International multicenter validation of GES score for HCC risk stratification in chronic hepatitis C patients.

We have recently demonstrated the ability of a simple predictive model (GES) score to determine the risk of hepatocellular carcinoma (HCC) after using direct-acting antivirals. However, our results were restricted to Egyptian patients with hepatitis C virus (HCV) genotype 4. Therefore, we studied a large, independent cohort of multiethnic populations through our international collaborative activity. Depending on their GES scores, patients are stratified into low risk (≤ 6/12.5), intermediate risk (> 6-7.5/12.5), and high risk (> 7.5/12.5) for HCC. A total of 12,038 patients with chronic HCV were analyzed in this study, of whom 11,202 were recruited from 54 centers in France, Japan, India, the U.S., and Spain, and the remaining 836 were selected from the Gilead-sponsored randomized controlled trial conducted across the U.S., Europe, Canada, and Australia. Descriptive statistics and log-rank tests. The performance of the GES score was evaluated using Harrell's C-index (HCI). The GES score proved successful at stratifying all patients into 3 risk groups, namely low-risk, intermediate-risk, and high-risk. It also displayed significant predictive value for HCC development in all participants (p < .0001), with HCI ranging from 0.55 to 0.76 among all cohorts after adjusting for HCV genotypes and patient ethnicities. The GES score can be used to stratify HCV patients into 3 categories of risk for HCC, namely low-risk, intermediate-risk, and high-risk, irrespective of their ethnicities or HCV genotypes. This international multicenter validation may allow the use of GES score in individualized HCC risk-based surveillance programs.

Sofosbuvir and risk of estimated glomerular filtration rate decline or end-stage renal disease in patients with renal impairment.

BACKGROUND: Sofosbuvir, a prodrug nucleoside inhibitor of hepatitis C virus, has a predominant circulating metabolite that is renally eliminated. Whether sofosbuvir is associated with chronic kidney disease (CKD) progression is not well understood. METHODS: We performed a retrospective analysis of patients with estimated glomerular filtration rate (eGFR) 30-89 mL/min/1.73 m2 treated with sofosbuvir in 76 Phase 2/3 registrational trials. We evaluated eGFR at each study visit. Separately, we performed a retrospective analysis of an administrative claims database (IQVIA PharMetrics Plus™) to compare the risk of incident end-stage renal disease (ESRD) associated with the use of sofosbuvir or non-sofosbuvir regimens among patients with CKD using propensity score methods. Exposure, CKD status and outcomes were determined using diagnosis and medication claim codes. Cox proportional hazards methods were used to estimate ESRD risk. RESULTS: Among 4642 trial participants with baseline stage 2 CKD (eGFR 60-89 ml/min/1.73 m2 ) and 682 trial participants with stage 3 CKD (eGFR 30-59 ml/min/1.73 m2 ) mean (SD) eGFR improved from baseline to 4 weeks post-treatment (+0.7 [9.3] and +2.6 [8.8] ml/min/1.73 m2 , respectively; p < 0.001 each). In the second analysis, among 2042 patients with CKD receiving sofosbuvir-based regimens compared to 431 receiving non-sofosbuvir-based regimens, after adjusting for baseline covariates and weighting based on treatment propensity scores, there was no significant difference in risk of ESRD (adjusted HR = 0.85, 95% CI: 0.51-1.42). CONCLUSIONS: Clinical trial participants with CKD did not experience worsening eGFR during sofosbuvir-based treatment, and sofosbuvir was not associated with an increased risk of ESRD in patients with CKD in a nationally-representative administrative claims database.

Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans.

The vanilloid receptor TRPV1 has been identified as a molecular target for the treatment of pain associated with inflammatory diseases and cancer. Hence, TRPV1 antagonists have been considered for therapeutic evaluation in such diseases. During Phase I clinical trials with AMG 517, a highly selective TRPV1 antagonist, we found that TRPV1 blockade elicited marked, but reversible, and generally plasma concentration-dependent hyperthermia. Similar to what was observed in rats, dogs, and monkeys, hyperthermia was attenuated after repeated dosing of AMG 517 (at the highest dose tested) in humans during a second Phase I trial. However, AMG 517 administered after molar extraction (a surgical cause of acute pain) elicited long-lasting hyperthermia with maximal body temperature surpassing 40 degrees C, suggesting that TRPV1 blockade elicits undesirable hyperthermia in susceptible individuals. Mechanisms of AMG 517-induced hyperthermia were then studied in rats. AMG 517 caused hyperthermia by inducing tail skin vasoconstriction and increasing thermogenesis, which suggests that TRPV1 regulates vasomotor tone and metabolic heat production. In conclusion, these results demonstrate that: (a) TRPV1-selective antagonists like AMG 517 cannot be developed for systemic use as stand alone agents for treatment of pain and other diseases, (b) individual susceptibility influences magnitude of hyperthermia observed after TRPV1 blockade, and (c) TRPV1 plays a pivotal role as a molecular regulator for body temperature in humans.

Bioequivalence of liquid and reconstituted lyophilized etanercept subcutaneous injections.

The objective of this study was to compare the pharmacokinetics of liquid and reconstituted lyophilized etanercept. This single-center, open-label study had a 2-period crossover design in which 36 healthy subjects were randomly assigned in a 1:1 ratio to etanercept (liquid/lyo or lyo/liquid). The treatments were separated by 28 days. Blood samples were obtained predose and at 10 predetermined time points postdose. Serum concentrations were determined by enzyme-linked immunosorbent assay. Noncompartmental pharmacokinetic parameters were analyzed using a standard crossover analysis of variance model. Thirty-three subjects completed both treatment periods. Geometric mean values (adjusted) of area under the serum drug concentration-time curve from time zero to the time of the final quantifiable sample, area under the serum drug concentration-time curve from time zero to infinity, and maximum concentration obtained with the 50-mg/mL liquid etanercept injection were 93.0%, 90.7%, and 98.5% of the respective parameters for 2 injections of 25 mg/mL reconstituted formulation. All associated confidence intervals were within the predefined equivalence interval of 80% to 125%. No differences in safety profiles of the 2 formulations were apparent. Liquid etanercept was bioequivalent to the reconstituted lyophilized etanercept formulation.

Factors affecting increasing radiation dose for mammography in North Carolina from 1997 through 2001: an analysis of Food and Drug Administration annual surveys.

RATIONALE AND OBJECTIVES: To determine which factors affected the increase in average glandular dose recorded at the annual US Food and Drug Administration Mammography Quality Standards Act inspections of mammography equipment in North Carolina from 1997 to 2001. MATERIALS AND METHODS: Average glandular dose, HVL, kVp, ambient light, luminance, equipment age, processing speed, and system speed for every mammography unit at all facilities in the state were collected by state inspectors. A mixed-effect model was used to assess the average changes of glandular dose over time and to identify the factors associated with these changes. RESULTS: There was a statistically significant increase in the average glandular dose in North Carolina in 1999, 2000, and 2001 when compared with the baseline year of 1997. Factors that were statistically significantly linked to this effect were changes in kVp, processing speed, and system speed. CONCLUSION: Average glandular dose for mammography has recently increased in North Carolina. This change is likely caused by changes in screen-film products and processing techniques.