the predicted AUC ratio of those applications fell within 1.2-fold [34,37,[41][42][43] or within the 90% CI of the predicted values [40,44]. ...
Purpose:
Physiologically based pharmacokinetic (PBPK) modeling, a mathematical modeling approach which uses a pharmacokinetic model to mimick human physiology to predict drug concentration-time profiles, has been used for the discover and development of drugs in various fields, including oncology, since 2000. There have been a few general review articles on the utilization of PBPK in the development of oncology drugs, but these do not include an evaluation of model prediction accuracy. We therefore conducted a systematic review to define the accuracy of PBPK model prediction and its utility throughout all the developmental phases of oncology drugs.
Methods:
A systematic search was performed in the PubMed, PubMed Central and Cochrane Library databases from 1980 to February 2017 for articles (1) written in English, (2) focused on oncology or antineoplastic or anticancer drugs, tumor or cancer or anticancer drugs listed in the U.S. National Institutes of Health and (3) involving a PBPK model. The absolute-average-folding-errors (AAFEs) of the area under the curve (AUC) between predicted and observed values in each article were calculated to assess model prediction accuracy.
Results:
Of the 2341 articles initially identified by our search of the databases, 40 were included in the review analysis. These articles reported on six types of studies, i.e. in vivo (n = 4), first-in-human (n = 5), phase II/III clinical trials (n = 9), organ impairment (n = 3), pediatrics (n = 4) and drug-drug interactions (n = 15). AAFEs of the predicted AUC for all groups of studies were within 1.3-fold of each other despite variations in experimental methodologies.
Conclusion:
PBPK modeling is a potential tool which can be effectively applied throughout all phases of oncology drug development. The number of experimental animals and human participants enrolled in the studies can be reduced using PBPK modeling and PBPK-population-PK modeling. The limited number of publications of unsuccessful model application to date may contribute to bias toward the usefulness of modeling.
... 9 Previously, PBPK modeling and VCS simulation approaches were applied to predict the levels of tamoxifen and endoxifen in patients with impaired CYP2D6 metabolism. 10,11 Yet, these previous modeling efforts did not adequately capture interindividual variability in endoxifen levels observed in clinical settings and more importantly did not link varying endoxifen levels to clinical response of tamoxifen therapy. ...
... 27,28 In fact, when the previous efforts of PBPK modeling and VCS approaches assumed an equal extent of variability across CYP2D6 genotypes, the simulation results did not adequately capture interindividual variability in endoxifen levels observed in clinical settings. 10,11 We constructed the virtual population that reflects the experimentally observed variability in the CYP2D6 activity (i.e., varying extent of variability among different CYP2D6 activity-based genotypes). 19 By doing so, we successfully captured the reported distribution of 4-OHT and endoxifen levels by CYP2D6 genotypes (Figure 3 and Figure S2). ...
The Tamoxifen Response by CYP2D6 Genotype‐based Treatment‐1 (TARGET‐1) study (n = 180) was conducted from 2012–2017 in Japan to determine the efficacy of tamoxifen dosing guided by cytochrome P450 2D6 (CYP2D6) genotypes. To predict its outcomes prior to completion, we constructed the comprehensive physiologically based pharmacokinetic (PBPK) models of tamoxifen and its metabolites and performed virtual TARGET‐1 studies. Our analyses indicated that the expected probability to achieve the end point (demonstrating the superior efficacy of the escalated tamoxifen dose over the standard dose in patients carrying CYP2D6 variants) was 0.469 on average. As the population size of this virtual clinical study (VCS) increased, the expected probability was substantially increased (0.674 for n = 260). Our analyses also informed that the probability to achieve the end point in the TARGET‐1 study was negatively impacted by a large variability in endoxifen levels. Our current efforts demonstrate the promising utility of the PBPK modeling and VCS approaches in prospectively designing effective clinical trials.
... As computing capacity has grown and new in silico and in vitro methodologies emerged, PBPK modeling and simulation has expanded to various clinically relevant fields during drug development and pharmacotherapy. PBPK has already made contributions in the prediction and assessment of (i) drug-drug-and druggene-interactions (DDI [72][73][74][75] and DGI [76][77][78][79] ) via metabolic enzymes and drug transporters and (ii) the PK of special populations, such as pediatric [80][81][82] , geriatric 83,84 and pregnant individuals 85,86 or patients with differing degrees of hepatic 87,88 or renal 89,90 impairment. ...
... However, as tamoxifen and other metabolites may also contribute to the overall clinical effect of tamoxifen, the sole administration of endoxifen may not be the optimal strategy. Therefore, a dosing strategy of tamoxifen at a dose of 20 mg in combination with endoxifen (at a dose dependent on CYP2D6 phenotype) has been suggested to be a better approach [35]. Nevertheless, these approaches need further investigation [32]. ...
Objective: to determine a possible correlation between the tumor response in patients suffering from breast cancer, initially treated with tamoxifen, and plasma concentration of this drug.Methods: we studied 27 elderly patients (age range: 62 to 82 y) with advanced breast carcinoma who were treated with a daily dose of 20 mg of oral tamoxifen, for 3 mo. Responders were followed-up for 19 mo, and nonresponders for 21 mo. We measured plasma tamoxifen citrate levels in order to determine their possible correlation with objective remission of the disease.Results: the correlation was found to be significant among responders (37%), whose median plasma tamoxifen level was 187.40ng. ml-1, when comparing to non-responders, whose median plasma tamoxifen level was 99.52ng. ml-1. The frequency distribution of patients in both groups with concentration of tamoxifen lower and higher than 182.60ng. ml-1 was significant (fisher’s test p-value<0,0011).Conclusion: considering the results herein, we suggest that patients whose plasma tamoxifen levels reach 182.60ng. ml-1 after 3 mo of treatment, with no tumor response, may not benefit from this treatment, and an alternative therapy should be regarded.
... That approach resulted in suggested fixed-dose combinations of tamoxifen (20 mg/d) and CYP2D6 genotype-specific amounts of endoxifen for IMs (1 mg/d) and PMs (3 mg/d). These combinations will now be prospectively evaluated in a clinical intervention trial (Dickschen et al., 2014; Figure 1 upper row). ...
... Genotype-specific fixed dose combinations for IMs and PMs were shown to equalize endoxifen exposure at steady-state in silico (Dickschen et al., 2014) (upper row). The fixed-dose combination of 20 mg tamoxifen and 3 mg endoxifen following this rationale is regarded as a standard for PMs, thus they were no longer evaluated in this analysis. ...
... The characteristic metabolite pattern resulting from tamoxifen daily dosing of 20 mg to CYP2D6 EMs was demonstrated to be well tolerated and highly beneficial over the past four decades (Early Breast Cancer Trialists' Collaborative Group (EBCTCG), 1992(EBCTCG), , 1998(EBCTCG), , 2005Stearns et al., 2003Stearns et al., , 2004. However, steady-state kinetics of tamoxifen metabolites require a very long period of time to develop which can be in the range of 3-4 months as demonstrated by our previously developed PBPK model (Wu et al., 2009;Dickschen et al., 2012Dickschen et al., , 2014. It was reported that endoxifen is the key contributor to tamoxifen's antitumoral activity exerting a concentration-dependent effect on tumor proliferation and growth (Johnson et al., 2004;Lim et al., 2005Lim et al., , 2006Wu et al., 2009). ...
Introduction: Tamoxifen is one of the most common treatment opportunities for hormonal positive breast cancer. Despite its good tolerability, patients demonstrate decreasing adherence over years impacting on therapeutic success. PBPK modeling was applied to demonstrate the impact of drug holidays on plasma levels of tamoxifen and its active metabolite endoxifen for different CYP2D6 genotypes.
Materials and Methods: A virtual study with 24,000 patients was conducted in order to investigate the development of tamoxifen steady-state kinetics in patient groups of different CYP2D6 genotypes. The impact of drug holidays on steady-state kinetics was investigated assuming changing drug holiday scenarios.
Results: Drug holidays in CYP2D6 extensive and intermediate metabolizers (EMs, IMs) exceeding 1 month lead to a decrease of endoxifen steady-state trough levels below the 5th percentile of the control group. Assuming drug holidays of 1, 2, or 3 months and administering a fixed-dose combination of 20 mg tamoxifen and 3 mg endoxifen EMs demonstrated re-established endoxifen steady-state trough levels after 5, 8, and 9 days. IMs receiving the same fixed-dose combination demonstrated re-established endoxifen steady-state trough levels after 7, 10, and 11 days.
Discussion: The PBPK model impressively demonstrates the impact of drug holidays in different CYP2D6 genotypes on PK. Population simulation results indicate that drug holidays of more than 2 weeks cause a tremendous decrease of plasma levels despite the long half-life of tamoxifen. To improve therapeutic success, PBPK modeling allows identifying genotype-specific differences in PK following drug holidays and adequate treatment with loading doses.
... Patients with an effective tamoxifen metabolism, burdened with a lower risk of relapse, should be persuaded to strictly comply with the therapy, whilst patients with plasma (Z)-endoxifen concentrations below the therapeutic threshold and an adverse drug metabolism, should be proposed personalised treatment through increasing the daily dose of tamoxifen or, if at all possible, by using an alternative drug. Work is currently undergoing to also determine whether standard doses of tamoxifen can be supplemented with pure (Z)-endoxifen [33]. Any final assertion on whether it is possible to personalise tamoxifen treatment requires separate and adequately controlled multicenter studies. ...
Tamoxifen is the most commonly used drug for treating those patients with breast cancer who are oestrogen receptor positive. The main active metabolite of tamoxifen is (Z)-endoxifen whose therapeutic efficacy depends on its plasma concentration. A therapeutically effective threshold level has indeed been defined for (Z)-endoxifen above which the breast cancer relapse rate is significantly reduced. Such steady-state concentrations are conditional on gene polymorphism, principally cytochrome P450 2D6 (CYP2D6), that modulates the activity of the encoded enzymes that convert tamoxifen to its active metabolites. This drug's metabolism however may become significantly altered when other medication is concomitantly taken, such as selective serotonin reuptake inhibitors, which inhibit CYP2D6. A recent study have demonstrated that the majority of tamoxifen treated women with breast cancer in Poland, may not in fact attain the therapeutic threshold levels of (Z)-endoxifen. In such cases, personalising optimal treatment should be based on direct monitoring of steady-state plasma concentrations of tamoxifen and its metabolites, which can thereby significantly improve therapeutic efficacy.
... Major breakthroughs will result not only from our ability to forecast such physiological implications during the early stages of the development of a drug [50], but also how these would interact beyond the local site of action. The consequences are twofold: to streamline the drug development process by increasing the likelihood of success and reducing time to market through optimal design of formulations, and to enable the development of patientspecific formulations increasing the likelihood of treatment success targeting specific patient sub-populations [25]. ...
Quantitative Systems Pharmacology (QSP) is receiving increased attention. As the momentum builds and the expectations grow it is important to (re)assess and formalize the basic concepts and approaches. In this short review, I argue that QSP, in addition to enabling the rational integration of data and development of complex models, maybe more importantly, provides the foundations for developing an integrated framework for the assessment of drugs and their impact on disease within a broader context expanding the envelope to account in great detail for physiology, environment, and prior history. I articulate some of the critical enablers, major obstacles, and exciting opportunities manifesting themselves along the way. Charting such overarching themes will enable practitioners to identify major and defining factors as the field progressively moves towards personalized and precision healthcare delivery.
... Endoxifen results from enzymatic conversion of either Tam or 4-OHT and accumulates at higher titers than 4-OHT in the blood of Tam-treated patients, suggesting either faster metabolic kinetics or increased stability in vivo [8][9][10]. Underlining its potency, Endoxifen has been successfully applied in ER-based tumor treatment of patients with deficient CYP2D6 metabolism that precludes classic Tam treatment [11]. ...
Mutant Estrogen Receptor (ERT2) ligand-binding domain fusions with Cre recombinase are a key tool for spatio-temporally controlled genetic recombination with the Cre/lox system. CreERT2 is efficiently activated in a concentration-dependent manner by the Tamoxifen metabolite trans-4-OH-Tamoxifen (trans-4-OHT). Reproducible and efficient Cre/lox experimentation is hindered by the gradual loss of CreERT2 induction potency upon prolonged storage of dissolved trans-4-OHT, which potentially results from gradual trans-to-cis isomerization or degradation. Here, we combined zebrafish CreERT2 recombination experiments and cell culture assays to document the gradual activity loss of trans-4-OHT and describe the alternative Tamoxifen metabolite Endoxifen as more stable alternative compound. Endoxifen retains potent activation upon prolonged storage (3 months), yet consistently induces half the ERT2 domain fusion activity compared to fresh trans-4-OHT. Using 1H-NMR analysis, we reveal that trans-4-OHT isomerization is undetectable upon prolonged storage in either DMSO or Ethanol, ruling out isomer transformation as cause for the gradual loss of trans-4-OHT activity. We further establish that both trans-4-OHT and Endoxifen are insensitive to light exposure under regular laboratory handling conditions. We attribute the gradual loss of trans-4-OHT potency to precipitation over time, and show that heating of aged trans-4-OHT aliquots reinstates their CreERT2 induction potential. Our data establish Endoxifen as potent and reproducible complementary compound to 4-OHT to control ERT2 domain fusion proteins in vivo, and provide a framework for efficient chemically controlled recombination experiments.
... Whereas additional studies designed for following up TAM treated patients for up to 15-20 years after BC diagnosis is of fundamental importance to determine the actual clinical relevance of our findings, 20 % and 45 % (IM + PM), respectively of our Hispanic and NHW population were potentially at risk for subtherapeutic levels of TAM (endoxifen). CYP2D6 phenotype-adjustment tamoxifen dosing for IM or PM patients and/or consomitant use of endoxifen might be reasonable alternatives treatment approaches for these patients [47]. ...
Ethnic differences in patient genetics and breast cancer (BC) biology contribute to ethnic disparities in cancer presentation and patient outcome. We prospectively evaluated SNPs within phase I and phase II tamoxifen (TAM) metabolizing enzymes, and the estrogen receptor gene (ESR1), aiming to identify potential pharmacogenomic ethnicity patterns in an ER-positive BC cohort constituted of Hispanic and Non-Hispanic White (NHW) women in South Texas. Plasma concentrations of TAM/metabolites were measured using HPLC. CYP2C9, CYP2D6 and SULT1A1 genotypes were determined by DNA sequencing/Pyrosequencing technology. ESR1 PvuII and XbaI SNPs were genotyped using Applied Biosystems Taqman(®) Allelic Discrimination Assay. Hispanics had higher levels of TAM, 4-hydroxytamoxifen, and endoxifen than NHWs. There was a higher prevalence of CYP2D6 EM within Hispanics than NHWs, which corresponded to higher endoxifen levels, but no differences were verified with regard to CYP2C9 and SULT1A1. We found a higher incidence of the wild type forms of the ESR1 in Hispanics than NHWs. The performance status, the disease stage at diagnosis, and the use of aromatase inhibitors might have overcome the overall favorable pharmacogenomics profile of Hispanics when compared to NHWs in relation to TAM therapy responsiveness. Our data strongly point to ethnical peculiarities related to pharmacogenomics and demographic features of TAM treated Hispanics and NHWs. In the era of pharmacogenomics and its ultimate goal of individualized, efficacious and safe therapy, cancer studies focused on the Hispanic population are warranted because this is the fastest growing major demographic group, and an understudied segment in the U.S.
