The Case for Expanding the FDA Box Warning on Clopidogrel to CYP2C19 Intermediate Metabolizers

2021 ◽  
Author(s):  
Michelle Liu ◽  
Dan M. Roden ◽  
Josh F. Peterson
Keyword(s):  
Intermediate Metabolizers

scholarly journals CYP2C19 Polymorphisms in Indonesia: Comparison among Ethnicities and the Association with Clinical Outcomes

Biology ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 300
Author(s):  
Muhammad Miftahussurur ◽  
Dalla Doohan ◽  
Ari Fahrial Syam ◽  
Iswan Abbas Nusi ◽  
Phawinee Subsomwong ◽  
...  
Keyword(s):  
Proton Pump Inhibitor ◽  
Clinical Outcomes ◽  
Proton Pump ◽  
Poor Metabolizers ◽  
Wild Type Allele ◽  
Wild Type ◽  
Type Allele ◽  
Sydney System ◽  
Intermediate Metabolizers ◽  
Cyp2c19 Polymorphisms

CYP2C19 polymorphisms are important factors for proton pump inhibitor-based therapy. We examined the CYP2C19 genotypes and analyzed the distribution among ethnicities and clinical outcomes in Indonesia. We employed the polymerase chain reaction-restriction fragment length polymorphism method to determine the CYP2C19 genotypes and evaluated inflammation severity with the updated Sydney system. For CYP2C19*2, 46.4% were the homozygous wild-type allele, 14.5% were the homozygous mutated allele, and 39.2% were the heterozygous allele. For CYP2C19*3, 88.6% were the homozygous wild-type allele, 2.4% were the homozygous mutated allele, and 9.0% were the heterozygous allele. Overall, the prevalence of rapid, intermediate, and poor metabolizers in Indonesia was 38.5, 41.6, and 19.9%, respectively. In the poor metabolizer group, the frequency of allele *2 (78.8%) was higher than the frequency of allele *3 (21.2%). The Papuan had a significantly higher likelihood of possessing poor metabolizers than the Balinese (OR 11.0; P = 0.002). The prevalence of poor metabolizers was lower compared with the rapid and intermediate metabolizers among patients with gastritis and gastroesophageal reflux disease. Intermediate metabolizers had the highest prevalence, followed by rapid metabolizers and poor metabolizers. Dosage adjustment should therefore be considered when administering proton pump inhibitor-based therapy in Indonesia.

scholarly journals Allele-Specific Change of Concentration and Functional Gene Dose for the Prediction of Steady-State Serum Concentrations of Amitriptyline and Nortriptyline in CYP2C19 and CYP2D6 Extensive and Intermediate Metabolizers

2004 ◽  
Vol 50 (9) ◽  
pp. 1623-1633 ◽  
Author(s):  
Werner Steimer ◽  
Konstanze Zöpf ◽  
Silvia von Amelunxen ◽  
Herbert Pfeiffer ◽  
Julia Bachofer ◽  
...  
Keyword(s):  
Functional Gene ◽  
Extensive Metabolizers ◽  
Specific Change ◽  
Gene Dose ◽  
Drug Concentrations ◽  
Steady State Serum ◽  
Ultrarapid Metabolizer ◽  
Allele Specific ◽  
Few Data ◽  
Intermediate Metabolizers

Abstract Background: Recently, new polymorphisms were described in connection with intermediate and ultrarapid CYP2D6 metabolism. These may allow a much desired prediction of metabolic activity within the extensive metabolizer group. The functional consequences are still being discussed with few data available for clinical patients. Methods: We conducted a prospective, blinded two-center study seeking correlations between CYP2C19 (*2,*3, and *4; conventional PCR) and CYP2D6 genotypes (*1 to *10, *35, and *41; real-time and multiplex PCR) and drug concentrations (Emit® and HPLC) in 50 Caucasians receiving amitriptyline (AT; 75 mg twice a day). Results: Eighteen CYP2C19 heterozygotes (*1/*2) had higher AT (P = 0.033) and lower nortriptyline (NT; P = 0.059) concentrations than 30 homozygotes (*1/*1). For CYP2D6, we calculated two new indices, i.e., the allele-specific change of concentration on identical background (ASCOC) and a quantitative functional gene dose. The ASCOC describes the change in NT concentration attributable to a mutant allele compared with the wild type. We found significantly higher concentrations for alleles *4 (95.6%; P <0.0001), *10 (63.3%; P <0.001), and *41 (39.8%; P <0.0001) but not for *2 and *35. Assigning of semiquantitative gene doses of 0, 0.5, or 1 to each allele instead of applying the current classification system (predicted phenotypes: 3 intermediate metabolizers, 46 extensive metabolizers, and 1 ultrarapid metabolizer) produced significant NT concentration differences: gene doses of 0.5 (n =3), 1 (n = 14), 1.5 (n = 11), 2 (n = 21) and 3 (n = 1; P <0.00001). Conclusions: AT and NT concentrations can be predicted within the group of CYP2D6 extensive metabolizers. The ASCOC provides substantial advantages compared with current methods of analysis. CYP2D6 but not CYP2C19 correlates with the sum of both concentrations used to guide AT therapy.

scholarly journals FREQUENCIES OF POLYMORPHISMS IN THE CYTOCHROME’S P450 GENES OF WARFARIN TRANSFORMATION IN A EUROPEAN POPULATION OF EASTERN SIBERIA

2018 ◽  
Vol 3 (5) ◽  
pp. 39-48 ◽  
Author(s):  
T. A. Bairova ◽  
E. A. Novikova ◽  
F. I. Belyalov ◽  
E. A. Shchedreeva ◽  
K. D. Ievleva ◽  
...  
Keyword(s):  
Mechanical Heart Valve ◽  
Warfarin Dose ◽  
European Population ◽  
Eastern Siberia ◽  
Risk Alleles ◽  
Cyp2c9 Gene ◽  
Polymerase Chain ◽  
Artery Disease ◽  
Functional Alleles ◽  
Intermediate Metabolizers

Background.Genotypes of the cytochrome p450 isoform (CYP2C9 and CYP4F2) determine warfarin dose requirements. Frequencies of risk alleles and genotypes of CYP2C9 and CYP4F2 gene vary in different races and ethnic groups.Aim.This study analyzed the frequencies of *2, *3 alleles of CYP2C9 gene and the 1347 C>T allele of CYP4F2 gene in the Caucasians of Eastern Siberia, and compare with other populations.Materials and methods.Participants were 147 patients (Caucasians): 67 (45.58 %) man and 80 (54.42 %) women), taking warfarin for the prevention of thrombosis with a mean age of 64.74 ± 14.29 years. There were patients with atrial fibrillation – 77 (52.38 %) persons, coronary artery disease – 10 (6.80 %), pulmonary embolism – 5 (3.40 %), 15 (10.20 %) patients after implantation of an mechanical heart valve, etc. The subjects were genotyped for CYP2C9 (*1,*2,*3), and CYP4F2 (1347 C>T) by real-time polymerase chain reaction (RT-PCR) using “Pharmacogenetics Warfarin” reagent kits (DNA technology, Russia).Results.69.4 % of Caucasians of Eastern Siberia (Russians), have two functional alleles (*1/*1) of CYP2C9 (they’re extensive/normal metabolizers), the number of intermediate metabolizers (*1/*2, *1/*3) was 29.8 % and 0.68 % of slow metabolizers (*3/*3). Homozygous carriers of two non-functional alleles *2 and *3 (*2/*2, *2/*3) were absent. Carriers of one coumarin-resistant Т-allele of CYP4F2 were 57 (38.7 %) respondents, two coumarin-resistant alleles – 10 (6.8 %) respondents.Conclusions.Frequencies of polymorphisms in the Cytochrome’s p450 genes of warfarin transformation in a European population of Eastern Siberia have no differences with other European populations of the world

scholarly journals Implications of Efavirenz Pharmacogenetics When Switching From Efavirenz- to Dolutegravir-containing Antiretroviral Regimens

2020 ◽  
Author(s):  
David W Haas ◽  
Edward P Acosta
Keyword(s):  
Half Life ◽  
Phase 1 ◽  
Interaction Study ◽  
Minimum Concentration ◽  
Intermediate Metabolizers ◽  
Slow Metabolizers

Abstract Many patients switch from efavirenz- to dolutegravir-based regimens. In a phase 1 dolutegravir-efavirenz interaction study, mean dolutegravir minimum concentration decreased by 60% and 85% among CYP2B6 normal and slow/intermediate metabolizers, respectively. Mean efavirenz half-life was 2.7 times greater in slow vs normal metabolizers. Slow metabolizers will experience more prolonged subtherapeutic dolutegravir concentrations.

scholarly journals A Personalized CYP2C19 Phenotype-Guided Dosing Regimen of Voriconazole Using a Population Pharmacokinetic Analysis

2019 ◽  
Vol 8 (2) ◽  
pp. 227 ◽  
Author(s):  
Yun Kim ◽  
Su-jin Rhee ◽  
Wan Beom Park ◽  
Kyung-Sang Yu ◽  
In-Jin Jang ◽  
...  
Keyword(s):  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Dependent Inhibition ◽  
Dosing Regimens ◽  
Three Compartment Model ◽  
Time Dependent Inhibition ◽  
Intermediate Metabolizers

Highly variable and non-linear pharmacokinetics of voriconazole are mainly caused by CYP2C19 polymorphisms. This study aimed to develop a mechanistic population pharmacokinetic model including the CYP2C19 phenotype, and to assess the appropriateness of various dosing regimens based on the therapeutic target. A total of 1,828 concentrations from 193 subjects were included in the population pharmacokinetic analysis. A three-compartment model with an inhibition compartment appropriately described the voriconazole pharmacokinetics reflecting auto-inhibition. Voriconazole clearance in the CYP2C19 intermediate metabolizers (IMs) and poor metabolizers (PMs) decreased by 17% and 53% compared to that in the extensive metabolizers (EMs). There was a time-dependent inhibition of clearance to 16.2% of its original value in the CYP2C19 EMs, and the extent of inhibition differed according to the CYP2C19 phenotypes. The proposed CYP2C19 phenotype-guided initial dosing regimens are 400 mg twice daily (bid) for EMs, 200 mg bid for IMs, and 100 mg bid for PMs. This CYP2C19 phenotype-guided initial dosing regimen will provide a rationale for individualizing the optimal voriconazole therapy.

Effect of PK-guided tamoxifen dose escalation on endoxifen serum concentrations in CYP2D6 intermediate and poor metabolizers.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 595-595
Author(s):  
Frans Opdam ◽  
Vincent O. Dezentje ◽  
Jan den Hartigh ◽  
Henk-jan Guchelaar ◽  
Trees Hessing ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Cancer Patients ◽  
Dose Escalation ◽  
Poor Metabolizers ◽  
Tamoxifen Treatment ◽  
Extensive Metabolizers ◽  
Breast Cancer Patients ◽  
One Step ◽  
Intermediate Metabolizers

595 Background: Breast cancer patients with absent or reduced CYP2D6 activity may benefit less from tamoxifen treatment because of impaired biotransformation to the active metabolite endoxifen. We investigated whether a temporary one-step dose escalation of tamoxifen in CYP2D6 poor (PM) and intermediate metabolizers (IM) could increase endoxifen serum concentration to a similar level observed in CYP2D6 extensive metabolizers (EM) without increasing toxicity. Methods: From a prospective study population of early breast cancer patients using tamoxifen, 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during two months. The escalation dose (120 mg maximum) was calculated by multiplying the individual’s endoxifen level divided by the median endoxifen concentration (33.7 nM) observed in CYP2D6 extensive metabolizers by 20 mg. Toxicity was assessed and all patients returned to the standard dose of 20 mg after two months. Results: Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased endoxifen concentrations (PMs: from 8.0 nM to 27.3 nM, p<0.001; IMs: from 17.8 nM to 30.3 nM, p=0.002) without increasing side effects. In intermediate but not in poor metabolizers dose escalation increased endoxifen to levels comparable with those observed in extensive metabolizers using tamoxifen 20 mg once daily (33.7 nM). Conclusions: CYP2D6 genotype and endoxifen guided tamoxifen dose escalation increased endoxifen concentrations without increasing short term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long term toxic effects is uncertain and needs to be explored. Clinical trial information: NTR1509.

A phase I study to evaluate the pharmacokinetics of a new oncology nce, apatinib mesylate tablets, with and without food following single and multiple doses in healthy subjects.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14049-e14049 ◽  
Author(s):  
Luana Pesco Koplowitz ◽  
Barry Koplowitz ◽  
Cheol Hee Park ◽  
Arlo N. McGinn
Keyword(s):  
Food Effect ◽  
Dose Proportionality ◽  
Metabolic Effects ◽  
Open Label ◽  
Male And Female ◽  
Study Section ◽  
Delayed Initiation ◽  
Dosing Regimens ◽  
Intermediate Metabolizers ◽  
Female Subjects

e14049 Background: Apatinib Mesylate (YN968D1) is a selective inhibitor of VEGFR-2 being developed for the treatment of advanced gastric cancer. Objectives: 1. Evaluate single- and multiple-dose PKs 2. Evaluate food effect on bioavailability 3. Evaluate dose-proportionality 4. Determine CYP3A4 and 2C19 metabolic effects on the PKs Methods: Single ascending-dose (SAD), open-label, crossover of 2 oral doses of apatinib mesylate tablets (100 mg and 250 mg, [81 mg and 201 mg apatinib]) in healthy male and female volunteers with a minimum 3-day washout between dosing, plus a multiple ascending-dose (MAD), open-label, crossover study of the same doses. Both doses were administered with and without food in a crossover for the SAD and MAD parts. PK blood samples were collected for each dosing period. Subjects were genotyped for CYP3A4 and CYP2C19. WinNonlin 6.4 used for analysis. Results: 24 male and female subjects completed the SAD study section. They were extensive or intermediate metabolizers of CYP2C19, and 23/24 were normal metabolizers of CYP3A4. 22 male and female subjects completed the MAD study section. Most were extensive, intermediate or ultra-rapid metabolizers of CYP2C19; 21/22 subjects were normal metabolizers of CYP3A4. Conclusions: For the 100 mg dose in the SAD and MAD parts of the study, there was no significant food effect. For the 250 mg dose in SAD and MAD parts, food appeared to increase bioavailability by 20–30% in the SAD part, and 30–40% in the MAD part. Noncompartmental PK analysis of the SAD and MAD showed medium tmaxvalue delayed at 2 doses when apatinib was administered with food. Compartmental PK analysis showed food delayed initiation in absorption and reduced first order absorption rate constant. Dose proportionality was confirmed only for the AUC0-∞ value from the SAD-fasted cohort but inconclusive for Cmax and AUC parameters under other dosing regimens. Visual inspection of the effect of CYP2C19 genotype on the clearance of apatinib did not show correlation. Inspection of CYP3A4 genotype on the calculated clearance values was tenuous given the intermediate metabolizers (N = 1), compared to extensive metabolizers.

The effect of dacomitinib (PF-00299804) on CYP2D6 activity in healthy volunteers who are extensive or intermediate metabolizers

2011 ◽  
Vol 69 (4) ◽  
pp. 991-997 ◽  
Author(s):  
Carlo L. Bello ◽  
Robert R. LaBadie ◽  
Grace Ni ◽  
Tanya Boutros ◽  
Carol McCormick ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Cyp2d6 Activity ◽  
Intermediate Metabolizers

Impaired expression of CYP2D6 in intermediate metabolizers carrying the *41 allele caused by the intronic SNP 2988G>A: evidence for modulation of splicing events

2006 ◽  
Vol 16 (10) ◽  
pp. 755-766 ◽  
Author(s):  
Claudia Toscano ◽  
Kathrin Klein ◽  
Julia Blievernicht ◽  
Elke Schaeffeler ◽  
Tanja Saussele ◽  
...  
Keyword(s):  
Intermediate Metabolizers

scholarly journals 1301. Breakthrough Invasive Fungal Infections based on CYP2C19 Levels in Patients Who were on Voriconazole as Primary Antifungal Prophylaxis in Acute Myeloid Leukemia (AML) undergoing Induction Chemotherapy

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S665-S665
Author(s):  
Hareesh v Singam ◽  
Yanina Pasikhova ◽  
Rod Quilitz ◽  
John N Greene ◽  
Aliyah Baluch
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Fungal Infections ◽  
Antifungal Prophylaxis ◽  
Invasive Fungal Infections ◽  
Cancer Center ◽  
Newly Diagnosed ◽  
Intermediate Metabolizers ◽  
Acute Myeloid

Abstract Background Voriconazole (Vori) is often used for prophylactic anti-fungal therapy in induction chemotherapy for Acute Myeloid Leukemia (AML) patients due to predictable absorption and an extended spectrum antifungal activity. Vori is metabolized predominately by CYP2C19 to metabolites with less antifungal activity. There has been a great interest in understanding CYP2C19 as it significantly affects drug metabolism and pharmacokinetics of numerous drugs including voriconazole. Approximately 39% of patients are genetically predicted to be CYP2C19 ultra-rapid or rapid metabolizers and thus are at an increased risk of breakthrough fungal infection. This study assesses the incidence of breakthrough invasive fungal infections (bIFI) at Moffitt Cancer Center based on CYP2C19 activity. bIFI is defined as new fungal infection while on vori, leading to treatment with liposomal amphotericin B, echinocandin, and/or different triazole. Methods This is a single-center retrospective analysis of patients who underwent induction chemotherapy for newly diagnosed AML and received voriconazole as the primary antifungal prophylaxis between July 2017 and June 2019. The patients enrolled were over 18 years old and did not have a history of stem cell transplant or solid organ transplant, Human Immunodeficiency Virus, relapsed AML or received systematic antifungal therapy 30 days prior. CYP2C19 were checked for each of the patients between July 2017 to June 2019 who were undergoing induction chemotherapy for newly diagnosed AML. It was checked within one week of admission. The patients were categorized as rapid metabolizers, intermediate metabolizers, normal metabolizers, and unknown CYP2C19. Results There was an incidence of 20.2% (18/89) bIFI in patients who were on Vori in this study. Of these patients with bIFI infections, 15.7% (3/19) of patients were rapid metabolizers, 14.7% (5/34) were normal metabolizers, 28.5% (4/14) were intermediate metabolizers and 0% (0/3) were poor metabolizers. There were 31% (6/19) breakthrough infections in patients with unknown CYP2C19 characteristics. Conclusion There is no significant statistical difference (p=0.6) among CYP2C19 categories with respect to breakthrough of invasive fungal infections at Moffitt Cancer Center between July 2017 - June 2019. Disclosures Rod Quilitz, Pharm D., Astellas (Advisor or Review Panel member)

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