Exploring Spatial-Temporal Changes in 18F-Sodium Fluoride PET/CT and Circulating Tumor Cells in Metastatic Castration-Resistant Prostate Cancer Treated With Enzalutamide.

PURPOSE: Intrapatient treatment response heterogeneity is under-recognized. Quantitative total bone imaging (QTBI) using 18F-NaF positron emission tomography/computed tomography (PET/CT) scans is a tool that allows characterization of interlesional treatment response heterogeneity in bone. Understanding spatial-temporal response is important to identify individuals who may benefit from treatment beyond progression. PATIENTS AND METHODS: Men with progressive metastatic castration-resistant prostate cancer (mCRPC) with at least two lesions on bone scintigraphy were enrolled and treated with enzalutamide 160 mg daily (ClinicalTrials.gov identifier: NCT02384382). 18F-NaF PET/CT scans were obtained at baseline (PET1), week 13 (PET2), and at the time of prostate-specific antigen (PSA) progression, standard radiographic or clinical progression, or at 2 years without progression (PET3). QTBI was used to determine lesion-level response. The primary end point was the proportion of men with at least one responding bone lesion on PET3 using QTBI. RESULTS: Twenty-three men were enrolled. Duration on treatment ranged from 1.4 to 34.1 months. In general, global standardized uptake value (SUV) metrics decreased while on enzalutamide (PET2) and increased at the time of progression (PET3). The most robust predictor of PSA progression was change in SUVhetero (PET1 to PET3; hazard ratio, 3.88; 95% CI, 1.24 to 12.1). Although overall functional disease burden improved during enzalutamide treatment, an increase in total burden (SUVtotal) was seen at the time of progression, as measured by 18F-NaF PET/CT. All (22/22) evaluable men had at least one responding bone lesion at PET3 using QTBI. CONCLUSION: We found that the proportion of progressing lesions was low, indicating that a substantial number of lesions appear to continue to benefit from enzalutamide beyond progression. Selective targeting of nonresponding lesions may be a reasonable approach to extend benefit.

Safety, pharmacokinetics, and pharmacodynamics of PD 0348292, an oral, direct factor Xa inhibitor, after single and multiple dosings in healthy subjects.

OBJECTIVE: The objective of this study was to evaluate PD 0348292 safety, pharmacokinetics, and pharmacodynamics in healthy subjects. METHODS: Three phase 1 studies were conducted. Studies 1001 and 1021 were single ascending-dose studies in healthy subjects randomized to oral PD 0348292 (2.5-150 and 0.1-2.5 mg, respectively) or placebo. Study 1003 was a multiple ascending-dose study in which 3 cohorts of young subjects received multiple doses of PD 0348292 (5-30 mg) every 12 hours or placebo, and 1 cohort of elderly subjects received a single dose (5 mg) of PD 0348292 or placebo. Drug plasma concentrations were measured. The effects of PD 0348292 on thrombin generation and typical coagulation measures such as prothrombin time, and international normalized ratio were evaluated. RESULTS: Single doses of PD 0348292 were well tolerated. Minor bleeding-related adverse events were observed following multiple doses of PD 0348292. PD 0348292 exposure increased less than proportionally at doses > 20 mg. Median peak concentrations occurred 3 to 4 hours following administration, and the mean terminal t1/2 value was approximately 10 hours. PD 0348292 demonstrated robust and concentration-dependent inhibition of thrombin generation, and modest and dose-related increases in typical coagulation measures. CONCLUSIONS: The safety, pharmacokinetics, and pharmacodynamics of PD 0348292 were acceptable for future clinical development.

Extended anticoagulation with apixaban reduces hospitalisations in patients with venous thromboembolism. An analysis of the AMPLIFY-EXT trial.

Treatment with apixaban versus placebo for 12 months significantly reduced symptomatic recurrent venous thromboembolism (VTE) or all-cause death without increasing the rate of major bleeding in the AMPLIFY-EXT trial. This analysis examined the effects of apixaban versus placebo on the rate of all-cause hospitalisations, time to first hospitalisation, and predictors of first hospitalisation in patients with VTE enrolled in AMPLIFY-EXT. Treatment with apixaban 2.5 mg and 5 mg twice daily significantly reduced the rate of all-cause hospitalisations versus placebo (hazard ratio [95% confidence interval], 0.64 [0.43, 0.95]; p=0.026 and 0.54 [0.36, 0.82]; p=0.004, respectively). Apixaban prolonged mean time to first hospitalisation versus placebo by 43 and 49 days for the 2.5-mg and 5-mg twice-daily groups, respectively. Median length of hospital stay during the first hospitalisation was longer for placebo than for apixaban 2.5 mg or 5 mg twice daily (7.0, 5.0, and 4.5 days, respectively). Treatment with apixaban was a significant predictor of lower rates of hospitalisations versus placebo, and severe/moderate renal impairment was a significant predictor of an increased rate. This study supports extended use of apixaban for reducing all-cause hospitalisations and extending time to first hospitalisation in patients with VTE enrolled in AMPLIFY-EXT (www.clinicaltrials.gov registration: #NCT00633893).

Apixaban for extended treatment of venous thromboembolism.

BACKGROUND: Apixaban, an oral factor Xa inhibitor that can be administered in a simple, fixed-dose regimen, may be an option for the extended treatment of venous thromboembolism. METHODS: In this randomized, double-blind study, we compared two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in patients with venous thromboembolism who had completed 6 to 12 months of anticoagulation therapy and for whom there was clinical equipoise regarding the continuation or cessation of anticoagulation therapy. The study drugs were administered for 12 months. RESULTS: A total of 2486 patients underwent randomization, of whom 2482 were included in the intention-to-treat analyses. Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 73 of the 829 patients (8.8%) who were receiving placebo, as compared with 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban (a difference of 7.2 percentage points; 95% confidence interval [CI], 5.0 to 9.3) and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (a difference of 7.0 percentage points; 95% CI, 4.9 to 9.1) (P<0.001 for both comparisons). The rates of major bleeding were 0.5% in the placebo group, 0.2% in the 2.5-mg apixaban group, and 0.1% in the 5-mg apixaban group. The rates of clinically relevant nonmajor bleeding were 2.3% in the placebo group, 3.0% in the 2.5-mg apixaban group, and 4.2% in the 5-mg apixaban group. The rate of death from any cause was 1.7% in the placebo group, as compared with 0.8% in the 2.5-mg apixaban group and 0.5% in the 5-mg apixaban group. CONCLUSIONS: Extended anticoagulation with apixaban at either a treatment dose (5 mg) or a thromboprophylactic dose (2.5 mg) reduced the risk of recurrent venous thromboembolism without increasing the rate of major bleeding. (Funded by Bristol-Myers Squibb and Pfizer; AMPLIFY-EXT ClinicalTrials.gov number, NCT00633893.).

Effect of gemfibrozil and fenofibrate on the pharmacokinetics of atorvastatin.

Coadministration of statins and fibrates is beneficial in some patients by allowing simultaneous reduction of triglycerides and low-density lipoprotein cholesterol alongside elevation of high-density lipoprotein cholesterol. However, the potential for drug interactions must be taken into consideration. Gemfibrozil increases systemic exposure to various different statins, whereas similar effects are not observed with fenofibrate, suggesting it may be a more appropriate choice for coadministration with statins. Gemfibrozil is reported to cause a moderate increase in the area under the curve (AUC) of atorvastatin, but the effect of fenofibrate on atorvastatin pharmacokinetics has not been described. This study compared the effects of multiple-dose administration of gemfibrozil and fenofibrate on the single-dose pharmacokinetics of atorvastatin. Gemfibrozil coadministration led to significant increases in the AUC of atorvastatin, 2-hydroxyatorvastatin, 2-hydroxyatorvastatin lactone, and 4-hydroxyatorvastatin lactone. In contrast, fenofibrate administration did not lead to clinically meaningful changes in the AUC for atorvastatin, atorvastatin lactone, 2-hydroxyatorvastatin, or 2-hydroxyatorvastatin lactone. The absence of a significant pharmacokinetic interaction between fenofibrate and atorvastatin is consistent with recent results showing no difference in safety profile between atorvastatin as monotherapy or in combination with fenofibric acid. Together, these data suggest that atorvastatin-fenofibrate combination therapy is unlikely to pose a risk to patients.

An improved total synthesis of triciribine: a tricyclic nucleoside with antineoplastic and antiviral properties.

We describe an efficient total synthesis of triciribine, a tricyclic nucleoside with antineoplastic and antiviral properties, starting from 4-amino-6-bromo-5-cyanopyrrolo[2,3-d]pyrimidine.

Synthesis and antiviral activity of 2-substituted analogs of triciribine.

Triciribine (TCN) and triciribine monophosphate (TCN-P) have antiviral and antineoplastic activity at low or submicromolar concentrations. In an effort to improve and better understand this activity, we have conducted a structure-activity relationship study to explore the effect of substitutions at the 2-position of triciribine. 2-Methyl- (2-Me-TCN), 2-ethyl- (2-Et-TCN), 2-phenyl- (2-Ph-TCN), 2-chloro- (2-Cl-TCN), and 2-aminotriciribine (2-NH2-TCN) were designed and synthesized to determine the effects of substitutions at the 2-position which change the steric, electronic, and hydrophobic properties of TCN, while maintaining the integrity of the tricyclic ring system. These compounds were evaluated for activity against human immunodeficiency virus (HIV-1), herpes simplex virus type 1 (HSV-1), and human cytomegalovirus (HCMV) and were found to be either less active than TCN and TCN-P or inactive at the highest concentrations tested, 100 microM. We conclude that substitutions at the 2-position of triciribine adversely affect the antiviral activity most likely because these analogs are not phosphorylated to active metabolites.