Steven G. Simonson

Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine.

Cyclosporine (INN, ciclosporin) increases the systemic exposure of all statins. Therefore rosuvastatin pharmacokinetic parameters were assessed in an open‐label trial involving stable heart transplant recipients (≥6 months after transplant) on an antirejection regimen including cyclosporine. Rosuvastatin has been shown to be a substrate for the human liver transporter organic anion transporting polypeptide C (OATP‐C). Inhibition of this transporter could increase plasma concentrations of rosuvastatin. Therefore the effect of cyclosporine on rosuvastatin uptake by cells expressing OATP‐C was also examined.

Comparative effects of rosuvastatin and atorvastatin across their dose ranges in patients with hypercholesterolemia and without active arterial disease.

The lipid-lowering effects of rosuvastatin and atorvastatin were determined across their dose ranges in a 6-week, randomized, double-blind trial. Three hundred seventy-four hypercholesterolemic patients with fasting low-density lipoprotein (LDL) cholesterol > or =160 but <250 mg/dl (> or =4.14 but <6.47 mmol/L) and fasting triglycerides <400 mg/dl (<4.52 mmol/L) and without active arterial disease within 3 months of entry received once-daily rosuvastatin (5, 10, 20, 40, or 80 mg [n = 209]) or atorvastatin (10, 20, 40, or 80 mg [n = 165]). The percentage decrease in plasma LDL cholesterol versus dose was log-linear for each drug, ranging from -46.6% to -61.9% for rosuvastatin 10 and 80 mg, compared with -38.2% to -53.5% for atorvastatin 10 and 80 mg. The dose curve for rosuvastatin yielded an 8.4% greater decrease in LDL cholesterol compared with atorvastatin at any given dose (p <0.001). Similarly greater decreases were observed for rosuvastatin across the dose range in total cholesterol (-4.9%), non-high-density lipoprotein (non-HDL) cholesterol (-7.0%), apolipoprotein B (-6.3%), and related ratios versus atorvastatin (all p <0.001). Because dose responses for HDL cholesterol, triglycerides, and apolipoprotein A-I were non-log-linear and nonparallel between the 2 drugs, percentage changes from baseline were compared at each dose. Significantly greater increases for rosuvastatin compared with atorvastatin were observed for HDL cholesterol at 40 and 80 mg, and for apolipoprotein A-I at 80 mg. Significantly greater triglyceride decreases were seen at 80 mg with atorvastatin over rosuvastatin. Both rosuvastatin and atorvastatin were well tolerated over 6 weeks.

Rosuvastatin improves the atherogenic and atheroprotective lipid profiles in patients with hypertriglyceridemia.

BackgroundWe examined the effects of rosuvastatin treatment on triglyceride levels and lipid measures in a parallel-group multicenter trial (4522IL/0035) in patients with hypertriglyceridemia (Fredrickson Type IIb or IV). MethodsAfter a 6-week dietary lead-in period while on a National Cholesterol Education Program step I diet, 156 patients with fasting triglyceride levels ≥300 and <800 mg/dl were randomized to 6 weeks of double-blinded treatment: once-daily rosuvastatin of 5, 10, 20, 40 or 80 mg or placebo. The primary end point was mean percentage change from baseline in total serum triglyceride levels at week 6 as determined by analysis of variance. ResultsRosuvastatin at all doses produced significant mean reductions in triglycerides compared with placebo (–18 to –40 compared with +2.9%, P ≤ 0.001); median reductions in triglycerides with rosuvastatin at 5–80 mg ranged from –21 to –46%. All doses of rosuvastatin significantly reduced levels of atherogenic lipoprotein and apolipoproteins over placebo, including low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, apolipoprotein B and apolipoprotein C-III. Statistically significant increases in high-density lipoprotein cholesterol were observed with rosuvastatin doses >5 mg. The occurrence of adverse events was generally low and not dose related, although some adverse events occurred more frequently in the rosuvastatin 80 mg group. ConclusionsRosuvastatin reduced triglyceride levels and improved the overall atherogenic and atheroprotective lipid profiles in hypertriglyceridemic patients.

Effect of Rosuvastatin on Warfarin Pharmacodynamics and Pharmacokinetics

The effect of rosuvastatin on warfarin pharmacodynamics and pharmacokinetics was assessed in 2 trials. In trial A (a randomized, double‐blind, 2‐period crossover study), 18 healthy volunteers were given rosuvastatin 40 mg or placebo on demand (o.d.) for 10 days with 1 dose of warfarin 25 mg on day 7. In trial B (an open‐label, 2‐period study), 7 patients receiving warfarin therapy with stable international normalized ratio values between 2 and 3 were coadministered rosuvastatin 10 mg o.d. for up to 14 days, which increased to rosuvastatin 80 mg if the international normalized ratio values were <3 at the end of this period. The results indicated that rosuvastatin can enhance the anticoagulant effect of warfarin. The mechanism of this drug‐drug interaction is unknown. Rosuvastatin had no effect on the total plasma concentrations of the warfarin enantiomers, but the free plasma fractions of the enantiomers were not measured. Appropriate monitoring of the international normalized ratio is indicated when this drug combination is coadministered.

A placebo-controlled, double-blind, dose-escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock

IntroductionTumor necrosis factor-alpha (TNF-α), an early mediator in the systemic inflammatory response to infection, is a potential therapeutic target in sepsis. The primary objective of this study was to determine the safety and tolerability of AZD9773, an ovine, polyclonal, anti-human TNF-α Fab preparation, in patients with severe sepsis. Secondary outcomes related to pharmacokinetic (PK) and pharmacodynamic (PD) parameters.MethodsIn this double-blind, placebo-controlled, multicenter Phase IIa study, patients were sequentially enrolled into five escalating-dose cohorts (single doses of 50 or 250 units/kg; multiple doses of 250 units/kg loading and 50 units/kg maintenance, 500 units/kg loading and 100 units/kg maintenance, or 750 units/kg loading and 250 units/kg maintenance). In each cohort, patients were randomized 2:1 to receive AZD9773 or placebo.ResultsSeventy patients received AZD9773 (n = 47) or placebo (n = 23). Baseline characteristics were similar across cohorts. Mean baseline APACHE score was 25.9. PK data demonstrated an approximately proportional increase in concentration with increasing dose and a terminal half-life of 20 hours. For the multiple-dose cohorts, serum TNF-α concentrations decreased to near-undetectable levels within two hours of commencing AZD9773 infusion. This suppression was maintained in most patients for the duration of treatment. AZD9773 was well tolerated. Most adverse events were of mild-to-moderate intensity and considered by the reporting investigator as unrelated to study treatment.ConclusionsThe safety, PK and PD data support the continued evaluation of AZD9773 in larger Phase IIb/III studies.

Evaluation of efficacy and safety of budesonide delivered via two dry powder inhalers

ABSTRACT Background: The dry powder inhaler (DPI) device for budesonide inhalation powder 200 μg (DPI‑A*) was redesigned to improve dosing consistency and provide new features (budesonide inhalation powder 90 μg and 180 μg; DPI‑B†). Objective: Two multicenter, parallel-group, double-blind, randomized, 12-week studies compared the efficacy and safety of budesonide delivered via each DPI versus placebo, and the systemic exposure of budesonide from each device. Methods: Asthmatic adults with mild-to-moderate asthma (N = 621) and patients 6–17 years with mild asthma (N = 516) received budesonide DPI‑B 360 μg or DPI‑A 400 μg twice-daily (total daily dose 720 μg or 800 μg), budesonide DPI‑B 180 μg or DPI‑A 200 μg once daily (total daily dose 180 μg or 200 μg), or matching placebo. Change in forced expiratory volume in 1 second (FEV1) and secondary variables (asthma symptoms, β2-adrenergic agonist use, peak expiratory flow [PEF], and withdrawals due to worsening asthma) versus placebo were measured. Results: In both studies, FEV1 significantly ( p < 0.05) improved for all active treatments versus placebo except once-daily budesonide DPI‑B 180 μg in adults. In the adult study, significantly ( p < 0.05) greater improvements in all secondary variables occurred with all active treatments versus placebo. In the pediatric/adolescent study, improvements in AM/PM PEF were significantly (p ≤ 0.011) greater with twice-daily budesonide DPI‑B 360 μg versus placebo. Numerically fewer patients in all active-treatment groups withdrew due to worsening asthma versus placebo. Adverse event profiles were similar among groups. In the pediatric/adolescent study, no significant differences in mean 24-h urine cortisol or cortisol : creatinine ratio assessments were observed between the active treatment groups and the placebo group. Although pharmacokinetic variables were generally similar across subgroups in the adult (n = 77) and pediatric/adolescent (n = 32) studies, pairwise treatment comparisons of twice-daily budesonide DPI‑B 360 μg versus DPI‑A 400 μg and once-daily budesonide DPI‑B 180 μg versus DPI‑A 200 μg showed large variability for the area under the drug plasma concentration–time curve over the dosing interval and the maximum detected drug plasma concentration. Conclusions: The efficacy and safety of budesonide DPI‑A and DPI‑B versus placebo were demonstrated across the low to medium inhaled corticosteroid dose range in children ≥ 6 years with very mild asthma and adolescents and adults with mild-to-moderate asthma. The study is limited by the evaluation of only two doses for each product in both studies. Additionally, the studies were not designed to test equivalence or noninferiority between the active products. Pharmacokinetic characterization was limited because of the small sample sizes.

Intravenous esomeprazole pharmacodynamics in critically ill patients

Abstract Objective: A widely held belief contends that food-induced proton pump activation is important for optimal proton pump inhibitor–induced inhibition of gastric acid secretion. This study was undertaken to assess intragastric acid control with intravenous (IV) esomeprazole in critically ill patients. Research design and methods: This open-label, single-arm, exploratory trial was conducted at five university or regional hospital intensive care units in the US. Adult patients admitted to an intensive care unit who required mechanical ventilation and had at least one additional risk factor for stress-induced ulcer received twice-daily IV esomeprazole 40 mg for 48 hours and could continue for another 24 hours if no prepyloric enteral feedings were planned. Clinical trial registration: Trial registration: ClinicalTrials.gov identifier: NCT00428701. Main outcome measures: The primary efficacy variable was the linear-interpolated percentage of time intragastric pH was ≥4 during 24–48 hours. Secondary efficacy variables included the interpolated percentage of time intragastric pH was ≥4 during 0–24, 0–48, and 48–72 hours, the percentage of gastric aspirates collected with pH ≥4 during 0–24, 24–48, 0–48, and 48–72 hours, and time to stable pH ≥4. Safety was assessed based on adverse events (AEs), physical examinations, vital signs, laboratory tests, and electrocardiograms. Results: Forty-five patients were enrolled (one was excluded because of previous partial gastrectomy). Interpolated mean percentage time pH ≥4 was 88.8%, 80.7%, and 83.5% for 24–48, 0–24, and 0–48 hours, respectively. For 0–72 hours, ≥78% of gastric aspirates had pH ≥4. Median time to stable pH was 1 hour (95% confidence interval: 0.67, 2.00). Treatment was well tolerated, with no evidence of gastrointestinal bleeding. A total of 75 AEs occurred in 34 patients, none considered treatment related. Conclusions: In this noncontrolled exploratory study, twice-daily IV esomeprazole 40 mg rapidly decreased intragastric acidity and effectively maintained pH ≥4 during 0–72 hours in fasting, critically ill, mechanically ventilated patients at high risk for stress ulcers.