Estimating the distribution of a novel clinical biomarker (FGF-23) in the US population using findings from a regional research registry.

Evidence of involvement of novel biomarkers in disease pathogenesis from research cohorts often precedes an understanding of their distributions in broader populations. This study aimed to estimate the distribution of fibroblast growth factor 23 (FGF-23), an endocrine hormone that helps to regulate serum phosphate levels, in the overall US population and in important subgroups. We used a predictive model generated using data from the Framingham Health Study to estimate FGF-23 values for adults in the US National Health and Nutrition Examination Survey and the size of patient subgroups with levels of FGF-23 above selected thresholds. To assess the face validity of our FGF-23 estimates, we examined the relationship between estimated FGF-23 and cardiovascular and all-cause mortality within NHANES using Kaplan-Meier estimates and Cox proportional-hazards regression models and compared it to that observed in Framingham. Estimated FGF-23 values from NHANES were lower (median [interquartile range] 47.4 [35.8, 64.0] vs. 67.0 [54.0, 85.0] RU/mL) than the observed FGF-23 values from the Framingham cohort. Age- and sex-adjusted 10-year all-cause mortality was significantly higher (hazard ratio 2.43 [95% confidence interval: 1.42, 4.16]) for subjects with estimated FGF-23 levels in the highest versus lowest quartile. Estimating the distribution of biomarker values in the general population by applying predictive equations from smaller research cohorts is feasible and can inform drug research decision making.

A prospective study of multiple protein biomarkers to predict progression in diabetic chronic kidney disease.

BACKGROUND: Diabetic nephropathy imposes a substantial cardiovascular and renal burden contributing to both morbidity and excess mortality. Progression of chronic kidney disease (CKD) in diabetes mellitus is variable, and few biomarkers are available to predict progression accurately. Identification of novel predictive biomarkers may inform clinical care and assist in the design of clinical trials. We hypothesized that urinary and plasma protein biomarkers predict CKD progression independently of the known clinical markers such as albuminuria and estimated glomerular filtration rate (eGFR) in diabetic nephropathy. METHODS: We studied 67 US veterans with CKD due to type 2 diabetes mellitus and 20 age-matched controls (no CKD, hypertension or cardiovascular disease). After clinical evaluation and the collection of blood and urine specimens for 24 biomarkers, we followed subjects prospectively for the next 2-6 years. CKD progression was defined in three ways: (i) clinically by examining eGFR versus time plots for each individual (slope progression), (ii) progression to end-stage renal disease (ESRD) and (iii) a composite outcome of ESRD or death. RESULTS: Among 17 urinary and 7 plasma biomarkers evaluated, the relationship of the biomarkers with outcome was as follows: (i) for progression identified by eGFR plots, urinary C-terminal fibroblast growth factor (FGF)-23 emerged to have the strongest primary association (adjusted odds ratio [aOR] 2.08, P = 0.008); (ii) for ESRD, plasma vascular endothelial growth factor (VEGF) had an association (aOR: 1.44, P = 0.027) and (iii) for the composite outcome of death and ESRD, plasma C-terminal FGF-23 also had a robust direct association (aOR: 3.07, P = 0.008). CONCLUSION: The relationship of biomarkers with future progression of CKD is complex and depends in part on how CKD progression is defined. Biomarkers in the FGF-23 and VEGF-A pathways predicted patient progression independently of albuminuria levels in this patient cohort. Additional studies in other cohorts will help further validate this pilot study.

Pharmacokinetics of ruboxistaurin are significantly altered by rifampicin-mediated CYP3A4 induction.

AIMS: The aim of this study was to evaluate the effect of rifampicin co-administration on the pharmacokinetics of ruboxistaurin and its active metabolite, N-desmethyl ruboxistaurin and, in addition, to compare the changes in pharmacokinetics of ruboxistaurin and N-desmethyl ruboxistaurin with the urinary 6beta-hydroxycortisol : cortisol ratio. Ruboxistaurin is a specific protein-kinase-C beta inhibitor in clinical development for the treatment of diabetic microvascular complications. METHODS: This was a two-period, one-sequence study. Sixteen healthy male subjects completed both study periods. In period one, a single 64 mg oral dose of ruboxistaurin was administered. In period two, 600 mg rifampicin was administered daily for 9 days, during which another single 64 mg ruboxistaurin dose was administered on day 7. Blood samples were collected and assayed for ruboxistaurin and N-desmethyl ruboxistaurin. CYP3A4 induction was assessed by ratios of urinary 6beta-hydroxycortisol : cortisol (6beta-OHC : C) obtained via 24 h and morning-spot sampling techniques. Results Following repeated doses of rifampicin, both the mean C(max) and AUC(0,infinity) of ruboxistaurin were significantly reduced by approximately 95% (P < or = 0.001). For the metabolite, the mean C(max) decreased by 68% (P < or = 0.001), and AUC(0,infinity) decreased by 77% (P < or = 0.001). The t(max) values did not appear affected. The 6beta-OHC : C ratios from both 24 h and morning spot methods increased significantly, consistent with CYP3A4 induction. CONCLUSIONS: The effect of rifampicin co-administration on the exposure of ruboxistaurin is consistent with ruboxistaurin being a substrate of CYP3A4. Therefore, co-administration with known CYP3A4 inducing agents (rifampicin, carbamazepine, phenobarbital, etc.) may decrease the concentrations of ruboxistaurin and N-desmethyl-ruboxistaurin. In this study, 6beta OHC : C ratios substantially underestimated the impact of rifampicin on ruboxistaurin.

Teriparatide has no effect on the calcium-mediated pharmacodynamics of digoxin.

BACKGROUND: Teriparatide (recombinant human parathyroid hormone [1-34]) stimulates bone formation and causes small transient increases in serum calcium concentration. We assessed whether teriparatide causes a change in digoxin pharmacodynamic effects by measuring systolic time intervals and heart rate. METHODS: Measurements were made by echocardiographic Doppler that examined 3 systolic time intervals, as follows: QS(2) (time from Q wave on electrocardiogram to the closure of the aortic valve), left ventricular ejection time, and pre-ejection period, all corrected for changes in heart rate. Fifteen healthy subjects (2 men and 13 women) were administered a single subcutaneous teriparatide dose (20 microg) on day 1 and then equilibrated on a daily oral dose of digoxin for 15 days. Subcutaneous placebo and teriparatide, 20 microg, were given in a randomized crossover design with the 14th (day 15) and 15th (day 16) digoxin doses. Serial systolic time interval and heart rate measurements were obtained on days 1, 15, and 16. RESULTS: After subjects were dosed to steady state with digoxin, there were statistically significant reductions in QS(2) corrected for heart rate (QS(2)c) of 23 to 25 ms and heart rate of 4 to 6 beats/min. However, there was no difference between treatment with digoxin plus placebo versus digoxin plus teriparatide. The study was powered to find a difference in QS(2)c as small as 6 ms (alpha =.05, beta =.2). CONCLUSION: Teriparatide, 20 microg subcutaneously, does not alter the cardiac effect of digoxin.