Melton B. Affrime

Effect of concomitant administration of piperacillin on the dispositions of isepamicin and gentamicin in patients with end-stage renal disease.

Piperacillin inactivation of the aminoglycosides isepamicin and gentamicin in 12 chronic hemodialysis patients was assessed. Six subjects each received isepamicin (7.5 mg/kg of body weight) or gentamicin (2 mg/kg) alone and in combination with piperacillin (4 g every 12 h for four doses). Isepamicin and gentamicin concentrations in plasma and urine were monitored over 48 h after each dose and analyzed by high-performance liquid chromatography and fluorescence polarization immunoassay, respectively. The pharmacokinetics of isepamicin were not significantly altered during combination treatment with piperacillin. The total body clearance (3.79 +/- 0.71 versus 3.94 +/- 1.05 ml/min), the steady-state volume of distribution (0.19 +/- 0.04 versus 0.18 +/- 0.03 liter/kg), and the terminal elimination half-life (47.91 +/- 7.20 versus 45.08 +/- 10.34 h) were not significantly altered in the presence of piperacillin. In contrast, the terminal elimination half-life (47.68 +/- 20.58 versus 35.67 +/- 11.18 h) of gentamicin was significantly reduced when gentamicin was given with piperacillin. The total body clearance (4.26 +/- 3.07 versus 4.89 +/- 1.94 ml/min) and the steady-state volume of distribution (0.19 +/- 0.04 versus 0.20 +/- 0.04 liter/kg) of gentamicin were not significantly altered during combination therapy; however, the nonrenal clearance of gentamicin administered in combination with piperacillin (3.56 +/- 0.38 ml/min) increased significantly compared with that of gentamicin (2.03 +/- 0.50 ml/min) given alone. The results of this study suggest that no additional dosage adjustment of isepamicin during concomitant therapy with piperacillin in hemodialysis patients is necessary. However, this does not preclude the need for appropriately ex vivo-handled specimens for monitoring isepamicin concentrations in plasma to ensure therapeutic efficacy and prevent toxicity. Furthermore, additional dosage adjustments may be necessary when gentamicin is used concomitantly with piperacillin, on the basis of the significant in vivo inactivation that takes place in end-stage renal disease patients.

Pharmacokinetics of ceftibuten-cis and its trans metabolite in healthy volunteers and in patients with chronic renal insufficiency.

The impact of renal insufficiency on the dispositions of 300 mg of orally administered ceftibuten-cis, a new broad-spectrum oral cephalosporin, and its primary metabolite ceftibuten-trans was characterized in 30 adult subjects. Subjects were divided into five groups of six subjects each on the basis of their 24-h ambulatory creatinine clearances (CLCR). The apparent total body clearance (CLP/F; where F is absolute bioavailability) and renal clearance of ceftibuten-cis were significantly lower in subjects with end-stage renal disease (on maintenance hemodialysis; group V) and in those with severe (CLCR, 5 to 29 ml/min; group IV) and moderate (CLCR, 30 to 49 ml/min; group III) renal insufficiency than in those with mild renal insufficiency (CLCR, 50 to 80 ml/min; group II) or normal renal function (CLCR, greater than 80 ml/min; group I). A significant correlation was observed between CLCR and ceftibuten-cis CLP/F. The mean apparent steady-state volume of distribution (V beta/F) of ceftibuten-cis ranged from 0.21 to 0.24 liter/kg in subjects in group I, II, III, and IV. V beta/F was significantly greater in the group V subjects with end-stage renal disease (V beta/F, 0.39 +/- 0.27 liters/kg). These changes in V beta/F cannot be separated from possible changes in bioavailability. The maximum concentration of ceftibuten-trans in plasma was significantly higher and occurred significantly later in group IV subjects than it did in subjects in the other groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Isepamicin disposition in subjects with various degrees of renal function.

The disposition of isepamicin, an investigational aminoglycoside antibiotic, was evaluated in 30 subjects with various degrees of renal function. The subjects were divided into five groups: those with normal renal function (creatinine clearance [CLCR], greater than 80 ml/min/1.73 m2), those with mild renal insufficiency (CLCR, 50 to 80 ml/min/1.73 m2), those with moderate renal insufficiency (CLCR, 30 to 49 ml/min/1.73 m2), those with severe renal insufficiency (CLCR, 5 to 29 ml/min/1.73 m2), and those maintained on hemodialysis (CLCR, less than 5 ml/min/1.73 m2). Subjects on hemodialysis were studied both during hemodialysis and during an interdialytic period. The volumes of distribution of isepamicin were not significantly different among the five groups of patients. The total body clearance (CLP) and renal clearance (CLR) of isepamicin significantly decreased as CLCR decreased. The CLP of isepamicin and CLCR were significantly related [(COP = 0.391.[CLCR] + 1.83; r2 = 0.878)]. Nonrenal clearance of isepamicin did not differ between groups. Hemodialysis augmented the CLP of isepamicin by approximately 25-fold. The amount of isepamicin recovered in the dialysate was 60.6 +/- 15.8% of the dose administered. The maximal rebound of the isepamicin concentration in plasma after cessation of hemodialysis was observed at 0.78 +/- 0.7 h. Concentrations in plasma increased 32.7 +/- 22.9% over that measured at the end of hemodialysis. These data indicate that dosage adjustments are necessary in subjects with decreased renal function.

Multiple-dose pharmacokinetics of ceftibuten in healthy volunteers.

The pharmacokinetics of ceftibuten, a new cephalosporin antibiotic, and its conversion product, ceftibutentrans, were studied in healthy male volunteers following daily oral administration of a 400-mg capsule for 7 days. Mean concentrations of ceftibuten in plasma obtained on day 5 were similar to those obtained on day 7. Analysis of variance indicated that the concentrations in plasma on days 5 and 7 were at steady state. The mean accumulation factor was 1.14 for day 5 and 1.13 for day 7. The half-life (2.4 h) was independent of the duration of drug administration, and the mean maximum concentration of drug in plasma was 18 to 19 micrograms/ml. Urinary excretion was the major elimination route for ceftibuten, by which 57 to 59% of the drug was excreted unchanged over a 24-h period. The amounts of ceftibuten-trans in plasma and urine were low.

Disposition of cefotaxime and desacetyl cefotaxime during continuous ambulatory peritoneal dialysis.

The disposition of cefotaxime (CTX) and desacetyl cefotaxime (DAC) was studied in eight noninfected patients on continuous ambulatory peritoneal dialysis. Each patient received a single intravenous (i.v.) infusion and an intraperitoneal (i.p.) instillation of 2 g of CTX. Multiple blood and dialysate samples were collected during the 72-h period after drug administration. The half-life, steady-state volume of distribution, and total body clearance of CTX following i.v. administration were 2.2 +/- 1.0 h (mean +/- standard deviation), 0.17 +/- 0.03 liters/kg, and 81.0 +/- 31.0 ml/min, respectively. No significant differences were observed in these parameters after i.p. administration. The continuous ambulatory peritoneal dialysis clearances of CTX and DAC were 1.82 +/- 0.43 and 2.84 +/- 0.70 ml/min, respectively, after i.v. administration. The bioavailability of CTX after i.p. instillation was 74.6 +/- 21.3%. Peak peritoneal dialysate CTX and DAC concentrations of 264.3 and 25.8 mg/liter, respectively, were observed after i.p. dosing. Administration (i.v.) of 2 g every 12 h or i.p. instillation of 2 g every 24 h may be used for the treatment of i.p. infections with highly susceptible organisms (MIC less than 1.0 microgram/ml).

Pharmacokinetics and metabolism of 14C-isepamicin in humans following intravenous administration.

Twelve healthy adult male volunteers received 1 g (base equivalent) of 14C-isepamicin (131 microCi) as an intravenous bolus over 5 min. The areas under the plasma concentration-time curves at infinity for isepamicin (196 micrograms*h/ml) and total radioactivity (164 micrograms*h/ml) were similar, indicating no biotransformation of isepamicin. The disappearance of isepamicin from plasma followed a triexponential decline, with half-lives of 0.17, 2.12, and 34 h for the alpha, beta, and gamma phases, respectively. However, the contribution of the gamma phase to the total area under the concentration-time curve was only 2.6%. There were no detectable metabolites in plasma and urine, confirming that isepamicin was not biotransformed. The cumulative levels of isepamicin and total radioactivity excretion in urine from 0 to 120 h were 97.3 and 92.1% of the dose, respectively, indicating that the drug was excreted mainly as unchanged isepamicin in urine.

Pharmacokinetics and dose proportionality of ceftibuten in men.

The pharmacokinetics and dose proportionality of ceftibuten were evaluated in healthy male volunteers receiving single oral doses of 200, 400, and 800 mg of ceftibuten. The drug was absorbed with similar times to the maximum concentration of drug in plasma for all three doses. Concentrations of ceftibuten in plasma increased with increasing dose. Analysis of variance was carried out on the dose-adjusted values for the maximum concentration of drug in plasma and the area under the plasma concentration-time curve; the results indicated that the concentrations in plasma after the 200- and 400-mg doses were dose proportional, and after the 800-mg of dose they were less than dose proportional. The elimination half-life from plasma ranged from 2.0 to 2.3 h and was independent of dose. The total excretion of unchanged ceftibuten in urine accounted for 53 to 68% of the dose, and the renal clearance was estimated to be 53 to 61 ml/min after all doses. The amount of ceftibuten-trans, the major in vitro and in vivo conversion product of ceftibuten, was low in both plasma and urine.

Pharmacokinetic equivalence of pediatric dosages of desloratadine syrup in children and standard 5-mg desloratadine tablets in adults

CONCLUSIONS: Fexofenadine rapidly reduced the symptoms of nasal congestion in PAR, and this effect was maintained throughout the 4week study period. This early effect may reflect the anti-allergic activity of fexofenadine, as nasal congestion is a symptom caused by allergic inflammation. This pilot study supports the clinical efficacy of fexofenadine in PAR, and provides further evidence of its efficacy in the management of nasal congestion. 2 7 R Pharmacokinetic Equivalence of Pediatric Dosages of DesloI 1 , 1 ratadine Syrup in Children and Standard 5-mg Desloratadine Tablets in Adults Christopher Banfield, Samir Gupta, Melton Affrime, Vijay Batra Schering Plough, Kenilworth, NJ Desloratadine (DL), a novel, nonsedating Hi-receptor antagonist, has previously demonstrated safety and efficacy in adult patients with seasonal allergic rhinitis and chronic idiopathic urticaria. In these studies, the pharmacokinetic profiles of 1.25-rag and 2.5-mg doses of DL syrup were evaluated in children 2-5 and 6-11 years of age, respectively, and compared with values obtained in adults receiving a standard 5-mg DL tablet. Two openlabel, single-dose trials (N = 18 for each) of DL syrup (0.5 mg/mL) were conducted in healthy male and female children. As in previous adult trials, blood samples were collected prior to drug administration and at ten prespecified time points over the course of 96 hours; AUC (from time 0 to the final measurable sampling time) and Cma x values were calculated for DL and its metabolite, 3-OH DL. Subjects were carefully monitored and questioned throughout the study for possible adverse events. A thorough physical examination, ECG, and clinical laboratory tests were performed upon entry and at study completion. The 1.25-rag and 2.5-mg doses of DL syrup produced pharmacokinetic values similar to those observed previously in adults administered a standard 5-mg DL tablet. The mean AUC and Cma x values for the 1.25 mg/2-5 y and 2.5 mg/6-11 y groups were 42.0 ng.hr/mL and 2.68 ng/mL, and 48.6 ng.hr/mL and 2.23 ng/mL, respectively. The corresponding mean values in adults receiving a 5-mg DL tablet were 45.8 ng.hr/mL and 2.44 ng/mL. Mean 3-OH DL pharmacokinetic values were also comparable between adults and each group of children. Desloratadine was safe and well tolerated in both age groups. No adverse events were reported. These studies demonstrate that 1.25-mg and 2.5-mg doses of DL syrup in children 2-5 and 6-11 years of age, respectively, produce a comparable degree of drug exposure to that observed in adults receiving the recommended 5-mg dose of DL. The pharmacokinetic equivalence of the adult and pediatric doses suggests that the efficacy and safety of DL may be comparable in pediatric and adult populations. 7 Q Fixed-Dose Desloratadine and Pseudoephedrine Relieves Mod/ ~ erate/Severe Nasal Congestion in Patients With Seasonal Allergic Rhinitis Eric Schenkel*, Jonathan Corren§, JJ Murray¥ *Valley Clinical Research Center, Easton, PA §Allergy Research Foundation Incorporated, Los Angeles, CA ¥Vanderbilt University, Nashville, TN Nasal congestion, the most bothersome symptom of seasonal allergic rhinitis (SAR) for many patients, typically responds poorly to antihistamines. Previous clinical studies, however, have suggested that desloratadine (DL), a next-generation, nonsedating HI-receptor antagonist, possesses intrinsic decongestant activity. While DL alone has been shown to effectively treat mild/moderate nasal congestion in patients with SAR, more severe congestion may require pseudoephedrine (PSE). The efficacy of a DL/PSE combination tablet was investigated in a multicenter, randomized, parallel-group, double-blind study, conducted during the fall allergy season, to determine if a therapeutic advantage was conferred to patients with moderate/severe congestion. Patients enrolled were aged 12-78 years with a minimum 2-year history of SAR and at least moderate nasal congestion at baseline, in addition to other SAR symptoms. Patients received DL/PSE 5/240 mg (n = 336) combination tablet, DL 5 mg (n = 340), or PSE 240 mg (n = 342) once each morning for 15 days. The severity of nasal congestion was measured using a 4-point scale (0 = none to 3 = severe). Scores were recorded every am and pm, to assess how patients felt over the previous 12 hours (reflective score). At baseline, the average congestion score for all groups was at least 2.54 (maximum = 3), indicating patients suffered from moderate/severe congestion. The effect of treatment on nasal congestion was measured as change from baseline in mean am/pro reflective nasal congestion score. Compared with DL (~).65) or PSE (~).70) alone, the DL/PSE combination tablet was significantly superior in reducing nasal congestion (~).85) over the entire 2-week study period (DL/PSE vs DL, P 0.05). Sneezing score was significantly lower in patients treated with loratadine and montelukast, cetirizine and montelukast, and cetirizine alone. We may conclude that 6 week pre-treatment with cetirizine and montelukast provides the most effective prevention of allergic rhinitis symptoms. Group 1 Group 2 Group 3 Group 4 Group 5 Congestion 1.05 +/0.07 0.95 +/0.07 1.00 +/0.06 1.00 +/0.06 0.52 +/0.05 Rhinorrhea 0.62 +/0.07 0.84 +/0.07 1.62 +/0.10 1.08 +/0.06 0.31 +/0.04 Itching 0.75 +/0.06 0.35 +/0.05 1.62 +/0.08 0.56 +/0.05 0.43 +/0.09 Sneezing 0.94+/-0.06 1.59+/-0.10 1.50+/-0.08 0.89+/-0.06 0.87+/-0.06