Intrapulmonary steady-state concentrations of clarithromycin and azithromycin in healthy adult volunteers.

The steady-state concentrations of clarithromycin and azithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained in intrapulmonary samples during bronchoscopy and bronchoalveolar lavage from 40 healthy, nonsmoking adult volunteers. Mean plasma clarithromycin, 14-(R)-hydroxyclarithromycin, and azithromycin concentrations were similar to those previously reported. Clarithromycin was extensively concentrated in ELF (range of mean +/- standard deviation concentrations, 34.4 +/- 29.3 microg/ml at 4 h to 4.6 +/- 3.7 microg/ml at 24 h) and AM (480 +/- 533 microg/ml at 4 h to 99 +/- 50 microg/ml at 24 h). The concentrations of azithromycin in ELF were 1.01 +/- 0.45 microg/ml at 4 h to 1.22 +/- 0.59 microg/ml at 24 h, and those in AM were 42.7 +/- 28.7 microg/ml at 4 h to 41.7 +/- 12.1 microg/ml at 24 h. The concentrations of 14-(R)-hydroxyclarithromycin in the AM ranged from 89.3 +/- 52.8 microg/ml at 4 h to 31.3 +/- 17.7 microg/ml at 24 h. During the period of 24 h after drug administration, azithromycin and clarithromycin achieved mean concentrations in ELF and AM higher than the concomitant concentrations in plasma.     

Intrapulmonary pharmacokinetics of telithromycin, a new ketolide, in healthy Japanese volunteers

The concentrations of telithromycin, a new ketolide antimicrobial agent, in alveolar macrophages (AMs) and bronchoalveolar epithelial lining fluid (ELF) were determined in order to investigate the transfer of the drug into target tissue, relative to plasma, following multiple oral doses of telithromycin. Twenty-four healthy male Japanese volunteers were randomly allocated to four groups. Each subject was given 600 or 800 mg of telithromycin once daily for 5 days, followed by bronchoalveolar lavage (BAL) 2 or 8 h after the last dose (group A and B: 600 mg, 2 and 8 h BAL time point; group C and D: 800 mg, 2 and 8 h BAL time point). The mean concentrations of the drug in AMs and ELF were 34.54 and 4.92 mg/liter in group A, 50.97 and 2.26 mg/liter in group B, 25.47 and 4.24 mg/liter in group C, and 108.22 and 4.31 mg/liter in group D, respectively, which markedly exceeded concentrations in plasma. These results demonstrated good transfer of telithromycin into AMs and ELF, suggesting good efficacy against common respiratory pathogens, including intracellular pathogens and atypical microorganisms.     

Multiple-dose pharmacokinetics and safety of oral amifloxacin in healthy volunteers.

The multiple-dose pharmacokinetics and safety of amifloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy male volunteers. Amifloxacin was administered orally at 200, 400, or 600 mg every 12 h (q12h) and 400, 600, or 800 mg every 8 h (q8h) for 10 days. An additional dose was administered on day 11. Concentrations of amifloxacin in plasma and urine were measured on days 1, 5, and 11 by high-performance liquid chromatography. Steady-state amifloxacin concentrations were reached by day 5. Mean +/- standard deviation maximum observed amifloxacin concentrations in plasma were 2.52 +/- 1.12, 4.98 +/- 1.44, 5.40 +/- 2.02, 4.59 +/- 2.17, 6.53 +/- 2.44, and 8.01 +/- 3.00 micrograms/ml after the initial dose and 2.30 +/- 0.98, 5.41 +/- 0.74, 8.05 +/- 1.68, 6.87 +/- 2.81, 9.53 +/- 0.50, and 11.9 +/- 1.92 micrograms/ml on day 11 of the study for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. Amifloxacin was rapidly absorbed, as evidenced by the mean time to the maximum observed amifloxacin concentration of 0.98 h. Mean values for the terminal amifloxacin half-life in plasma ranged from 3.58 to 5.78 h. Mean amifloxacin concentrations in urine on day 11 in samples collected 0 to 2 h after dosing were 105, 417, 376, 336, 518, and 464 micrograms/ml for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. The mean amount of the dose excreted in the urine as amifloxacin was 53.9%. Amifloxacin was generally well tolerated, although there was a tendency for the subjects who received amifloxacin to experience more gastrointestinal, central nervous system, and cutaneous complaints than did those who received placebo. Clinically significant adverse reactions, including pruritus and transaminase elevations, occurred only at doses of 1,200 mg/day or above. Clinical and pharmacokinetic data suggest that orally administered amifloxacin may have utility in the treatment of urinary tract infections.     

Pharmacokinetics of rufloxacin in healthy volunteers after repeated oral doses.

Rufloxacin is a new broad-spectrum fluoroquinolone antibacterial agent. The pharmacokinetics and safety of rufloxacin were evaluated after repeated oral administration to healthy volunteers. The drug was administered once a day for 6 consecutive days following two different dose schedules. The first group of 11 subjects was given a loading dose of 300 mg on the first day and 150 mg on the subsequent 5 days. The second group of 12 subjects was given a loading dose of 400 mg and 200 mg for 5 days. Serum levels and urine concentrations of rufloxacin were determined by microbiological assay. A simultaneous fit of all data points for each subject was done according to a one-compartment open model. The drug was rapidly absorbed (absorption half-life 17 +/- 6 min in the 300 + 150 mg and 11 +/- 5 min in the 400 + 200 mg dose regimen group) and reached maximal serum concentrations (2.77 +/- 0.24 and 3.62 +/- 0.35 micrograms/ml) 4.2 +/- 0.4 and 4.0 +/- 0.9 h after the first administration. Steady-state serum concentrations (3.19 +/- 0.31 and 4.06 +/- 0.33 micrograms/ml) were reached in 3.7 +/- 0.7 and 4.5 +/- 0.4 days. Elimination half-lives were 29.5 +/- 2.4 and 36.0 +/- 2.8 h. Apparent volumes of distribution were 111 +/- 8 and 136 +/- 16 liters and apparent plasma clearances were 46 +/- 5 and 44 +/- 4 ml/min. Renal clearances were 18 +/- 3 and 17 +/- 2 ml/min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Safety and pharmacokinetics of multiple doses of intravenous ofloxacin in healthy volunteers.

The safety and pharmacokinetics of ofloxacin in 48 healthy male volunteers were studied in a two-center, randomized, double-blind, placebo-controlled study. Ofloxacin (200 or 400 mg) or placebo was administered as 1-h infusions every 12 h for 7 days. Plasma ofloxacin concentrations were measured by high-performance liquid chromatography. Mean harmonic half-lives ranged from 4.28 to 4.98 h in the 200-mg dosing group and from 5.06 to 6.67 h in the 400-mg dosing group. Intragroup comparisons of trough plasma concentration-versus-time data from study days 2 through 7 revealed that steady state was achieved by day 2 of both multiple-dose regimens. Intergroup comparisons of mean harmonic half-lives, the areas under the concentration-time curve from 0 to 12 and 0 to 60 h, clearance, and apparent volume of distribution (area method) revealed that the pharmacokinetics of ofloxacin are dose independent. Both ofloxacin dosage regimens appeared to be reasonably well tolerated. The two dosage regimens of ofloxacin, 200 or 400 mg every 12 h, appear to be safe and provide serum drug concentrations in excess of the MICs for most susceptible pathogens over the entire dosing interval.     

Teicoplanin pharmacokinetics in healthy volunteers after administration of intravenous loading and maintenance doses.

Teicoplanin is an investigational glycopeptide antibiotic that is structurally and microbiologically similar to vancomycin. Since teicoplanin possesses a very long elimination half-life, the manufacturer suggests that the drug be administered every 12 h for the first day of therapy and once daily thereafter. We studied the multiple-dose (6 mg/kg per dose) pharmacokinetics of teicoplanin in volunteers following intravenous administration every 12 h for 5 days and then every 24 h for 9 days in an attempt to identify the optimal duration of the every-12-h loading-dose regimen. Multiple serum samples were obtained throughout the study, including intensive sampling after the first and last doses; urine was collected during the entire study. A three-exponential equation was fitted to the serum concentration data. The mean terminal-phase half-life was 157 +/- 93 h. Concentrations of teicoplanin in serum similar to those observed after the administration of the last dose (day 14) were observed following the fourth or fifth dose given every 12 h. Therefore, it is suggested that for clinical dosing regimens for teicoplanin, dosing every 12 h for approximately 48 h should be used, followed by once-daily dosing thereafter.     

Sensitive and specific radioimmunoassay for fialuridine: initial assessment of pharmacokinetics after single oral doses to healthy volunteers.

Fialuridine (FIAU) is a halogen-substituted analog of thymidine that was undergoing clinical investigation as a drug for the treatment of chronic hepatitis B viral infection. However, clinical trials of FIAU were terminated after adverse events occurred following chronic oral administration. Prior to the termination of clinical trials, a sensitive assay was needed for the measurement of FIAU because of the anticipated low dose administered to patients. We therefore undertook the development of a radioimmunoassay (RIA). A specific antiserum was raised in rabbits following immunization with a 5'-O-hemisuccinate analog of FIAU coupled to keyhole limpet hemocyanin. Radiolabeled FIAU was synthesized by a destannylation procedure by using sodium [125I]iodide. We developed a competitive-binding procedure and used precipitation with polyethylene glycol as the method for separating the bound and free forms of FIAU. The RIA is sensitive (0.2 ng/ml), specific (negligible interference from known metabolites and endogenous nucleosides), and reproducible (interassay coefficients of variation range from 5 to 19.7% for serum controls). We used the RIA to assess the pharmacokinetics of FIAU in healthy adult volunteers following administration of a single 5-mg oral dose. The sensitivity of the RIA permitted the detection of a prolonged elimination phase for FIAU in healthy volunteers and dogs, with mean elimination half-lives of 29.3 and 35.3 h, respectively. We conclude the RIA is a valid method for the quantification of FIAU in biological fluids.     

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.     

Multiple-dose pharmacokinetics of amdinocillin in healthy volunteers.

The pharmacokinetics of amdinocillin (mecillinam) after multiple intravenous doses to healthy subjects are described. Assay of plasma and urine samples was carried out with a sensitive and specific high-pressure liquid chromatographic technique. A dose of 10 mg/kg of body weight was administered every 4 h for six doses. No accumulation was noted. Mean peak plasma concentrations were approximately 50 micrograms/ml, and the plasma half-life was approximately 53 min. Total plasma clearance was 4.6 ml/min per kg after the first dose, which declined slightly to 4.1 ml/min per kg after the last dose. Renal clearance remained fairly constant at approximately 2.9 ml/min per kg, or twice the creatinine clearance. The fraction excreted unchanged totaled 63% during the 4-h interval after the first dose and was nearly 70% overall. The steady-state volume of distribution was calculated to be 0.26 liter/kg. Urinary concentrations of amdinocillin were far in excess of the usual inhibitory concentrations for susceptible pathogens and were as high as 3,000 micrograms/ml. Dose of amdinocillin every 4 h provide plasma and urine concentrations which should be effective for the treatment of infections.     

Suction-induced blister fluid penetration of cefdinir in healthy volunteers following ascending oral doses.

The pharmacokinetics and suction-induced blister fluid penetration of cefdinir following single oral administrations of 200, 300, 400, and 600 mg were studied in 16 healthy young male volunteers according to a Latin square design. Plasma, blister, and urine samples were assayed by high-pressure liquid chromatography. We observed a nonlinear relationship (P = 0.02) between the dose and the maximum concentration in plasma as well as between the dose and the area under the concentration-time curve (AUC) in plasma (P < 0.001), which may be indicative of a limited absorption process. This resulted in a lower AUC value than expected as well as a smaller fraction of cefdinir excreted unchanged at a dose of 600 mg. Renal clearance decreased with increasing doses (P < 0.006; analysis of variance with the Latin square design and Games-Howell procedure). Maximal cefdinir concentrations in blister fluid were delayed compared with concentrations in plasma. Blister fluid penetration measured by the ratio of the AUC in blister fluid to the AUC in plasma was extensive (92.4 to 108.4%). Cefdinir concentrations in blister fluid remained equal to or higher than the concentrations in plasma from 6 to 12 h following cefdinir administration. On the basis of the concentrations in blister fluid and the in vitro MIC data, we estimated that cefdinir at 200 to 400 mg administered twice daily would be adequate to treat uncomplicated skin infections caused by Streptococcus pyogenes. Seven volunteers experienced episodes of light-to-moderate diarrhea. These adverse events occurred irrespective of dose.     

Effect of omeprazole on the pharmacokinetics of oral gemifloxacin in healthy volunteers

This randomized, double-blind, 2-way crossover study investigated the effect of omeprazole on the pharmacokinetics of gemifloxacin, a novel fluoroquinolone. Thirteen healthy male volunteers received a 320 mg oral dose of gemifloxacin after 4 days of dosing with either omeprazole (40 mg once daily) or matching placebo. Blood was sampled for 48 h after dosing for determination of pharmacokinetic parameters. The mean area under the plasma concentration-time curve extrapolated to infinity (AUC(0-infinity)) and maximum plasma concentration (C(max)) for gemifloxacin were increased by, on average, 10% (90% confidence interval [CI], 0.89, 1.36) and 11% (90% CI, 0.87, 1.43), respectively, when gemifloxacin was given after omeprazole compared with after placebo. Neither the time to C(max) (T(max)) nor the half-life of gemifloxacin appeared to be affected by administration of omeprazole. There were no clinically relevant changes in adverse events, vital signs or the results of laboratory investigations after co-administration of omeprazole compared with placebo. In view of the modest increase in systemic exposure and the likely maximal increases indicated by the CIs, the effect of omeprazole on gemifloxacin pharmacokinetics is not considered to be clinically significant. Gemifloxacin and omeprazole can therefore be co-administered with no requirement for a dose adjustment. Copyright Copyright 1999 S. Karger AG, Basel     

Serum and WBC pharmacokinetics of 1500 mg of azithromycin when given either as a single dose or over a 3 day period in healthy volunteers

Owing to azithromycin's prolonged half-life, shorter and shorter dosage regimens are being studied for treatment of respiratory tract infections. Previous studies have concluded that the 3 and 5 day (1.5 g total) regimens not only provide at least equal serum and WBC exposures but also equal efficacy rates. An earlier clinical study using the entire 1.5 g dose at once or the current 3 day regimen in patients with atypical pneumonia noted equal efficacy. Similar trials are currently underway in both adult and paediatric populations. The goal of the present study was to investigate whether there were equal serum and WBC exposures when azithromycin was dosed as the current 3 day regimen or as a single large dose. Equal exposures would help validate future clinical trials of single dose regimens. Twelve healthy volunteers received both azithromycin regimens (1.5 g single dose and 500 mg/day for 3 days) in random order. Serum and WBC samples were collected at baseline and repeatedly for 10 days following the first dose of each regimen. Serum samples were assayed via HPLC (CV% < 10) and WBC samples via liquid chromatography/mass spectrometry (CV% < 10). Data were modelled using noncompartmental methods. Statistics were via ANOVA with significance defined as P < 0.05. All subjects completed both regimens with minimal incidence of adverse effects. Serum data [mean (range)] demonstrated no significant difference in exposure between the two regimens [single 13.1 (3.02-20.6) mg x h/L versus 3 day 11.2 (2.98-24.5) mg x h/L: P = 0.12], although it favoured the shorter regimen. WBC results demonstrated much higher exposures than seen with serum, but no significant difference between the two regimens was identified. These results suggest that a single oral 1.5 g regimen of azithromycin for respiratory tract infections should provide exposure at least equal to currently approved treatment regimens.     

Bioavailability and pharmacokinetics of ofloxacin in healthy volunteers.

The pharmacokinetics and bioavailability of ofloxacin in 20 healthy male volunteers were studied in an open-label, randomized, two-way crossover study. Ofloxacin (400 mg) was administered either as a 1-h infusion or as an oral tablet. The mean peak concentration after intravenous infusion was 4.30 +/- 0.69 microgram/ml, and that after oral administration was 3.14 +/- 0.53 microgram/ml, occurring 1.74 +/- 0.57 h after dosing. The bioavailability (F) of the oral dosage form of ofloxacin was virtually identical to that of the intravenous form (F = 105% +/- 7%). This complete bioavailability of ofloxacin is supportive of the use of the oral dosage form for the treatment of infections in hospitalized patients either as a replacement for intravenous ofloxacin therapy or in streamlining therapy from the intravenous to the oral route.     

Pharmacokinetic interaction between single oral doses of diltiazem and sirolimus in healthy volunteers

AIM AND BACKGROUND: The pharmacokinetic interaction between sirolimus, a macrolide immunosuppressant metabolized by CYP3A4, and the calcium channel blocker diltiazem was studied in 18 healthy subjects. Several clinically important interactions have previously been reported for other immunosuppressive drugs that are metabolized by the same enzyme and for calcium antagonists. METHODS: Healthy subjects who were 20 to 43 years old participated in an open, three-period, randomized, crossover study of the pharmacokinetics of a single 10-mg oral dose of sirolimus, a single oral 120-mg dose of diltiazem, and the two drugs given together. The three study periods were separated by a 21-day washout phase. RESULTS: The geometric mean (90% confidence interval) whole blood sirolimus area under the plasma concentration time-curve increased 60% (35%-90%), from 736 to 1178 ng x h/mL, and maximum concentration increased 43% (14%-81%), from 67 to 96 ng/mL, with diltiazem coadministration, whereas the mean elimination half-life of sirolimus decreased slightly, from 79 to 67 hours. Apparent oral clearance and volume of distribution of sirolimus decreased with 38% and 45%, respectively, when sirolimus was given with diltiazem. The plasma maximum concentration and area under the plasma concentration-time curve of diltiazem, desacetyldiltiazem, and desmethyldiltiazem were unchanged after coadministration of sirolimus, and no potentiation of the effects of diltiazem on diastolic or systolic blood pressure or on the electrocardiographic parameters was seen. CONCLUSIONS: Single-dose diltiazem coadministration leads to higher sirolimus exposure, presumably by inhibition of the first-pass metabolism of sirolimus. Because of the pronounced intersubject variability in the extent of the sirolimus-diltiazem interaction, whole blood sirolimus concentrations should be monitored closely in patients treated with the two drugs.     

Safety and pharmacokinetics of escalating daily doses of the antituberculosis drug rifapentine in healthy volunteers

Rifapentine (RP T) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RI F).The maximal tolerated daily dose of RP T and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high asa prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RP T concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration–time curve (AU C0–24) and maximum concentration (Cmax)were similar in the 15- and 20-mg/kg cohorts. Although RP T pharmacokinetics (PK) appeared to be time-dependent,accumulation occurred with daily dosing. The mean AU C0–12 of oral midazolam (MDZ), a cytochrome 3A (CYP 3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01).Changes in the oral clearance of MDZ did not vary by RP T dose. In conclusion, RP T was tolerated at doses as high as20 mg/kg/day, its PK were less than dose-proportional, and its CYP 3A induction was robust.     

Clinical pharmacokinetics of oral azithromycin in epididymal tissue

ObjectivesChlamydia trachomatis is one of the major pathogens causing acute epididymitis. Azithromycin (AZM) has a good efficacy against C. trachomatis; however, the ability of AZM to penetrate into human epididymal tissue has not yet been fully elucidated. Here, we examined the appropriate dosage of oral AZM for human epididymal tissue by site-specific pharmacokinetic/pharmacodynamic (PK/PD) analysis.MethodsPatients with prostate cancer who underwent orchiectomy were included in this study. All patients received a 1-g dose of AZM before orchiectomy. Both epididymal tissue and blood samples were collected during surgery, and the drug concentrations were measured by high-performance liquid chromatography. All concentration-time data were analyzed with a three-compartment model with first-order absorption and elimination processes to simulate AZM concentrations in serum and epididymal tissue.ResultsA total of 10 patients were enrolled in the current study. For the observed values, the ratio of the epididymal concentration to the serum concentration was 5.13 ± 3.71 (mean ± standard deviation). For the simulated values, the maximum concentrations were 0.64 μg/mL at 2.42 h in serum and 1.96 μg/g at 4.10 h in epididymal tissue. The 24-h concentrations were 0.239 μg/mL in serum and 0.795 μg/g in epididymal tissue.ConclusionsThe penetration of oral AZM into human epididymal tissue was examined to assess the potential application of AZM for the treatment of acute epididymitis. Based on the previous reports mentioning drug-susceptibility of C. trachomatis, multiple doses of oral AZM 1 g would be recommended for epididymitis based on the site-specific PK/PD.     

The pharmacokinetics of etanercept in healthy volunteers

OBJECTIVE: To describe the pharmacokinetics of etanercept when administered by subcutaneous injection in single doses to healthy volunteers. METHODS: Twenty-six healthy volunteers between 19 and 50 years of age received single doses of etanercept 25 mg by subcutaneous injection into the abdomen. Serial serum samples were collected for 21 days. An enzyme-linked immunosorbent assay with a quantitation limit of 0.3 ng/mL was used to measure the drug concentrations. RESULTS: Etanercept was well tolerated by healthy volunteers. A one-compartment model was found to best describe the concentration-time data and was used to determine the pharmacokinetic parameters. Etanercept is slowly absorbed from the site of injection with a time of peak concentration (+/- SD) of 51 +/- 14 hours; peak concentration was 1.46 +/- 0.72 mg/L. The AUC was 235 +/-98 mg x h/L, apparent clearance was 132 +/- 85 mL/h, apparent volume of distribution was 12 +/- 6 L, and the half-life was 68 +/- 19 hours. CONCLUSIONS: Etanercept was slowly absorbed and slowly eliminated after subcutaneous administration. Dosing at the recommended rate of 25 mg twice weekly would be expected to result in concentrations of approximately 3 mg/L. Intersubject variability for apparent clearance in healthy volunteers was 64%.     

Comparative distribution of azithromycin in lung tissue of patients given oral daily doses of 500 and 1000 mg

OBJECTIVES: The administration of antibacterial agents should be optimized on the basis of their distribution to enhance drug exposure and obtain bacterial eradication. This study examines the pharmacokinetics of azithromycin in plasma, lung tissue and bronchial washing in patients after oral administration of 500 mg versus 1000 mg once daily for 3 days. PATIENTS AND METHODS: Samples of plasma, lung tissue and bronchial washing were obtained from a cohort of 48 patients during open-chest surgery for lung resection up to 204 h after the last drug dose, and assayed for antibiotic concentrations. RESULTS: Azithromycin was widely distributed within the lower respiratory tract and sustained levels of the drug were detectable at the last sampling time in lung tissue. Doubling the dose of the antibiotic resulted in a proportional increase in lung area under the curve (AUC, 1245.4 versus 2514.2 h x mg/kg) and peak tissue concentration (Cmax, 8.93 +/- 2.05 versus 18.6 +/- 2.20 mg/kg). The pharmacodynamic parameter AUC/MIC for susceptible and intermediate strains of Streptococcus pneumoniae (MICs 0.5 and 2 mg/L, respectively) increased after administration of the 1000 mg schedule compared with 500 mg (AUC/MIC0.5 2414 versus 1144 and AUC/MIC2 2112 versus 814.1 h x mg/kg, respectively) in pulmonary tissue. CONCLUSIONS: Lung exposure to azithromycin is increased proportionally by doubling the dose, which results in a predictable pharmacokinetic behaviour of the drug in the lower respiratory tract.     

Pharmacokinetics and serum bactericidal titers of ciprofloxacin and ofloxacin following multiple oral doses in healthy volunteers.

Fourteen adult males participated in a randomized three-way crossover study to compare the pharmacokinetics and serum bactericidal titers (SBTs) of 500 mg of ciprofloxacin (regimen A), 750 mg of ciprofloxacin (regimen B), and 400 mg of ofloxacin (regimen C) administered every 12 h for seven doses. Mean steady-state peak concentrations in serum for regimens A, B, and C were 3.0, 4.4, and 6.5 micrograms/ml, respectively (P < 0.01, all comparisons) and mean half-lives were 4.5, 4.3, and 6.5 h, respectively (P < 0.05, C versus A and B). Mean steady-state areas under the concentration-time curve were 14.1, 21.1, and 48.1 micrograms/h/ml for regimens A, B, and C, respectively (P < 0.05, all comparisons). SBTs were determined at different times postdose for three isolates each of Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, Enterobacter cloacae, and Pseudomonas aeruginosa. Mean steady-state peak SBTs for regimens A, B, and C, respectively, were as follows: S. pneumoniae, < 1:2, 1:8, 1:8, S. aureus, 1:16, 1:16, 1:16; E. coli, 1: > or = 128, 1: > or = 128, 1:64; E. cloacae, 1: > or = 128, 1: > or = 128, 1:64; P. aeruginosa, 1:8, 1:8, 1:2. These differences in SBTs within each genus were statistically significant. The majority of predicted SBTs were within one dilution of measured SBTs. Areas under the serum bactericidal time curves for E. coli, E. cloacae, and P. aeruginosa were significantly higher for ciprofloxacin; areas under the serum bactericidal time curves for S. pneumoniae and S. aureus were significantly greater for ofloxacin. Ofloxacin achieved higher concentrations in serum than ciprofloxacin, but differences in in vitro activity were a more important determinant of SBTs.     

Safety and pharmacokinetics of CS-834, a new oral carbapenem antibiotic, in healthy volunteers.

CS-834, (+)-[pivaloyloxymethyl (4R,5S,6S)-6-[(R)-1-hydroxyethyl]-4-methyl-7-oxo-3-[[(R)-5-oxopyrroli din-3-yl]thio]-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate], is an ester-type oral carbapenem prodrug, and an active metabolite is R-95867, which has antibacterial activity. CS-834 was administered orally to healthy male volunteers at single doses of 50, 100, 200, and 400 mg and at a multiple dose of 150 mg three times a day for 7 days to investigate its safety and pharmacokinetic profiles. Other studies were conducted to examine the effect of food intake on the bioavailability of CS-834 and also the effect of the coadministration of probenecid on the pharmacokinetics of CS-834. In the fasting state, the concentration of R-95867 in plasma reached maximum levels from 1.1 to 1.7 h after the oral administration of CS-834, followed by a monoexponential decrease. The maximum concentrations of R-95867 in serum (C[max]s) after the administration of CS-834 at doses of 50, 100, 200, and 400 mg were 0.51, 0.97, 1.59, and 2.51 microg/ml, respectively. The half-lives (t1/2s) were almost constant, approximately 0.7 h. The areas under the concentration-time curves (AUCs) were proportional to the doses, ranging from 50 to 400 mg x h/ml. The cumulative recoveries in urine were approximately 30 to 35% until 24 h after drug administration. The C(max), AUC, t1/2, and recovery in urine were not affected by food intake. Probenecid coadministration prolonged the t1/2, and it increased the C(max) and AUC for R-95867 by approximately 1.5- and 2.1-fold, respectively. The multiple-dose study showed no change in the pharmacokinetics from those for the single doses and no drug accumulation in the body. A mild transient soft stool was observed in one volunteer in the study with a single dose of 400 mg. In the multiple-dose study, mild transient soft stools were observed in six volunteers, one volunteer had mild transient diarrhea, and one volunteer had elevated serum glutamic oxalacetic transaminase and serum glutamic pyruvic transaminase levels (1.4- and 2.8-fold compared with the upper limits of normal, respectively). There were no other abnormal findings for objective symptoms or laboratory findings, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, blood chemistry, and urinalysis.