An open-label, multicenter, phase Ib study investigating the effect of apalutamide on ventricular repolarization in men with castration-resistant prostate cancer

Purpose: Phase Ib study evaluating the effect of apalutamide, at therapeutic exposure, on ventricular repolarization by applying time-matched pharmacokinetics and electrocardiography (ECG) in patients with castration-resistant prostate cancer. Safety of daily apalutamide was also assessed. Methods: Patients received 240 mg oral apalutamide daily. Time-matched ECGs were collected via continuous 12-lead Holter recording before apalutamide (Day − 1) and on Days 1 and 57 (Cycle 3 Day 1). Pharmacokinetics of apalutamide were assessed on Days 1 and 57 at matched time points of ECG collection. QT interval was corrected for heart rate using Fridericia correction (QTcF). The primary endpoint was the maximum mean change in QTcF (ΔQTcF) from baseline to Cycle 3 Day 1 (steady state). Secondary endpoints were the effect of apalutamide on other ECG parameters, pharmacokinetics of apalutamide and its active metabolite, relationship between plasma concentrations of apalutamide and QTcF, and safety. Results: Forty-five men were enrolled; 82% received treatment for ≥ 3 months. At steady state, the maximum ΔQTcF was 12.4 ms and the upper bound of its associated 90% CI was 16.0 ms. No clinically meaningful effects of apalutamide were reported for heart rate or other ECG parameters. A concentration-dependent increase in QTcF was observed for apalutamide. Most adverse events (AEs) (73%) were grade 1–2 in severity. No patients discontinued due to QTc prolongation or AEs. Conclusion: The effect of apalutamide on QTc prolongation was modest and does not produce a clinically meaningful effect on ventricular repolarization. The AE profile was consistent with other studies of apalutamide

Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature

The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people We designed a mechanistically unbiased approach based on chemical genetics to identify chemical starting points for interfering with HCV replication. Our differentiating strategy centred on the identification of compounds functionally distinct from those acting on the traditional targets of antiviral research in this field, the NS3 protease and the NS5B RNA-dependent RNA polymerase 10 . BMS-858 formed the basis of an extensive series of chemical refinements that focused on improving antiviral potency, broadening inhibitory activity to encompass the HCV 1a genotype, and optimizing for oral bioavailability and sustained pharmacokinetic properties. After defining symmetry as an important contributor to antiviral activity 10 , a discovery that preceded the disclosure of structural information (see below), we subsequently identified BMS-79005

Stereoselective pharmacokinetics and placental transfer of fluoxetine and norfluoxetine in pregnant sheep under steady-state conditions

Fluoxetine (FX) is one of the most popular SSRIs used for the treatment of depression. Its use in treating depressed pregnant woman has increased substantially in recent years. A considerable amount of attention in the literature regarding the use of FX in pregnancy has been devoted to the assessment of birth outcomes following in utero FX exposures while studies that focus on pharmacokinetics during pregnancy are relatively sparse. Previous FX experiments in pregnant sheep using single dose intravenous (i.v.) bolus administration have focused primarily on the acute exposure and effects of the drug on both the mother and fetus. In the present studies, experiments were conducted to investigate the stereoselective pharmacokinetics of FX and norfluoxetine (NFX) under steady-state conditions in nonpregnant sheep and pregnant sheep at late gestation via continuous 8-day i.v. infusion of FX to the ewe. Drug infusions were conducted at two dose levels (i.e. low dose and high dose) in nonpregnant sheep that allowed the examination of nonlinear pharmacokinetics of FX in sheep. The pregnant sheep infusion experiment was to determine the impacts of pregnancy on the stereoselective pharmacokinetics of FX and NFX, and to assess the exposure of the fetus to FX and NFX enantiomers at steady-state. Moreover, a continuous 4- day direct fetal i.v. FX infusion experiment was conducted to study the pharmacokinetics of FX and NFX in fetal lambs in attempt to explore intrinsic drug elimination capability by the fetus. In nonpregnant sheep, FX and NFX enantiomers exhibited significant pharmacokinetic differences under steady-state conditions, confirming the observations made in previous i.v. bolus experiments. For FX, the R-enantiomer had a lower steady-state concentration (Css) level but a longer elimination half-life (t½β) than the S-enantiomer while for NFX, both the R- and S-enantiomers had similar Cs s levels but the t½β was slightly longer for R-NFX compared to S-NFX. FX and NFX also displayed stereospecific protein binding, with free fractions of the R-enantiomers that were about 2 to 3-fold higher than those of the Senantiomers. In comparison to humans, quantitative differences exist but qualitatively the overall stereoselective disposition of FX and NFX are similar between sheep and humans. Using the literature reported value for hepatic blood flow in sheep, the intrinsic clearances (CLint) for the FX enantiomers were determined. CLint of R-FX was estimated to be ~50% higher than that of S-FX, indicating that, in addition to stereoselective protein binding, stereoselective metabolism also played a pivotal role in the overall stereoselective disposition of FX. Moreover, FX displayed a disproportional change in pharmacokinetics in sheep upon long-term administration, characterized by a decrease in total body clearance (CLTB) and increase in dose normalized area under the curve (AUC) with higher dose. This nonlinearity may be due to inhibition of a CYP2D6-like enzyme in the sheep liver, as this is the major drug metabolizing enzyme for FX in humans. In pregnant sheep, the stereoselective pharmacokinetics of FX and NFX under steady-state conditions were similar to those observed in nonpregnant animals. No remarkable changes in the S/R ratio of FX and NFX were observed. Similarly, no change in FX clearance was observed as opposed to the previous finding of a higher clearance in pregnant sheep following single i.v. bolus administration. Protein binding did not appear to differ between pregnant and nonpregnant sheep for either FX and NFX. FX and NFX exhibited moderate degrees of placental transfer upon chronic administration, with a fetal-to-maternal (F/M) AUC ratios of about 0.40 and 0.33, respectively. When concentrations were corrected for the difference in free fraction between the maternal and fetal compartments, the F/M ratio still remained less than unity, suggesting the presence of other nonplacental routes of elimination for FX in the fetus. Analyses of amniotic and fetal tracheal fluids showed that excretion of FX and NFX into these fluids resulted in levels not exceeding those in fetal plasma and significant accumulations were therefore unlikely. Comparisons of F/M ratios between the R- and S-enantiomers revealed no difference between R-FX and S-FX, while S-NFX was slightly higher (-25%) compared to R-NFX, indicating that NFX distributed between the mother and the fetus in a stereoselective manner. Following fetal i.v. infusion of FX, alterations in fetal blood gas status, characterized by decreases in PO2 and O2 saturation, and increases in PCO2 and pH, were noted. Due to variability between animals, the majority of these effects did not reach statistical significance. The stereoselective pharmacokinetics of FX and NFX in fetal lambs were similar to those observed in adult sheep, but the extent of stereoselectivity in terms of the S/R ratio was less. The differential steady-state concentrations of the FX enantiomers observed in the fetal circulation were likely due to stereoselective protein binding in fetal plasma and differential maternal-to-fetal placental transfer of the enantiomers preceded by maternal stereoselective metabolism. Based on the F/M ratios for NFX (-0.62) following fetal FX infusion, it appears that the fetus has limited metabolic capability, if any, to biotransform FX to NFX. It is not fully known, however, whether other metabolic pathways such as the formation of trifluoromethylphenol via O-dealkylation are functional in the fetus. Renal excretion of FX and NFX did not contribute substantially to their overall clearance in the fetus (<1% of CLJB). In comparison to maternal and nonpregnant adult sheep, weight normalized CLTB, CLrenal, and Vdss were significantly higher in the fetus. Unbound fractions of FX and NFX were also higher in the fetus owning to the lower concentration of plasma protein in fetal plasma. The intrinsic capability of the fetus to eliminate FX was assessed by calculating the maternal and fetal placental and nonplacental clearances based on the 2-compartment model for the maternal-fetal unit. The results indicated that both placental and nonplacental routes were equally important in fetal elimination of FX. It is concluded that other elimination routes are likely present in the fetus but these remain to be elucidated.Pharmaceutical Sciences, Faculty ofGraduat

Efficacy and Safety Exposure-Response Relationships of Apalutamide in Patients with Nonmetastatic Castration-Resistant Prostate Cancer.

To evaluate the relationship between exposure of apalutamide and its active metabolite, N-desmethyl-apalutamide, and selected clinical efficacy and safety parameters in men with high-risk nonmetastatic castration-resistant prostate cancer. An exploratory exposure-response analysis was undertaken using data from the 1,207 patients (806 apalutamide and 401 placebo) enrolled in the SPARTAN study, including those who had undergone dose reductions and dose interruptions. Univariate and multivariate Cox regression models evaluated the relationships between apalutamide and N-desmethyl-apalutamide exposure, expressed as area under the concentration-time curve at steady state, and metastasis-free survival (MFS). Univariate and multivariate logistic regression models assessed the relationship between apalutamide and N-desmethyl-apalutamide exposure and common treatment-emergent adverse events including fatigue, fall, skin rash, weight loss, and arthralgia. A total of 21% of patients in the apalutamide arm experienced dose reductions diminishing the average daily dose to 209 mg instead of 240 mg. Within the relatively narrow exposure range, no statistically significant relationship was found between MFS and apalutamide and N-desmethyl-apalutamide exposure. Within apalutamide-treated subjects, skin rash and weight loss had a statistically significant association with higher apalutamide exposure. The use of apalutamide at the recommended dose of 240 mg once daily provided a similar delay in metastases across the SPARTAN patient population, regardless of exposure. The exploratory exposure-safety analysis supports dose reductions in patients experiencing adverse events

HSD3B1(1245A>C) variant regulates dueling abiraterone metabolite effects in prostate cancer

BACKGROUND: A common germline variant in HSD3B1(1245A>C) encodes for a hyperactive 3beta-hydroxysteroid dehydrogenase 1 (3betaHSD1) missense that increases metabolic flux from extragonadal precursor steroids to DHT synthesis in prostate cancer. Enabling of extragonadal DHT synthesis by HSD3B1(1245C) predicts for more rapid clinical resistance to castration and sensitivity to extragonadal androgen synthesis inhibition. HSD3B1(1245C) thus appears to define a subgroup of patients who benefit from blocking extragonadal androgens. However, abiraterone, which is administered to block extragonadal androgens, is a steroidal drug that is metabolized by 3betaHSD1 to multiple steroidal metabolites, including 3-keto-5alpha-abiraterone, which stimulates the androgen receptor. Our objective was to determine if HSD3B1(1245C) inheritance is associated with increased 3-keto-5alpha-abiraterone synthesis in patients. METHODS: First, we characterized the pharmacokinetics of 7 steroidal abiraterone metabolites in 15 healthy volunteers. Second, we determined the association between serum 3-keto-5alpha-abiraterone levels and HSD3B1 genotype in 30 patients treated with abiraterone acetate (AA) after correcting for the determined pharmacokinetics. RESULTS: Patients who inherit 0, 1, and 2 copies of HSD3B1(1245C) have a stepwise increase in normalized 3-keto-5alpha-abiraterone (0.04 ng/ml, 2.60 ng/ml, and 2.70 ng/ml, respectively; P = 0.002). CONCLUSION: Increased generation of 3-keto-5alpha-abiraterone in patients with HSD3B1(1245C) might partially negate abiraterone benefits in these patients who are otherwise more likely to benefit from CYP17A1 inhibition. FUNDING: Prostate Cancer Foundation Challenge Award, National Cancer Institute