24-hour Dosing Interval Research Articles

Estimated Dose Exposure of the Neonate to Buprenorphine and Its Metabolite Norbuprenorphine via Breastmilk During Maternal Buprenorphine Substitution Treatment

The aim of the present study was to estimate the dose of buprenorphine and its primary metabolite norbuprenorphine that a breastfed infant would receive during maternal maintenance treatment with buprenorphine. Seven pregnant opioid-dependent women taking buprenorphine (median, 7 mg/day; range, 2.4-24 mg) and who intended to breastfeed were recruited. After lactation was established, several milk samples were collected from each subject over a 24-hour dose interval, and buprenorphine and norbuprenorphine concentrations were measured by liquid chromatography-tandem mass spectrometry. The average concentration (C(avg)) across the dose interval was estimated as for both buprenorphine and norbuprenorphine (as buprenorphine equivalents). Absolute infant dose (AID), defined as C(avg) × daily milk intake, and relative infant dose (RID), defined as 100×AID/weight-adjusted maternal daily dose, via milk were calculated, assuming a milk intake of 0.15 L/kg/day. The infant's health and progress were assessed directly and by questionnaire on the study day. Mean (95% confidence interval) norbuprenorphine concentration in milk and AID values (1.94 [0.79-3.08] μg/L and 0.29 [0.12-0.46] μg/kg/day, respectively) were approximately half those for buprenorphine (3.65[1.61-5.7] μg/L and 0.55 [0.24-0.85] μg/kg/day, respectively). Similarly, the mean RID values were 0.18% (0.11-0.25%) for norbuprenorphine and 0.38% (0.23-0.53%) for buprenorphine. The breastfed infants showed no adverse effects, were all in good health, and were progressing as expected. Thus the dose of buprenorphine and norbuprenorphine received via milk is unlikely to cause any acute adverse effects in the breastfed infant.

A Randomized, Open-Label, Crossover Study Evaluating the Effect of Food on the Relative Bioavailability of Linagliptin in Healthy Subjects

Objective The objective of this study was to determine the relative bioavailability of the dipeptidyl-peptidase-4 (DPP-4) inhibitor linagliptin when administered with and without food, in accordance with regulatory requirements to support dosing recommendations for patients. Methods This was a randomized, open-label, crossover study involving 32 healthy white male and female subjects. All subjects received a single dose of 5 mg linagliptin after an overnight fast of at least 10 hours, or immediately after ingestion of a high-fat, high-calorie breakfast. These treatments were separated by a period of 5 weeks. Plasma samples for pharmacokinetic analysis were collected before dosing and at prespecified time points after dosing. The concentration of linagliptin in these samples was analyzed by high-performance liquid chromatography coupled to tandem mass spectrometry. Relative bioavailability was assessed by the total area under the curve between 0 and 72 hours (AUC 0–72) and maximum measured plasma concentration (C max) of linagliptin. Tolerability was also assessed. Results In 32 subjects (mean age, 34.8 years; weight, 74.3 kg; male, 53%; white race, 100%), intake of a high-fat meal resulted in comparable bioavailability with regard to AUC 0–72 (geometric mean ratio [GMR] between the fed and fasted group means was 103.5%; 90% CI, 98.1%–109.2%). Individuals' responses to food ranged from a maximum increase in exposure of 38% to a decrease of 32% relative to the fasted state. The concurrent intake of food increased the time to reach maximum plasma concentration (T max) by approximately 2 hours and reduced C max by about 15% (GMR 84.7%; 90% CI, 75.9%–94.6%). Since adequate drug exposure for inhibition of DPP-4 was still given for the entire 24-hour dosing interval, this result was considered to be of no clinical relevance. Linagliptin was well tolerated during the study. Conclusions Intake of a high-fat meal reduced the rate of linagliptin absorption but had no influence on the extent of absorption; this finding suggests that food has no relevant influence on the efficacy of linagliptin.

Steady-State Pharmacokinetics of Once-Daily Cyclobenzaprine Extended Release: A Randomized, Double-Blind, 2-Period Crossover Study in Healthy Volunteers

Background The single-dose pharmacokinetic profile of cyclobenzaprine extended-release (CER) has been previously characterized and compared with the pharmacokinetics of cyclobenzaprine immediate-release (CIR) administered 3 times daily for 3 doses. Objective The objective of this study was to characterize the multiple-dose pharmacokinetic properties of once-daily CER 30 mg and CIR 10 mg TID formulations in healthy volunteers. Methods In this double-blind, single-center, 2-period crossover study, healthy subjects were randomized to dosing sequences with once-daily CER 30 mg or CIR 10 mg TID for 7 days. Subjects crossed over to the alternative regimen following a 14-day washout period. Pharmacokinetic assessments at steady state included area under the plasma cyclobenzaprine concentration–time curve over the dosing interval (AUC 0–τ,ss), peak plasma cyclobenzaprine concentration (C max,ss), time to observed C max (T max,ss), observed minimum cyclobenzaprine concentration (C min,ss), average cyclobenzaprine concentration (C avg,ss), accumulation ratio (R ac), and terminal elimination half-life (t ½). Tolerability and safety assessments were conducted. Results A total of 36 subjects were randomized; 34 completed both dosing periods (1 subject was lost to follow-up, 1 withdrew consent). Steady state was reached for CER 30 mg on day 7. Mean C max,ss, C min,ss, and C avg,ss were 41.1, 21.4, and 31.4 ng/mL, respectively. The median T max,ss for CER 30 mg was 7.0 hours, with a mean t ½ of 34.8 hours. At steady state, CER produced a sustained plasma cyclobenzaprine concentration with a single peak in plasma concentration during the 24-hour dose interval. The R ac for CER was 2.65. Because of a protocol violation (insufficient data), no steady-state pharmacokinetic assessments could be performed for CIR. Most adverse events were mild or moderate in intensity. Somnolence was the most frequently reported adverse event (100% of subjects) in those receiving CER, followed by dry mouth (58%), dizziness (19%), and headache (17%). Conclusions Once-daily CER 30 mg delivered sustained plasma cyclobenzaprine levels over 24 hours at steady state. Owing to a protocol violation, steady-state pharmacokinetic properties for CIR could not be assessed.

Management of Hypertension in Patients With Diabetes Using an Amlodipine-, Olmesartan Medoxomil-, and Hydrochlorothiazide-Based Titration Regimen

The safety and efficacy of an amlodipine/olmesartan medoxomil (OM)-based titration regimen was assessed in patients with type 2 diabetes mellitus and hypertension. After a 2- to 3-week placebo run-in period, 207 patients received amlodipine 5 mg and were uptitrated to amlodipine/OM 5/20, 5/40, and 10/40 mg and then amlodipine/OM 10/40 mg plus hydrochlorothiazide 12.5 and 25 mg in a step-wise manner at 3-week intervals if the seated blood pressure (BP) remained ≥120/70 mm Hg. The primary end point was the change from baseline in the mean 24-hour ambulatory systolic BP after 12 weeks of treatment. The baseline mean ± SD seated cuff systolic/diastolic BP was 158.8 ± 13.1/89.1 ± 10.1 mm Hg and the mean ± SD 24-hour ambulatory systolic/diastolic BP was 144.4 ± 11.7/81.6 ± 9.8 mm Hg. At week 12, the change from baseline in the mean ± SEM 24-hour ambulatory systolic/diastolic BP was -19.9 ± 0.8/-11.2 ± 0.5 mm Hg (p<0.0001 vs baseline), and 70% of patients had achieved a 24-hour ambulatory BP target of <130/80 mm Hg. At the end of 18 weeks of active treatment in patients uptitrated to amlodipine/OM 10/40 mg plus hydrochlorothiazide 25 mg, the change from baseline in the mean ± SEM seated BP was -28.0 ± 1.5/-13.7 ± 1.0 mm Hg (p<0.0001 vs baseline), with 62% of patients reaching the guideline-recommended seated BP goal of <130/80 mm Hg. Drug-related treatment-emergent adverse events occurred in 19.3% of patients. The most frequent events were peripheral edema (6%), dizziness (3%), and hypotension (2%). In conclusion, this amlodipine/OM-based titration regimen was well tolerated and effectively lowered BP throughout the 24-hour dosing interval in patients with hypertension and type 2 diabetes.

Morning and evening efficacy evaluation of rupatadine (10 and 20 mg), compared with cetirizine 10 mg in perennial allergic rhinitis: a randomized, double-blind, placebo-controlled trial

Background:A circadian rhythm of symptoms has been reported in allergic rhinitis (AR). Severity of all major symptoms of AR, including runny nose, sneezing, and nasal congestion, is typically at its peak in the morning. The objective of this study was to explore the efficacy of the antihistamine and platelet activating factor (PAF) antagonist rupatadine in the morning and evening and to evaluate whether rupatadine provides effective symptom relief throughout the 24-hour dosing interval.Methods:A total of 308 patients ≥18 years of age with PAR was randomly assigned to once-daily rupatadine 10 mg, rupatadine 20 mg, or cetirizine 10 mg for 4 weeks in a placebo-controlled, double-blind study. The main outcome was the morning/evening reflective total symptom score (5TSS) over the treatment period. Secondary endpoints included morning/evening reflective nasal total symptom score (4NTSS), individual symptoms, Pdmax1 as percentage of days with daily severest symptom score ≤1, and subject/investigator evaluation of therapeutic response.Results:All active groups were significantly more effective than placebo in improving morning and evening evaluations of 5TSS (P < 0.001) and 4NTSS (P < 0.001) at 2 or 4 weeks. At morning evaluation, there was a significant reduction from baseline for 5TSS with rupatadine 10 mg (−36.8%, P < 0.01) and 20 mg (−46.3%, P < 0.01) compared with placebo. Similarly, 4NTSS was reduced significantly more with rupatadine 10 mg (−34%, P < 0.05) and 20 mg (−41%, P < 0.01) compared with placebo. In the cetirizine 10 mg group, the reduction was −32.7% and −32.2% for 5TSS and 4NTSS, respectively, but this reduction was not significant compared with placebo. The percentage reduction was greater at evening than at morning evaluation. 5TSS reduction with rupatadine 10 mg (−40.7%, P < 0.05) and 20 mg (−49.9%, P < 0.01) and cetirizine 10 mg (−40.1%, P < 0.05) was significantly better than with placebo. 4NTSS values for active groups were also significantly improved versus placebo. When individual symptoms were assessed, statistically significant differences for rhinorrhea (P < 0.01), nasal itching (P < 0.01), and sneezing (P < 0.01) were shown in all active groups compared with placebo at morning and evening evaluations. Pdmax1 index was significantly improved for all active groups and the overall efficacy assessed by patients or investigators showed a significant improvement (P < 0.01) versus placebo at 2 and 4 weeks. The incidence of somnolence was significantly greater in all active groups versus placebo.Conclusion:The sustained 24-hour action of rupatadine 10 mg provides an effective control of morning and evening symptoms in patients with PAR treated for up to 4 weeks.

Linagliptin

Linagliptin, a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, has a favourable pharmacokinetic profile in terms of its predominantly non-renal elimination. It shows highly selective, potent, dose-dependent inhibition of DPP-4, with ≥ 80% inhibition of DPP-4 throughout the 24-hour dosing interval. In two double-blind, multicentre trials (n >350 evaluable patients/trial) in adult patients with inadequately controlled type 2 diabetes mellitus, oral linagliptin monotherapy (5 or 10 mg once daily) was significantly more effective than placebo in improving glycaemic control and several parameters of pancreatic function, with placebo-corrected adjusted mean changes in glycosylated haemoglobin (HbA(1c)) levels of -0.69% to -0.88% after 12 or 24 weeks. Linagliptin 5 or 10 mg once daily was also significantly more efficacious than voglibose 0.2 mg three times daily in terms of improving glycaemic control in a 26-week, double-blind, multicentre trial (n >450 evaluable patients). In several similarly designed trials (n >250 evaluable patients/trial) of 12-24 weeks' duration in adult patients with inadequately controlled type 2 diabetes, oral linagliptin (5 mg once daily) as add-on therapy to metformin, a sulfonylurea drug or metformin plus a sulfonylurea drug, or in combination with pioglitazone, improved glycaemic control significantly more than placebo plus the respective oral antihyperglycaemic therapy, with improvements in adjusted mean HbA(1c) levels considered clinically relevant. Linagliptin, as monotherapy or in combination with other oral antihyperglycaemic drugs, was generally well tolerated in clinical trials, having neutral or minimal effects on bodyweight and generally being associated with a very low incidence of hypoglycaemia.

Pharmacokinetics and Pharmacodynamics Clinical Pharmacokinetics, Platelet Response, and Safety of Eltrombopag at Supratherapeutic Doses of up to 200 mg Once Daily in Healthy Volunteers

This was a double-blind, placebo-controlled, randomized, parallel, dose-escalation study to assess the pharmacokinetics, platelet response, safety, and tolerability of supratherapeutic doses of eltrombopag (100 mg, 150 mg, and 200 mg once daily) administered for 5 days to 33 healthy adult volunteers. Plasma eltrombopag concentrations accumulated between days 1 and 5, with average increases of 66% to 81% for area under the plasma concentration-time curve from time zero to the end of the 24-hour dosing interval (AUC(0-τ)) and 32% to 45% for maximum observed plasma concentration (C(max)) across doses. After 5 days of dosing, AUC(0-τ) was dose-proportional and C(max) was less than dose-proportional over eltrombopag 100 to 200 mg with slope estimates (90% confidence intervals) of 0.92 (0.45-1.39) and 0.76 (0.29-1.22), respectively. Platelet counts peaked at day 14, and maximum change from baseline platelet count increased dose-dependently, with mean platelet count increases of 14, 67, 107, and 150 Gi/L for placebo and eltrombopag 100 mg, 150 mg, and 200 mg, respectively. There was no notable difference in day 14 mean platelet aggregation between eltrombopag (59 to 74%) and placebo (67%), although this was not tested statistically. There was no notable difference in adverse event frequency across eltrombopag doses. Eltrombopag pharmacokinetics and platelet response were dose-dependent, and doses up to 200 mg/d were well tolerated, with safety profiles similar to placebo.

Why an aspirin a day no longer keeps the doctor away …

Aspirin, which has just celebrated its 111th anniversary, remains one of the most widely used antiplatelet agents worldwide (1). Its high efficacy has made aspirin the cornerstone of treatment in patients suffering from cardiovascular diseases; indeed, daily aspirin therapy reduces the risk of stroke, myocardial infarction and death by approximately 25% (2). Early investigation into aspirin’s pharmacology revealed an asymmetry between its pharmacokinetics and pharmacodynamics (3). Despite aspirin’s short half-life in blood of approximately 30 minutes, once daily aspirin administration in doses as low as 40 mg per day has been shown to induce cumulative, profound and sustained inhibition of platelet function (4). Moreover, there is no clear evidence to suggest that doses higher than 100 mg daily increase aspirin’s antithrombotic efficacy, whereas the bleeding risk associated with taking aspirin appears to be dose-dependent (2). For this reason, a fixed regimen of once daily low-dose aspirin has been adopted into all relevant treatment guidelines. While it is true in most cases that an aspirin a day keeps the doctor away, it would also appear that not all patients benefit from the drug to the same extent as others (5). In this issue of Thrombosis and Haemostasis, Henry et al. have explored whether once daily low-dose aspirin provides sustained inhibition of platelet function throughout the 24-hour dosing interval in 150 stable coronary artery disease (CAD) patients (6). The major finding of the study is that in up to 25% of patients, platelets recover their ability to aggregate within 24 hours of the last aspirin dose, thus potentially leaving patients unprotected against thrombotic events at the end of the dosing interval (6). The study leaves the reader with a number of unanswered questions: (a) what are the underlying mechanisms leading to this uncharacteristically fast recovery of platelet function in some CAD patients taking aspirin daily; and (b) what can be done about it? To answer the first question, one must first consider whether this phenomenon is substantiated. In this regard, it is interesting to note that this is not the first report of significant recovery of platelet function within 24 hours of aspirin administration. Perneby et al. have shown in healthy volunteers that platelets can recover their ability to aggregate within 24 hours of various doses of aspirin ranging from 37.5 mg to 960 mg (7). Recovery of platelet function was also shown in stable CAD patients in a small series of 11 patients on daily aspirin therapy (8). Thus, the study by Henry et al. confirms and extends these findings to a larger CAD population. Taken together, these studies suggest that while aspirin is effective in inhibiting platelet aggregation within one hour of administration (thus eliminating the most common causes of a lack of platelet inhibition by aspirin, such as non compliance, reduced aspirin bioavailability, and drug interactions), this inhibition is not sustained for the whole dosing interval in certain individuals. This of course begs the question why. Aspirin inhibits platelet aggregation by irreversibly acetylating a key enzyme in the conversion of arachidonic acid into thromboxane (Tx) A2, namely cyclooxygenase (COX)-1 (9). As a result, TxA2 formation and consequent platelet aggregation is almost completely abolished throughout the platelet lifespan of 7–10 days, and platelet function is regained by Correspondence to: Dr. Marie Lordkipanidze Centre for Cardiovascular Sciences Institute of Biomedical Research College of Medical and Dental Sciences University of Birmingham Edgbaston, Birmingham B15 2TT, UK Tel: +44 121 415 8680, Fax: +44 121 415 8817 E-mail: m.lordkipanidze@bham.ac.uk

Olmesartan/amlodipine: a review of its use in the management of hypertension

Combination therapy is an effective strategy to increase antihypertensive efficacy in those patients with poor blood pressure (BP) control. In order to achieve BP targets, at least 75% of patients may require combination therapy, and European guidelines advocate this approach, particularly in those patients with a high cardiovascular risk. Evidence from large, randomized controlled trials, and the European hypertension treatment guidelines is supportive of the use of an angiotensin receptor blocker (ARB) with a calcium channel blocker (CCB). Fixed-dose combination formulations of olmesartan medoxomil, an ARB, and the CCB amlodipine are approved in several European countries for patients with essential hypertension. The olmesartan/amlodipine combination has demonstrated greater efficacy than its component monotherapies in reducing BP in patients with mild-to-severe hypertension. Significantly greater reductions in seated diastolic BP were observed between baseline and after eight weeks of treatment with olmesartan/amlodipine, compared with equivalent doses of olmesartan or amolodipine monotherapy (P < 0.001), in the factorial Combination of Olmesartan Medoxomil and Amlodipine Besylate in Controlling High Blood Pressure (COACH) trial. About 85% of the maximal BP reductions after the 8-week treatment period were already observed after two weeks. Uptitration as necessary, with or without hydrochlorothiazide, allowed the majority of patients to achieve BP control in a 44-week open-label extension treatment period to the COACH trial. The use of olmesartan/amlodipine allowed up to 54% of patients, with previously inadequate responses to amlodipine or olmesartan monotherapy, to achieve their BP goals. Data from post-registration studies using tight BP control and forced titration regimens have further demonstrated the high efficacy of olmesartan/amlodipine in achieving BP goal rates. Moreover, consistent reductions in BP were observed over the 24-hour dosing interval using ambulatory measurements. Olmesartan/amlodipine was generally well tolerated over the short- and long-term, with a lower frequency of peripheral edema with olmesartan/amlodipine 40/10 mg than with amlodipine 10 mg monotherapy.

Estimation ofrac-Amisulpride Transfer into Milk and of Infant Dose via Milk During Its Use in a Lactating Woman with Bipolar Disorder and Schizophrenia

This case describes the transfer of the antipsychotic drug amisulpride into milk and the estimation of infant exposure via breastfeeding. The dyad investigated was a 28-year-old lactating woman and her 13-month-old daughter. The woman had been taking 400 mg of amisulpride daily for 9 days and provided eight milk samples and one blood sample over a 24-hour dose interval. Amisulpride concentrations in these samples were measured by high-performance liquid chromatography, and infant dose was calculated by standard methods. The infant's health and progress were evaluated by a neonatal pediatrician. Transfer of amisulpride into milk was high, with a milk:plasma distribution ratio of 19.5 (5,188 μg/L in milk and 266 μg/L in plasma). The average amisulpride concentration in milk was 3,562 μg/L, which, when multiplied by an average milk intake of 0.15 L/kg/day, gave an absolute infant dose of 534 μg/kg/day. The relative infant dose was 10.7% of the maternal weight-adjusted dose (5,000 μg/kg/day), which is slightly above the usual 10% safety recommendation. The infant was in good health with an appropriate Denver development score for her age. She showed no acute drug-related adverse effects. Given that the infant had already benefited from 13 months of breastfeeding, that amisulpride has potential adverse effects, and that its relative infant dose was 10.7%, we recommended cessation of breastfeeding in the near-term.

Once- vs Twice-Daily Budesonide/Formoterol in 6- to 15-Year-Old Patients With Stable Asthma

To assess efficacy/tolerability of once-daily budesonide/formoterol pressurized metered-dose inhaler (pMDI) versus budesonide pMDI (primary) and twice-daily budesonide/formoterol (secondary) in children/adolescents with asthma stabilized with twice-daily budesonide/formoterol. This 12-week multicenter, double-blind randomized controlled study (www.clinicaltrials.gov identifier NCT00646321) included 521 patients aged 6 to 15 years with mild/moderate persistent asthma. Patients stabilized during a 4- to 5-week run-in with twice-daily budesonide/formoterol pMDI 40/4.5 microgx2 inhalations (160/18 microg daily) received twice-daily budesonide/formoterol pMDI 40/4.5 microgx2 inhalations (160/18 microg daily), once-daily budesonide/formoterol pMDI 80/4.5 microgx2 inhalations (160/9 microg daily; evening), or once-daily budesonide pMDI 80 microgx2 inhalations (160 microg daily; evening). Once- or twice-daily budesonide/formoterol was more effective than budesonide for evening peak expiratory flow (primary variable) at the end of the 24-hour once-daily dosing interval (P<or=.027). Twice-daily budesonide/formoterol demonstrated better efficacy versus once-daily treatments for evening predose forced expiratory volume in 1 second (P<or=.011), versus budesonide for daytime/nighttime rescue medication (P<or=.023), and versus once-daily budesonide/formoterol for daytime rescue medication (last 12 hours of once-daily dosing) (P=.032). There were no significant between-group differences for daytime/nighttime asthma symptoms, nighttime awakenings attributed to asthma, or health-related quality of life. Fewer patients experienced asthma worsening (predefined criteria) with twice-daily budesonide/formoterol (8.2%) versus once-daily budesonide (15.5%) (P=.036) or once-daily budesonide/formoterol (19.6%) (P=.002). All treatments were well tolerated. Once-daily budesonide/formoterol demonstrated significantly better efficacy than once-daily budesonide for most pulmonary-function variables. Twice-daily budesonide/formoterol (160/18 microg daily) maintenance therapy was generally more effective than stepping down to once-daily dosing (160/9 microg daily). Treatments were well tolerated, and there was no evident safety benefit for once- versus twice-daily dosing.

Saxagliptin and metformin XR combination therapy provides glycemic control over 24 hours in patients with T2DM inadequately controlled with metformin

Objective:To assess 24-hour glycemic control with saxagliptin compared with placebo as add-on treatment to metformin in patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control.Research design and methods:This was a 4-week, multicenter, randomized, double-blind, placebo-controlled Phase IIIb trial comparing the antihyperglycemic activity of saxagliptin 5 mg once daily in combination with a stable dose of metformin extended release (XR) vs. placebo in combination with metformin XR in patients with T2DM inadequately controlled (screening glycated hemoglobin [HbA1c] 7–10%) with stable doses of metformin immediate release or metformin XR ≥ 1500 mg/day. Ninety-three adult patients were randomized and received treatment. The primary outcome measure was change from baseline to week 4 in 24-hour mean weighted glucose (MWG).Results:The reduction from baseline in 24-hour MWG was significantly greater for saxagliptin 5 mg + metformin XR (−13.8 mg/dL; −0.77 mmol/L) compared with placebo + metformin XR (3.0 mg/dL; 0.17 mmol/L) (p = 0.0001). At week 4, the mean decrease in plasma glucose was sustained through a 24-hour period in saxagliptin-treated patients. Treatment with saxagliptin 5 mg + metformin XR resulted in significant mean reductions from baseline in 4-hour mean weighted postprandial glucose (PPG), 2-hour PPG, 3-day average mean daily glucose, and fasting plasma glucose levels compared with placebo + metformin XR (p ≤ 0.001). The proportion of adverse events (AEs) was similar in the two treatment groups, with no reported hypoglycemic AEs in saxagliptin-treated patients. The 4-week evaluation period may have been insufficient to evaluate longer term effects on hyperglycemia or to identify additional AEs.Conclusions:In patients with T2DM treated with metformin XR, saxagliptin 5 mg orally administered once daily in the evening for 4 weeks effectively lowered plasma glucose concentrations through the 24-hour dosing interval and was well tolerated.

Efficacy of amlodipine and olmesartan medoxomil in patients with hypertension: the AZOR Trial Evaluating Blood Pressure Reductions and Control (AZTEC) study

The aim of the present study was to use ambulatory blood pressure (BP) monitoring (ABPM) to determine the efficacy of a fixed-dose combination of amlodipine (AML) and olmesartan medoxomil (OM) over the 24-hour dosing interval. This 12-week, titrate-to-goal study was conducted in 185 patients with hypertension. Patients were initially treated with AML 5 mg/ day and uptitrated to AML/OM 5/20, 5/40, and 10/40 mg/day every 3 weeks if mean seated BP (SeBP) was ≥ 120/80 mmHg. The primary efficacy endpoint was the change from baseline in mean 24-hour systolic BP at week 12 as assessed by ABPM. At baseline, the mean 24-hour ambulatory BP (± standard deviation [SD]) was 144.8 ± 11.1/85.7 ± 7.9 mmHg. At week 12, the change from baseline in mean 24-hour ambulatory BP (± standard error of the mean [SEM]) was -21.4 ± 0.8/-12.7 ± 0.5 mmHg (p < 0.0001 versus baseline). At baseline, the mean SeBP (± SD) was 158.2 ± 12.6/92.8 ± 8.6 mmHg and at week 12, the mean SeBP change (± SEM) from baseline (last observation carried forward) was -24.1 ± 1.1/-12.1 ± 0.7 mmHg (p < 0.0001 versus baseline). Proportions of patients achieving mean 24-hour ambulatory BP prespecified study targets were 70.9% (<130/80 mmHg), 48.3% (<125/75 mmHg), and 40.7% (<120/80 mmHg). Cumulatively, 76.8% of patients uptitrated to AML/OM 10/40 mg/day attained an SeBP goal of <140/90 mmHg. The study drug was well tolerated with few adverse events (peripheral edema, 2.2%; dizziness, 1.1%). An AML/OM-based titration regimen effectively reduces BP in patients with hypertension.

Comparison of Steady-State Plasma Concentrations of Armodafinil and Modafinil Late in the Day Following Morning Administration

Armodafinil, the R- and longer-lasting isomer of modafinil, may maintain higher plasma drug concentrations compared with racemic modafinil because of stereospecific differences in elimination of its isomers. This analysis set out to compare the steady-state pharmacokinetic profiles of armodafinil and modafinil on a milligram-to-milligram basis following once-daily administration. A post hoc analysis of two multiple-dose pharmacokinetic studies in healthy male subjects aged 18-50 years was conducted to compare dose-normalized (200 mg/day) plasma drug concentration and pharmacokinetic data for subjects in each study who completed 7 days of once-daily (morning) administration of armodafinil (n = 34) or modafinil (n = 18). Dose-normalized plasma concentrations of armodafinil on day 7 were higher than those of modafinil, with the greatest differences being observed later in the day. Across the 24-hour dose interval, plasma drug concentration fluctuation and swing were 28% and 42% less, respectively, with armodafinil than with modafinil. In addition, average late-day (3 pm to 7 pm after an 8 am dosing) plasma drug concentrations and partial values for the area under the plasma concentration versus time curve for 7-11 hours after dosing were both 44% higher with armodafinil. At steady state, armodafinil produces consistently higher plasma drug concentrations late in the day than modafinil when compared on a milligram-to-milligram basis. The distinct pharmacokinetic profile of armodafinil compared with that of the racemate may result in fundamentally different durations of action. These differences between the two medications cannot be made equivalent by increasing the dose of the racemate without introducing potential safety concerns.

The Effects of an Olmesartan Medoxomil–Based Treatment Algorithm on 24‐Hour Blood Pressure Levels in Elderly Patients Aged 65 and Older

This study examined the effect of olmesartan medoxomil (OM) +/- hydrochlorothiazide (HCTZ) on mean 24-hour ambulatory blood pressure, mean seated cuff (Se) blood pressure (BP), and SeBP goal achievement in elderly (65 years and older) patients with hypertension. After a 2- to 3-week placebo run-in period, patients received OM 20 mg, up-titrated to OM 40 mg, and then added HCTZ 12.5 mg to 25 mg in a stepwise manner at 3-week intervals if SeBP remained >or=120/70 mm Hg. The primary end point was change from baseline in mean 24-hour ambulatory systolic BP. At study end, mean 24-hour ambulatory BP had decreased by 25.7/12.3 mm Hg (n=150) and mean SeBP by 25.4/10.5 mm Hg (n=176; all P<.00001 vs baseline). Drug-related treatment-emergent adverse events, most commonly dizziness (3.4%), hypotension (2.2%), and headache (1.1%), were observed in 11.8% of patients. An OM-based treatment algorithm effectively lowers BP in an elderly patient population throughout the 24-hour dosing interval without compromising tolerability.

Safety, Efficacy, and Pharmacokinetic Overview of Low-Dose Daily Administration of Tadalafil

Several phosphodiesterase type 5 (PDE5) inhibitors are commercially available for the treatment of erectile dysfunction (ED). Development of the first once-daily alternative dosing regimen with a PDE5 inhibitor was motivated by the behavioral complexities associated with sexual intimacy. To provide an alternative dosing option for certain men who may benefit from the removal of the temporal linkage between administration of an ED therapy and sexual intimacy or for men and their partners who anticipate at least twice-weekly sexual activity. Pharmacokinetic predictions of tadalafil plasma concentrations were generated based upon empirical data following 20-mg, single-dose administration coupled with tadalafil usage patterns from as-needed clinical trials. To support the pharmacokinetic simulations and pharmacodynamic assumptions, clinical trials were conducted to demonstrate the efficacy and safety of once-daily, low-dose tadalafil 2.5 and 5 mg. Simulated tadalafil plasma concentrations and comparison with safety and efficacy measures from clinical trials. Based upon pharmacodynamic and pharmacokinetic data, once-daily doses of tadalafil 5 mg were predicted to provide therapeutic concentrations that would be maintained throughout the 24-hour dosing interval. Additionally, for a subgroup of men who anticipate at least twice-weekly sexual activity and are currently taking tadalafil 20 mg, a reduction in daily tadalafil exposure was predicted. To support the hypothesis that low-dose, once-daily tadalafil may be a safe and effective treatment alternative, clinical trials were conducted to demonstrate the safety and efficacy of once-daily tadalafil 2.5 and 5 mg. These results were similar to those of historical as-needed studies evaluating tadalafil 10 and 20 mg. Consistent with pharmacokinetic predictions, data from clinical trials indicate that once-daily use of low-dose tadalafil is a safe and effective treatment for men with ED.

Major Depressive Disorder and Patient Satisfaction in Relation to Methadone Pharmacokinetics and Pharmacodynamics in Stabilized Methadone Maintenance Patients

Many patients enrolled in methadone maintenance treatment experience significant interdose opioid withdrawal. Mood states have been related to patient satisfaction with treatment and may influence how methadone patients experience opioid withdrawal. The objective of this study was to investigate the influence of major depressive disorder on response to methadone in patients on methadone maintenance treatment. Seventeen methadone patients (7 depressed and 10 not depressed) had pharmacokinetic and pharmacodynamic assessments (opioid withdrawal, drug effects, and mood) over one 24-hour dosing interval. Subjects were also divided based on their satisfaction with methadone treatment: 12 holders and 5 nonholders. Depressed subjects experienced more dysphoric opioid effects as measured by the Addiction Research Centre Inventory (area under the effect versus time curve, 14 +/- 32 vs -31 +/- 47, P < 0.04) and had higher scores on the Subjective Opioid Withdrawal Scale (area under the effect versus time curve, 33 +/- 97 vs -74 +/- 67, P < 0.02) over the dosage interval. Hamilton Depression scores significantly correlated with trough subjective opioid withdrawal scale scores (r = 0.7, P < 0.004). Nonholders had significantly higher exposure to unbound (S)-methadone compared with holders, specifically: trough concentration (6.1 +/- 2.7 ng/mL vs 2.7 +/- 1.7 ng/mL, P < 0.01), average steady-state concentration (7.6 +/- 4.0 ng/mL vs 4.1 +/- 2.5 ng/mL, P < 0.05), maximum concentration (14.6 +/- 7.1 ng/mL vs 7.5 +/- 4.2 ng/mL, P < 0.04), and area under the curve (183 +/- 95 h*ng/mL vs 99 +/- 61 h*ng/mL, P < 0.05). Study findings suggest that (S)-methadone may relate to patients' dissatisfaction with methadone treatment. Depressed methadone patients may be more sensitive to negative opioid effects and opioid withdrawal.

Pharmacokinetics, pharmacodynamics, and tolerability of the dipeptidyl peptidase IV inhibitor LC15-0444 in healthy Korean men: A dose—block-randomized, double-blind, placebo-controlled, ascending single-dose, phase I study

Background: LC15-0444 is a selective inhibitor of dipeptidyl peptidase (DPP) IV under investigation in Korea for the treatment of type 2 diabetes.Objective: The aim of this study was to investigate the pharmacokinetic (PK), pharmacodynamic (PD), and tolerability profiles of a single dose of LC15-0444 in healthy male subjects.Methods: A dose—block-randomized, double-blind, placebo-controlled, ascending single-dose, Phase I study was performed in healthy Korean male subjects assigned to receive 25, 50, 100, 200, 400, or 600 mg of LC15-0444 capsules. Blood and urine samples were collected up to 72 hours after administration. Plasma and urine drug concentrations were determined by tandem mass spectrometry coupled with high-performance liquid chromatography. DPP IV activity was measured by continuous spectrophotometric assay. An additional food effect study was performed in the 100-mg dose group; changes in PK and PD parameters after highfat diet were evaluated. Adverse events (AEs) were detected through investigator inquiries, spontaneous reports, and clinical evaluations such as physical examinations, vital sign measurements, 12-lead electrocardiography, clinical laboratory tests (eg, hematology, blood chemistry, coagulation, urinalysis), and computerized impedance cardiography.Results: Sixty Korean men (mean age, 25.3 years [range, 19-39 years]; weight, 68.3 kg [range, 53.6-84.9 kg]) were enrolled, providing 10 subjects for each dose group. After administration, LC15-0444 reached Tmax at 0.5 to 5.1 hours, and was eliminated with a t½ of 16.7 to 21.3 hours. The mean fraction of unchanged drug excreted in urine ranged from 0.21 to 0.34 and mean renal clearance was 15.5 to 23.6 L/h. The dose-normalized AUC exhibited dose-linearity over the range of 50 to 400 mg. All doses of LC15-0444 =200 mg were found to inhibit 80% of DPP IV activity for 24 hours. High-fat diet did not significantly influence the AUC of LC15-0444. LC15-0444 was generally well tolerated. None of the subjects developed any serious clinical or laboratory AEs or discontinued the study due to an AE. All AEs were mild or moderate, and no dose-related trends were observed. Fortysix AEs were reported in 18 subjects (30.0%). AEs considered to be related to the study drug were headache (6 cases), dizziness (2), nausea (1), epistaxis (1), and increased heart rate (1). All AEs resolved spontaneously.Conclusions: A single dose of LC15-0444 exhibited linear PK properties over the range of 50 to 400 mg in these healthy Korean male subjects. PK characteristics were not significantly influenced by food. In addition, doses ≥200 mg of LC15-0444 inhibited plasma DPP IV activity by >80% over a 24-hour dosing interval, and a 600-mg dose increased active glucagon-like peptide-1 levels after a standardized meal. LC15-0444 was generally well tolerated.

Once-daily Dosing of Gentamicin in Obstetrics and Gynecology

Gentamicin, an aminoglycoside with broad antimicrobial activity, is commonly used in both obstetrics and gynecology. Traditional dosing regimens for gentamicin have called for 3 times daily dosing, but recent insights into the pharmacodynamics of the drug have led to multiple studies of once-daily dosing regimens. Many studies have demonstrated efficacy, safety, and economy of the 24-hour dosing interval, resulting in recommendations that this become the standard for aminoglycoside administration. However, because of the unique considerations for drug administration in pregnant and postpartum women, the once-daily dosing regimens have not been widely adopted. Additional studies in pregnant and postpartum women have demonstrated therapeutic noninferiority, no increase in adverse events, and significant cost savings with once-daily dosing versus 3 times daily dosing of gentamicin. We review the literature and present rationale based on multiple controlled studies supporting single-daily dosing of gentamicin, 5 mg/kg/d actual body weight, for many common obstetrics-gynecology infections.

Olmesartan Medoxomil

Olmesartan medoxomil (Olmetec, Benicar) is an angiotensin II type 1 (AT(1)) receptor antagonist (angiotensin receptor blocker [ARB]) that inhibits the actions of angiotensin II on the renin-angiotensin-aldosterone system, which plays a key role in the pathogenesis of hypertension. Oral olmesartan medoxomil 10-40 mg once daily is recommended for the treatment of adult patients with hypertension. In those with inadequate BP control using monotherapy, fixed-dose olmesartan medoxomil/hydrochlorothiazide (HCTZ) [Olmetec plus, Benicar-HCT] combination therapy may be initiated. Extensive clinical evidence from several large well designed trials and the clinical practice setting has confirmed the antihypertensive efficacy and good tolerability profile of oral olmesartan medoxomil, as monotherapy or in combination with HCTZ, in patients with hypertension, including elderly patients with isolated systolic hypertension (ISH). Notably, BP control is sustained throughout the 24-hour dosage interval, including during the last 4 hours of this period. In clinical trials, olmesartan medoxomil monotherapy provided better antihypertensive efficacy than losartan, candesartan cilexetil or irbesartan monotherapy, and was at least as effective as valsartan treatment, with a faster onset of action than other ARBs in terms of reductions from baseline in diastolic BP (DBP) and, in most instances, systolic BP (SBP). Combination therapy with olmesartan medoxomil plus HCTZ was superior to that with benazepril plus amlodipine, as effective as that with losartan plus HCTZ, noninferior to that with atenolol plus HCTZ, but less effective than that with telmisartan plus HCTZ, in individual trials. Data from ongoing clinical outcome trials are required to more fully determine the relative position of olmesartan medoxomil therapy in the management of hypertension. In the meantime, the consistent antihypertensive efficacy during the entire 24-hour dosage interval and good tolerability profile of olmesartan medoxomil, with or without HCTZ, make it a valuable option for the treatment of adult patients with hypertension, including the elderly.