Times Daily Research Articles

Phase I Study of Tivozanib Eye Drops in Healthy Volunteers and Patients with Neovascular Age-Related Macular Degeneration

PurposeTo evaluate the safety, pharmacokinetics, and exploratory efficacy of tivozanib eye drops in healthy volunteers and patients with neovascular age-related macular degeneration (nAMD). DesignThis multicenter, group-sequential dose escalation phase 1 study consisted of a placebo-controlled, double-masked study of healthy volunteers (Cohorts 1 and 2) and an open-label study of nAMD patients (Cohort 3). ParticipantsHealthy volunteers: Japanese or White men aged 20 to <50 years. Patients with nAMD with central subfield thickness ≥300 μm and best-corrected visual acuity score ≥23 letters in the study eye. MethodsIn the single-dose cohort of healthy men (Cohort 1: Steps 1–5), 1 or 2 tivozanib eye drops (30 μL/drop, 5-minute interval; 0.5, 1.0, and 2.0 w/v%) or placebo were administered in 1 eye once. In the multiple-dose cohort of healthy men (Cohort 2: Steps 1–6), 1 or 2 tivozanib eye drops (0.5, 1.0, and 2.0 w/v%) or placebo were administered 3 times daily (TID) in 1 eye for 21 days. In the multiple-dose cohort of nAMD patients (Cohort 3, Steps 1–3), 1 or 2 tivozanib eye drops (0.5 and 1.0 w/v%) were administered TID in 1 affected eye for 21 days. Main Outcome MeasuresThe safety outcome measures included adverse events (AEs). The pharmacokinetic outcome was serum tivozanib concentration. Among the exploratory efficacy outcomes, central subfield thickness (CST) was evaluated. ResultsIn total, 40, 48, and 28 participants were enrolled in Cohorts 1, 2, and 3, respectively. Serious AEs did not occur in Cohorts 1–3. The most frequent AE in multiple-dose cohorts was reversible punctate keratitis: placebo arm, 8.3% (healthy men, 1/12); tivozanib arm, 47.2% (healthy men, 17/36) and 14.3% (nAMD, 4/28). Serum tivozanib exposure increased dose-dependently and was similar in healthy men and patients with nAMD. In patients with nAMD, mean CST changes from baseline to Day 22 were −27.6 ± 54.88 (0.5 w/v%; 1 drop, TID), −35.6 ± 49.64 (1.0 w/v%; 1 drop, TID), and −43.7 ± 55.19 μm (1.0 w/v%; 2 drops, TID). ConclusionsTivozanib eye drops showed a favorable safety profile in healthy Japanese and White men and Japanese patients with nAMD.

Danicopan As Add-on Therapy to Ravulizumab or Eculizumab Versus Placebo in Patients with Paroxysmal Nocturnal Hemoglobinuria and Clinically Significant Extravascular Hemolysis: Phase 3 Long-Term Data

Background C5 inhibitors eculizumab (Ecu) and ravulizumab (Rav) have transformed the natural history of paroxysmal nocturnal hemoglobinuria (PNH). Ecu resulted in patient (pt) survival comparable to that of the general population over 20 y of follow-up under real-world conditions. Overall survival rate at 6 years for pts treated with Rav was 98.4%. Where available, Rav is the standard of care for PNH, inhibiting terminal complement activation to prevent intravascular hemolysis (IVH) and thrombosis. Of pts with PNH treated with Rav/Ecu, 10-20% experience clinically significant extravascular hemolysis (cs-EVH). Efficacy and safety of the first-in-class oral factor D inhibitor danicopan (Dan; ALXN2040) as add-on treatment to Rav or Ecu for pts with PNH and cs-EVH were assessed in a phase 3, randomized, double-blind, placebo (Pbo)-controlled superiority clinical trial (ALPHA, NCT04469465). 12-wk data (double-blind treatment period [TP] 1) showing superiority of Dan vs Pbo on primary and key secondary endpoints were previously reported and represent the final analysis set for the trial. Open-label 24-wk (TP2) and ongoing long-term extension (LTE) data are presented. Methods Pts (≥18 y) with PNH and cs-EVH (hemoglobin [Hgb] ≤9.5 g/dL; absolute reticulocyte count [ARC] ≥120×10 9/L) on Rav/Ecu &amp;gt;6 mos were randomized double-blind 2:1 to Dan or Pbo add-on therapy for 12 wks (TP1). At wk 12, Pbo arm pts switched to Dan (Pbo-Dan) and Dan arm pts continued Dan (Dan-Dan) for another 12 wks (TP2), followed by a 1-y LTE in which all pts received Dan add-on therapy. The initial Dan dose of 150 mg 3 times daily (TID) could be escalated to 200 mg TID based on clinical response at investigator discretion. Primary endpoint was change from baseline (CFB) at wk 12 in Hgb. Other secondary endpoints: proportions of pts with Hgb increase ≥2 g/dL in absence of transfusion and with transfusion avoidance through wk 24; CFB in Hgb at wk 24; and CFB in ARC, lactate dehydrogenase (LDH), and C3 fragment deposition on PNH red blood cells at wks 12 and 24. Safety assessments included treatment-emergent adverse events (TEAEs) and laboratory abnormalities throughout the study. Results As of 20 September 2022, 86 pts were randomized; 60 completed TP2 (Dan n=40; Pbo n=20). Baseline characteristics were similar between arms ( Table). At wk 24 ( Fig), mean Hgb level was maintained in the Dan-Dan arm and increased from wk 12 in Pbo-Dan arm. ARC ( Fig) and other secondary endpoints were maintained in the Dan-Dan arm and improved in Pbo-Dan arm ( Table) at wk 24. The proportion of pts with Hgb increase of ≥2 g/dL in the absence of transfusion was maintained in the Dan-Dan arm and improved in the Pbo-Dan arm from wk 12 (Dan, 59.5%; Pbo, 0%) to wk 24 (Dan-Dan 46.3%; Pbo-Dan, 35.0%). Transfusion avoidance was maintained in the Dan-Dan arm and increased in Dan-Pbo arm from wk 12 (Dan, 83.3%; Pbo, 38.1%) to wk 24 (Dan-Dan 78.0%; Pbo-Dan, 90.0%). Mean LDH levels were maintained from wk 12 to 24 ( Table) and were near normal (&amp;lt;1.5×ULN) in both arms. Transfusions decreased in the Pbo-Dan arm from wk 12 (Pbo; mean [SD], 2.2 [2.3]) through 24 wks (Pbo-Dan; mean [SD], 0.1 [0.5]). The safety analysis included the n=80 pts exposed to Dan during the trial. At wk 24, study drug compliance was 98.8% (10.35) in the Dan-Dan arm and 98.3% (3.95) in Pbo-Dan arm. Escalation to 200 mg TID occurred for 41/57 (71.9%) pts in the Dan-Dan arm and 14/23 (60.9%) in Pbo-Dan arm. There were no deaths, meningococcal infections, or discontinuations due to hemolysis. Through data cut-off, 90% (72/80; 464 events) of pts had ≥1 TEAE after exposure to Dan. Serious AEs related to Dan were reported by 2 pts (gastrointestinal disorders/increased blood bilirubin; headache). 6 events in 4 pts led to withdrawal of study drug. 4 events were reported as breakthrough hemolysis (BTH) based on investigator discretion. Only 1 AE was associated with LDH &amp;gt;2×ULN (actual value 2.2×ULN) and potentially met the BTH definition used in other clinical studies. This AE was related to a complement-amplifying condition, COVID-19. This pt continued the study and BTH was resolved. Conclusions Danicopan as add-on to Rav or Ecu significantly improves Hgb and ARC levels and reduces the need for transfusion by addressing cs-EVH while maintaining control of IVH through 48 wks of treatment. Danicopan demonstrated a favorable benefit-risk profile with no deaths, meningococcal infections, or discontinuations due to hemolysis.

Developmental Population Pharmacokinetics-Pharmacodynamics of Meropenem in Chinese Neonates and Young Infants: Dosing Recommendations for Late-Onset Sepsis.

The pharmacokinetic (PK) studies of meropenem in Chinese newborns with late-onset sepsis (LOS) are still lacking. Causative pathogens of LOS and their susceptibility patterns in China differ from the data abroad. We, therefore, conducted a developmental population pharmacokinetic−pharmacodynamic analysis in Chinese newborns with the goal to optimize meropenem dosing regimens for LOS therapy. An opportunistic sampling strategy was used to collect meropenem samples, followed by model building and validation. A Monte Carlo simulation was performed to show the probability of target attainment (PTA) for various dosages. The information from 78 newborns (postmenstrual age: 27.4−46.1 weeks) was compiled and had a good fit to a 1-compartment model that had first order elimination. The median (range) values of estimated weight−normalized volume of distribution (V)and clearance (CL) were 0.60 (0.51−0.69) L/kg and 0.16 (0.04−0.51) L/h/kg, respectively. Covariate analysis revealed that postnatal age (PNA), gestational age (GA) and current weight (CW) were the most important factors in describing meropenem PK. Simulation results showed for LOS with a minimal inhibitory concentration (MIC) of 8 mg/L, the doses of 30 mg/kg 3 times daily (TID) as a 1-h infusion for newborns with GA ≤ 37 weeks and 40 mg/kg TID as a 3-h infusion for those with GA > 37 weeks were optimal, with PTA of 71.71% and 75.08%, respectively. In conclusion, we proposed an evidence-based dosing regimen of meropenem for LOS in Chinese newborns by using the population pharmacokinetic−pharmacodynamic analysis, based on domestic common pathogens and their susceptibility patterns.

A Multicenter, Double-Blind, Randomized, Placebo-Controlled Phase 2b Trial of Cytisinicline in Adult Smokers (The ORCA-1 Trial).

IntroductionCytisinicline (known as cytisine), a nicotinic acetylcholine receptor partial agonist, is a smoking cessation aid currently marketed in Central and Eastern Europe using a 1.5-mg/tablet 25-day downward titration schedule. No prior studies have evaluated other doses or administration schedules. This study evaluated the effects of a higher dosage and simplified dosing schedule on drug efficacy and tolerability.MethodsORCA-1 was a double-blind, randomized, placebo-controlled clinical trial that provided cytisinicline or placebo tablets plus behavioral support for 25 days. Adult smokers (>10 cigarettes daily) committed to quitting smoking were randomized to compare 2 cytisinicline doses (1.5 mg and 3 mg) versus placebo, and 2 administration schedules [downward titration versus 3 times daily (TID)]. Primary outcome was a reduction in expected cigarettes smoked at end of treatment; secondary outcomes were biochemically confirmed 7-day abstinence at Week 4 and continuous abstinence from Weeks 5 to 8.ResultsAmong 254 participants, those in cytisinicline arms (regardless of dose or schedule) had greater reductions in cigarettes smoked versus placebo, with differences observed in 3 cytisinicline arms statistically significant versus placebo. All cytisinicline arms had statistically significantly higher abstinence rates at Week 4 versus placebo. Both cytisinicline arms using TID schedules had statistically significantly higher continuous abstinence rates from Weeks 5 to 8 compared with placebo. Participants in the cytisinicline 3-mg TID arm had the highest abstinence rate. There were no safety concerns with either 1.5-mg or 3-mg cytisinicline.ConclusionBased on simpler dose scheduling, excellent tolerability, and best-continued abstinence rate, cytisinicline 3-mg TID was selected for future Phase 3 studies.ImplicationsAlthough the 1.5-mg 25-day titration schedule has been marketed in Central and Eastern Europe for decades, this study explored using a higher dosage and a simplified dosing schedule for impact on cytisinicline efficacy and tolerability. Based on these results, a Phase 3 program was initiated using cytisinicline 3-mg tablets on a TID schedule for potential market approval in the United States.

NaPi-IIb Inhibition for Hyperphosphatemia in CKD Hemodialysis Patients

IntroductionChronic kidney disease (CKD) has a prevalence of 9.1% globally, and frequently results in elevated serum phosphate, increasing cardiovascular morbidity and mortality risk in hemodialysis (HD) patients. DS-2330b, an oral NaPi-IIb inhibitor, reduced intestinal phosphate absorption in preclinical studies, but its effect in patients with CKD is unknown. This 2-part, randomized, placebo- and active-controlled, single- and repeated-dose, phase 1b study evaluated safety and efficacy of DS-2330b in patients with CKD on HD.MethodsPart A, a 2-period, 2-way study, evaluated safety and pharmacokinetics of DS-2330b 250 mg in solution and tablet formulations. Part B assessed the safety of DS-2330b in solution (chosen based on results of part A) and its effect on serum phosphate. Patients were randomized to placebo 3 times daily (TID), DS-2330b 400 mg TID, DS-2330b 400 mg with sevelamer 1.6 g TID, and sevelamer 1.6 g with placebo TID for 14 days. Safety endpoints included adverse event (AE) monitoring.ResultsSix patients completed part A. Two patients experienced serious AEs considered unrelated to DS-2330b treatment. Thirty-two patients enrolled and completed part B. Serum phosphate mean change from baseline ± SD was −2.2±1.5 mg/dl versus −1.9 ± 1.1 mg/dl for DS-2330b monotherapy versus placebo. Patients receiving DS-2330b with sevelamer or sevelamer with placebo experienced the greatest serum phosphate decrease from baseline. Nine patients (28.1%) experienced ≥1 treatment-emergent AE (TEAE); 7 patients experienced drug-related TEAEs. The TEAE incidence was comparable between DS-2330b and control groups.ConclusionsDS-2330b, alone or in combination with sevelamer, was safe and well tolerated but did not demonstrate clinically meaningful efficacy in HD patients.

Osteonecrosis of the jaw and dental extractions: A single-center experience

The aim of this study was to investigate the frequency of osteoradionecrosis/medication-related osteonecrosis of the jaw (ORN/MRONJ) after dental extraction with use of postextraction antibiotic coverage without prophylactic hyperbaric oxygen (HBO) in patients who received radiotherapy to head and neck (RT-HN) or antiresorptive medications and to determine possible associated factors. A retrospective study was conducted in patients who had a history of RT-HN or exposure to antiresorptives and who underwent dental extractions from 2003 to 2019. According to the clinical protocol, patients received amoxicillin 500 mg, 3 times daily (TID) for at least 14 days, and chlorhexidine 0.12% rinses, 2 times daily (BID), after extraction (or an alternative antibiotic if allergic to amoxicillin). HBO was not used for patients with RT-HN. Ninety patients underwent a total of 243 extractions. Fifty patients (55.5%) received a median of 54.1 Gray to the extraction site and 40 (44.4%) were on antiresorptives. None of the patients received both RT and antiresorptives. Of 40 patients, 3 (7.5%) developed MRONJ, and of 50 patients, 1 (2%) developed ORN. Among those at risk for MRONJ, male gender and concomitant immunosuppressant medications were associated with MRONJ development (P < .05). In our patient cohort, the rate of postextraction ORN/MRONJ was lower and comparable with the rates reported in the literature. Larger prospective studies are required to validate the efficacy of postextraction antibiotics in reducing ONJ.

Sodium zirconium cyclosilicate increases serum bicarbonate concentrations among patients with hyperkalaemia: exploratory analyses from three randomized, multi-dose, placebo-controlled trials.

BackgroundSodium zirconium cyclosilicate (SZC) binds potassium and ammonium in the gastrointestinal tract. In addition to serum potassium reduction, Phase 2 trial data have shown increased serum bicarbonate with SZC, which may be clinically beneficial because maintaining serum bicarbonate ≥22 mmol/L preserves kidney function. This exploratory analysis examined serum bicarbonate and urea, and urine pH data from three SZC randomized, placebo-controlled Phase 3 studies among patients with hyperkalaemia [ZS-003 (n = 753), HARMONIZE (n = 258) and HARMONIZE-Global (n = 267)].MethodsIn all studies, patients received ≤10 g SZC 3 times daily (TID) for 48 h to correct hyperkalaemia, followed by randomization to maintenance therapy with SZC once daily (QD) versus placebo for ≤29 days among those achieving normokalaemia.ResultsSignificant dose-dependent mean serum bicarbonate increases from baseline of 0.3 to 1.5 mmol/L occurred within 48 h of SZC TID in ZS-003 (all P < 0.05), which occurred regardless of chronic kidney disease (CKD) stage. Similar acute increases in HARMONIZE and HARMONIZE-Global were maintained over 29 days. With highest SZC maintenance doses, patient proportions with serum bicarbonate <22 mmol/L fell from 39.4% at baseline to 4.9% at 29 days (P = 0.005) in HARMONIZE and from 87.9% to 70.1%, (P = 0.006) in HARMONIZE-Global. Path analyses demonstrated that serum urea decreases (but not serum potassium or urine pH changes) were associated with SZC effects on serum bicarbonate.ConclusionsSZC increased serum bicarbonate concentrations and reduced patient proportions with serum bicarbonate <22 mmol/L, likely due to SZC-binding of gastrointestinal ammonium. These SZC-induced serum bicarbonate increases occurred regardless of CKD stage and were sustained during ongoing maintenance therapy.

Rifaximin is associated with modest, transient decreases in multiple taxa in the gut microbiota of patients with diarrhoea-predominant irritable bowel syndrome

ABSTRACTRifaximin, a non-systemic antibiotic, is efficacious for the treatment of diarrhoea-predominant irritable bowel syndrome (IBS-D). Given the emerging association between the gut microbiota and IBS, this study examined potential effects of rifaximin on the gastrointestinal microbial community in patients with IBS-D. TARGET 3 was a randomised, double-blind, placebo-controlled, phase 3 study. Patients with IBS-D initially received open-label rifaximin 550 mg 3 times daily (TID) for 2 weeks. Patients who responded to the initial treatment and then relapsed were randomised to receive 2 repeat courses of rifaximin 550 mg TID or placebo for 2 weeks, with each course separated by 10 weeks. Stool samples were collected at the beginning and end of open-label treatment, at the beginning and end of the first double-blind treatment, and at the end of the study. As a secondary analysis to the TARGET 3 trial, the composition and diversity of the gut microbiota were assessed, from a random subset of patients, using variable 4 hypervariable region 16S ribosomal RNA gene sequencing. Samples from 103 patients were included. After open-label rifaximin treatment for 2 weeks, 7 taxa (e.g. Peptostreptococcaceae, Verrucomicrobiaceae, Enterobacteriaceae) had significantly lower relative abundance at a 10% false discovery rate threshold. The effects of rifaximin were generally short-term, as there was little evidence of significantly different changes in taxa relative abundance at the end of the study (up to 46 weeks) versus baseline. The results suggest that rifaximin has a modest, largely transient effect across a broad range of stool microbes. Future research may determine whether the taxa affected by rifaximin are causally linked to IBS-D.ClinicalTrials.gov identifier number: NCT01543178.

Endoscopic comparison of gastroduodenal injury with over-the-counter doses of new fast-dissolving ibuprofen and paracetamol formulations: a randomized, placebo-controlled, 4-way crossover clinical trial.

BackgroundWhile gastrointestinal (GI) effects of standard ibuprofen and N-acetyl-p-aminophenol (APAP) have been reported, upper GI injury following treatment with fast-dissolving (FD) formulations of these analgesics has not been investigated. We evaluated upper GI effects of over-the-counter doses of 2 FD ibuprofen products and 1 FD-APAP product.MethodsIn a randomized, placebo-controlled, endoscopist-blinded, 4-way crossover study, 28 healthy subjects received FD ibuprofen 2×200 mg liquid capsules 3 times daily (TID), ibuprofen 2×200 mg tablets TID, FD-APAP 2×500 mg tablets 4 times daily (QID), and placebo 2×500 mg tablets QID for 7 days. The primary end point was gastric mucosal damage assessed by endoscopy using the Lanza scale: 0=normal stomach or proximal duodenum, 1=mucosal hemorrhages only, 2=1 or 2 erosions, 3=numerous (3–10) erosions, and 4=large number of erosions (>10) or ulcer. Secondary end points included duodenal mucosal damage (Lanza scale); gastroduodenal mucosal injury, classified as present (gastric and/or duodenal endoscopy score ≥2) or absent (gastric and/or duodenal endoscopy score <2); and number of hemorrhages, erosions, and ulcers counted separately in the stomach and duodenum.ResultsSignificantly greater gastric mucosal injury was observed after treatment with both ibuprofen products vs FD-APAP (p<0.0001 and p=0.0095, respectively). FD-APAP showed no difference from placebo (p=0.4794). The odds of having an incidence of gastroduodenal mucosal injury were over 6 times greater from FD ibuprofen liquid capsule treatment (odds ratio [OR]=6.19, 95% confidence interval [CI]: 1.60, 23.97) and over 3 times greater from ibuprofen tablet treatment (OR=3.19, 95% CI: 0.8, 12.74) vs FD-APAP.ConclusionTreatment with 2 ibuprofen products was associated with significant gastric mucosal injury. Of the 4 treatments studied, FD ibuprofen liquid capsules had the highest risk of incidence of gastroduodenal mucosal injury. Treatment with FD-APAP did not induce any clinically or statistically significant gastroduodenal mucosal injury.

Squamous Cell Cancer of an Unknown Primary Head and Neck Site: Is Upfront Neck Dissection Still Relevant in the Era of Chemoradiation?

(NPM) is commonly used but often results in incomplete pain control and is associated with its own side effects. Single-institution retrospective reports have provided evidence that prophylactic gabapentin (GP) may reduce the need for NPM in patients undergoing RT, however the ideal dosing schedule is unknown. The purpose of this study was to evaluate whether the use of 300 mg 3 times daily (TID) of GP in a community oncology center will result in reduced need for NPM or reduced weight loss (WL) in patients undergoing RT with or without chemotherapy for oropharyngeal cancer. Materials/Methods: We performed a retrospective chart review of all patients treated with RT for oropharyngeal cancer in our clinic over the last 33 months. From these data, we stratified patients by the use of GP and compared the amount of NPM, the time to initiation of NPM, and the amount of WL between patients who did and did not receive GP. Two-tailed t tests were used to determine significance with a for significance set at P .05. Results: From November 2012 through July 2015, 64 patients with oropharyngeal cancer completed their prescribed RT course and at least 1 month of post-RT follow-up at our institution. Thirty-one patients received GP (at least 300 mg TID) within the first 2 weeks of RT. Patients who received GP had less unintentional WL (9.03 vs 15.82 lbs, PZ.004) and initiated NPM later in their RT course (34.6 vs 22.3 days, P<.001). On subset analysis, patients who underwent upfront surgery and patients with p16-positive disease had less unintentional WL with the use of GP. Oropharyngeal subsite did not influence the effect of GP. No adverse effects were attributed to GP. Conclusion: Patients who initiated at least 300 mg TID of GP within the first 2 weeks of RT for oropharyngeal cancer experienced less WL and a longer time to initiation of NPM compared to those that did not initiate GP. These differences were independent of oropharyngeal subsite. No adverse effects were attributed to GP. Patients who underwent upfront surgery and patients with p16-positive disease derived the greatest benefit from the use of GP. These data support continued exploration of GP use in this patient population. Our institution intends to continue to explore the effect of higher GP dosing in future patients to elucidate potential dose-response relationships. Author Disclosure: T. Dong: None. A. Reed: None. G.C. Jones: None. D. Scoble: None. J. Deeken: None. G.K. Bajaj: None.

Pharmacokinetics of 3 Times a Day Dosing of Oral Treprostinil in Healthy Volunteers

Treprostinil diolamine (oral treprostinil) is an orally available prostacyclin analog that was developed for the treatment of pulmonary arterial hypertension. This study aimed to evaluate the pharmacokinetics (PK), safety, and tolerability of 3 times daily (TID) dosing of oral treprostinil. This was a 9-day, open-label, single-center study in which 19 healthy subjects received 0.5 mg oral treprostinil TID for 7 days. On the morning of day 1, subjects received a single 0.5 mg dose and on days 2-7, subjects received 3 doses of 0.5 mg oral treprostinil with a meal (at approximately 8 AM, 2 PM, and 8 PM). On the morning of day 8, subjects received a final 0.5 mg dose. Intensive 24-hour PK sampling occurred after the AM doses on days 1, 7, and 8. Additional trough plasma samples were collected before the morning and evening doses on days 4, 5, and 6. Nineteen subjects (9 men, 10 women) with a mean age of 35.2 years (range, 20-54 years) were enrolled. The majority of subjects were white (n = 17). The mean (% CVb) Cmax was 0.538 (37%), 0.714 (51%), and 0.559 (45%) ng/mL on days 1, 7, and 8, respectively. After a single dose on day 1 (first dose) and day 8 (last dose), mean (CVb%) AUC0-24 was 2.45 (26%) and 2.96 (28%) h·ng·mL, respectively. The mean (% CVb) steady-state AUC0-24 after TID regimen (on day 7) was 6.53 (34%) h·ng·mL, which was not significantly different from mean AUC0-∞ (7.39 h·ng·mL) on day 1 adjusted for 3 doses. Mean apparent t1/2 was similar on days 1, 7, and 8 (1.1-1.4 hours). Trough concentrations of treprostinil were comparable across study days ranging from 0.046 to 0.053 ng/mL before the AM dose and from 0.27 to 0.39 ng/mL before the evening dose. Steady state was achieved within 2 days of TID dosing. Treprostinil PK after TID dosing of oral treprostinil follows linear kinetics and can be predicted based on PK data after a single dose. Sixteen adverse events occurred in 7 subjects and included prostacyclin related adverse events such as headache, diarrhea, and jaw pain. Three times daily dosing of 0.5 mg oral treprostinil for 7 days was well tolerated in healthy subjects and provided sustained plasma exposure throughout the day at steady state without drug accumulation. This study provides data to support further evaluation of TID dosing regimen of oral treprostinil.

Comparison of QD and TID Oral Mesalazine for Maintenance of Remission in Quiescent Ulcerative Colitis

Mesalazine preparations are widely used to treat mild to moderately severe ulcerative colitis (UC). We compared once-daily administration of oral mesalazine in patients with quiescent UC with the established 3-times-daily prescription, assessing the efficacy and safety of each method in maintaining remission for 52 weeks. This was a double-blind, double-dummy, randomized, multicenter noninferiority study in which 301 patients with quiescent UC were randomly assigned to treatment groups and administered prolonged-release oral mesalazine at doses of 1.5 to 2.25 g/d once daily (QD) or 3 times daily (TID) for 52 weeks. The primary endpoint was whether remission was maintained after 52 weeks of administration or until the time of discontinuation, as represented by the Ulcerative Colitis Disease Activity Index score. The proportion of patients still in remission after 52 weeks of administration was 79.4% in the QD group and 71.6% in the TID group. The between-group difference was 7.8% (2-tailed 95% confidence interval [CI]: -2.2% to 17.8%), and the noninferiority of QD administration to TID administration was verified with a noninferiority margin of -10%. In the safety analysis, the incidence of adverse events in each group was 72.4% for the QD group and 76.5% for the TID group, showing no statistically significant difference between the 2 groups (P = 0.4305). This double-blind parallel-group comparison verified for the first time the noninferiority of QD administration of oral mesalazine 1.5 to 2.25 g/d to TID administration in terms of maintaining remission in patients with UC.

Three-Times-Daily Subcutaneous Unfractionated Heparin and Neuraxial Anesthesia

Subcutaneous (SC) unfractionated heparin (UFH) administered 3 times daily (TID) is widely used for venous thromboembolism prophylaxis in the perioperative period. There are no data in the literature regarding the incidence of adverse outcomes with neuraxial analgesia in the setting of this regimen. In this retrospective review, we report the incidence of untoward events related to anticoagulation with SC UFH TID in patients with indwelling epidural catheters. We queried the electronic hospital databases to identify patients receiving thoracic epidural analgesia in conjunction with 5000 U UFH SC TID from July 2008 to October 2010. In this group, we identified the diagnoses of neuraxial hematoma, deep vein thrombosis, or pulmonary embolism and examined measured blood coagulation parameters. In addition, we determined the percentage of patients receiving concomitant therapy with ketorolac. We identified 928 patients who received thoracic epidural analgesia in conjunction with 5000 U UFH SC TID during this period. There were no cases of neuraxial bleeding. Seven patients had a diagnosed deep vein thrombosis or pulmonary embolism. Thirty-four percent (315/928) of patients received ketorolac. The measured activated thromboplastin time was more than 40 seconds (35 seconds being the upper limit of normal) in 115 patients (12%). Given the rare incidence of neuraxial hematoma, statements regarding the appropriateness of epidural analgesia in the setting of TID SC UFH cannot be made from this limited sample size. At present, information regarding epidural hematoma in the setting of a TID SC UFH dosing regimen does not exist in the literature. Our study represents an initial step in the accumulation of data needed to prove or disprove the safety of this practice.

Medication Adherence and Symptom Reduction in Adults Treated with Mixed Amphetamine Salts in a Randomized Crossover Study

Objectives: The study objectives were to 1) evaluate medication adherence for adults with attention-deficit/hyperactivity disorder (ADHD) treated with 3 times daily (TID) mixed amphetamine salts immediate release (MAS IR) versus once-daily (qAM) MAS extended release (MAS XR) in a randomized, crossover study; and 2) to examine the associations between adherence and efficacy for MAS IR and MAS XR. Methods: Sixty-two adults with ADHD were enrolled and 49 completed the study. The treatment condition order (TID-qAM or qAM-TID) was counterbalanced across participants, with an intervening washout period of ≤ 7 days. Adherence was assessed via 3 measures: 1) self-report, 2) pill count, and 3) the Medication Event Monitoring System (MEMS®). The primary efficacy measure was the ADHD Rating Scale (ADHD-RS); secondary measures included the Time-Sensitive ADHD Symptom Scale (TASS) and Clinical Global Impressions-Severity of Illness (CGI-S) scale. Results: Adherence to treatment as measured by self-report and pill count was not significantly different between MAS XR and MAS IR. Adherence was significantly better for MAS XR than MAS IR for all of the MEMS® measures. The mean change in ADHD-RS, TASS, and CGI-S scores at endpoint was significantly improved for both MAS IR and MAS XR and did not differ significantly between groups. There was not a significant adherence by efficacy interaction. Conclusion: Adults with ADHD adhered equally well with MAS IR as with MAS XR when assessed by pill count and self-report, but not by the MEMS® measures. Both treatments significantly reduced ADHD symptoms, and efficacy was not significantly different between groups. Adherence was not associated with treatment outcome.

Clinical Update: A Nonhealing Fractured Mandible

Bisphosphonates have shown significant clinical benefit in reducing skeletal fractures in patients with multiple myeloma or bone: penicillin VK 500 mg or amoxicillin 500 mg; both 4 times daily (QID) initially and twice daily (BID) for maintenance, If penicillin allergic: 1. Clindamycin 150 to 300 mg QID. 2. Vibramycin 100 mg once daily (QD). 3. Erythromycin ethylsuccinate 400 mg 3 times daily (TID). 4. Antifungals when required: 5. Nystatin oral suspension 5 to 15 mL QID or 100,000 IU/mL. 6. Mycelex troches (clotrimazole 10 mg) x 5/day. 7. Fluconazole 200 mg initially, then 100 mg QD. 8. Other potential systemic antifungals include itraconazole or ketoconazole. 9. Antivirals, if required: 10. Acyclovir 400 mg BID. 11. Valacyclovir hydrochloride 500 mg to 2g BID.

Pregabalin: The Next New Thing

Safety and Efficacy of Two Pregabalin Regimens for Add-on Treatment of Partial Epilepsy Beydoun A, Uthman BM, Kugler AR, Greiner MJ, Knapp LE, Garofalo EA; Pregabalin 1008-009 Study Group Neurology 2005;64:475–480 Objective To evaluate the efficacy, tolerability, and safety of two pregabalin regimens administered as adjunctive therapy to that of placebo in patients with medically refractory partial epilepsy. Methods A multicenter, double-blind, randomized, parallel-group, placebo-controlled trial was performed. After a prospective 8-week baseline phase, patients were randomized to 12 weeks of double-blind treatment with placebo or pregabalin, 600 mg/day, administered twice daily (BID) or 3 times daily (TID). Primary efficacy was measured as change in seizure frequency from baseline of either pregabalin regimen compared with placebo. Secondary efficacy comparisons included the proportion of patients experiencing ≥50% reduction in seizure frequency (responder rate) and median percentage change from baseline in seizure frequency. Safety/tolerability assessments included adverse events (AEs), physical and neurologic examinations, and clinical laboratory evaluation. Efficacy and safety analyses were performed on the intent-to-treat (ITT) population. Results Pregabalin treatment resulted in seizure frequency reductions: 53% for pregabalin TID ( P ≤ 0.0001) and 44% for pregabalin BID ( P ≤ 0.0001) compared with a 1% increase for placebo. Responder rates were 49% for pregabalin TID and 43% for pregabalin BID compared with 9% for placebo ( P ≤ 0.001). Both pregabalin regimens were similar in efficacy and tolerability. The most common AEs were dizziness, somnolence, and ataxia. Conclusions Pregabalin administered at 600 mg/day is safe, generally well tolerated, and efficacious as adjunctive therapy for the treatment of patients with partial seizures, with or without secondary generalizations. This dose can be administered on a twice-daily or 3-times-daily schedule with similar efficacy and tolerability results.

Efficacy And Safety Of Extended-release Acetaminophen Vs Ibuprofen For Treatment Of Ankle Sprains

PURPOSE To compare the efficacy and safety of acetaminophen extended-release (APAP ER) 3900 mg/day with that of ibuprofen (IBU) 1200 mg/day for treatment of signs and symptoms of grade I or II lateral ankle sprain. METHODS This was a multicenter, randomized, double-blind, parallel-group study of 260 patients ≥18 years of age with grade I or II (Leach Classification) lateral ankle sprain. For inclusion, patients had to report a score of ≥40 mm on a 100-mm visual analog scale (VAS) for pain on walking. Patients were stratified according to grade of ankle sprain and randomized to receive APAP ER 1300 mg 3 times daily (TID) or IBU 400 mg TID for 9 days. All patients were instructed to use rest, ice, compression, and elevation. Primary efficacy end point was change from baseline (Day 1) to Day 4 in pain upon walking. Other end points included change from baseline to Day 9 in pain upon walking; change from baseline to Days 4 and 9 in ability to walk and in ankle swelling, bruising, and range of motion; overall satisfaction with treatment at Days 4 and 9; percentage of patients with positive Anterior Drawer Test (ADT) at Day 4; and time to resume normal activity. Efficacy end points involved VAS measurements except ADT and time to resume normal activity. Safety assessments consisted of reported adverse events (AEs). RESULTS Baseline characteristics were similar for all groups. There were no significant differences between treatment groups in any end point (Table). Both study drugs were well tolerated and no serious drug-related AEs were reported.Table: Efficacy end points: least squares mean change from baselineConclusion APAP ER 3900 mg/day was comparable to IBU 1200 mg/day for treatment of grade I or II lateral ankle sprain. Both treatments were well tolerated by patients in the study.