Jerry M. Herron

Safety and Tolerability of Once-Daily Mometasone Furoate Aqueous Nasal Spray in Children

Sensitive and reproducible assessments of hypothalamic-pituitary-adrenal (HPA) axis function were used to assess the systemic exposure and tolerability of mometasone furoate aqueous nasal spray (MFNS) in 96 children aged 3 to 12 years with allergic rhinitis. In the first phase of the study, older children (aged 6 to 12 years) received MFNS at 50, 100, or 200 micrograms or placebo once daily for 7 days, and plasma cortisol concentrations were measured by radioimmunoassay before and after treatment. Plasma cortisol concentrations were not statistically significantly different from baseline values on day 7 or day 8 (1 day after treatment was stopped). Also, the mean plasma cortisol and 24-hour urinary free-cortisol concentrations of the MFNS-treated and placebo groups were not statistically significantly different. Additionally, mometasone furoate was undetectable in almost all plasma samples collected at 0.5, 1, and 2 hours after dosing on days 1 and 7. Because these findings indicated that MFNS could be safely administered to patients aged 6 to 12 years, a more rigorous assessment was conducted in younger patients (aged 3 to 5 years). The younger patients also received MFNS at 50, 100, or 200 micrograms or placebo once daily, but for a longer duration (14 days). HPA axis function was determined by the response to cosyntropin stimulation on the final day of treatment. The younger patients demonstrated a normal cortisol response to cosyntropin stimulation on day 14; that is, all the patients had an increase in plasma cortisol concentration of at least 7 micrograms/dL to at least 18 micrograms/dL. Mean plasma cortisol concentrations for the MFNS-treated groups were not statistically significantly different from the mean concentration for the placebo group, either before or after cosyntropin stimulation. MFNS was also found to be well tolerated by both the younger and older children, with headache the most frequently reported adverse event in both the placebo- and MFNS-treated groups. No clinically relevant changes in the results of physical examinations, clinical laboratory determinations, or electrocardiography were noted. These results indicate that the intranasal administration of up to 200 micrograms of MFNS once daily for up to 14 days in children aged 3 to 12 years who have allergic rhinitis is well tolerated and does not result in clinically relevant systemic exposure.

Effects of Age, Gender, and Race/Ethnicity on the Pharmacokinetics of Posaconazole in Healthy Volunteers

ABSTRACT Posaconazole is a triazole antifungal for prophylaxis of invasive fungal infection and treatment of oropharyngeal candidiasis. We evaluated the effects of gender, age, and race/ethnicity (black or white) on the steady-state pharmacokinetics of posaconazole in two studies on healthy adult subjects (≥18 years of age). Additionally, we explored the effect of P-glycoprotein expression and MDR1 genotype on posaconazole pharmacokinetics in black and white subjects. Age, gender, and race/ethnicity had no clinically relevant effects on posaconazole pharmacokinetics. No association was observed between any MDR1 single-nucleotide polymorphism and the area under the concentration-time curve for posaconazole. Posaconazole was safe and well tolerated regardless of age, gender, or race/ethnicity. In conclusion, age, gender, and race/ethnicity have no clinically relevant effects on the steady-state pharmacokinetics of posaconazole in healthy adults; therefore, dosage adjustments based on these covariates are unnecessary.

Desloratadine Has No Clinically Relevant Electrocardiographic or Pharmacodynamic Interactions with Ketoconazole

AbstractObjective: This study was performed to assess the electrocardiographic safety and pharmacokinetics of desloratadine in combination with the CYP3A4 inhibitor ketoconazole. Design: A randomised, placebo-controlled, third-party—blind, 2-way crossover study. Participants: 24 healthy volunteers (12 men, 12 women; age 19 to 50 years). Interventions: 7.5mg of desloratadine orally per day in combination with placebo or with 200mg of ketoconazole every 12 hours for 10 days. After a minimum 7-day washout period, participants received the alternative treatment. Main outcome measures: ECG parameters. Results: Comparable maximum corrected QT (QTc) intervals were observed after coadministration of desloratadine and placebo or ketoconazole (431 and 435 msec, respectively). The desloratadine/ketoconazole combination did not induce any statistically significant or clinically relevant changes in QTc, QT, PR or QRS intervals compared with desloratadine alone; ventricular rate was slightly slower when desloratadine was given with ketoconazole. At steady state, coadministration of ketoconazole resulted in no significant change in area under the desloratadine concentration-time curve (AUC) from 0 to 24 hours compared with desloratadine/placebo. Coadministration of desloratadine and ketoconazole resulted in a 1.3-fold increase in desloratadine maximum concentration (Cmax) that was not clinically relevant. The most common adverse event was headache, reported in 42 and 38% of individuals, respectively, after coadministration of desloratadine/placebo and desloratadine/ketoconazole. There were no reports of dizziness or syncope. Conclusion: Coadministration of desloratadine and ketoconazole was well tolerated and was associated with minimal increase in AUC and Cmax. The combination did not induce any clinically relevant electrocardiographic changes.

Lack of hypothalamic-pituitary-adrenal axis suppression with once-daily or twice-daily beclomethasone dipropionate aqueous nasal spray administered to patients with allergic rhinitis

The potential for a newly developed, double-strength (0.084%) beclomethasone dipropionate (BDP) aqueous (AQ) nasal suspension to produce effects associated with exposure to systemic corticosteroids was assessed by the plasma cortisol response to cosyntropin stimulation induced by a 6-hour intravenous infusion of 250 micrograms of cosyntropin in 500 mL of normal saline. Sixty-four patients with allergic rhinitis were enrolled in this study. Patients were randomly assigned to one of the following four treatment groups: (1) BDP AQ Forte (0.084%) nasal spray 336 micrograms once daily; (2) BDP AQ (0.042%) nasal spray 168 micrograms twice daily; (3) placebo nasal spray twice daily; or (4) oral prednisone 10 mg once daily in the morning. After 36 consecutive days of treatment, there was a significant (P < 0.01) difference in the plasma cortisol response to cosyntropin stimulation between the prednisone and placebo groups; however, there were no significant differences between the BDP AQ Forte or the BDP AQ groups compared with the placebo group. Secondary analyses comparing BDP AQ Forte administered as 336 micrograms once daily with BDP AQ administered as 168 micrograms twice daily showed no significant differences in plasma cortisol responses to cosyntropin stimulation. No serious adverse events were reported. Adverse events consisted of headache, pharyngitis, or nasal irritation, with headache being reported most frequently. These adverse events were similarly distributed among active treatment groups and were similar to placebo. No clinically relevant changes were observed in any treatment group in findings on clinical laboratory tests, physical examination, or electrocardiography. Vital signs, obtained daily, were consistent with values observed in healthy individuals. No patient exhibited signs of oral candidiasis. All patients met the plasma cortisol concentration criteria for discharge relative to expected hypothalamic-pituitary-adrenal axis function. In conclusion, there were no significant differences in plasma cortisol responses to cosyntropin stimulation between groups of patients with allergic rhinitis treated with either BDP AQ Forte (0.084%) nasal spray 336 micrograms once daily or BDP AQ (0.042%) nasal spray 168 micrograms twice daily compared with the placebo group. These results indicate that the dosing regimens of BDP AQ nasal suspensions used in this study lack systemic effects and are safe and well tolerated.

The pharmacokinetics, electrocardiographic effects, and tolerability of loratadine syrup in children aged 2 to 5 years

OBJECTIVE We assessed the pharmacokinetics and tolerability of 5 mg loratadine syrup (1 mg/mL) in children aged 2 to 5 years. METHODS Two studies were undertaken. A single-dose, open-label bioavailability study was performed to characterize the pharmacokinetic profiles of loratadine and its metabolite desloratadine. Plasma concentrations of loratadine and desloratadine were determined at 0, 1, 2, 4, 8, 12, 24, 48, and 72 hours after a single administration of 5 mg loratadine syrup to 18 healthy children (11 male, 7 female; 12 black, 5 white, 1 other; mean age +/- SD, 3.8 +/- 1.1 years; mean weight +/- SD, 17.4 +/- 4.4 kg). In addition, a randomized, double-blind, placebo-controlled, parallel-group study was performed to assess the tolerability of 5 mg loratadine syrup after multiple doses. Loratadine (n = 60) or placebo (n = 61) was given once daily for 15 days to children with a history of allergic rhinitis or chronic idiopathic urticaria. In the loratadine group, 27 boys and 33 girls (52 white, 8 black) were enrolled, with a mean age +/- SD of 3.67 +/- 1.13 years and a mean weight +/- SD of 17.2 +/- 3.8 kg. In the placebo group, 27 boys and 34 girls (53 white, 7 black, 1 Asian) were enrolled, with a mean age +/- SD of 3.52 +/- 1.12 years and a mean weight +/- SD of 17.3 +/- 2.9 kg. Tolerability was assessed based on electrocardiographic results, occurrence of adverse events, changes in vital signs, and results of laboratory tests and physical examinations. RESULTS The peak plasma concentrations of loratadine and desloratadine were 7.78 and 5.09 ng/mL, respectively, observed 1.17 and 2.33 hours after administration of loratadine; the areas under the plasma concentration-time curve to the last quantifiable time point for loratadine and desloratadine were 16.7 and 87.2 ng x h/mL, respectively. Single and multiple doses were well tolerated, with no adverse events occurring with greater frequency after multiple doses of loratadine than after placebo. Electrocardiographic parameters were not altered by loratadine compared with placebo. There were no clinically meaningful changes in other tolerability assessments. CONCLUSION Loratadine was well tolerated in this small, selected group of children aged 2 to 5 years at a dose providing exposure similar to that with the adult dose (ie, 10 mg once daily).

Pharmacokinetics/Pharmacodynamics of Desloratadine and Fluoxetine in Healthy Volunteers

The authors assessed the potential for a pharmacokinetic/pharmacodynamic interaction between desloratadine and fluoxetine. This randomized, placebo‐controlled, open‐label study was conducted in 54 healthy volunteers. Subjects received 1 of 3 treatments: desloratadine 5 mg plus fluoxetine 20 mg, desloratadine 5 mg plus placebo, or fluoxetine 20 mg plus placebo. Serial electrocardiograms (ECGs) were performed at baseline and day 35. Treatment effects on Cmax and AUC were assessed. During coadministration of desloratadine with fluoxetine, the ratio of the mean log‐transformed Cmax and AUC values for desloratadine following concomitant fluoxetine therapy revealed a small increase in Cmax values of 15% (90% confidence interval [CI], 95%–139%) but no increase for AUC values (90% CI, 82%–123%). Corresponding values for 3‐OH desloratadine demonstrated small increases in mean log‐transformed Cmax and AUC ratios: 17% (90% CI, 100%–136%) and 13% (90% CI, 96%–132%), respectively. Statistical evaluation of the ratio of the mean Cmax and AUC values for fluoxetine following concomitant desloratadine therapy revealed small decreases of 9% (90% CI, 72%–115%) and 11% (90% CI, 69%–113%), respectively. Corresponding values for norfluoxetine demonstrated modest increases in mean log‐transformed Cmax and AUC ratios: 22% (90% CI, 100%–139%) and 18% (90% CI, 101%–136%), respectively. Coadministration of desloratadine with a potent inhibitor of CYP2D6 did not result in clinically relevant changes in its pharmacokinetic parameters. Desloratadine administration was not associated with clinically important changes in the pharmacokinetics of fluoxetine, a drug metabolized by CYP2D6. The most common adverse event in all groups was headache (65%). Desloratadine plus fluoxetine caused no significant changes in ECGs or ventricular rate.

Desloratadine Demonstrates Dose Proportionality in Healthy Adults After Single Doses

AbstractObjective: To evaluate the dose proportionality and linearity and pharmacokinetic profile of desloratadine after single oral doses over the range of 5 to 20mg. Design: Single centre, randomised, open-label, 4-way crossover study in which healthy adults received single doses of desloratadine (5, 7.5, 10 and 20mg) in 4 different treatment periods. Desloratadine was administered each morning after a 10-hour fast. A washout period of at least 14 days separated each dose. Plasma concentrations were measured prior to each treatment and over the 168 hours after drug administration to determine the area under the plasma concentration-time curve (AUC) and maximum observed plasma concentration (Cmax). Participants: 20 healthy male volunteers (3 White, 17 Black) ranging in age from 19 to 45 (mean 37) years and weighing 54 to 91 (mean 75) kg were enrolled and completed this study. Main outcome measures: The primary parameter to assess dose proportionality and linearity was AUC from time zero to final concentration time point (AUCs). Results: The Cmax for all doses was observed approximately 4 hours after administration, revealing no dose-related differences in absorption rate. The half-life (t1/2) ranged from 21.2 to 24.1 hours. Cmax and AUCs increased in a doseproportional manner over a dose range of 5 to 20mg. Although the recommended clinical dose is 5mg, doses up to 20mg were well tolerated. Conclusion: In this study, single doses of desloratadine as high as 4 times the recommended clinical dose of 5mg were well tolerated. The Cmax and AUCs for doses of 5 to 20mg increased in a dose-proportional manner.

Metabolic effects of antihypertensive therapy with a calcium antagonist

The effect of diuretics to increase serum glucose, low-density lipoprotein cholesterol and triglycerides, as well as the adverse changes in triglycerides and high-density lipoprotein cholesterol produced by nonselective beta blockers, have been largely ignored in the treatment of hypertension. However, a number of trials have shown that reductions in serum lipids can alter cardiovascular mortality. Calcium antagonists have become major drugs in the treatment of hypertension, and some data suggest that calcium antagonists may increase serum glucose levels. Significantly less data on lipid effects have been published. Lipid and glucose effects were examined in an 8-week antihypertensive study using a sustained-release preparation of diltiazem titrated from 240 to 360 mg/day in a twice-daily regimen in a randomized, double-blind, placebo-controlled parallel trial in 96 patients. Average supine blood pressure at week 8 was 156/98 mm Hg, standing blood pressure with placebo 152/100 mm Hg, and with diltiazem 147/91 and 144/93 mm Hg. There were no statistically significant changes in serum lipids or glucose in the diltiazem or placebo group or between the groups. Mean values (mg/dl) at baseline and week 8 in the diltiazem group were, respectively, for cholesterol 215 and 218, high-density lipoprotein cholesterol 50 and 51, low-density lipoprotein cholesterol 128 and 133, triglycerides 169 and 175, and glucose 113 and 110. Thus, this large and placebo-controlled study shows that diltiazem is among the antihypertensives with no adverse long-term lipid or glucose effects.

Sustained‐Release Diltiazem: Duration of Antihypertensive Effect

The antihypertensive activity of a sustained‐release preparation of diltiazem (given each 12 hours) was assessed in 96 patients with supine diastolic blood pressure (BP) between 95 and 110 mm Hg in a multicenter, randomized, double‐blind, placebo run‐in, parallel‐group trial comparing optimally titrated doses of diltiazem and placebo. The aim was to assess the onset of action as well as the extent and variability of BP control of this formulation during the 12‐hour interval. Diltiazem was titrated from 120 mg bid to 180 mg bid as necessary to lower BP. At baseline, on the first day of titration, and at the end of 8 weeks, BP was evaluated at 0, 1, 2, 3, 4, 5, 6, 8, 10, and 12 hours after dosing. The onset of action was within 2 hours, and the effect was maintained throughout the 12‐hour period. Mean BP for the diltiazem group at baseline was 154/101 mm Hg. At week 8, BP was 148/93 mm Hg at hour “0” (P < .02 and P = .0001 for systolic and diastolic BP vs. placebo), 139/84 mm Hg at the nadir at hour 5 (P = .0001), and 149/91 mm Hg at the end of the 12‐hour period (P < .02 and P = .0001 for systolic and diastolic BP). Diltiazem was significantly more effective than placebo (P = .0001) with 50% of patients controlled to a diastolic pressure of <90 mm Hg at 7 of the 10 evaluation points, including the evaluation point of 12 hours post‐dose. There was no exaggeration of the magnitude of daily BP fluctuation nor any increase in orthostatic effect noted.

Pharmacokinetic profile of cisapride 20 mg after once- and twice-daily dosing

Cisapride is a substituted piperidinyl benzamide. It is chemically related to metoclopramide but lacks the antidopaminergic properties of metoclopramide that affect the central nervous system and cause extrapyramidal side effects. Cisapride is indicated for the symptomatic treatment of patients with nocturnal heartburn due to gastroesophageal reflux disease. Based on extensive assessment of the drugs pharmacokinetic profile, the currently approved initial oral dosing regimen for cisapride is 10 mg QID. However, the pharmacokinetics of cisapride after oral administration of 20 mg BID have not been investigated. We present here findings from an open-label trial assessing the pharmacokinetics of cisapride 20-mg tablets after a single dose and at steady state (BID dosing). The results indicate that 20-mg BID and 10-mg QID regimens produce similar steady-state concentrations.