Activity of ebastine (10 and 20 mg) and cetirizine at 24 hours of a steady state treatment in the skin of healthy volunteers

We have compared the inhibitory effects of ebastine (10 mg), ebastine (20 mg) and cetirizine (10 mg) on histamine-induced wheal and flare skin reactions 24 h following a 6-day-long treatment. This was a double-blind, randomised, crossover, placebo-controlled study involving 24 healthy volunteers (18-65 years) with negative skin prick tests and the absence of specific IgEs to common allergens. Subjects were randomised to receive each of the following treatments once daily for 6 days: ebastine (10 mg), ebastine (20 mg), cetirizine (10 mg) or placebo with a washout period of 5 days. Twenty-four hours after the last dose of each treatment, histamine skin prick tests were performed (0, 0.5, 1, 2.5, 5, 10, 20, 50, 100 and 200 mg/mL), and wheal and flare responses were measured. All active treatments produced significant inhibition of the wheal responses compared to placebo (P < 0.001). Wheal response inhibition was significantly better with 20 mg of ebastine compared with 10 mg of ebastine and 10 mg of cetirizine. In a comparison to histamine concentrations required to produce a wheal surface area of 10 mm2, 20 mg of ebastine was also significantly better than ebastine 10 mg and cetirizine (P < 0.001), and 10 mg ebastine was significantly better than cetirizine (P < 0.05). Highly significant (P < 0.001) effects on the flare response were observed with each active treatment compared to placebo, with no difference between groups. The frequency of adverse events, primarily somnolence, was similar among the four treatment groups. Our results clearly indicate that ebastine, at either recommended dosage of 10 and 20 mg, and cetirizine produced significant inhibition of the histamine-induced wheal and flare reaction compared to placebo for up to 24 h. A superior efficacy of 20 mg of ebastine is observed compared with 10 mg of ebastine and 10 mg of cetirizine on the skin wheal response 24 h after the last dose of a 6-day-long treatment. This study clearly proves ebastine to be an effective, truly once-daily antihistamine.     

Pharmacokinetic and pharmacodynamic studies of the H1-receptor antagonist hydroxyzine in the elderly

The pharmacokinetics and pharmacodynamics of the antipruritic H1-receptor antagonist hydroxyzine hydrochloride were studied in nine healthy, fasting subjects (mean age 69.5 +/- 3.7 years) who ingested a single dose of hydroxyzine syrup, 0.7 mg/kg (mean dose 49.0 +/- 6.7 mg). Blood samples were collected hourly for 6 hours, every 2 hours from 6 to 12 hours, at 24 hours, and then every 24 hours for 144 hours. At these times an intradermal injection of 0.01 ml of a 0.1 mg/ml histamine phosphate solution was performed, and wheal and flare areas were computed. The serum elimination t1/2 of hydroxyzine was 29.3 +/- 10.1 hours; the volume of distribution was 22.5 +/- 6.3 L/kg; the clearance rate was 9.6 +/- 3.2 ml/min/kg, and the AUC was 1383.1 +/- 1039.0 ng.hr/ml. The mean serum elimination t1/2 of cetirizine, the active metabolite of hydroxyzine generated in vivo, was 24.8 +/- 7.7 hours, not significantly different from that of the parent compound (p = 0.05). After a single dose of hydroxyzine the mean wheal and flare areas were significantly suppressed from 1 to 144 hours, compared with the mean predose wheal and flare sizes (p less than 0.01). Maximum wheal suppression, compared with all other wheals measured during the study, occurred from 4 to 10 hours, inclusive, and maximum flare suppression occurred from 2 to 72 hours, inclusive (p less than 0.01). Hydroxyzine has a long t1/2 and a large volume of distribution in the elderly. The suppressive effect on the wheal and flare after a single dose of hydroxyzine is also extremely prolonged, suggesting the possibility of enhanced H1-receptor activity in old age.     

Comparison of on-site and photographic evaluations of the suppressive effects of cetirizine, loratadine, and fexofenadine on skin response to histamine lontophoresis: A double-blind, crossover study in healthy volunteers

Background:

The standard method used to determine the potency of antihistaminesis to assess the degree of suppression of skin response to histamine challenge.

Objectives:

The aims of this study were to compare the efficacy of 3 antihistaminesusing a histamine challenge test and the usefulness of on-site evaluation with that of photographic evaluation of skin-test reactions.

Methods:

In this prospective, double-blind, crossover study, healthy volunteerswere given cetirizine 5 mg (CTZ-5) and 10 mg (CTZ-10), loratadine 10 mg (LOR), fexofenadine 60 mg BID (FEX), and placebo (PLC), in a randomly assigned order, with an interval of at least 1 week between treatments. Before and 0.5 to 24 hours after administration, the areas of flare and wheal induced by histamine iontophoresis were measured directly (on site) by 1 evaluator and by another evaluator using photographic images on a computer monitor.

Results:

Ten healthy volunteers (6 men, 4 women; mean age, 28.2 years[range, 20-39 years]; mean weight, 60.7 kg [range, 41-81 kg]) were enrolled. The data from 9 subjects were analyzed; the data from 1 subject were omitted because the subject used an over-the-counter cold medication containing diphenhydramine several times during the study. By both methods, all antihistamines were shown to suppress flare significantly from 4 to 24 hours after administration. CTZ was most potent in suppressing both flare and wheal. For flare, the areas as measured using on-site evaluation were larger overall than those measured using photographic evaluation, but the shapes of the time-course graphs were similar for both. Overall, the flare area measurements started to decrease significantly from baseline values 4 hours after drug administration, reached a nadir at 10.5 hours, and remained significantly lower compared with baseline values at 24 hours. Comparisons between antihistamines showed significant differences in mean flare areas between the 2 doses of CTZ and LOR from 8 to 12 hours after administration in both evaluation methods. The wheal areas were significantly reduced from baseline values by most of the antihistamines 4 to 12 hours after drug administration, reached their lowest values at 10.5 hours, and returned to near-baseline values at 24 hours. Comparisons with PLC values at each time point, however, showed significant differences only for CTZ-5 and CTZ-10 from 4 to 12 hours after administration. Comparison between antihistamines showed significant differences in mean flare areas between the 2 doses of CTZ and LOR from 8 to 12 hours after administration in both evaluation methods. Although the flare areas measured by both methods correlated linearly (r = 0.90; P < 0.001), the correlation for wheal areas was weaker (r = 0.76; P < 0.001).

Conclusions:

In this study in healthy volunteers, single doses of CTZ 5 mg and CTZ 10 mg were more potent compared with single-dose LOR 10 mg and FEX 60 mg BID in suppressing skin response. Although linear correlations were found between skin-response areas, as measured by on-site and photographic evaluation, it was difficult to differentiate between wheal and flare by photographic evaluation, especially when a typical wheal was suppressed to slightly edematous erythema by antihistamines.     

Double-blind comparison of cetirizine and loratadine in children ages 2 to 6 years with perennial allergic rhinitis.

Antihistamines are the pharmacologic cornerstone of treatment for allergic rhinitis. The comparative effects of the newer, more specific H (1) -antagonists cetirizine and loratadine among younger patients are not well characterized. The efficacy and safety of cetirizine and loratadine were compared in a prospective, randomized, double-blind, longitudinal, parallel-group study of 80 children, 2 to 6 years of age, with perennial allergic rhinitis caused by house dust mites or plant pollens (verified by a radioallergosorbent or skin test). Patients received cetirizine or loratadine at 0.2 mg/kg once daily in the morning for 28 days. Histamine skin tests and eosinophil counts from nasal smears were performed at baseline and at the end of treatment. Individual rhinitis symptoms were assessed by the investigator at baseline and on day 28 and by parents at baseline and daily in symptom diaries. Global assessments were made by using a visual analog scale at baseline and at the end of treatment. Cetirizine produced significantly greater inhibition of the wheal response compared with loratadine (P <.0001). Eosinophil counts were improved to a comparable degree with both agents. Cetirizine and loratadine produced comparable improvements in symptoms and according to a global evaluation as assessed by the investigator at the end of treatment. Both agents produced substantial symptomatic relief according to patients' daily diary assessments; however, cetirizine was more effective than loratadine in relieving the symptoms of rhinorrhea, sneezing, nasal obstruction, and nasal pruritus (P <. 0001). Both treatments were well tolerated; two patients receiving cetirizine were dropped from the study because of adverse events. Cetirizine and loratadine provided effective, well-tolerated relief of the symptoms of perennial allergic rhinitis in small children. Cetirizine was more effective than loratadine in inhibiting the wheal response to histamine challenge and afforded greater reductions in most individual symptoms assessed daily by the parent.     

Pharmacokinetic and pharmacodynamic modeling of mizolastine in healthy volunteers with an indirect response model

OBJECTIVE: The aim of this work was to model the pharmacokinetic and pharmacodynamic relationship of mizolastine, a new H1-receptor antagonist obtained from histamine-induced wheal and flare inhibition test. METHODS: Fifteen healthy volunteers participated in this double-blind crossover study and randomly received single doses of 5, 10, 15, and 20 mg of mizolastine and placebo at 1 week intervals. Simultaneous histamine tests and blood samples were performed before and at 9 different times up to 24 hours after each dosing. Pharmacokinetic and pharmacodynamic modeling were performed subject by subject for the 4 doses altogether by nonlinear regression. First, plasma concentrations were fit according to a two-compartment open model with zero order absorption and first order elimination. Then an indirect response model with inhibition of the formation rate was developed to describe the pharmacodynamic relationships between flare or wheal raw areas and plasma concentrations with the use of the pharmacokinetic parameters that were previously estimated. RESULTS: Mizolastine dose dependently inhibited the histamine-induced wheal and flare formation with a submaximum effect attained after 10 mg. The mean values of the pharmacodynamic parameters of apparent zero-order rate constant for the flare or wheal spontaneous appearance (k(in)), the first-order rate constant for the flare or wheal disappearance, the mizolastine concentration that produced 50% suppression of the maximum attainable inhibition of k(in), and the maximum attainable inhibition of the effect production were 14.1 cm2/h (coefficient of variation [CV], 32%), 0.68 h(-1) (CV, 24%), 21.1 ng/mL (CV, 77%), and 0.92 (CV, 8%), respectively, for the flare and 1.9 cm2/h (CV, 64%), 0.63 h-1 (CV, 39%), 43.9 ng/mL (CV, 68%), and 0.87 (CV, 12%), respectively, for the wheal inhibition. CONCLUSION: Pharmacokinetic and pharmacodynamic relationships of mizolastine were reliably described with the use of an indirect pharmacodynamic model; this led to an accurate prediction of the pharmacodynamic activity of mizolastine.     

Dermal objective pharmacodynamic profile of cetirizine and epinastine: two controlled,randomised, double-blind,crossover studies

Two double-blind clinical pharmacology studies were performed in healthy volunteers to compare the dermal pharmacodynamic profile of epinastine with cetirizine, a well-documented anti-H1 antagonist, after oral administration at the usual recommended dosage, i.e. 10 mg cetirizine and 20 mg epinastine (versus placebo). Histamine skin challenges (prick test) were evaluated before and at 1, 2, 4, 8 and 24 hr after drug intake by measuring the wheal and flare area (studies 1 and 2) along with laser Doppler monitoring of the microvascular responses (study 2). A decrease in wheal and flare areas was observed following intake of both drugs compared with placebo controls. With the notable exception of 1 hr post dose wheal values, which were consistently smaller after epinastine, cetirizine was superior to epinastine for both wheal and flare at all other times. At the prick test site, treatment with epinastine and cetirizine accentuated the increase in blood flow induced by histamine. This reflects the decrease of the whealing but there was no significant difference between the two active test compounds. At 1 cm from the prick test site, the administration of both active treatments inhibited the increase of blood flow, and cetirizine showed a more potent inhibitory effect from 8 hr post dose. This reflects the reduction of the flare induced after histamine-receptor activation of the axon reflex. In conclusion, epinastine shows a rapidly greater (within 1 hr post dose on the wheal only) but vanishing effect than cetirizine. At all other time points, cetirizine was generally more effective than epinastine.     

Temelastine, a new H1-receptor antagonist

Temelastine is a selective, competitive histamine H1-receptor antagonist which does not penetrate the central nervous system. The effect of varying doses of temelastine was compared in a randomized, double-blind, controlled study by measuring the inhibition of cutaneous histamine wheals. In twelve subjects single oral doses of 50, 100 and 200 mg of temelastine produced dose-dependent reductions in wheal areas. The inhibition of wheal size was maximal by 2 hr after dosing and was present at 8 hr. At 2 hr the 50, 100, and 200 mg doses reduced the wheal size by 53, 64, and 78%, respectively. Chlorpheniramine, 4 mg, reduced wheal size by 32% at the same period. The ability of temelastine to antagonize the histamine-induced skin reaction over 20 hr was evaluated in a second randomized, double-blind study. Eight subjects participated. Temelastine, 100 mg, produced reductions of 64, 49, 56 and 51% in histamine wheal area at 8, 12, 16 and 20 hr, respectively. Plasma concentrations at these times were 4.04, 2.77, 1.88, and 1.44 mumol/l, respectively. These data suggest that blood levels as low as 1.44 mumol/l may be sufficient to produce an antihistaminic effect, and that daily or twice daily dosing with 100 mg may be adequate to control allergic symptoms.     

Morphine-induced skin wheals: a possible model for the study of histamine release

We evaluated the ability of morphine to release histamine when injected intradermally in man. Mathematic analysis of the dose-response (wheal) relationship suggested that two different effects were involved. The effect of low doses of morphine (0.05 to 1 microgram) was clearly antagonized by naloxone (0.4 or 1.2 mg im 30 minutes before), whereas the effect of higher doses (5 to 50 micrograms) was not modified. The median effective doses of morphine (ED50) for the low dose range effect were 0.07 +/- 0.01 and 0.08 +/- 0.01 microgram before naloxone and 0.14 +/- 0.02 and 0.15 +/- 0.03 microgram after 0.4 and 1.2 mg doses, respectively. Astemizole (45 mg po 30 minutes before) and oxatomide (60 mg po 120 minutes before) produced similar inhibition of histamine-induced wheals, but there were clear differences in their effects on wheals elicited by morphine. Morphine ED50 values for the low dose range effect rose from 0.09 +/- 0.01 to 0.20 +/- 0.01 microgram after astemizole and from 0.08 +/- 0.01 to 0.46 +/- 0.04 microgram after oxatomide. Opiate receptors may be involved in some of the effects produced by morphine injection in the human skin, but morphine-induced wheals seem to offer a suitable model for the evaluation of agents capable of inhibiting histamine release in man.     

Loratadine versus cetirizine: assessment of somnolence and motivation during the workday

OBJECTIVE: This parallel-group, double-blind study compared the somnolence and motivation profiles of 2 second-generation antihistamines, loratadine and cetirizine, in patients with allergic rhinitis. BACKGROUND: Second-generation antihistamines were developed to provide symptomatic relief from allergic disorders without the unwanted side effects of first-generation antihistamines, including somnolence. Recent research has indicated that not all second-generation antihistamines are comparable with respect to somnolence and other cognitive processes. METHODS: Patients aged > or = 12 years and actively exhibiting symptoms of allergic rhinitis were randomized to 2 treatment groups to receive 10 mg loratadine or 10 mg cetirizine daily at 8:00 AM for 1 week. After patients took the medication, their somnolence and degree of motivation to perform activities were recorded in an electronic diary using a visual analog scale 4 times during the workday (8:00 AM, 10:00 AM, noon, and 3:00 PM). RESULTS: Sixty patients (31 men, 29 women) were randomized to treatment. Somnolence scores were similar for both groups at baseline and at the time of dosing (8:00 AM). However, there was a statistically significant difference in somnolence scores between the loratadine and cetirizine groups at 10:00 AM (P = 0.008), noon (P = 0.001), and 3:00 PM (P < 0.001), with the cetirizine group showing a greater degree of somnolence. The scores on motivation to perform activities were similar for both groups at the baseline and 8:00-AM measurements. In parallel with the somnolence scores, there were statistically significant differences in motivation scores between the loratadine and cetirizine groups at 10:00 AM (P = 0.014), noon (P = 0.001), and 3:00 PM (P < 0.001), indicating that patients taking loratadine were relatively more motivated during the workday. CONCLUSION: The results of this study demonstrate that in patients aged > or = 12 years who had allergic rhinitis, cetirizine use promoted somnolence and decreased motivation to perform activities during the workday compared with loratadine.     

Nasal effect of cetirizine and loratadine at 24 hours in patients with allergic rhinitis

Numerous studies have compared the duration of the cutaneous effect of cetirizine and loratadine. We assessed their nasal effects 24 hours after administration in patients with allergic rhinitis, using a randomized, double-blind, crossover, placebo-controlled trial. Nasal challenge was performed by nebulization of increasing doubling dosages of histamine (0.04-1.28 mg/nostril) in 12 patients (seven males, five females, aged 31 +/- 7 years). Nasal airway resistance was measured by posterior rhinomanometry 24 hours after intake of cetirizine (10 mg), loratadine (10 mg), or placebo. Baseline nasal airway resistance was identical on all study days (2.86 +/- 0.10 cm H2 O/L per second). Twenty-four hours after intake, the dose-response curve of nasal obstruction to histamine was significantly lower after treatment with cetirizine compared with placebo (P < 0.05). However, although the curve was lower on loratadine than on placebo, the curves did not differ significantly. In conclusion, our study shows significant efficacy of cetirizine, but not of loratadine, in the nose at 24 hours after a single dose. This suggests that the nasal action of cetirizine is longer lasting than that of loratadine in patients with allergic rhinitis.     

Pharmacological modulation by cetirizine and loratadine of antigen and histamine-induced skin weals and flares, and late accumulation of eosinophils

In a double-blind, randomized, crossover study performed in atopic subjects, the inhibitory effects of single doses of 10 mg cetirizine and 10 mg loratadine on histamine- and grass pollen-induced skin reactions were evaluated 4 h after drug intake. Cetirizine significantly inhibited histamine- and antigen-induced skin reactions, as well as the accumulation of eosinophils measured 24 h after antigen challenge. Loratadine, however, did not significantly inhibit the skin reactions induced by histamine and grass pollen, nor eosinophil accumulation.     

Cetirizine in the treatment of chronic urticaria

The effects of oral cetirizine on spontaneous and provoked urticaria were evaluated in two studies. In a double-blind crossover trial, 30 patients with idiopathic urticaria received 10 or 20 mg of cetirizine or placebo. Cetirizine was significantly more effective than placebo in reducing the incidence of erythema, wheals, and pruritus. No serious side effects were reported. In the second study of ten patients with chronic urticaria, immediate and delayed reactions to injected autologous serum, histamine, kallikrein, and synthetic platelet-activating factor (PAF)-acether were inhibited by 10 mg of cetirizine. These results suggest that the mechanism of action of cetirizine may involve inhibition of PAF-induced influx of eosinophils.     

The relative antihistaminic and psychomotor effects of hydroxyzine and cetirizine

Twelve healthy subjects with atopy received single doses of hydroxyzine, 25 mg, its metabolite cetirizine, 10 and 20 mg, and placebo in a four-way crossover study randomized by Latin square design. Skin wheal response to histamine, psychomotor effects, and serum concentrations of each drug were measured for 36 hours after each dose. Central nervous system (CNS) effects were measured with critical flicker frequency, Stroop word testing, and visual analog scales. All three active treatments (cetirizine, 10 mg, cetirizine, 20 mg, and hydroxyzine) produced an equivalent suppression of skin wheal response to histamine that was significantly greater than placebo (P less than 0.01). Hydroxyzine produced a significant change compared with placebo in all three CNS parameters. Neither cetirizine, 10 mg, nor cetirizine, 20 mg, produced any significant change in CNS parameters. Both the intensity and time course of CNS effects were related significantly (P less than 0.05) to hydroxyzine concentrations. The CNS changes measured after oral hydroxyzine are the result of the parent drug, whereas its metabolite cetirizine when administered alone produced significant antihistaminic effects without CNS changes.     

The pharmacokinetics of loratadine in normal geriatric volunteers

The pharmacokinetics of loratadine, a non-sedating anti-histamine, were studied in 12 normal geriatric volunteers. In an open label fashion, each volunteer received one 40 mg loratadine capsule. Blood was collected prior to and at specified times (up to 120 h) after dosing. Plasma loratadine concentrations were determined by a specific radioimmunoassay and those of an active metabolite, descarboethoxyloratadine, by high performance liquid chromatography. Concentrations of loratadine in the disposition phase were fitted to a biexponential equation and those of descarboethoxyloratadine to either a monoexponential or biexponential equation for pharmacokinetic analysis. Loratadine was rapidly absorbed, reaching a maximum plasma concentration of 50.5 ng/ml at 1.5 h after dosing. The disposition half-lives of loratadine in the distribution and elimination phases were 1.5 and 18.2 h, respectively. The area under the plasma concentration-time curve, was 146.7 h.ng/ml. Descarboethoxyloratadine had a maximum plasma concentration of 28.0 ng/ml at 2.9 h post-dose and an area under the concentration-time curve of 394.9 h.ng/ml. Its disposition half-lives in the distribution and elimination phases were 2.8 and 17.4 h, respectively. Comparison of these data with those from a previous study of loratadine in young adults showed no clear differences in the disposition half-lives between the two groups. The clearance of loratadine tends to be lower in the elderly, but inter-individual variation within each age group appears greater than any age effect.     

Comparative efficacy of once daily loratadine versus terfenadine in the treatment of allergic rhinitis

This 1 week study compared the efficacy of once daily administration of 10 mg loratadine with 120 mg terfenadine in out-patients with seasonal allergic rhinitis. It focussed on the efficacy of treatment at the end of the 24 h period following a daily dose. The study was designed as a double-blind, randomized, parallel-group trial, and 41 patients were enrolled and evaluated for efficacy. Patients took an initial dose at the study site and returned on days 2 and 8. At day 2 (24 h after the initial dose), according to the physician's evaluation 57% of loratadine-treated patients had a good or excellent response, compared to 50% of those given terfenadine. At day 8, 24 h after the final dose, 71% of the loratadine-treated patients and 35% of the terfenadine-treated patients had a good or excellent response (P = 0.03). At days 2 and 8, reductions in mean symptom scores measured 22, 23 and 24 h after the initial and final doses showed an indication of being greater with loratadine than with terfenadine (nonsignificant due to small sample size). The incidence of sedation was similar in both groups. It is concluded that 10 mg loratadine, administered once daily, controls the symptoms of rhinitis more effectively than 120 mg terfenadine given once daily in the last few hours of the 24 h dosing period.     

Pharmacokinetics-pharmacodynamics of gatifloxacin in a lethal murine Bacillus anthracis inhalation infection model

We determined the pharmacokinetic-pharmacodynamic (PK-PD) measure most predictive of gatifloxacin efficacy and the magnitude of this measure necessary for survival in a murine Bacillus anthracis inhalation infection model. We then used population pharmacokinetic models for gatifloxacin and simulation to identify dosing regimens with high probabilities of attaining exposures likely to be efficacious in adults and children. In this work, 6- to 8-week-old nonneutropenic female BALB/c mice received aerosol challenges of 50 to 75 50% lethal doses of B. anthracis (Ames strain, for which the gatifloxacin MIC is 0.125 mg/liter). Gatifloxacin was administered at 6- or 8-h intervals beginning 24 h postchallenge for 21 days, and dosing was designed to produce profiles mimicking fractionated concentration-time profiles for humans. Mice were evaluated daily for survival. Hill-type models were fitted to survival data. To identify potentially effective dosing regimens, adult and pediatric population pharmacokinetic models for gatifloxacin and Monte Carlo simulation were used to generate 5,000 individual patient exposure estimates. The ratio of the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) to the MIC of the drug for the organism (AUC(0-24)/MIC ratio) was the PK-PD measure most predictive of survival (R(2) = 0.96). The 50% effective dose (ED(50)) and the ED(90) and ED(99) corresponded to AUC(0-24)/MIC ratios of 11.5, 15.8, and 30, respectively, where the maximum effect was 97% survival. Simulation results indicate that a daily gatifloxacin dose of 400 mg for adults and 10 mg/kg of body weight for children gives a 100% probability of attaining the PK-PD target (ED(99)). Sensitivity analyses suggest that the probability of PK-PD target attainment in adults and children is not affected by increases in MICs for strains of B. anthracis to levels as high as 0.5 mg/liter.     

Effect of itraconazole on the pharmacokinetics and pharmacodynamics of fexofenadine in relation to the MDR1 genetic polymorphism

OBJECTIVE: Our objective was to evaluate the effect of itraconazole, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of fexofenadine, a P-glycoprotein substrate, in relation to the multidrug resistance 1 gene (MDR1) G2677T/C3435T haplotype. METHODS: A single oral dose of 180 mg fexofenadine was administered to 7 healthy subjects with the 2677GG/3435CC (G/C) haplotype and 7 with the 2677TT/3435TT (T/T) haplotype. One hour before the fexofenadine dose, either 200 mg itraconazole or placebo was administered to the subjects in a double-blinded, randomized, crossover manner with a 2-week washout period. Histamine-induced wheal and flare reactions were measured to assess the effects on the antihistamine response. RESULTS: In the placebo phase, pharmacokinetic parameters of fexofenadine showed no statistically significant difference between 2 MDR1 haplotypes; the area under the curve from time 0 to infinity (AUC(0-infinity)) of fexofenadine in the T/T and G/C groups was 5194.0 +/- 1910.8 and 4040.4 +/- 1832.2 ng.mL(-1).h(-1), respectively (P = .271), and the oral clearance (CL/F) was 530.9 +/- 191.1 and 806.0 +/- 355.3 mL.h(-1).kg(-1), respectively (P = .096). The disposition of itraconazole, a substrate of P-glycoprotein, was not significantly different between the 2 haplotypes. After itraconazole pretreatment, however, the differences in fexofenadine pharmacokinetics became statistically significant; the mean fexofenadine AUC(0-infinity) in the T/T group was significantly higher than that in the G/C group (15,630.6 +/- 5070.0 and 9252.9 +/- 2044.1 ng/mL.h, respectively; P = .007), and CL/F of the T/T subjects was lower than that of the G/C subjects (167.0 +/- 33.3 and 292.3 +/- 42.2 mL.h(-1).kg(-1), respectively; P < .001). Itraconazole pretreatment caused more than a 3-fold increase in the peak concentration of fexofenadine and the area under the curve to 6 hours compared with the placebo phase. This resulted in a significantly higher suppression of the histamine-induced wheal and flare reactions in the itraconazole pretreatment phase compared with those in the placebo phase. CONCLUSION: The effect of MDR1 G2677T/C3435T haplotypes on fexofenadine disposition are magnified in the presence of itraconazole. Itraconazole pretreatment significantly altered the disposition of fexofenadine and thus its peripheral antihistamine effects.     

Steady-State Pharmacokinetics and Electrocardiographic Pharmacodynamics of Clarithromycin and Loratadine after Individual or Concomitant Administration

To evaluate the potential for an interaction between clarithromycin and loratadine, healthy male volunteers (n = 24) received each of the following regimens according to a randomized crossover design: 500 mg of clarithromycin orally every 12 h (q12h) for 10 days, 10 mg of loratadine orally q24h for 10 days, and the combination of clarithromycin and loratadine. A washout interval of 14 days separated regimens. The addition of loratadine did not statistically significantly affect the steady-state pharmacokinetics of clarithromycin or its active metabolite, 14(R)-hydroxy-clarithromycin. However, the addition of clarithromycin statistically significantly altered the steady-state maximum observed plasma concentration and the area under the plasma concentration-time curve over a dosing interval for loratadine (+36 and +76%, respectively) and for descarboethoxyloratadine (DCL), the active metabolite of loratadine (+69 and +49%, respectively). Clarithromycin probably inhibits the oxidative metabolism of loratadine and DCL by the cytochrome P-450 3A subfamily. Electrocardiograms (n = 12) were obtained over 24-h periods at baseline and steady state (day 10). The mean maximum QTc interval and area under the QTc interval-time curve on day 10 were modestly increased (<3%) from baseline for all three regimens, but no QTc interval exceeded 439 ms for any subject. Elevated steady-state concentrations of loratadine and DCL do not appear to be associated with adverse cardiovascular effects related to prolongation of the QTc interval. Loratadine and clarithromycin were well tolerated, alone and in combination.     

Pharmacokinetics of Loratadine in Pediatric Subjects

The pharmacokinetics of loratadine, a new nonsedating antihistamine, was studied in 14 pediatric volunteers between the ages of 8 to 12 years. In an open-label design, one volunteer (with body weight less than 30 kg) received 5 mg of loratadine syrup and 13 volunteers (with body weights greater than 30 kg) received 10 mg of loratadine syrup. Blood samples were collected up to 72 h after dosing. Plasma concentrations of loratadine and its metabolite, descarboethoxyloratadine, were determined by a specific and sensitive gas-liquid chromatographic method. Following a 10-mg dose as a syrup, plasma concentrations of loratadine and descarboethoxyloratadine could be determined up to 8 and 48 h, respectively. The maximum concentration (C(max)) of loratadine and descarboethoxyloratadine were approximately 4 ng ml(minus sign1) each. However, the AUC of the metabolite was about six times that of loratadine. The elimination phase half-life of descarboethoxyloratadine averaged about 13.8 hr. The pharmacokinetics of loratadine in pediatric subjects was similar to that in healthy adult volunteers.     

Daptomycin dose-effect relationship against resistant gram-positive organisms

Daptomycin exhibits in vitro bactericidal activity against clinically significant gram-positive bacteria. We employed pharmacodynamic modeling to determine a once-daily dosing regimen of daptomycin that correlates to pharmacodynamic endpoints for different resistant gram-positive clinical strains. An in vitro pharmacodynamic model with an initial inoculum of 6 log(10) CFU/ml was used to simulate daptomycin regimens ranging in dose from 0 to 9 mg/kg of body weight/day, with corresponding exposures reflecting free-daptomycin concentrations in serum. Bacterial density was profiled over 48 h for two methicillin-resistant Staphylococcus aureus (MRSA-67 and -R515), two glycopeptide intermediate-resistant S. aureus (GISA-992 and -147398), and two vancomycin-resistant Enterococcus faecium (VREF-12366 and -SF12047) strains. A sigmoid dose-response model was used to estimate the effective dose required to achieve 50% (ED(50)) and 80% (ED(80)) bacterial density reduction at 48 h. Daptomycin MICs for study isolates ranged from 0.125 to 4 micro g/ml. Model fitting resulted in an r(2) of >0.80 for all tested isolates. Control growths at 48 h ranged from 7.3 to 8.5 log(10) CFU/ml. Sigmoid relationships were not superimposable between categorical resistant species: ED(50) and ED(80) values were 1.9 and 3.1, 4.2 and 5.6, and 5.4 and 6.8 mg/kg for MRSA, GISA, and VREF isolates, respectively. Doses required to achieve ED(50) and ED(80) values correlated with MIC differences between tested organisms. Corresponding area under the concentration-time curve from 0 to 24 h/MIC exposure ratios demonstrated a wide range of ED(80) values among the tested isolates. Doses ranging between 3 and 7 mg/kg produced significant bactericidal activity (ED(80)) against these multidrug-resistant S. aureus and E. faecium isolates.