Pharmacokinetics and safety of montelukast oral granules in children 1 to 3 months of age with bronchiolitis.

The single-dose pharmacokinetics of montelukast 4-mg oral granules and tolerability of daily administration of 2 different doses of montelukast (4 mg and 8 mg given once daily for 7 days) versus placebo were evaluated in 12 infants 1 to 3 months of age with bronchiolitis or a history of bronchiolitis and asthma-like symptoms. The population area under the concentration-time curve estimate after a single 4-mg dose of montelukast was 13 195.7 +/- 2309.8 (standard error) ng.hr/mL, 3.6 times higher than historical values in infants 3 to 24 months of age. Six patients had 10 total clinical adverse experiences; none was considered serious or drug related. Three patients had transient drug-related increases in aspartate aminotransferase (montelukast 8 mg [n = 2]; placebo [n = 1]). Despite increased systemic exposure after administration of a single dose of montelukast 4-mg oral granules in infants 1 to 3 months of age compared with that in pediatric patients 3 to 24 months of age, administration of montelukast at 4 and 8 mg once daily for 7 days in 1- to 3-month-old infants was generally well tolerated.

Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes.

Efficacy and tolerability of sitagliptin, a dipeptidyl peptidase-4 inhibitor, were assessed in Japanese patients with type 2 diabetes. In a multicenter, double-blind, randomized, placebo-controlled trial in Japan, 151 patients with inadequate glycemic control [HbA(1c) > or =6.5% to <10%, fasting plasma glucose (FPG) > or =126 to < or =240 mg/dL] were randomized to once-daily sitagliptin 100mg or placebo for 12 weeks. After 12 weeks, the least squares (LS) mean change from baseline HbA(1c) was -0.65% (95% CI: -0.80, -0.50) with sitagliptin versus 0.41% (0.26, 0.56) with placebo [between-group difference=-1.05% (-1.27, -0.84); p<0.001]. LS mean change from baseline FPG was -22.5mg/dL (95% CI: -28.0, -17.0) with sitagliptin versus 9.4 mg/dL (3.9, 14.9) with placebo [between-group difference=-31.9 mg/dL (95% CI: -39.7,-24.1); p<0.001]. More patients achieved HbA(1c) <7% or <6.5% with sitagliptin than with placebo (p<0.001). Following a meal tolerance test, 2-h postprandial glucose was significantly reduced with sitagliptin relative to placebo. Clinical and laboratory adverse experiences were similar between treatments, with no reported hypoglycemia adverse events with sitagliptin. Body weight was unchanged relative to baseline in the sitagliptin group (-0.1 kg), but significantly (p<0.01) different relative to the placebo group (-0.7 kg). In this study, once-daily sitagliptin 100mg for 12 weeks improved fasting and postprandial glycemic control and was generally well tolerated in Japanese patients with type 2 diabetes.

A Comparison of Cardiovascular Biomarkers in Patients Treated for Three Months with Etoricoxib, Celecoxib, Ibuprofen, and Placebo.

OBJECTIVES: Selective cyclooxygenase (COX)-2 inhibitors are effective analgesic and anti-inflammatory agents with improved gastrointestinal safety and tolerability compared with traditional NSAIDs. However, data from long-term, placebo-controlled studies have shown an increased risk of thrombotic cardiovascular (CV) events for COX-2 inhibitors. Changes in levels of CV biomarkers are potentially useful surrogate measures of pathologic changes associated with CV risk. METHODS: We randomized 433 patients with osteoarthritis to etoricoxib 90 mg once daily, celecoxib 200 mg twice daily, ibuprofen 800 mg three times daily, or placebo for 12 weeks. The hypothesis was that etoricoxib would be non-inferior or superior to placebo in effect on C-reactive protein (CRP), LDL-cholesterol, homocysteine, and fibrinogen. RESULTS: Relative to placebo, etoricoxib was noninferior for effect on CRP (decreased 7.8% vs. placebo; 97.5% CI of the difference: -30.5, 22.4), LDL-C (-4.0% vs. placebo; 97.5% CI: -10.6, 3.2), homocysteine (-3.9% vs. placebo; 97.5% CI: -11.6, 4.6), and fibrinogen (-3.7% vs. placebo; 97.5% CI: -9.4, 2.3). Etoricoxib was not different from placebo, celecoxib, or ibuprofen for any biomarker. CONCLUSION: Etoricoxib was comparable to placebo, celecoxib, and ibuprofen for effects on the CV risk markers measured.

Effect of aprepitant on the pharmacokinetics of intravenous midazolam.

Oral aprepitant 125 mg, an antiemetic and a moderate inhibitor of the metabolism of oral midazolam, was assessed for interaction with intravenous midazolam in 12 subjects randomized to intravenous midazolam 2 mg +/- oral aprepitant 125 mg. The hypothesis was that midazolam AUC would not change by more than 2-fold (consistent with no more than weak inhibition) when midazolam + aprepitant was compared with midazolam alone. An AUC geometric mean ratio (midazolam + aprepitant/midazolam) with 90% confidence interval upper bound < or =2.0 (an increase in midazolam felt to be of modest clinical significance in the highly monitored perioperative period) was prespecified. Aprepitant increased intravenous midazolam AUC(0-infinity) 1.47-fold (90% confidence interval, 1.36-1.59), which fell within the prespecified criterion.

Lack of effect of aprepitant on hydrodolasetron pharmacokinetics in CYP2D6 extensive and poor metabolizers.

To prevent chemotherapy-induced nausea and vomiting, aprepitant is given with a corticosteroid and a 5-hydroxytryptamine type 3 antagonist, such as dolasetron. Dolasetron is converted to the active metabolite hydrodolasetron, which is cleared largely via CYP2D6. The authors determined whether aprepitant, a moderate CYP3A4 inhibitor, alters hydrodolasetron pharmacokinetics in CYP2D6 poor and extensive metabolizers. Six CYP2D6 poor and 6 extensive metabolizers were randomized in an open-label, crossover fashion to treatment A (dolasetron 100 mg on day 1) and treatment B (dolasetron 100 mg plus aprepitant 125 mg on day 1, aprepitant 80 mg on days 2-3). For hydrodolasetron area under the concentration-versus-time curve (AUC0-infinity) and peak plasma concentration (Cmax), geometric mean ratios (B/A) and 90% confidence intervals (CIs) fell below the predefined limit (2.0) for clinical significance (AUC0-infinity, 1.09 [90% CI, 1.01-1.18], Cmax, 1.08 [90% CI, 0.94-1.24]). Aprepitant did not affect the pharmacokinetics of hydrodolasetron, regardless of CYP2D6 metabolizer type, and was generally well tolerated when coadministered with dolasetron in volunteers.

A double-blind, dose-response study of losartan in hypertensive children.

BACKGROUND: The aim of this study was to determine the dose-response relationship for losartan, 2.5 to 100 mg, and to assess the safety and tolerability of losartan in hypertensive children 6 to 16 years of age. METHODS: This was a multicenter, randomized, double-blind, dose-response study. In Period 1, a total of 175 patients were stratified by weight (<50 kg and >/=50 kg) and randomized to one of three dose groups by stratum (low, 2.5/5.0 mg; middle, 25/50 mg; or high, 50/100 mg) for 3 weeks. The ratio of the three dose levels for both weight strata was 1:10:20. In Period 2, patients in each dose group were randomized to continue the same treatment or placebo washout for 2 additional weeks. RESULTS: In Period 1, sitting trough diastolic blood pressure (DBP) decreased in a dose-dependent manner (P < .0001). At week 3, changes in DBP from baseline in the low-, middle-, and high-dose groups were -6.0 mm Hg, -11.7 mm Hg, and -12.2 mm Hg, respectively. In Period 2, DBP increased significantly in patients who switched from middle- and high-dose losartan to placebo (mean increase 6.0 mm Hg, P = .003) relative to DBP in patients who remained on active treatment; however, these levels remained stable in those patients who switched from low-dose losartan to placebo (mean increase 1.1 mm Hg, P = .628). CONCLUSIONS: In hypertensive children 6 to 16 years of age, losartan given once daily reduced blood pressure in a dose-dependent fashion. A once-daily starting dose of losartan, 0.75 mg/kg (maximum 50 mg) effectively lowered DBP within 3 weeks. Losartan up to a dosage of 1.44 mg/kg (maximum 100 mg) once daily is generally well tolerated.

Lack of effect of aprepitant on the pharmacokinetics of docetaxel in cancer patients.

BACKGROUND: Aprepitant is a selective neurokinin-1 receptor antagonist that is effective for the prevention of nausea and vomiting caused by highly emetogenic chemotherapy. In vitro, aprepitant is a moderate inhibitor of the CYP3A4 enzyme, which is involved in the clearance of several chemotherapeutic agents. In this study we examined the potential for aprepitant to affect the pharmacokinetics and toxicity of intravenously administered docetaxel, a chemotherapeutic agent that is primarily metabolized by CYP3A4. METHODS: A total of 11 cancer patients (4 male, 7 female, aged 50-68 years) were enrolled in this multicenter, randomized, open-label, two-period, crossover study. Patients received a single infusion of docetaxel monotherapy, 60-100 mg/m(2), on two occasions at least 3 weeks apart. During one of the cycles (treatment A), patients received docetaxel alone. During the alternate cycle (treatment B), they also received aprepitant 125 mg orally 1 h prior to docetaxel infusion (day 1), and a single oral dose of aprepitant 80 mg on days 2 and 3. The pharmacokinetic profile of docetaxel was assessed over 30 h following docetaxel infusion. Blood counts were monitored on days 1, 4, 7, and 14. RESULTS: Ten patients completed the study. Concomitant administration of aprepitant did not cause any statistically or clinically significant changes in docetaxel pharmacokinetics. Values for docetaxel alone (treatment A) versus docetaxel with aprepitant (treatment B) were as follows: geometric mean AUC(0-last) was 3.26 vs 3.17 microg h/ml (P>0.25; ratio B/A 0.97); geometric mean AUC(0-infinity) 3.51 vs 3.39 microg h/ml (P>0.25; ratio B/A 0.96); geometric mean C(max) was 3.53 vs 3.37 microg/ml (P>0.25; ratio B/A 0.95); and geometric mean plasma clearance was 23.3 vs 24.2 l/h/m(2) (P>0.25; ratio B/A 1.04). The corresponding harmonic mean half-life values were 10.1 and 8.5 h. The two treatment regimens had similar tolerability profiles; the median absolute neutrophil count nadirs were 681/mm(3) during treatment with docetaxel alone and 975/mm(3) during aprepitant coadministration. CONCLUSIONS: Aprepitant had no clinically significant effect on either the pharmacokinetics or toxicity of standard doses of docetaxel in cancer patients. Aprepitant at clinically recommended doses may have a low potential to affect the pharmacokinetics of intravenous chemotherapeutic agents metabolized by CYP3A4.