Azithromycin and terfenadine: lack of drug interaction.

A double-blind placebo-controlled study was conducted in healthy men to determine the effect of coadministration of azithromycin on the pharmacodynamics and pharmacokinetics of terfenadine. Administration of 500 mg azithromycin for 1 day and 250 mg on 4 subsequent days did not affect the pharmacokinetics of the pharmacologically active terfenadine carboxylate metabolite when 60 mg terfenadine was given twice daily for 12 days, starting 7 days before azithromycin administration. Terfenadine alone resulted in a 0.010 msec increase in the rate-corrected QT interval (QTc), but the incremental effects of azithromycin and placebo on QTc in volunteers receiving terfenadine were not statistically different. It is concluded that the potentially life-threatening disorders that have been attributed to a pharmacokinetic interaction between macrolide antibiotics and terfenadine are unlikely to take place in patients treated simultaneously with azithromycin and terfenadine.

Pharmacokinetics of azithromycin in pediatric patients after oral administration of multiple doses of suspension.

Azithromycin is an azalide antibiotic. On the basis of data in adults, azithromycin appears to have a greater distribution into tissues, a longer elimination half-life, and a lower incidence of adverse effects than the macrolide antibiotic erythromycin. However, little about the pharmacokinetics of azithromycin in children is known. The objective of our study was to characterize the pharmacokinetics of azithromycin after oral administration of multiple doses of suspension to children with streptococcal pharyngitis. Fourteen children (6 to 15 years of age) received a single oral dose of 10 mg of azithromycin per kg of body weight on day 1 followed by single daily doses of 5 mg/kg on days 2 to 5. Each child fasted overnight before receiving the final dose on day 5. Blood samples were collected at 0, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, and 72 h after this last dose. Concentrations of azithromycin in serum were measured by a specific high-performance liquid chromatography-mass spectrometry method. The mean +/- standard deviation for maximum concentration of drug in serum, time to maximum concentration of drug in serum, and area under the curve (0 to 24 h) were 383 +/- 142 ng/ml, 2.4 +/- 1.1 h, and 3,109 +/- 1,033 ng.h/ml, respectively. Concentrations in serum at 0 h (predose) and at 24, 48, and 72 h after the final dose were 67 +/- 31, 64 +/- 24, 41 +/- 17, and 29 +/- 14 ng/ml, respectively. Thus, once-daily administration of azithromycin resulted in sustained systemic exposure to the drug.

Interaction between cyclosporine and fluconazole in renal allograft recipients.

To determine the effect of fluconazole on cyclosporine concentrations, we used a randomized, double-blind, placebo-controlled study design to evaluate 16 stable renal transplant recipients receiving a constant cyclosporine dose. The two groups of patients were given identical capsules of either placebo or fluconazole 200 mg daily for 14 days. Compliance with the protocol was ensured by watching each patient take all the drug doses. Frequent whole-blood cyclosporine trough concentrations, measured by high-performance liquid chromatography, and two area under the blood concentration time curves were determined before and after 14 days of fluconazole or placebo. The results show that cyclosporine trough concentrations, in patients given fluconazole, increased from a mean +/- SD of 27 +/- 16 to 58 +/- 28 ng/ml (P = 0.001) while patients given placebo did not change--35 +/- 26 vs. 37 +/- 35 ng/ml (P = 0.7). Mean cyclosporine AUC increased in the fluconazole patients from 2167 +/- 1039 to 3989 +/- 1675 ng.hr/ml (P = 0.02) while the placebo patients did not change, 3089 +/- 2439 vs. 2954 +/- 2216 ng.hr/ml (P = 0.9). The pre- and post-treatment cyclosporine AUC difference (day 16 minus day 2) for fluconazole vs. placebo was 1822 +/- 1083 vs. -134 +/- 831 ng.hr/ml (P = 0.001). Mean cyclosporine clearance decreased an average of 55% in the fluconazole patients from 1.2 +/- 0.5 to 0.7 +/- 0.4 ml/hr.kg (P = 0.03); the placebo patients did not change--1.4 +/- 1.1 vs. 1.7 +/- 2.3 ml/hr.kg (P = 0.07). During the study period, serum creatinine concentrations did not increase after fluconazole vs. placebo treatment; they were 1.4 +/- 0.3 vs. 1.3 +/- 0.3 mg% (P = 0.8) initially, and 1.4 +/- 0.2 vs. 1.3 +/- 0.3 mg% (P = 0.5) after 14 days. This study indicates that fluconazole 200 mg daily can slowly increase cyclosporine concentrations over two weeks of therapy, approximately doubling the cyclosporine trough concentrations. The management of this interaction requires prospective planning for adjustments in the cyclosporine dosage, guided by cyclosporine concentrations, while transplant recipients are receiving fluconazole.

Induction of fluconazole metabolism by rifampin: in vivo study in humans.

The effects of rifampin on the pharmacokinetics of fluconazole were analyzed in an open-label, placebo-controlled, parallel study. Sixteen healthy male volunteers, randomized into two groups, received 200 mg of oral fluconazole on days 1 and 22. On days 8 through 27, group I received oral rifampin, 600 mg/d, and group II received placebo. Fluconazole in serum was analyzed by HPLC. On days 1 and 22, respectively, the AUC (micrograms.hr/mL) (mean +/- SD) was 160.5 +/- 19.5 and 124 +/- 22.2 in group I, 152 +/- 25 and 152.8 +/- 33.9 in group II; the Kel (hr-1) was .0211 +/- .0030 and .0264 +/- .0040 in group I, .0219 +/- .0036 and .0216 +/- .0053 in group II. Cmax and Tmax did not change significantly in either group. Urinary 6 beta-hydroxycortisol/cortisol increased from 3.47 +/- 1.04 to 15.2 +/- 5.07 in group I, but was unchanged (3.54 +/- 1.33-4.26 +/- 2.36) in group II on days 1 and 22, respectively. The findings in this study indicate that rifampin induces the metabolism of fluconazole.

Effect of fluconazole on the disposition of phenytoin.

In a randomized, placebo-controlled, parallel study, phenytoin was given in the presence and absence of fluconazole. Twenty healthy male subjects received phenytoin, 200 mg orally, on study days 1 to 3 and 18 to 20 and 250 mg intravenously on study days 4 and 21. Ten subjects received fluconazole, 200 mg orally, and 10 received placebo daily on study days 8 to 21. Serial blood samples were collected during a 24-hour period after the intravenous phenytoin dose. Fluconazole trough concentrations were determined on days 14, 18, and 21. Serum phenytoin area under the concentration-time curve from 0 to 24 hours increased 75% and minimum plasma drug concentration increased 128% after administration of fluconazole, 200 mg/day, for 14 days. These values were significantly greater than the 5% increase in area under the concentration-time curve from 0 to 24 hours and 11.6% increase in minimum plasma drug concentration in the placebo group. Fluconazole trough concentrations remained unchanged during the coadministration of phenytoin. The increased phenytoin concentrations in the presence of fluconazole suggest that fluconazole inhibits phenytoin metabolism. Serum concentration monitoring with a reduction in phenytoin dosage is clinically warranted in patients receiving phenytoin and concomitant fluconazole therapy.

The effects of an antacid or cimetidine on the serum concentrations of azithromycin.

The effects of an antacid and of cimetidine on the serum concentrations of azithromycin were examined in volunteers. Ten subjects were given 500 mg azithromycin alone and immediately after being given 30 mL Maalox (Rorer, Fort Washington, PA) in a crossover design. There were no statistically significant differences in Tmax or AUC0-48 after administration of azithromycin alone or with antacid, but mean values of Cmax were reduced by 24% (P = .015). Thus, although Cmax was decreased, the extent of absorption of azithromycin was not affected by coadministration with an antacid. Two groups of six volunteers were given 500 mg azithromycin on day 1. On day 8, one group was given 800 mg cimetidine 2 hours before a dose of azithromycin; the remaining group received placebo before azithromycin. There were no differences in the pharmacokinetic parameters produced by administration with cimetidine or placebo, relative to those on day 1. Thus, cimetidine administered 2 hours before a dose of azithromycin had no apparent effect on the serum concentrations of azithromycin.

The clinical pharmacology of fluconazole.

The pharmacokinetic profile of fluconazole clearly distinguishes it from other antifungal agents; oral bioavailability is more than 90%, and plasma protein binding is 12%. The volume of distribution approximates that of total body water. Both peak and minimum plasma concentrations are linearly proportional to dose over a range of 50 to 400 mg. Fluconazole is metabolically stable. Renal clearance is the predominant route of elimination, with only 11% of a single dose excreted as metabolites. The mean elimination half-life is approximately 30 hours. Consequently, dosage requirements in the presence of renal insufficiency are predictable from and dependent on renal function. Fluconazole has been extensively studied regarding drug interactions that may occur during concomitant therapy with cimetidine, rifampin, warfarin, oral hypoglycemics, phenytoin, and cyclosporin A. Results indicate that fluconazole can be safely administered with these drugs, as well as a number of other commonly used drugs.

Two-compartment gentamicin pharmacokinetics in premature neonates: a comparison to adults with decreased glomerular filtration rates.

Eleven premature neonates received gentamicin sulfate for treatment of suspected gram-negative sepsis with accompanying respiratory distress syndrome. Serum gentamicin concentrations were measured during and after treatment to monitor therapy and to determine the two-compartment distribution and elimination characteristics of the drug. The measured pharmacolinetic parameters were compared to those of 14 adult patients with similar glomerular filtration rates. Neonates, like adults and children, had a prolonged persistence of gentamicin in the serum after treatment was stopped. Although there were marked differences between neonates and adults in administered dose, clearance, and distribution volume when the data were expressed on the basis of body weight, these differences were no longer apparent when the data were expressed relative to body surface area. Differences in gentamicin disposition cannot explain the apparent lack of aminoglycoside nephrotoxicity among premature neonates.

Factors affecting theophylline pharmacokinetics in premature infants with apnea.

Theophylline disposition was examined in 17 premature neonates (birth weight 760--1,480 g) at cessation of therapy for primary apnea Mean +/- SD of clearance (22.9 +/- 3.9 ml/h/kg) and apparent volume of distribution (0.630 +/- 0.150 1/kg) were somewhat greater than previously reported for newborn infants at 4--15 days. Better correlations were found between maturational factors and clearance adjusted for body surface area than for clearance adjusted for weight. A limited correlation (r = 0.53) was found between clearance/body surface area and duration of therapy. No significant differences in pharmacokinetics occurred in patients who received parenteral alimentation. While some variability and age dependence exists in theophylline disposition in newborns, such variability is substantially less than found in older children and in adults.

Interaction of chloramphenicol with phenytoin and phenobarbital. Case report.

The effect of chloramphenicol therapy (48 mg/kg/day) on the serum concentrations of phenytoin and phenobarbital was studied in a patient previously stabilized on anticonvulsant medications. Phenytoin, 12 mg/kg/day, and phenobarbital, 5 mg/kg/day resulted in serum concentrations averaging 10.8 microgram/ml before and 30.5 microgram/ml, after chloramphenicol therapy. A reduction in dose of both phenytoin and phenobarbital was required to minimize adverse effects during the course of chloramphenicol therapy. An average daily dose of phenytoin of 9.1 mg/kg resulted in an average serum concentration of 17.8 microgram/ml. A daily dose of phenobarbital of 4.0 mg/kg resulted in an average serum concentration of 37.1 microgram/ml. These changes indicate 50.5% and 40.4% decreases in clearance of phenytoin and phenobarbital. Multiple-dose nonlinear regression analysis of phenytoin and phenobarbital serum concentration data obtained during chloramphenicol therapy indicated a 62.5% and a 29.5% decrease in clearance. Subsequent serum concentration monitoring demonstrated a similar reduction in phenobarbital clearance when chloramphenicol was added to phenobarbital alone.