Extensive Metabolizer Patients Research Articles

Abstract 1150: Pharmacokinetics and pharmacogenetics of liposomal cytarabine in AML patients treated with CPX-351

Abstract CPX-351 is a liposomal form encapsulating cytarabine and daunorubicin for treating Acute Myeloid Leukemia (AML) patients. Cytidine Deaminase (CDA) catabolizes free cytarabine in the liver, but to what extent it could affect as well the pharmacokinetics of liposomal cytarabine is yet to be investigated. Here we have studied the pharmacokinetics (PK) of released, liposomal and total cytarabine using a population-modeling approach in adult AML patients treated with CPX-351. Impact of CDA status (i.e., Poor Metabolizer (PM) vs. Extensive Metabolizer (EM)) on cytarabine exposure levels (AUC, trough levels, Cmax) and PK parameters were analyzed. All patients showed febrile neutropenia and one toxic-death was observed. Overall response rate was 75%. The ratio free:total cytarabine monitored in our patients was higher than expected (i.e., 47%). Inter-individual variability on pharmacokinetics parameters and subsequent exposure levels was >60%. A trend towards severe toxicities was observed in patients with higher exposure of cytarabine. Results showed that liposomal CPX-351 led to sustained exposure with reduced clearance (Cl = 0.16 L/h) and prolonged half-life (T1/2 = 28 h). Of note, liposomes were observed transiently in bone marrow on D15, with cytarabine levels 2.3-time higher than in plasma. Sequencing CDA gene was not contributive and CDA status was primarily evaluated upon phenotyping patients. PM status was found in 77% of the patients with a marked impact on cytarabine PK parameters, i.e., PM patients had higher exposure than EM patients (AUC: 5536 vs. 1784 ng/mL.h), prolonged half-life (T1/2: 33.9 vs. 13.7 h), and reduced clearance (Cl: 0.12 vs. 0.29 L/h). This pilot study suggests that despite being encapsulated in a liposomal vehicle as CPX-351, cytarabine fate in the body is highly dependent upon CDA activity, suggesting that liver metabolism is only partly skipped by the nanoparticle. Here, CDA status proved to have a major impact on cytarabine PK and possibly safety in AML patients treated with CPX-351. Indeed PM patients displayed higher exposure levels with higher risk for severe non-hematological toxicities. This study suggests that CDA status could be used as a covariate to customize CPX-351 dosing in AML patients. Citation Format: Melanie Donnette, Mourad Hamimed, Joseph Ciccolini, Regis Costello, Laure Delassus, Geoffroy Venton, Raphaelle Fanciullino. Pharmacokinetics and pharmacogenetics of liposomal cytarabine in AML patients treated with CPX-351 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1150.

Pharmacokinetics and pharmacogenetics of liposomal cytarabine in AML patients treated with CPX-351

CPX-351 is a liposome encapsulating cytarabine and daunorubicin for treating Acute Myeloid Leukemia (AML) patients. To what extent differences in cytidine deaminase (CDA) activity, the enzyme that catabolizes free cytarabine in the liver, can affect the pharmacokinetics of liposomal cytarabine as well, is unknown.We have studied the pharmacokinetics (PK) of released, liposomal and total cytarabine using a population-modeling approach in 9 adult AML patients treated with liposomal CPX-351. Exposure levels and PK parameters were compared with respect to the patient's CDA status (i.e., Poor Metabolizer (PM) vs. Extensive Metabolizer (EM)).Overall response rate was 75%, and 56% of patients had non-hematological severe toxicities, including one lethal toxicity. All patients had febrile neutropenia. A large (>60%) inter-individual variability was observed on pharmacokinetics parameters and subsequent drug levels. A trend towards severe toxicities was observed in patients with higher exposure of cytarabine. Results showed that liposomal CPX-351 led to sustained exposure with reduced clearance (Cl = 0.16 L/h) and prolonged half-life (T1/2 = 28 h). Liposomal nanoparticles were observed transiently in bone marrow with cytarabine levels 2.3-time higher than in plasma. Seven out of 9 patients were PM with a strong impact on the PK parameters, i.e., PM patients showing higher cytarabine levels as compared with EM patients (AUC: 5536 vs. 1784 ng/mL.h), sustained plasma exposure (T1/2: 33.9 vs. 13.7 h), and reduced clearance (Cl: 0.12 vs. 0.29 L/h).This proof-of-concept study suggests that CDA status has a major impact on cytarabine PK and possibly safety in AML patients even when administered as a liposome.

Pharmacokinetic and Adsorptive Analyses of Administration of Oral Voriconazole Suspension via Enteral Feeding Tube in Intensive Care Unit Patients.

For intensive care unit (ICU) patients, injectable voriconazole (VRCZ) is difficult to use because the patients often develop acute kidney injury. Since many ICU patients have consciousness disturbance, oral ingestion of tablet formulation is also difficult, and administration of a suspension via enteral feeding tube is required when using VRCZ. In this study, we investigated the in vitro adsorption property of oral VRCZ to feeding tube and performed pharmacokinetic analysis of VRCZ prepared by powdering and simple suspension for ICU patients. VRCZ was tube-administered to five ICU patients at a loading dose of 300 mg and plasma VRCZ concentrations before and at 1, 2, 4, 8, 12 h after the first dose were measured using HPLC. Pharmacokinetic parameters were calculated by non-compartmental model analysis. The recovery rate of VRCZ after infusion of the suspension through feeding tube was 89.8 ± 8.3%, but the cumulative rates after the first and second re-infusion were 102.7 ± 20.7 and 99.3 ± 10.3%, respectively, suggesting almost no residual drug in the tube after re-infusion. Metabolic phenotype was extensive metabolizer (EM) in two patients and intermediate metabolizer (IM) in three patients. The values of total clearance (CLtot/F) calculated by moment analysis were 0.51 and 0.55 L/h/kg in two EM patients, and 0.09, 0.29 and 0.31 L/h/kg in three IM patients. The CLtot/F was apparently lower in IM patients compared to EM. In conclusion, powdered and suspended VRCZ administered via enteral feeding tube showed pharmacokinetics depending on CYP2C19 gene polymorphism, similar to that observed in usual oral administration.

Effects of individualized antiplatelet therapy based on CYP2C19 genotype and platelet function on the prognosis of patients after PCI.

To evaluate the effect of individualized antiplatelet therapy based on CYP2C19 genotype and platelet function on the prognosis of patients after percutaneous coronary intervention (PCI) compared with conventional antiplatelet therapy. Patients diagnosed with acute coronary syndromes (ACS) in Shandong Provincial Qianfoshan Hospital from December 2014 to December 2017 were included in this prospective study and randomly divided into conventional (CA) and individualized antiplatelet therapy group (IA) at 1:1 ratio. Patients in the CA group received clopidogrel 75 mg once a day (QD). Group IA was divided into extensive, intermediate, and poor metabolizers according to the results of the CYP2C19 gene test. Three genotypes were given clopidogrel 75 mg QD, 75 mg twice daily (BID) and ticagrelor 90 mg BID respectively. After taking these medicines for a period of time, platelet function was monitored by thromboelastography (TEG) and MAADP values were recorded. MAADP indicates the adenosine diphosphate (ADP) induced platelet function that not inhibited by medicine. High platelet reactivity (HPR) was defined as MAADP > 47mm, indicating a high risk of thrombus, and MAADP ≤ 31 mm indicates a high risk of hemorrhage. For extensive metabolizers (EMs) and intermediate metabolizers (IMs) patients with HPR, the antiplatelet therapy would be changed by the clinician according to the patient's conditions. Major adverse cardiovascular events (MACE) and hemorrhage events were monitored during 1-year follow-up. The patients with MAADP > 47 mm were 89 (28.6%) in the IA group. There were 50 EMs patients with MAADP > 47 mm (33.3%). Of which, there were 2 cases which changed the dosage of clopidogrel to 75 mg BID, 14 cases who changed clopidogrel to ticagrelor. There were 36 IMs patients with MAADP > 47 mm (30.8%). Of which, there were 19 cases who changed clopidogrel to ticagrelor. There was no significant difference in the value of MAADP between EMs and IMs patients. Within 1 year after PCI, the occurrence of MACE in the IA group was significantly lower than that in the CA group (p=0.010). (1) Patients with a CYP2C19 loss-of-function (LOF) gene who take double doses of clopidogrel overcome the decreased efficacy of clopidogrel which partly due to CYP2C19 LOF gene, without increasing the risk of hemorrhage. (2) Individualized antiplatelet therapy based on CYP2C19 genotype and platelet function can significantly reduce the occurrence of MACE (mainly acute non-fatal myocardial infarction) after PCI without increasing the risk of moderate or severe hemorrhage.

Comparison of the effects of esomeprazole 40 mg, rabeprazole 20 mg, lansoprazole 30 mg, and pantoprazole 40 mg on intragastrıc pH in extensive metabolizer patients with gastroesophageal reflux disease.

Studies on the therapeutic efficacy of proton pump inhibitors (PPIs) in patients with gastroesophageal reflux disease (GERD) have been recently published. In most of these studies, comparison of only two PPIs have been made. There are few studies on the comparison of four or more PPIs. We aimed to compare the acid inhibitory effects of esomeprazole 40 mg, rabeprazole 20 mg, lansoprazole 30 mg, and pantoprazole 40 mg on days 1 and 5 of treatment in patients with GERD, who were extensive metabolizers in regard to the CYP2C19 genotype. Helicobacter pylori-negative with typical symptoms of GERD patients were randomly divided into four treatment groups. Efficacy analysis on days 1 and 5 were performed on the four groups which comprised 10 (esomeprazole), 11 (rabeprazole), 10 (lansoprazole), and 10 (pantoprazole) patients. On day 1 of PPI treatment, the mean percentage of time with intragastric Ph>4 were 54%, 58%, 60%, and 35% for the groups, respectively, and on day 5, these values were 67%, 60%, 68%, and 59%, respectively. Esomeprazole, rabeprazole, and lansoprazole were found to be superior to pantoprazole on the first day of treatment. Pantoprazole is a less potent proton pump inhibitor than the other PPIs tested on the first day of treatment. When the time needed to raise the intragatric pH to over 4 was evaluated, esomeprazole was found to have the most rapid action, followed by lansoprazole and rabeprazole.

Population Pharmacokinetics of Voriconazole and Optimization of Dosage Regimens Based on Monte Carlo Simulation in Patients With Liver Cirrhosis

Because voriconazole metabolism is highly influenced by liver function, the dose regimen of voriconazole should be carefully assessed in patients with liver cirrhosis. We aimed to identify significant factors associated with plasma concentrations. Blood samples were collected from patients with liver cirrhosis who received voriconazole, and voriconazole concentrations were determined. One-compartment model with first-order absorption and elimination appropriately characterized the in vivo process of voriconazole. The typical population value of voriconazole clearance (CL) was 1.45 L/h and the volume of distribution (V) was 132.12 L. The covariate analysis identified that CYP2C19 gene phenotype and Child-Pugh classification were strongly associated with CL and body weight had a significant influence on V. The results of the Monte Carlo simulation suggested that CYP2C19 gene phenotype was a critical factor for determining voriconazole dosage in patients with liver cirrhosis. The extensive metabolizer patients with Aspergillus fumigatus infections could be treated effectively with a recommended dose of 75 mg twice daily in mild to moderate liver cirrhosis and 100 mg once daily in moderate severe liver cirrhosis. However, the recommended dosage for Candida albicans infections patients was not achieved in present study.

Anti-Platelet Therapy in Mild Cerebral Infarction Patients on the Basis of CYP2C19 Metabolizer Status

This study aimed to investigate the effects of CYP2C19 metabolizer status on the clinical therapeutic efficacy of cerebral infarction. Patients with cerebral infarction (n = 180; NIHSS score ≤ 5) were recruited and divided into Group A and Group B according to CYP2C19 metabolizer status. In Group A, patients received routine clopidogrel therapy for 1 year; in Group B, the patients with extensive metabolizer (EM) were treated with clopidogrel, and patients with intermediate metabolizer (IM) and poor metabolizer (PM) were treated with aspirin for 1 year. On admission, National Institutes of Health Stroke Scale score was determined, and the therapeutic efficacy was evaluated with Modified Rankin Scale score after 1 year of treatment. The outcomes and adverse effects were recorded during the treatment. After routine clopidogrel treatment, the efficacy in EM patients was significantly better than in PM and IM patients. After adjustment of therapeutic protocol, the therapeutic efficacy in PM and IM patients was markedly improved, which was accompanied by significant reduction in recurrence rate of cerebral infarction. Although the adverse effects increased in patients receiving aspirin treatment, they resolved after symptomatic therapy. CYP2C19 metabolizer status is closely related to the clinical efficacy of clopidogrel. Thus, it is necessary to adjust the anti-platelet treatment according to the CYP2C19 metabolizer status to maximize therapeutic efficacy without increasing recurrence and adverse effects.

Abstract 3892: Upfront DPD screening with adaptive dosing to secure 5-FU administration in head and neck cancer patients

Abstract Upfront screening for dihydropyrimidine dehydrogenase (DPD) deficiency in patients scheduled for 5-FU-based protocols should reduce the risk of treatment-related toxicities by preventive adaptive dosing. Our group has developed a simple, rapid and cheap functional testing that helps categorizing patients on their DPD status and detecting poor metabolizer (PM) patients, using UH2/U ratio measurement in plasma as a surrogate for DPD activity. 5-FU dosing can be next tailored using a geometric scale, according to the level of DPD deficiency. We report here the performances of this adaptive dosing strategy implemented in routine clinical practice in head and neck cancer patients. A total of 218 evaluable adult patients were scheduled for a 5-FU-regimen (mostly TPF protocol), with prospective search for DPD deficiency and, if required, tailored dosing. Overall, 20 patients (9%) were identified as PM and received subsequently an average 20-50% reduced dose of 5-FU as compared with extensive metabolizer (EM) patients (2102 ± 254 mg VS. 2577 ±353mg, p<0.001 t-test). Gender (Female) was associated with higher risk for being PM (p=0.01, Pearson's Chi-square test), whereas age was not. Early severe toxicities were seen only in 5% of patients, a figure markedly lower than the one usually reported with 5-FU-based regimen in head-and-neck cancer patients. Similarly, all severe toxicities (i.e; including now the delayed or cumulative ones) were observed in 12.8% of patients only. No statistical difference was evidenced in overall toxicities between PM patients with adapted dosing (10%) and EM patients with standard dosing (13%, p=0.7014, Chi-square test), suggesting that being DPD-deficient is not anymore a risk for severe or life-threatening toxicities with 5-FU, provided that corrective action is undertaken. As for early toxicities, incidence of global toxicities was lower than the 30-40% usually described with 5-FU in this setting. Finally, despite an average -20% reduction in 5-FU dosing between PM and EM patients, clinical efficacy was not statistically different between the two groups (CR+PR: 56% VS. 40%, SD: 11% VS. 5%, PD: 22% VS. 43%, p = 0.2774, chi-square test), thus demonstrating how cutting 5-FU dose in PM patients does not hinder treatment efficacy. In conclusion, this study shows that 5-FU-related toxicities can be avoided at low cost by the upfront detection of DPD deficient patients with simple adaptive dosing strategies. Of note, reducing 5-FU dosing in PM patients did not affect negatively treatment efficacy, while limiting the incidence of treatment-related toxicities, thus improving the efficacy/toxicity balance of this drug. Citation Format: Joseph Ciccolini, Manon Launay, Charlotte Dupuis, Florence Duffaud, Bruno Lacarelle, Sébastien Salas. Upfront DPD screening with adaptive dosing to secure 5-FU administration in head and neck cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3892.

UPFRONT DPD DEFICIENCY DETECTION TO SECURE 5-FU ADMINISTRATION: PART 2- APPLICATION TO HEAD-AND-NECK CANCER PATIENTS.

Upfront screening for dihydropyrimidine dehydrogenase (DPD) deficiency in patients scheduled for 5-FU should help reduce the risk of toxicities by preventive adaptive dosing. Our group has developed a simple functional testing categorizing patients upon their DPD status, i.e. extensive metabolizer (EM) or poor metabolizer (PM) patients, using UH2/U ratio measurement in plasma as a surrogate for DPD activity. 5-FU dosing can then be tailored according to DPD deficiency status. We present here an observational study of this strategy implemented in routine clinical practice when treating head-and-neck cancer patients. A total of 218 evaluable adult patients were treated with a 5-FU-regimen, with DPD-based adaptive dosing. Among them, 20 (9%) were identified as PM and received subsequently a 20-50% reduced dosing of 5-FU as compared with EM patients (2102 ±254 mg VS. 2577 ±353mg, p<0.001 ttest). Gender (Female) was associated with higher risk for being PM (p=0.01, Pearson's Chi squared test). Overall, early severe toxicities were seen only in 5% of patients, all being EM with standard dosing. Similarly, overall severe toxicities were observed in 12.8% of patients only, both figures being markedly lower than usually reported with standard 5-FU. Despite the average -20% reduction in 5-FU dosing between PM and EM patients, clinical efficacy was not statistically different between the two groups (p = 0.2774, chi-square test). This study shows that 5-FU-related toxicities can be greatly reduced in routine clinical practice by the upfront detection of DPD deficient patients with simple adaptive dosing strategy.

PS 05-55 IMPACT OF CYP2C19 VARIANTS ON DRUG EFFICACY OF CLOPIDOGREL AND 1-YEAR CLINICAL OUTCOMES IN CORONARY HEART PATIENTS UNDERGOING PCI

Objective: To investigate the following: 1) the association between CYP2C19 variants involved in clopidogrel-mediated platelet effects; 2) the association between CYP2C19 variants involved in clopidogrel-mediated inflammatory, endothelial effects; 3) CYP2C19 variants involved in the risk of major adverse cardiovascular events(MACE). Design and Method: We detected the residual platelet aggregation rate (RPA), maximal aggregation rate (MAR) and the plasma levels of sCD40L, sP-selectin, MMP-9, sVCAM-1 and sE-selectin after 24 hours of PCI in 559 patients undergoing PCI treated with clopidogrel, and followed up for one year for MACE. Results: The levels of RPA, MAR, sE-selectin, sCD40l, sP-selectin, MMP-9 and sVCAM-1 in CYP2C19 intermediate metabolizers (IM), poor metabolizers (PM) or both together patients were higher than those in extensive metabolizers (EM) patients. During one-year follow-up, there were 69 cases (13.3%) suffering MACE. The risk of MACE in CYP2C19 IM + PM patients is 2.664 times higher than that in CYP2C19 EM patients (OR = 2.664(1.397–5.193), P = 0.004). Our results suggest that CYP2C19 metabolizers modulate clopidogrel drug efficacy in coronary heart patients undergoing PCI and further impact on the risk of MACE. Conclusions: Thus it is benefit for coronary heart patients undergoing PCI treated with clopidogrel if carried out individualized treatment according to CYP2C19 metabolizers.

Tamoxifen Dose Escalation in Patients With Diminished CYP2D6 Activity Normalizes Endoxifen Concentrations Without Increasing Toxicity.

Polymorphic CYP2D6 is primarily responsible for metabolic activation of tamoxifen to endoxifen. We previously reported that by increasing the daily tamoxifen dose to 40 mg/day in CYP2D6 intermediate metabolizer (IM), but not poor metabolizer (PM), patients achieve endoxifen concentrations similar to those of extensive metabolizer patients on 20 mg/day. We expanded enrollment to assess the safety of CYP2D6 genotype-guided dose escalation and investigate concentration differences between races. PM and IM breast cancer patients currently receiving tamoxifen at 20 mg/day were enrolled for genotype-guided escalation to 40 mg/day. Endoxifen was measured at baseline and after 4 months. Quality-of-life data were collected using the Functional Assessment of Cancer Therapy-Breast (FACT-B) and Breast Cancer Prevention Trial Menopausal Symptom Scale at baseline and after 4 months. In 353 newly enrolled patients, genotype-guided dose escalation eliminated baseline concentration differences in IM (p = .08), but not PM (p = .009), patients. Endoxifen concentrations were similar in black and white patients overall (p = .63) and within CYP2D6 phenotype groups (p > .05). In the quality-of-life analysis of 480 patients, dose escalation did not meaningfully diminish quality of life; in fact, improvements were seen in several measures including the FACT Breast Cancer subscale (p = .004) and limitations in range of motion (p < .0001) in IM patients. Differences in endoxifen concentration during treatment can be eliminated by doubling the tamoxifen dose in IM patients, without an appreciable effect on quality of life. Validation of the association between endoxifen concentration and efficacy or prospective demonstration of improved efficacy is necessary to warrant clinical uptake of this personalized treatment strategy. This secondary analysis of a prospective CYP2D6 genotype-guided tamoxifen dose escalation study confirms that escalation to 40 mg/day in patients with low-activity CYP2D6 phenotypes (poor or intermediate metabolizers) increases endoxifen concentrations without any obvious increases in treatment-related toxicity. It remains unknown whether endoxifen concentration is a useful predictor of tamoxifen efficacy, and thus, there is no current role in clinical practice for CYP2D6 genotype-guided tamoxifen dose adjustment. If future studies confirm the importance of endoxifen concentrations for tamoxifen efficacy and report a target concentration, this study provides guidance for a dose-adjustment approach that could maximize efficacy while maintaining patient quality of life.

Impact of CYP2C19 Metabolizer Status on Patients With ACS Treated With Prasugrel Versus Clopidogrel

BackgroundCertain alleles of the CYP2C19 gene are associated with higher platelet reactivity and increased ischemic events among patients treated with clopidogrel. However, the relationship of CYP2C19 genotype and outcomes in medically managed patients with acute coronary syndromes (ACS) is not known. ObjectivesThis study sought to assess the effect of CYP2C19 genotype on ischemic outcomes in patients with ACS initially managed medically without revascularization who were randomized to either clopidogrel or prasugrel. MethodsWe classified patients as extensive metabolizers (EM) or reduced metabolizers (RM) based on CYP2C19 genotype and evaluated ischemic outcomes and platelet reactivity. Among 9,326 patients enrolled from 2008 to 2011, 5,736 participated in the genetics cohort; of these, 2,236 had platelet function testing data. ResultsThere was no association between CYP2C19 metabolizer status (EM vs. RM) and the primary composite endpoint of cardiovascular death, myocardial infarction (MI), or stroke (hazard ratio [HR]: 0.86). EM and RM patients had similar rates of the primary endpoint whether treated with prasugrel (HR: 0.82) or clopidogrel (HR: 0.91; p for interaction = 0.495). After adjusting for clinical and treatment variables, EM patients had a lower risk of MI versus RM patients (HR: 0.80), but risks of other outcomes were similar. RM patients had significantly higher mean P2Y12 reaction units versus EM patients when treated with clopidogrel (39.93), but not with prasugrel (3.87). ConclusionsCYP2C19 metabolizer status is not associated with the composite outcome of cardiovascular death, MI, or stroke in medically managed ACS patients treated with clopidogrel or prasugrel. Our findings do not support routine CYP2C19 genetic testing in this population. (A Comparison of Prasugrel and Clopidogrel in Acute Coronary Syndrome Subjects [TRILOGY ACS]; NCT00699998)

Influence of CYP2D6 and CYP3A4 Phenotypes, Drug Interactions, and Vitamin D Status on Tamoxifen Biotransformation

In view of the large variability on therapeutic response and the multiple factors associated to tamoxifen (TAM) metabolic activation, this study aimed to evaluate the effect of CYP2D6 and CYP3A4 phenotypes, drug interactions, and vitamin D exposure on TAM metabolism in a group of breast cancer patients. Trough blood samples were collected from 116 patients. TAM and metabolites endoxifen (EDF), N-desmethyltamoxifen, and 4-hydroxytamoxifen (HTF) were measured in plasma by liquid chromatography-tandem mass spectrometry. CYP2D6 and CYP3A4 phenotyping were obtained according to [dextromethorphan]/[dextrorphan] and [omeprazole]/[omeprazole sulfone] metabolic ratios, measured by high-performance liquid chromatography in plasma collected 3 hours after oral administration of 33 mg of dextromethorphan and 20 mg of omeprazole. Vitamin D3 was measured in plasma by high-performance liquid chromatography-ultraviolet. Data on concomitant use of drug considered as CYP2D6 and CYP3A4 inhibitor or inducer and vitamin D supplementation were recorded. About 20% of patients had reduced CYP2D6 metabolic activity and 7% CYP3A4 impaired metabolism. EDF levels diminished proportionally to the reduction of CYP2D6 metabolic activity (poor metabolizer 2.79 ng·mL, intermediate metabolizer (IM) 5.36 ng·mL, and extensive metabolizer 10.65 ng·mL, P < 0.01). Median plasma levels of TAM (161.50 ng·mL) and HTF (1.32 ng·mL) in CYP2D6 IM/CYP3A4 poor metabolizer patients were higher (P < 0.05) than those from CYP2D6 IM/CYP3A4 extensive metabolizer patients (122.07 ng·mL and 0.61 ng·mL, respectively). Seasons contributed to the interpatient variability of EDF and HTF levels; summer concentrations were 24% and 42% higher compared with winter. Vitamin D3 was not associated to CYP3A4 metabolic activity, indicating that other mechanisms might be involved in the relation between TAM metabolism and vitamin D exposure. CYP3A4 contributes to the bioactivation of TAM through formation of HTF and becomes increasingly important in case of reduced or absent CYP2D6 activity. EDF and HTF exposure were associated to seasonal variations, with considerable higher plasma concentrations during summer.

Effects of CYP2C19 allelic variants on inhibition of platelet aggregation and major adverse cardiovascular events in Japanese patients with acute coronary syndrome: The PRASFIT-ACS study

BackgroundWe examined the effects of cytochrome P450 2C19 (CYP2C19) polymorphisms on the efficacy and safety of prasugrel and clopidogrel in a post hoc analysis of the PRASugrel compared with clopidogrel For Japanese patIenTs with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) (PRASFIT-ACS) study. MethodsJapanese ACS patients undergoing PCI were randomized (double-blind) to receive prasugrel (loading/maintenance dose: 20/3.75mg) or clopidogrel (300/75mg) plus aspirin for 24–48 weeks. Pharmacogenomic analyses were conducted in 773/1363 patients. P2Y12 reaction units (PRU) were determined using the VerifyNow® P2Y12 assay (Accumetrics, San Diego, CA, USA). CYP2C19 genotypes were classified as extensive metabolizers (EM), intermediate metabolizers (IM), and poor metabolizers (PM). ResultsOverall, 39.2% and 60.8% of patients in the prasugrel group and 35.2% and 64.8% of patients in the clopidogrel group were classified as EM and IM+PM, respectively. Among EM patients, PRU was significantly lower in the prasugrel group than in the clopidogrel group at 2–4 and 5–12h after the loading dose, but was similar in both groups from week 4 onwards. Among IM+PM patients, PRU was significantly lower in the prasugrel group than in the clopidogrel group throughout the study. Among EM patients, the incidence of major adverse cardiovascular events (MACE) at 24 weeks was 11.8% in the prasugrel group and 11.9% in the clopidogrel group [hazard ratio (HR): 0.99, 95% confidence interval (CI): 0.50–1.96]. Among IM+PM patients, the incidence of MACE was 9.3% in the prasugrel group and 12.5% in the clopidogrel group (HR: 0.78, 95% CI: 0.45–1.35). The incidences of major, minor, and clinically relevant bleeding were similar between the two groups for each genotype. ConclusionsPrasugrel showed more consistent antiplatelet effects than clopidogrel in Japanese ACS patients irrespective of the CYP2C19 phenotype.

Correlation between the CYP2C19 phenotype status and the results of three different platelet function tests in cardiovascular disease patients receiving antiplatelet therapy: an emphasis on newly introduced platelet function analyzer-200 P2Y test.

BackgroundAn association has been reported between CYP2C19 polymorphism and the altered antiplatelet activity of clopidogrel. We investigated this association using the newly introduced platelet function analyzer (PFA)-200 (INNOVANCE PFA-200 System; Siemens Healthcare, Germany) P2Y test.MethodsPolymorphisms of CYP2C19*2, *3, *17 and the degree of inhibition of platelet function were determined in 83 patients. Three different platelet function tests were used to evaluate the degree of platelet inhibition and to check the association with genotype.ResultsThe post-procedure PFA-200 values of extensive metabolizers (EM) patients (285.3±38.8) were higher than those of intermediate metabolizers (IM) and poor metabolizers (PM) patients (227.7±98.3 and 133.7±99.2, respectively; P=0.024). Light transmittance aggregometry (LTA) and the VerifyNow system showed that the post-procedure values for EM patients were lower than those of IM and PM patients (LTA: 24.4±15.7, 34.1±17.6, and 42.2±16.9, respectively, P<0.001; VerifyNow: 133.2±60.5, 171.5±42.6, and 218.7±59.3, respectively, P<0.001). The high residual platelet reactivity (HPR) rates were significantly different among the EM, IM, and PM groups using PFA-200 (PM:IM:EM=82.4:40.6:11.8, P<0.001).ConclusionsApproximately, 59.0% of Korean patients with cardiovascular disease receiving clopidogrel had CYP2C19 loss-of-function genotypes classified as IM or PM, and the frequency was similar to the data from Asian people. The PFA-200, LTA, and VerifyNow platelet function tests revealed evidence of a significant association between the efficacy of clopidogrel and CYP2C19 genotypes.

Inflammation-induced phenoconversion of polymorphic drug metabolizing enzymes: hypothesis with implications for personalized medicine.

Phenoconversion transiently converts genotypic extensive metabolizers (EMs) into phenotypic poor metabolizers (PMs) of drugs, potentially with corresponding changes in clinical response. This phenomenon, typically resulting from coadministration of medications that inhibit certain drug metabolizing enzymes (DMEs), is especially well documented for enzymes of the cytochrome P450 family. Nonclinical evidence gathered over the last two decades also strongly implicates elevated levels of some proinflammatory cytokines, released during inflammation, in down-regulation of drug metabolism, especially by certain DMEs of the P450 family, thereby potentially causing transient phenoconversion. Clinically, phenoconversion of NAT2, CYP2C19, and CYP2D6 has been documented in inflammatory conditions associated with elevated cytokines, such as human immunodeficiency virus infection, cancer, and liver disease. The potential of other inflammatory conditions to cause phenoconversion has not been studied but experimental and anecdotal clinical evidence supports infection-induced down-regulation of CYP1A2, CYP3A4, and CYP2C9 as well. Collectively, the evidence supports a hypothesis that certain inflammatory conditions associated with elevated proinflammatory cytokines may cause phenoconversion of certain DMEs. Since inflammatory conditions associated with elevated levels of proinflammatory cytokines are highly prevalent, phenoconversion of genotypic EM patients into transient phenotypic PMs may be more frequent than appreciated. Since drug pharmacokinetics, and therefore the clinical response, is influenced by DME phenotype rather than genotype per se, phenoconversion (whatever its cause) can have a significant impact on the analysis and interpretation of genotype-focused clinical outcome association studies. There is a risk that focusing on genotype alone may miss important associations between clinical outcomes and DME phenotypes, thus compromising future prospects of personalized medicine.

Concomitant use of tamoxifen and endoxifen in postmenopausal early breast cancer: prediction of plasma levels by physiologically-based pharmacokinetic modeling.

PurposeTo 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 comprehensively we used a physiologically-based pharmacokinetic (PBPK) modeling approach.MethodsFirstly simulation of increasing tamoxifen dosages was performed by a virtual clinical trial including populations of CYP2D6 poor (PM), intermediate (IM) and extensive metabolizers (EM) (N = 8,000). Secondly we performed PBPK-simulations under consideration of tamoxifen use plus concomitant increasing dosages of endoxifen (N = 7,000).ResultsOur virtual study demonstrates that dose escalation of tamoxifen in IMs resulted in endoxifen steady-state plasma concentrations similar to CYP2D6 EMs whereas PMs did not reach EM endoxifen levels. Steady-state plasma concentrations of tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen were similar in CYP2D6 IMs and PMs versus EMs using once daily dosing of 20 mg tamoxifen and concomitant CYP2D6 phenotype-adjusted endoxifen dosing in IMs and PMs (1 mg/d and 3 mg/d, respectively).ConclusionIn conclusion, we suggest that co-administration of endoxifen in tamoxifen treated early breast cancer women with impaired CYP2D6 metabolism is a promising alternative to reach plasma concentrations comparable to CYP2D6 EM patients.

Analysis of CYP2D6 genotype and response to tetrabenazine

Tetrabenazine is effective in the treatment of the chorea associated with Huntington disease and other hyperkinetic movement disorders. Following oral administration, tetrabenazine is hepatically transformed into 2 active metabolites that are CYP2D6 substrates. There are 4 CYP2D6 genotypes: poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultrarapid metabolizers. CYP2D6 genotyping was performed on sequential subjects treated with tetrabenazine, but results were not known at the time of titration. Duration of titration to a stable dose, total daily dose, response rating scores, and adverse events were retrospectively collected and subsequently analyzed. Of 127 patients, the majority (n = 100) were categorized as extensive metabolizers, 14 as intermediate metabolizers, 11 as poor metabolizers, and 2 as ultrarapid metabolizers. Ultrarapid metabolizer patients needed a longer titration (8 vs 3.3, 4.4, and 3 weeks, respectively; P < .01) to achieve optimal benefit and required a higher average daily dose than the other patients, but this difference did not reach statistical significance. The treatment response was less robust in the intermediate metabolizer group when compared with the extensive metabolizer patients (P = .013), but there were no statistically significant differences between the various groups with regard to adverse effects. Our findings demonstrate that, aside from the need for a longer titration in the ultrarapid metabolizers, there are no distinguishing features of patients with various CYP2D6 genotypes, and therefore the current recommendation to systematically genotype all patients prescribed more than 50 mg/day of tetrabenazine should be reconsidered.

Genotype-Guided Tamoxifen Dosing Increases Active Metabolite Exposure in Women With Reduced CYP2D6 Metabolism: A Multicenter Study

We examined the feasibility of using CYP2D6 genotyping to determine optimal tamoxifen dose and investigated whether the key active tamoxifen metabolite, endoxifen, could be increased by genotype-guided tamoxifen dosing in patients with intermediate CYP2D6 metabolism. One hundred nineteen patients on tamoxifen 20 mg daily ≥ 4 months and not on any strong CYP2D6 inhibiting medications were assayed for CYP2D6 genotype and plasma tamoxifen metabolite concentrations. Patients found to be CYP2D6 extensive metabolizers (EM) remained on 20 mg and those found to be intermediate (IM) or poor (PM) metabolizers were increased to 40 mg daily. Eighty-nine evaluable patients had tamoxifen metabolite measurements repeated 4 months later. As expected, the median baseline endoxifen concentration was higher in EM (34.3 ng/mL) compared with either IM (18.5 ng/mL; P = .0045) or PM (4.2 ng/mL; P < .001). When the dose was increased from 20 mg to 40 mg in IM and PM patients, the endoxifen concentration rose significantly; in IM there was a median intrapatient change from baseline of +7.6 ng/mL (-0.6 to 23.9; P < .001), and in PM there was a change of +6.1 ng/mL (2.6 to 12.5; P = .020). After the dose increase, there was no longer a significant difference in endoxifen concentrations between EM and IM patients (P = .84); however, the PM endoxifen concentration was still significantly lower. This study demonstrates the feasibility of genotype-driven tamoxifen dosing and demonstrates that doubling the tamoxifen dose can increase endoxifen concentrations in IM and PM patients.

Tailoring Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A CYP2D6 Multiple-Genotype-Based Modeling Analysis and Validation

PurposePrevious studies have suggested that postmenopausal women with breast cancer who present with wild-type CYP2D6 may actually have similar or superior recurrence-free survival outcomes when given tamoxifen in place of aromatase inhibitors (AIs). The present study established a CYP2D6 multiple-genotype-based model to determine the optimal endocrine therapy for patients harboring wild-type CYP2D6.MethodsWe created a Markov model to determine whether tamoxifen or AIs maximized 5-year disease-free survival (DFS) for extensive metabolizer (EM) patients using annual hazard ratio (HR) data from the BIG 1-98 trial. We then replicated the model by evaluating 9-year event-free survival (EFS) using HR data from the ATAC trial. In addition, we employed two-way sensitivity analyses to explore the impact of HR of decreased-metabolizer (DM) and its frequency on survival by studying a range of estimates.ResultsThe 5-year DFS of tamoxifen-treated EM patients was 83.3%, which is similar to that of genotypically unselected patients who received an AI (83.7%). In the validation study, we further demonstrated that the 9-year EFS of tamoxifen-treated EM patients was 81.4%, which is higher than that of genotypically unselected patients receiving tamoxifen (78.4%) and similar to that of patients receiving an AI (83.2%). Two-way sensitivity analyses demonstrated the robustness of the results.ConclusionsOur modeling analyses indicate that, among EM patients, the DFS/EFS outcome of patients receiving tamoxifen is similar to that of patients receiving an AI. Further prospective clinical trials are needed to evaluate the value of the CYP2D6 genotype in the selection of endocrine therapy.