Management of Patients with Metastatic Castration-Sensitive Prostate Cancer in the Real-World Setting in the United States.

PURPOSE: This study provides a contemporary assessment of the treatment patterns, health care resource utilization (HRU) and costs among metastatic castration-sensitive prostate cancer (mCSPC) patients in the U.S. MATERIALS AND METHODS: Adults with mCSPC were selected from Optum's de-identified Clinformatics® Data Mart Database (Commercial insurance/Medicare Advantage [COM/MA]; January 1, 2014-July 31, 2019) or Medicare Fee-for-Service (FFS; January 1, 2014-December 31, 2017). The index date was the first metastatic disease diagnosis date on/after the first prostate cancer diagnosis (without prior evidence of castration resistance). Patients were observed for 12 months pre-index (baseline) through their mCSPC period (from index until castration resistance or followup end). First-line (1L) mCSPC therapy was assessed during the mCSPC period; all-cause HRU and health plan-paid costs per-patient-per-year (PPPY) were measured during baseline and mCSPC periods. RESULTS: Among 6,517 COM/MA and 13,324 Medicare-FFS mCSPC patients over ∼10 months (median mCSPC period), 38% and 48% remained untreated/deferred treatment, and 45% and 46% received 1L androgen deprivation therapy (ADT) monotherapy, respectively. 1L abiraterone acetate and docetaxel were used among 7% and 6% of COM/MA and 1% and 2% of Medicare-FFS patients, respectively. HRU increased from baseline to mCSPC period, resulting in increased health plan-paid costs from $21,201 to $108,767 in COM/MA and from $16,819 to $69,639 PPPY in Medicare-FFS. CONCLUSIONS: This study highlights the limited use of newer therapies that improve survival in men with mCSPC in the U.S. HRU and costs increased substantially after onset of metastasis. Given the emergence of newer effective mCSPC therapies, further evaluation of future real-world mCSPC treatment patterns and outcomes is warranted.

Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction: The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I).

BACKGROUND: Human or recombinant apolipoprotein A-I (apoA-I) has been shown to increase high-density lipoprotein-mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apoA-I that has been studied in normal subjects or those with stable coronary artery disease. This study aimed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of CSL112 in patients with a recent acute myocardial infarction. METHODS: The AEGIS-I trial (Apo-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomized 1:1:1 to CSL112 (2 g apoA-I per dose) and high-dose CSL112 (6 g apoA-I per dose), or placebo for 4 consecutive weekly infusions. Coprimary safety end points were occurrence of either a hepatic safety event (an increase in alanine transaminase >3 times the upper limit of normal or an increase in total bilirubin >2 times the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement for renal replacement therapy). RESULTS: A total of 1258 patients were randomized, and 91.2% received all 4 infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4%. Similarly, the difference in incidence rates for an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol-defined noninferiority margin of 5%. CSL112 was associated with increases in apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. In regard to the secondary efficacy end point, the risk for the composite of major adverse cardiovascular events among the groups was similar. CONCLUSIONS: Among patients with acute myocardial infarction, 4 weekly infusions of CSL112 are feasible, well tolerated, and not associated with any significant alterations in liver or kidney function or other safety concern. The ability of CSL112 to acutely enhance cholesterol efflux was confirmed. The potential benefit of CSL112 to reduce major adverse cardiovascular events needs to be assessed in an adequately powered phase 3 trial. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02108262.

Identification of patients with metastatic castration-sensitive or metastatic castration-resistant prostate cancer using administrative health claims and laboratory data.

OBJECTIVE: To develop algorithms to identify metastatic castration-sensitive prostate cancer (mCSPC) patients and castration-resistant prostate cancer (mCRPC) patients, using health claims data and laboratory test results. METHODS: A targeted literature review summarized mCSPC and mCRPC patient selection criteria previously used in real-world retrospective studies. Novel algorithms to identify mCSPC and mCRPC were developed based on diagnosis codes indicating hormone sensitivity/resistance, prostate-specific antigen (PSA) test results, and claims for castration and mCRPC-specific treatments. These algorithms were applied to claims data from Optum Clinformatics Extended DataMart (Date of Death) Databases (commercial insurance/Medicare Advantage [COM/MA]; 01 January 2014-31 July 2019) and Medicare Fee-for-Service (Medicare-FFS; 01 January 2014-31 December 2017). RESULTS: Previous real-world studies identified mCSPC primarily based on metastasis diagnosis codes, and mCRPC based on mCRPC-specific drugs. Using the current study's algorithms, 7034 COM/MA and 19,981 Medicare-FFS patients were identified as having mCSPC, and 2578 COM/MA and 11,554 Medicare-FFS as having mCRPC. Most mCSPC patients were identified based on evidence of being hormone/castration-naive. Patients were identified as having mCRPC most commonly based on rising PSA (COM/MA), or at the metastasis diagnosis date if it occurred after castration (Medicare-FFS). Among patients with mCSPC, 14-17% had evidence of progression to castration resistance during a median 1-year follow-up period, mostly based on use of mCRPC-specific drugs. CONCLUSIONS: Comprehensive algorithms based on claims and laboratory data were developed to identify and distinguish patients with mCSPC and mCRPC. This will facilitate appropriate identification of mCSPC and mCRPC patients based on health claims data and better understanding of patient unmet needs in real-world settings.

Moderate Renal Impairment Does Not Impact the Ability of CSL112 (Apolipoprotein A-I [Human]) to Enhance Cholesterol Efflux Capacity.

CSL112 (apolipoprotein A-I [human]) is a novel intravenous formulation of plasma-derived apolipoprotein A-I (apoA-I) that enhances cholesterol efflux capacity. Renal impairment is a common comorbidity in acute myocardial infarction patients and is associated with impaired lipid metabolism. The aim of this phase 1 study was to assess the impact of moderate renal impairment on the pharmacokinetic and pharmacodynamic profile of CSL112. Sixteen subjects with moderate renal impairment and 16 age-, sex-, and weight-matched subjects with normal renal function participated in the study. Within each renal function cohort, subjects were randomized 3:1 to receive a single intravenous infusion of CSL112 2 g (n = 6) or placebo (n = 2) or CSL112 6 g (n = 6) or placebo (n = 2). At baseline, subjects with moderate renal impairment versus normal renal function had higher total cholesterol efflux, ABCA1-dependent cholesterol efflux capacity, and pre-ß1-high-density lipoprotein (HDL) levels. Infusing CSL112 resulted in similar, immediate, robust, dose-dependent elevations in apoA-I and cholesterol efflux capacity in both renal function cohorts and significantly greater elevations in pre-ß1-HDL (P < .05) in moderate renal impairment. Lecithin-cholesterol acyltransferase activity, demonstrated by a time-dependent change in the ratio of unesterified to esterified cholesterol, did not differ by renal function. No meaningful changes in proatherogenic lipid levels were observed. Moderate renal impairment did not impact the ability of CSL112 to enhance cholesterol efflux capacity. CSL112 may represent a novel therapy to reduce the risk of early recurrent cardiovascular events following acute myocardial infarction in patients with or without moderate renal impairment.

Infusion of Reconstituted High-Density Lipoprotein, CSL112, in Patients With Atherosclerosis: Safety and Pharmacokinetic Results From a Phase 2a Randomized Clinical Trial.

BACKGROUND: CSL112 is a new formulation of human apolipoprotein A-I (apoA-I) being developed to reduce cardiovascular events following acute coronary syndrome. This phase 2a, randomized, double-blind, multicenter, dose-ranging trial represents the first clinical investigation to assess the safety and pharmacokinetics/pharmacodynamics of a CSL112 infusion among patients with stable atherosclerotic disease. METHODS AND RESULTS: Patients were randomized to single ascending doses of CSL112 (1.7, 3.4, or 6.8 g) or placebo, administered over a 2-hour period. Primary safety assessments consisted of alanine aminotransferase or aspartate aminotransferase elevations >3× upper limits of normal and study drug-related adverse events. Pharmacokinetic/pharmacodynamic assessments included apoA-I plasma concentration and measures of the ability of serum to promote cholesterol efflux from cells ex vivo. Of 45 patients randomized, 7, 12, and 14 received 1.7-, 3.4-, and 6.8-g CSL112, respectively, and 11 received placebo. There were no clinically significant elevations (>3× upper limit of normal) in alanine aminotransferase or aspartate aminotransferase. Adverse events were nonserious and mild and occurred in 5 (71%), 5 (41%), and 6 (43%) patients in the CSL112 1.7-, 3.4-, and 6.8-g groups, respectively, compared with 3 (27%) placebo patients. The imbalance in adverse events was attributable to vessel puncture/infusion-site bruising. CSL112 resulted in rapid (T(max)≈2 hours) and dose-dependent increases in apoA-I (145% increase in the 6.8-g group) and total cholesterol efflux (up to 3.1-fold higher than placebo) (P<0.001). CONCLUSIONS: CSL112 infusion was well tolerated in patients with stable atherosclerotic disease. CSL112 immediately raised apoA-I levels and caused a rapid and marked increase in the capacity of serum to efflux cholesterol. This potential novel approach for the treatment of atherosclerosis warrants further investigation. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01499420.

Pharmacokinetics of armodafinil and modafinil after single and multiple doses in patients with excessive sleepiness associated with treated obstructive sleep apnea: a randomized, open-label, crossover study.

BACKGROUND: Armodafinil (the R-isomer of racemic modafinil) and modafinil are wakefulness-promoting medications for excessive sleepiness associated with treated obstructive sleep apnea (OSA). The R-isomer of racemic modafinil has a half-life of approximately15 hours; the S-isomer has a half-life of 4 to 5 hours. The R-and S-isomers are equipotent, producing equivalent pharmacologic activity at equal concentrations. OBJECTIVE: The aim of this work was to compare the pharmacokinetic profiles of armodafinil (R-modafinil) and modafinil (racemic mixture with equal quantities of R- and S-isomers) at equal doses in patients with residual excessive sleepiness associated with continuous positive airway pressure-treated OSA. METHODS: This open-label study was conducted at 5 US centers from July 2008 to March 2009. Patients were randomized to 1 of 2 crossover administration sequences, ABCD or BADC, where A was a single armodafinil 200-mg dose, B was a single modafinil 200-mg dose, C was multiple daily modafinil 200-mg doses, and D was multiple daily armodafinil 200-mg doses. During multiple-dose administration, patients received 100 mg once daily for days 1 and 2, and 200 mg once daily for days 3 through 10. The pharmacokinetic parameters of principal interest for assessing the bioequivalence of armodafinil and modafinil were maximum concentration at 7 to 11 hours after dosing and the concentration-versus-time curve for this period. Analysis was performed via achiral high-performance liquid chromatography with ultraviolet detection using blood samples obtained over 72 hours after single-dose administration and over 24 hours after the multiple-dose regimen. For post hoc evaluation of bioequivalence, 90% CI values were also constructed for the geometric mean ratios of armodafinil to modafinil. Tolerability was assessed by the reported adverse events, clinical laboratory testing, vital sign measurements, ECGs, and physical exams. RESULTS: The study population was 83.3% male (35/42) and 76.2% white (32/42) with a mean (SD) age of 47.0 (8.30) years and a weight range of 66.3 to 127.4 kg. Plasma drug concentration-versus-time curves suggested comparable terminal half-lives (mean [SD] values were 16.5 [4.44] and 14.4 [3.22] hours for armodafinil and modafinil, respectively) but higher systemic exposure with armodafinil than modafinil (mean [SD] AUC(0-∞) values were 108.8 [31.66] and 66.4 [20.06] microg · h/mL for armodafinil and modafinil, respectively), as indicated by the high geometric mean ratios for the AUC (the AUC(0-∞)) ratio after a single dose was 1.64 [95% CI, 1.60-1.68; P < 0.001], and the AUC(0-τ) ratio after multiple doses was 1.69 [95% CI, 1.65-1.72; P < 0.001]) and, to a lesser extent, the ratio of the maximum plasma drug concentration after multiple doses (C(max) ratio = 1.37 [95% CI, 1.33-1.41; P < 0.001]). In addition, the ratios and associated 90% CIs for Cmax (137 [1.341.40]) and AUC(0-τ) (169 [1.66-1.75]) after multiple-dose administration did not meet the US Food and Drug Administration (FDA) criteria for bioequivalence (ie, ratio of geometric means between 80% and 125%). Reported adverse events were mild to moderate in intensity. The most frequently reported adverse events while receiving armodafinil or modafinil were headache (29% and 2%, respectively), diarrhea (12% and 5%), nausea (10% and 2%), and dizziness (10% and 5%). CONCLUSIONS: In this crossover study of patients with treated OSA, overall systemic exposure after armodafinil 200-mg administration was greater than that following modafinil 200-mg administration after both single and multiple doses. The pharmacokinetic profiles of the 2 drugs were notably different and did not meet the FDA criteria for bioequivalence.

A pharmacokinetic and safety study of intravenous arsenic trioxide in adult cancer patients with renal impairment.

PURPOSE: This study evaluated the pharmacokinetic and safety profiles of arsenic trioxide given twice per week in adult cancer patients with advanced malignancies and varying degrees of renal function. METHODS: Patients received intravenous arsenic trioxide 0.15 mg/kg twice weekly for 4 weeks, followed by a 2-week rest period. The pharmacokinetic profiles of the pharmacologically active arsenical species, arsenious acid (As(III)), and its metabolites, monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)), were evaluated during the first cycle for 72 h following doses on days 1 and 22. Safety assessments were made at each treatment visit. RESULTS: Twenty patients received an average of 11 doses. Compared with normal renal function, mild to severe renal impairment decreased urinary excretion of As(III) and increased exposure to MMA(V) and DMA(V) 1.4- to 8-fold after multiple dose administration. Only severe renal impairment substantially increased exposure to As(III) (AUC(0-t ) increased by 18% after a single dose and 40% after multiple doses). The safety profile of arsenic trioxide after limited treatment on a twice-per-week schedule was comparable across all renal function groups. CONCLUSION: Renal impairment did increase the systemic exposure to arsenic and its methylated metabolites following standard daily dosing of arsenic trioxide. The data from the limited number of patients with severe renal dysfunction did not suggest that severe renal impairment affected the safety profile of arsenic trioxide in cancer patients who received limited treatment with arsenic trioxide.