Determinants of the Over-Anticoagulation Response during Warfarin Initiation Therapy in Asian Patients Based on Population Pharmacokinetic-Pharmacodynamic Analyses

<div><p></p><p>To clarify pharmacokinetic-pharmacodynamic (PK-PD) factors associated with the over-anticoagulation response in Asians during warfarin induction therapy, population PK-PD analyses were conducted in an attempt to predict the time-courses of the plasma <i>S</i>-warfarin concentration, Cp(S), and coagulation and anti-coagulation (INR) responses. In 99 Chinese patients we analyzed the relationships between dose and Cp(S) to estimate the clearance of <i>S</i>-warfarin, CL(S), and that between Cp(S) and the normal prothrombin concentration (NPT) as a coagulation marker for estimation of IC₅₀. We also analyzed the non-linear relationship between NPT inhibition and the increase in INR to derive the non-linear index λ. Population analyses accurately predicted the time-courses of Cp(S), NPT and INR. Multivariate analysis showed that <i>CYP2C9*3</i> mutation and body surface area were predictors of CL(S), that <i>VKORC1</i> and <i>CYP4F2</i> polymorphisms were predictors of IC₅₀, and that baseline NPT was a predictor of λ. CL(S) and λ were significantly lower in patients with INR≥4 than in those with INR<4 (190 mL/h vs 265 mL/h, P<0.01 and 3.2 vs 3.7, P<0.01, respectively). Finally, logistic regression analysis revealed that CL(S), ALT and hypertension contributed significantly to INR≥4. All these results indicate that factors associated with the reduced metabolic activity of warfarin represented by CL(S), might be critical determinants of the over-anticoagulation response during warfarin initiation in Asians.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="http://clinicaltrials.gov/ct2/show/NCT02065388" target="_blank">NCT02065388</a></p></div

The population pharmacokinetic-pharmacodynamic (PK-PD) models of warfarin.

<p>Three models were employed to describe the time courses of the plasma concentration of <i>S</i>-warfarin, Cp(S) by the 1-compartment model (Eq.1) and normal prothrombin (NPT) by the indirect model (Eq.2) and the INR by the nonlinear model (Eq.3). Population parameters of CL(S) in PK, IC₅₀ and Kout in PD-1 and λ in PD-2 were estimated.</p

Impacts of predictors extracted from PK-PD analyses.

<p>Influences of <i>CYP2C9*3</i> mutation and body surface area (BSA) on CL(S) in the time courses of Cp(S) (A), <i>VKORC1*2</i> and <i>CYP4F2*3</i> on IC₅₀ in the time courses of NPT (B and C, respectively) and NPT₀ on λ in the relationship between NPT and INR (D) were predicted in typical Chinese patients with a BSA of 1.77 m² (165 cm and 70 kg) after administration of racemic warfarin at 3.0 mg/d.</p

Logistic regression analysis of predictors associated with INR≥4.

<p><b>β = </b>regression coefficient; <b>OR = </b>Odds Ratio; <b>95% CI</b> = 95% confidence interval.</p

Summary of population PK-PD parameters for Cp(S), NPT and INR.

a<p>Mean of 1,000 bootstrap analyses for PK and PD-2 estimates and mean of 100 bootstrap analyses for PD-1 estimates.</p>b<p>The 2.5th and 97.5th values of the ranked bootstrap parameter estimates.</p>c<p>CL(S) mL/h = 240×0.543^CYP2C9*³×(BSA_individual/1.74)^2.14, where CYP2C9*3 = 0 in patients with <i>CYP2C9*1/*1</i> and CYP2C9*3 = 1 in patients with <i>CYP2C9*1/*3</i>. BSA_median is 1.74 m².</p>d<p>IC₅₀µg/mL = 0.0725×2.07^VKORC1*²×1.30^CYP4F2*³, where VKORC1*2 = 0 in patients with <i>VKORC1*2/*2</i>, VKORC1*2 = 1 in patients with <i>VKORC1*1/*2</i>, CYP4F2*3 = 0 in patients with <i>CYP4F2*1/*1</i> and CYP4F2*3 = 1 in patients with <i>CYP4F2*1/*3</i> or <i>CYP4F2*3/*3</i>.</p>e<p>λ = 3.48×exp{0.00588×(NPT_0individual–119)}, where NPT_0median is 119 µg/mL.</p

Diagnostic plots employed to evaluate population analyses.

<p>Relationships between population predictions of Cp(S) (A), NPT (B) and INR (C) and the observed values (left panel), those between individual predictions of Cp(S) (A), NPT (B) and INR (C) and the corresponding observed values (middle panel), and those between population predictions of Cp(S) (A), NPT (B) and INR (C) and weighted residuals (right panel).</p

Patient demographics.

a<p>Data are mean values ± SD or number (%).</p>b<p>Maintenance doses were determined in 89 of 99 patients.</p>c<p>Data are mean values of all measured INRs.</p>d<p>P-value between the INR≥4 and <4 groups.</p

Flow diagram of the randomized trial of the control and genotype groups.

<p>The patient numbers participated during the entire date range of the study were shown in parentheses and samples analyzed in this study were collected from 2010 to 2012.</p

SNP (–617C>A) in ARE-Like Loci of the NRF2 Gene: A New Biomarker for Prognosis of Lung Adenocarcinoma in Japanese Non-Smoking Women

<div><p>Purpose</p><p>The transcription factor NRF2 plays a pivotal role in protecting normal cells from external toxic challenges and oxidative stress, whereas it can also endow cancer cells resistance to anticancer drugs. At present little information is available about the genetic polymorphisms of the <i>NRF2</i> gene and their clinical relevance. We aimed to investigate the single nucleotide polymorphisms in the <i>NRF2</i> gene as a prognostic biomarker in lung cancer.</p><p>Experimental Design</p><p>We prepared genomic DNA samples from 387 Japanese patients with primary lung cancer and detected SNP (c.–617C>A; rs6721961) in the ARE-like loci of the human <i>NRF2</i> gene by the rapid genetic testing method we developed in this study. We then analyzed the association between the SNP in the <i>NRF2</i> gene and patients’ overall survival.</p><p>Results</p><p>Patients harboring wild-type (WT) homozygous (c.–617C/C), SNP heterozygous (c.–617C/A), and SNP homozygous (c.–617A/A) alleles numbered 216 (55.8%), 147 (38.0%), and 24 (6.2%), respectively. Multivariate logistic regression models revealed that SNP homozygote (c.–617A/A) was significantly related to gender. Its frequency was four-fold higher in female patients than in males (10.8% female vs 2.7% male) and was associated with female non-smokers with adenocarcinoma. Interestingly, lung cancer patients carrying <i>NRF2</i> SNP homozygous alleles (c.–617A/A) and the 309T (WT) allele in the <i>MDM2</i> gene exhibited remarkable survival over 1,700 days after surgical operation (log-rank p = 0.021).</p><p>Conclusion</p><p>SNP homozygous (c.–617A/A) alleles in the <i>NRF2</i> gene are associated with female non-smokers with adenocarcinoma and regarded as a prognostic biomarker for assessing overall survival of patients with lung adenocarcinoma.</p></div

Clinicopathological profiling of 24 patients harboring homozygous SNP alleles (–617A/A) in the <i>NRF2</i> gene.

<p>Abbreviation: Ad, adenocarcinoma; Mix, adenocarcinoma and squamous cell carcinoma; Ple, pleomorphic carcinoma; Sq, squamous cell carcinoma; F, female; M, male; Wt, wild type.</p>†<p>Patient (case 5) died because of primary pancreatic cancer.</p