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.     

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.     

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 and safety of intravenous voriconazole in children after single- or multiple-dose administration

We conducted a multicenter study of the safety, tolerability, and plasma pharmacokinetics of the parenteral formulation of voriconazole in immunocompromised pediatric patients (2 to 11 years old). Single doses of 3 or 4 mg/kg of body weight were administered to six and five children, respectively. In the multiple-dose study, 28 patients received loading doses of 6 mg/kg every 12 h on day 1, followed by 3 mg/kg every 12 h on day 2 to day 4 and 4 mg/kg every 12 h on day 4 to day 8. Standard population pharmacokinetic approaches and generalized additive modeling were used to construct the structural pharmacokinetic and covariate models used in this analysis. In contrast to that in adult healthy volunteers, elimination of voriconazole was linear in children following doses of 3 and 4 mg/kg every 12 h. Body weight was more influential than age in accounting for the observed variability in voriconazole pharmacokinetics. Elimination capacity correlated with the CYP2C19 genotype. Exposures were similar at 4 mg/kg every 12 h in children (median area under the concentration-time curve (AUC), 14,227 ng. h/ml) and 3 mg/kg in adults (median AUC, 13,855 ng. h/ml). Visual disturbances occurred in 5 (12.8%) of the 39 patients and were the only drug-related adverse events that occurred more than once. No withdrawals from the study were related to voriconazole. We conclude that pediatric patients have a higher capacity for elimination of voriconazole per kilogram of body weight than do adult healthy volunteers and that dosages of 4 mg/kg may be required in children to achieve exposures consistent with those in adults following dosages of 3 mg/kg.     

Determination of Vancomycin Pharmacokinetics in Neonates To Develop Practical Initial Dosing Recommendations

Variability in neonatal vancomycin pharmacokinetics and the lack of consensus for optimal trough concentrations in neonatal intensive care units pose challenges to dosing vancomycin in neonates. Our objective was to determine vancomycin pharmacokinetics in neonates and evaluate dosing regimens to identify whether practical initial recommendations that targeted trough concentrations most commonly used in neonatal intensive care units could be determined. Fifty neonates who received vancomycin with at least one set of steady-state levels were evaluated retrospectively. Mean pharmacokinetic values were determined using first-order pharmacokinetic equations, and Monte Carlo simulation was used to evaluate initial dosing recommendations for target trough concentrations of 15 to 20 mg/liter, 5 to 20 mg/liter, and ≤20 mg/liter. Monte Carlo simulation revealed that dosing by mg/kg of body weight was optimal where intermittent dosing of 9 to 12 mg/kg intravenously (i.v.) every 8 h (q8h) had the highest probability of attaining a target trough concentration of 15 to 20 mg/liter. However, continuous infusion with a loading dose of 10 mg/kg followed by 25 to 30 mg/kg per day infused over 24 h had the best overall probability of target attainment. Initial intermittent dosing of 9 to 15 mg/kg i.v. q12h was optimal for target trough concentrations of 5 to 20 mg/liter and ≤20 mg/liter. In conclusion, we determined that the practical initial vancomycin dose of 10 mg/kg vancomycin i.v. q12h was optimal for vancomycin trough concentrations of either 5 to 20 mg/liter or ≤20 mg/liter and that the same initial dose q8h was optimal for target trough concentrations of 15 to 20 mg/liter. However, due to large interpatient vancomycin pharmacokinetic variability in neonates, monitoring of serum concentrations is recommended when trough concentrations between 15 and 20 mg/liter or 5 and 20 mg/liter are desired.     

Pharmacokinetics of cefprozil in infants and children.

Twenty pediatric patients (ages, between 8 months and 8 years) received a single oral dose of cefprozil at levels of 15 and 30 mg/kg of body weight. Cefprozil consists of cis (BMY-28100) and trans (BMY-28167) isomers in an approximately 90:10 ratio. Six plasma samples were collected from each pediatric patient and assayed for drug concentrations. As measured by a microbiological assay, peak concentrations of 11.16 and 15.93 micrograms of cefprozil per ml occurred at 1 h for patients who received the 15- and 30-mg/kg doses, respectively. The respective mean half-lives of cefprozil were 1.77 and 2.14 h, and the respective mean areas under the curve were 28.05 and 45.28 micrograms.h/ml for patients who received the 15- and 30-mg/kg doses. When measured by a high-pressure liquid chromatography method, peak concentrations of 12.09 and 18.04 micrograms of the cis isomer per ml were obtained at 1 h, with mean half-lives of 1.63 and 2.06 h and mean areas under the curve of 30.48 and 49.34 micrograms.h/ml in patients who received the 15- and 30-mg/kg doses, respectively. For the trans isomer, peak concentrations of 1.16 and 1.63 micrograms/ml occurred at 1 h, respectively, with mean half-lives of 1.61 and 1.65 h and mean areas under the curve of 2.89 and 4.34 micrograms.h/ml in patients who received the 15- and 30-mg/kg doses, respectively.     

Single- and Multiple-Dose Pharmacokinetics of Reduced Metabolite (MDL 74,156) following Oral Administration of Dolasetron Mesylate to Normal Male Subjects

Dolasetron, a 5-hydroxytryptamine(3) receptor antagonist, is under investigation for prevention of nausea and vomiting due to chemotherapy. The keto-reduced metabolite of dolasetron has been identified in human plasma and is likely responsible for the antiemetic activity. This study evaluated single and multiple dose pharmacokinetics of the reduced metabolite following oral administration of dolasetron mesylate in healthy male subjects. Five groups (six active/two placebo each) of subjects received either oral doses of dolasetron mesylate ranging from 25 to 200 mg or placebo on day 1 and every 12 h on days 2 through 9. Because plasma dolasetron concentrations were low and sporadic, pharmacokinetics of the parent compound could not be determined. The reduced metabolite appeared rapidly in the plasma and reached a maximal plasma concentration in about 1 h. The maximal plasma concentrations and areas under plasma concentration--time curves were proportional to the dose. The mean apparent oral clearance ranged from 9.89 to 23.10 ml min(minus sign1) kg(minus sign1). The half-life ranged from 5.20 to 10.80 h. Mean renal clearance and fraction of dose excreted in urine were 0.97 to 3.97 ml min(minus sign1) kg(minus sign1) and 7.47 to 31.9%, respectively. The pharmacokinetics of reduced metabolite appears to be dose independent after single and multiple dosing.     

Pharmacokinetics of a syrup formulation of amoxycillin-potassium clavulanate in children

The pharmacokinetics of a syrup formulation consisting of four parts of amoxycillin and one part of potassium clavulanate (Augmentin) were studied in 11 paediatric patients, 3 to 14 years of age. Single oral doses of 25 mg of Augmentin per kg body weight (20 mg of amoxycillin per kg plus 5 mg of potassium clavulanate per kg, i.e. 1 mg of the syrup per kg) were administered on an empty stomach, and were well accepted and tolerated. Mean peak plasma concentrations 60-90 min after dosing were 7.2 mg/l for amoxycillin and 2.0 mg/l for clavulanic acid. Mean terminal phase plasma half-lives were 1.4 and 1.0 h, respectively. It is concluded that 25-mg/kg doses of this syrup formulation of Augmentin administered three times daily should be adequate therapy for various childhood bacterial infections.     

Single-dose pharmacokinetics of piperacillin and tazobactam in infants and children.

The pharmacokinetics of piperacillin and tazobactam were assessed after single-dose administration to 47 infants and children. Study subjects ranging in age from 2 months to 12 years were randomized to receive one of two different doses of a piperacillin-tazobactam combination (8:1): a low dose (n = 23) of 50 and 6.25 mg of piperacillin and tazobactam per kg of body weight, respectively, or a high dose (n = 24) of 100 and 12.5 mg, respectively. The pharmacokinetic behavior of tazobactam was very similar to that observed for piperacillin, supporting the use of these two agents in a fixed-dose combination. No differences in the pharmacokinetics of piperacillin or tazobactam were observed between the two doses administered. The elimination parameters half-life and total body clearance decreased and increased, respectively, with increasing age, whereas volume parameters (volume of distribution and steady-state volume of distribution) remained relatively constant for both compounds. The primary metabolite of tazobactam, metabolite M1, was measurable in the plasma of 18 of the 47 study subjects; 17 of these 18 subjects received the high doses. More than 70% of the administered piperacillin and tazobactam doses were excreted unchanged in the urine over a 6-h collection period. These data combined with the known in vitro susceptibilities of a broad range of pediatric bacterial pathogens indicate that a dose of 100 mg of piperacillin and 12.5 of mg tazobactam per kg of body weight administered as a fixed-dose combination every 6 to 8 h would be appropriate to initiate clinical efficacy studies in infants and children for the treatment of systemic infections arising outside of the central nervous system.     

Pharmacokinetics of meropenem (ICI 194,660) and its metabolite (ICI 213,689) in healthy subjects and in patients with renal impairment.

The pharmacokinetics of meropenem (ICI 194,660) and its open-ring metabolite (ICI 213,689) were studied in 6 healthy volunteers and 16 patients with moderate to severe renal impairment after a single intravenous dose of 500 mg given as a 30-min infusion. Concentrations of unchanged meropenem in plasma and urine were measured by both microbiological and high-pressure liquid chromatographic (HPLC) assays. A good correlation was found between the two techniques. Pharmacokinetic parameters of unchanged meropenem were determined by using the HPLC data. The terminal half-life of unchanged meropenem increased in relation to the degree of renal impairment, being 1.2 h in subjects with normal renal function and 10 h in patients with end-stage renal failure. Total body clearance and renal clearance of unchanged meropenem are linearly related to creatinine clearance. The concentrations of the metabolite in plasma, which are very low in healthy subjects, significantly increased in uremic patients. The apparent half-life of ICI 213,689 increased in uremic patients and was about 35 h in patients with severe renal insufficiency. Meropenem and its metabolite are effectively removed by hemodialysis. The dialysis clearance of the unchanged drug was 81 +/- 22 ml/min. Dosage adjustments of meropenem will be necessary in patients with severe renal impairment.     

Pharmacokinetics of gatifloxacin in infants and children

Gatifloxacin is an 8-methoxy fluoroquinolone effective against a broad spectrum of pathogens common in pediatric infections. The safety and pharmacokinetics of a single dose of gatifloxacin were studied in pediatric patients from 6 months to 16 years of age. Seventy-six pediatric patients (average age, 6.7 +/- 5.0 years) were administered a single oral dose of gatifloxacin suspension (5, 10, or 15 mg/kg of body weight; 600-mg maximum) in a dose-escalating manner. Subjects were stratified by age into 4 groups. An additional 12 children, greater than 6 years of age, received gatifloxacin as the tablet formulation at a dose of approximately 10 mg/kg. Gatifloxacin's apparent clearance and half-life were 5.5 +/- 2.1 ml/min/kg and 5.1 +/- 1.4 h. The maximum concentration of drug in plasma and area under the concentration-time curve (AUC) increased in a manner approximately proportional to the dose. At the 10-mg/kg dose, the bioavailability was similar between the suspension and tablet formulation. The apparent oral clearance of gatifloxacin, normalized for body weight, exhibited a small but statistically significant decrease with increasing age. In all subjects receiving gatifloxacin at 10 mg/kg, the AUC exceeded 20 microg . h/ml (estimated free AUC/MIC ratio of > or =34 for MIC of < or =0.5 microg/ml). These data suggest that gatifloxacin at a dose of 10 mg/kg every 24 h will achieve therapeutic concentrations in plasma in infants and children.     

Amikacin pharmacokinetics in pediatric patients with malignancy.

The pharmacokinetics of amikacin were evaluated in 50 pediatric patients (1 to 17 years of age) with malignancies and normal renal function. Dosage regimens of 5 mg/kg per dose were administered intravenously (i) over 30 min every 8 h, (ii) over 60 min every 8 h, and (iii) over 60 min every 6 h. Administration of amikacin over 30 min produced concentrations in serum of 29.3 +/- 5.7 micrograms/ml at the end of the infusion and subtherapeutic concentrations 4 h after the infusion. The regimen of 20 mg/kg per 24 h, divided into doses given every 6 h infused over 60 min, achieved concentrations in serum at the end of the infusion of 17.2 +/- 1.7 micrograms/ml and at 6 h of 1.2 +/- 0.3 microgram/ml. The serum half-life was 1.24 +/- 0.09 h, volume of distribution was 0.26 +/- 0.02 liter/kg, and total body clearance rate was 131 +/- 10 ml/min per 1.73 m2. No accumulation of amikacin was noted, and no significant side effects could be attributed to the drug. This study suggests that the optimal initial dosage regimen of amikacin in children is 20 mg/kg per 24 h administered in equal doses every 6 h over 60 min; however, optimal therapy requires individualization of dosage based on measured serum concentrations and susceptibility data on bacterial pathogens isolated.     

Pharmacokinetics of intravenously administered isepamicin in men.

The pharmacokinetics of isepamicin, a broad-spectrum aminoglycoside antibiotic, were studied in men after intravenous administration. Three groups of six volunteers received isepamicin for 10 consecutive days by 0.5-h intravenous infusions at respective dosages of 7.5 mg/kg of body weight once daily, 7.5 mg/kg twice daily, and 15 mg/kg once daily. Levels of isepamicin in plasma and urine were determined by a specific high-performance liquid chromatography method. For all three groups, steady-state concentrations of the drug in plasma were attained with the first dose. The area under the concentration-time curve for plasma and urinary drug excretion were dose proportional. A half-life ranging from 2.0 to 2.5 h was independent of the dosage regimen. Isepamicin excreted in urine over 24 h accounted for about 100% of the dose. The results show that the pharmacokinetics of isepamicin are linear with these dosage regimens. The drug does not accumulate upon multiple dosing, undergoes no detectable biotransformation, and is cleared solely by urinary excretion.     

Pharmacokinetics of amdinocillin in healthy adults.

The pharmacokinetics of amdinocillin (mecillinam) were determined in 10 healthy volunteers. Single doses of 10 and 15 mg/kg of body weight were administered intravenously and intramuscularly in a crossover study. Plasma concentrations of amdinocillin were determined by microbiological assay. Mean peak plasma concentrations were 49 and 87 micrograms/ml after intravenous doses of 10 and 15 mg/kg, respectively. The terminal half-life value of 0.89 h was similar for both doses. After intramuscular injections, the mean concentration of drug in plasma was 26.2 micrograms/ml for the 10-mg/kg dose and 29.6 micrograms/ml for the 15-mg/kg dose, with terminal half-lives of 0.96 and 0.86 h, respectively. The mean apparent volumes of distribution at steady state were 18 and 16 liters/100 kg for the intravenous doses of 10 and 15 mg/kg, respectively. Drug concentrations in plasma at 4 h were above the minimal inhibitory concentrations for gram-negative organisms categorized as susceptible to this drug.     

Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects

The purpose of this paper is to establish the pharmacokinetics and safety of escalating, once-daily doses of daptomycin, a novel lipopeptide antibiotic active against gram-positive pathogens, including those resistant to methicillin and vancomycin. This phase 1, multiple-dose, double-blind study involved 24 healthy subjects in three dose cohorts (4, 6, and 8 mg/kg of body weight) who were randomized to receive daptomycin or the control at a 3:1 ratio and administered the study medication by a 30-min intravenous infusion every 24 h for 7 to 14 days. Daptomycin pharmacokinetics was assessed by blood and urine sampling. Safety and tolerability were evaluated by monitoring adverse events (AEs) and laboratory parameters. Daptomycin pharmacokinetics was linear through 6 mg/kg, with a slight ( approximately 20%) nonlinearity in the area under the curve and trough concentration at the highest dose studied (8 mg/kg). The pharmacokinetic parameters measured on the median day of the study period, (day 7) were half-life ( approximately 9 h), volume of distribution ( approximately 0.1 liters/kg), systemic clearance ( approximately 8.2 ml/h/kg), and percentage of the drug excreted intact in urine from 0 to 24 h ( approximately 54%). Daptomycin protein binding (mean amount bound, 91.7%) was independent of the drug concentration. No gender effect was observed. All subjects who received daptomycin completed the study. The frequencies and distributions of treatment-emergent AEs were similar for the subjects who received daptomycin and the control subjects. There were no serious AEs and no pattern of dose-related events. The pharmacokinetics of once-daily administration of daptomycin was linear through 6 mg/kg. For all three doses, plasma daptomycin concentrations were consistent and predictable throughout the dosing interval. Daptomycin was well tolerated when it was administered once daily at a dose as high as 8 mg/kg for 14 days.     

Pharmacokinetics of cefpirome in pediatric patients.

Cefpirome is a new investigational cephalosporin. We designed a study to determine the pharmacokinetics and tolerance of cefpirome in pediatric patients. A single dose of cefpirome was administered intravenously over 15 min to 18 patients (age 0.5 to 18 years). The doses were 10 mg/kg of body weight for five patients, 25 mg/kg of body weight for seven patients, and 50 mg/kg of body weight for six patients. Blood samples were collected at 0, 0.25, 0.5, 1, 3, 5, and 8 h after the dose, and cefpirome was measured by a high-performance liquid chromatography method. The maximum concentration in serum ranged from about 53.6 to 454 micrograms/ml after doses of 10 to 50 mg/kg. The total body clearance, apparent volume of distribution, and elimination half-life were 2.15 +/- 0.70 ml/min/kg, 0.32 +/- 0.32 liter/kg, and 1.8 +/- 1.3 h, respectively. No significant adverse effects were attributed to cefpirome. These data may be useful in conducting efficacy and safety studies of cefpirome in pediatric patients.     

PHARMACOKINETICS OF INTRAVENOUS CAFFEINE IN CRITICALLY ILL PATIENTS

The pharmacokinetics of intravenous caffeine used to measure liver function were evaluated in 20 critically ill patients. Each patient received a single dose of 3.0 mg/kg of caffeine benzoate as a 30-min i.v. infusion. Caffeine serum concentrations were analysed by an enzyme-multiplied immunoassay technique (EMIT). Caffeine pharmacokinetics fitted an open one-compartment model. The mean value for the half-life (t1/2) was 9.46 +/- 4.32 h, the volume of distribution was 0.55 +/- 0.13 l/kg, and the plasma clearance (Cl) was 0.85 +/- 0.44 ml/min/kg. The pharmacokinetics parameters of caffeine in critically ill patients compared with normal volunteers were characterized by a reduction in plasma clearance and prolongation in plasma half-life, whereas the volume of distribution remained unchanged.     

Pharmacokinetic properties of single-dose loratadine and ambroxol alone and combined in tablet formulations in healthy men

BACKGROUND: Due to Mexico's complicated socioeconomic environment, causing a high occurrence of >1 person sharing a single room, respiratory conditions are spread easily. Respiratory conditions are the main reason for consultation with a physician. The most frequent symptoms are throat soreness and cough; therefore, a new formulation combining loratadine and ambroxol hydrochloride was designed to treat these 2 major symptoms. The combination is expected to provide relief when coprescribed with more specific therapies, such as antibiotics. OBJECTIVE: This study determined the pharmacokinetic profile of single-dose loratadine-ambroxol hydrochloride combination therapy versus each component given separately. The analyses included descarboethoxyloratadine (DCL), the primary active metabolite of loratadine. METHODS: This was a 4-week, single-center, randomized, open-label, 3-period crossover study in adult male volunteers aged 18 to 50 years and in good general health. Subjects were randomized to receive single doses of treatment A (2 loratadine 5-mg tablets + ambroxol 30-mg tablets), B (2 ambroxol 30-mg tablets), or C (1 loratadine 10-mg tablet) in 1 of 3 sequences (ABC, BCA, or CAB) per period. A 14-day washout period separated each treatment period. Plasma concentration-time data curves for each subject and treatment were analyzed by noncompart-mental methods to obtain values for area under the curve (AUC), maximum plasma concentration (C(max)), and time to reach C(max) (T(max)). RESULTS: Thirty subjects (mean [SD] age, 22.5 [2.6] years) were enrolled. All treatments were well tolerated. Formulations A and C produced similar loratadine and DCL AUC from time 0 to 24 hours (AUC(0-24)) values, but showed slightly high C(max). values for loratadine and slightly low C(max) values for DCL, indicating failure to demonstrate bioinequivalence. Formulations A and B produced similar ambroxol C(max), T(max), and AUC(0-24) values. CONCLUSIONS: In this population of healthy mate volunteers, results showed the bioavailability of loratadine and ambroxol from the new formulation and did not show impairment of absorption when the drugs were formulated in a combination tablet.     

Compartmental pharmacokinetics and tissue distribution of the antifungal triazole ravuconazole following intravenous administration of its di-lysine phosphoester prodrug (BMS-379224) in rabbits

OBJECTIVES: Ravuconazole is a broad-spectrum antifungal triazole in clinical development. We investigated the compartmental plasma pharmacokinetics and tissue distribution of ravuconazole following administration of its novel intravenous (i.v.) di-lysine phosphoester prodrug, BMS-379224. METHODS: Normal catheterized rabbits received the prodrug at 1.25, 2.5, 5, 10, 20 and 40 mg/kg once daily as 5 min i.v. bolus for 8 days. Serial plasma levels were collected at days 1 and 7, and tissues were obtained 30 min after the eighth dose. Concentrations of ravuconazole were determined by a validated HPLC method. Plasma concentration data were fitted to a three-compartment pharmacokinetic model. Pharmacokinetic parameters were estimated by weighted non-linear least squares regression analysis using the WinNonlin computer program. RESULTS: Following single dosing, ravuconazole demonstrated linear plasma pharmacokinetics across the investigated dosage range. Cmax, AUC(0-infinity), V(ss), CL and terminal half-life (means +/- SEM) ranged from 2.03 to 58.82 mg/L, 5.80 to 234.21 mg x h/L, 5.16 to 6.43 L/kg, 0.25 to 0.18 L/h/kg and 20.55 to 26.34 h, respectively. Plasma data after multiple dosing revealed non-linear disposition at the 20 and 40 mg/kg dosage levels as evidenced by a dose-dependent decrease in CL (from 0.104-0.147 to 0.030 and 0.022 L/h/kg; P = 0.1053) and an increase in the dose-normalized AUC(0-infinity) (from 2.40-3.01 up to 11.90 and 14.56 mg x h/L; P = 0.0382). Tissue concentrations 30 min after the last dose were highest in the liver (12.91-562.68 microg/g), adipose tissue (10.57-938.55 microg/g), lung (5.46-219.12 microg/g), kidney (3.95-252.44 microg/g) and brain tissue (2.37-144.85 microg/g). CONCLUSIONS: The pharmacokinetics of ravuconazole fitted best to a three-compartment pharmacokinetic model. The compound revealed non-linear pharmacokinetics at higher dosages, indicating saturable clearance and/or protein binding. Ravuconazole displayed a long elimination half-life and achieved substantial plasma and tissue concentrations including in the brain.     

Serum and sputum concentrations of netilmicin in combination with acylureidopenicillin and cephalosporins in clinical treatment of pulmonary exacerbations in cystic fibrosis

The pharmacokinetics of netilmicin was studied in 14 patients with cystic fibrosis, aged 4-21 years (mean 16 years) during treatment of pulmonary exacerbations of pseudomonas infection. The patients received 24 courses of netilmicin (10 mg/kg/day) in combination with azlocillin (600 mg/kg/day), cefsulodin (200 mg/kg/day) or ceftazidime (150 mg/kg/day) for 9-14 days. Seven patients received two or three courses of different combinations. Serum and sputum concentrations of netilmicin were determined on day 2 and 6. Mean (+/- S.E.M.) trough serum values were 1.4 +/- 0.2 mg/l (same on day 2 and 6), peak values at 10 min 13.6 +/- 1.0 and 13.7 +/- 0.9 mg/l, and serum concentration at 1 h 7.5 +/- 0.6 and 7.5 +/- 0.5 mg/l, on days 2 and 6 respectively. The half-life was about 1 h. The pharmacokinetics did not differ on day 2 and 6. Sputum concentrations increased up to 2-3 h after administration, mean (+/- S.E.M.) peak values being 2.6 +/- 0.6 and 1.5 +/- 0.4 mg/l at day 2 and 6, respectively. The study shows that the pharmacokinetics of netilmicin was not influenced by different combinations with beta-lactams. All patients improved clinically, but pseudomonas growth was only reduced in nine courses. In one case transient resistance to netilmicin developed during the treatment. The clinical efficacy and tolerance were good and similar to those seen with combinations with other aminoglycosides.