Subcutaneous in situ gel delivered leuprolide acetate's consistent and prolonged drug delivery maintains effective testosterone suppression independent of age and weight in men with prostate cancer.

Objectives: To assess the impact of patient age and weight on the pharmacokinetics (PK), testosterone (T) suppression and safety from four fixed dosing regimens (7.5, 22.5, 30, or 45 mg for 1-, 3-, 4-, or 6-months, respectively) of subcutaneous in situ gel delivered leuprolide acetate (Gel-LA) injected via the ATRIGEL Delivery System in patients with prostate cancer (PCa). Patients and methods: Two patient populations were specified for analysis: a small cohort of surgically castrated PCa patients and a large, pooled population of PCa patients from four pivotal trials of Gel-LA. Two separate analyses of the impact of age and weight on study endpoints were conducted: (1) PK and safety of a single monthly dose of Gel-LA in a Phase 1 study with PCa patients who had undergone bilateral surgical orchiectomy ("Bilaterally orchiectomized male study"); (2) PK/pharmacodynamic (PD) effects and safety using pooled data from four pivotal trials assessing 1-, 3-, 4-, and 6-month dosing of Gel-LA in patients with advanced PCa, stratified by age and body weight (pivotal trials). Results: Eight orchiectomized patients from the "Bilaterally orchiectomized male study" and 438 patients from the pivotal trials were included in the analyses. Age and body weight did not appear to affect the PK results in the orchiectomized patient population. Pooled pivotal trial data showed that serum T levels did not appear to be influenced by age or weight; ≥90% of patients across all age groups and ≥92% of patients across all weight groups achieved T ≤ 50 ng/dL by week 4. Median T levels for castration (T ≤ 50 ng/dL) were maintained from week 3 until the end of the study and all subgroups achieved median T ≤ 20 ng/dL by week 4. Patients from the orchiectomized patient study did not report any serious treatment-related adverse events (AEs) and there were no AE-related withdrawals from the study. The most common AEs were hot flashes and injection site events. The safety profiles from pivotal trials have been previously described and, as expected, were consistent with known effects of LHRH agonist therapy and suppression of T levels. Conclusion: PK and PD of Gel-LA appear to be unaffected by age and body weight, as demonstrated by persistence of effective drug levels through the dosing period and consistent T suppression across different ages and body weights.

The Impact of Late Luteinizing Hormone-Releasing Hormone Agonist Dosing on Testosterone Suppression in Patients with Prostate Cancer: An Analysis of United States Clinical Data.

PURPOSE: We evaluated the timeliness of androgen deprivation therapy dosing, the impact of dosing nonadherence on testosterone, and the frequency of testosterone and prostate specific antigen testing in patients with prostate cancer. MATERIALS AND METHODS: We retrospectively analyzed the records of 22,860 patients with prostate cancer treated with luteinizing hormone-releasing hormone agonists. Analyses were done using 2 definitions of month, including a 28-day month (late dosing after day 28, 84, 112 or 168) and an extended month (late after day 32, 97, 128 or 194) for 1, 3, 4 and 6-month formulations, respectively. The prevalence of late dosing, associated testosterone values, and the frequency of testosterone and prostate specific antigen testing were assessed. Statistical significance was assessed with the unpaired t-test. RESULTS: Of the injections 84% and 27% were late for the 28-day and extended month analyses, respectively. For the 28-day month 60% and 29% of injections were late by more than 1 and more than 2 weeks, respectively. Of testosterone values 4% were greater than 50 ng/dl for early/on time injections using both definitions, and 15% and 27% were greater than 50 ng/dl when late, and for the 28-day month and the extended month, respectively. For early/on time vs late injections 22% vs 31% of testosterone values were greater than 20 ng/dl for the 28-day month and 21% vs 43% for the extended month. Mean testosterone was higher when late (49 ng/dl for 28-day month, 79 ng/dl for extended month) vs early/on time (both 21 ng/dl). Of the injections prostate specific antigen measurements were performed in 83% and testosterone assessment was done in only 13%. CONCLUSIONS: Luteinizing hormone-releasing hormone agonists were frequently (84%) administered later than the schedules used in pivotal trials. Nearly half of the late testosterone values for the extended month were greater than 20 ng/dl and mean testosterone was almost double the castration level. Elevated testosterone remained unidentified with infrequent testing.

Lack of electrocardiographic effect of dexlansoprazole MR, a novel modified-release formulation of the proton pump inhibitor dexlansoprazole, in healthy participants.

The effect of the proton pump inhibitor dexlansoprazole, an enantiomer of lansoprazole, on QT intervals was assessed after oral administration of a modified-release formulation of dexlansoprazole (dexlansoprazole MR). In this randomized, positive-comparator, placebo-controlled, 4-period crossover study, 40 healthy participants received single doses of dexlansoprazole MR 90 mg, dexlansoprazole MR 300 mg, moxifloxacin 400 mg, and placebo separated by 5-day washout intervals. Twenty-four-hour electrocardiograms were obtained at baseline and during each dosing period. The number and percentage of participants experiencing an increase in QT interval from baseline to maximum postdose value were evaluated during each dosing regimen, and pharmacokinetic profiles of dexlansoprazole and moxifloxacin were obtained. The mean maximum Fridericia-corrected QT (QT(cF)) intervals were similar for both doses of dexlansoprazole MR and placebo but were significantly greater with moxifloxacin (P < or = .001). With both doses of dexlansoprazole MR, the placebo-adjusted mean change from baseline in QT(cF) intervals was <5 ms, and the upper boundaries of the 95% 1-sided confidence intervals were <10 ms at all time points. Pharmacokinetic analysis indicated that QT intervals were measured at the time of maximum drug plasma concentration. Neither dexlansoprazole MR 90 mg nor 300 mg prolonged QT(cF) intervals in healthy participants. Both doses were well tolerated.

Effects of dexlansoprazole MR, a novel dual delayed release formulation of a proton pump inhibitor, on plasma gastrin levels in healthy subjects.

Dexlansoprazole MR is a modified release formulation of a proton pump inhibitor being developed for the treatment of acid-related disorders. The purpose of this study is to characterize the plasma gastrin (PG) profile associated with administration of dexlansoprazole MR. Forty-two healthy subjects receive dexlansoprazole MR 90 mg, dexlansoprazole MR 120 mg, and lansoprazole 30 mg once daily for 5 days in a randomized, open-label, 3-period crossover study with at least 14-day washout intervals. Twenty-four-hour PG profiles are obtained at baseline (day -1 of period 1) and on days 1 and 5 in each period. Fasting PG levels are determined on days 8 and 12 in periods 1 and 2. On day 1, 24-hour PG levels increase from baseline to a similar extent with all regimens. On day 5, 24-hour PG levels with both dexlansoprazole MR regimens increase further and to a similar extent and are slightly higher than PG levels with lansoprazole. For all regimens, fasting PG levels on days 5 and 6 are higher than baseline levels (P<.05) and start to decrease by day 8, returning to near baseline at day 12. In this study, dexlansoprazole MR administration results in moderate increases in PG, similar to lansoprazole, which return to baseline levels within 7 days post dosing.

Pharmacokinetics and pharmacodynamics of a known active PPI with a novel Dual Delayed Release technology, dexlansoprazole MR: a combined analysis of randomized controlled clinical trials.

BACKGROUND: Dexlansoprazole MR is a novel Dual Delayed Release formulation of dexlansoprazole, an enantiomer of lansoprazole, designed to prolong the plasma concentration-time profile of dexlansoprazole and extend duration of acid suppression with once-daily (QD) dosing. OBJECTIVES: To assess the pharmacokinetics and pharmacodynamics of dexlansoprazole at different doses of dexlansoprazole MR and delineate the exposure-response relationship following oral administration of dexlansoprazole MR. METHODS: Dexlansoprazole MR was evaluated in two prospective randomized studies in healthy subjects. In study 1 (n = 40), subjects received dexlansoprazole MR 60, 90, and 120 mg and lansoprazole 30 mg QD. In study 2 (n = 45), subjects received dexlansoprazole MR 30 and 60 mg and lansoprazole 15 mg QD. Data from these trials were pooled and analyzed to describe the relationship between intragastric pH and dexlansoprazole systemic exposure. RESULTS: Data from 83 subjects were analyzed. The dexlansoprazole plasma concentration-time profile following administration of dexlansoprazole MR was characterized by two distinct peaks and a prolonged drug exposure during the 24-h dosing interval. Approximate dose proportionality was observed for mean peak plasma concentration and area under the plasma-concentration time curve after administration of dexlansoprazole MR. In each study, doses of dexlansoprazole MR generally produced greater gastric acid suppression than lansoprazole. Based on the exposure-response analysis using combined data from these two trials, the predicted mean 24-h intragastric pH values were 4.06 and 4.35 for the dexlansoprazole MR 30- and 90-mg doses, respectively. The percent of time pH > 4 over 24 h values were 59.2% and 66.7% for dexlansoprazole MR 30 and 90 mg, respectively. No appreciable additional gain in the pharmacodynamic response was predicted for dexlansoprazole MR 120 mg. Despite combining data from two studies to evaluate a broader dose range, this analysis provided a reasonable estimate of the pharmacodynamic parameters and a good characterization of the dexlansoprazole MR exposure-response relationship. CONCLUSIONS: Dexlansoprazole MR, a proton pump inhibitor that uses Dual Delayed Release technology, produced a pharmacokinetic profile with a plasma concentration-time curve characterized by two distinct peaks and an extended duration of pharmacologically active dexlansoprazole concentration in plasma. Exposure-response analysis indicated a progressive increase in the pharmacodynamic response as dexlansoprazole MR doses increased from 30 to 90 mg.