Pharmacokinetics and absolute oral bioavailability of an 800-mg oral dose of telithromycin in healthy young and elderly volunteers.

BACKGROUND: This two-way, randomized, single-dose, crossover study determined the pharmacokinetics and absolute oral bioavailability of telithromycin in young and elderly healthy subjects. METHODS: Twelve young (18-40 years) and 12 elderly (>65 years and

Penetration of telithromycin (HMR 3647), a new ketolide antimicrobial, into inflammatory blister fluid following oral administration.

The penetration of telithromycin (HMR 3647), a novel ketolide antimicrobial, has been assessed in an open, single-dose study in eight healthy male subjects. Following a single, oral, 600 mg dose the mean ratio of the concentration of telithromycin in blister fluid over plasma was 1.38. Significant blister fluid concentrations were maintained up to 24 h post-dose. These results indicate that telithromycin penetrates well into inflammatory extracellular fluid, achieving high and sustained concentrations in this medium.

HT29-MTX and Caco-2/TC7 monolayers as predictive models for human intestinal absorption: role of the mucus layer.

The permeability of 19 compounds in both the Caco-2/TC7 and HT29-MTX models was determined, and the ability of each model to predict intestinal absorption in humans was compared. Similar apparent permeability values (log P(app)) were obtained in both models for the majority of compounds tested, and plots of log P(app) versus fraction absorbed in humans gave comparable sigmoidal curves. A linear correlation was also observed between the log P(app) values derived from these two models, which suggests that HT29-MTX is an alternative model for absorption prediction in humans. The similarity of both the diffusion coefficients and permeability values obtained for a range of hydrophilic and lipophilic compounds in the two models indicates that the mucus layer secreted by the human adenocarcinoma HT29-MTX goblet cells does not constitute a diffusion barrier to such compounds. The lack of P-glycoprotein (P-gp) in the HT29-MTX cell line may explain the higher permeability values obtained for cimetidine and sumatriptan in this model compared with those derived from the Caco-2/TC7 monolayers. The results suggest that the HT29-MTX model can be used to rank order the passive permeability of compounds, irrespective of their potential interaction with P-gp, which may facilitate optimization of the physicochemical features of compounds within a chemical series.

Pharmacokinetics of the new ketolide telithromycin (HMR 3647) administered in ascending single and multiple doses.

Telithromycin (HMR 3647) is a novel ketolide antimicrobial with good activity against both common and atypical respiratory pathogens, including many resistant strains. This randomized, three-period crossover study determined the dose proportionality of telithromycin pharmacokinetics after single and multiple dosing in healthy subjects. In each treatment period, subjects received a single oral dose of 400, 800 or 1,600 mg of telithromycin followed 4 days later by the same dose once daily for 7 days. Blood and urine samples were taken throughout the study for determination of pharmacokinetic parameters for telithromycin and RU 76363, its main metabolite. Telithromycin and RU 76363 achieved steady state within 2 to 3 days of once-daily dosing. A slight accumulation of telithromycin was observed after 7 days of therapy, with values of the area under the concentration-time curve from 0 to 24 h approximately 1.5 times higher than those achieved with the single dose. The pharmacokinetics of telithromycin and RU 76363 deviated moderately from dose proportionality. At a dose of 800 mg/day, telithromycin attained mean maximal and trough plasma concentrations of 2.27 and 0. 070 mg/liter respectively. Elimination was biphasic; initial and terminal half-lives were 2.87 and 9.81 h for the 800-mg dose. Study medication was well tolerated, although adverse events tended to be more frequent at the 1,600-mg dose. This study showed that telithromycin was generally well tolerated and suggests that a once-daily 800-mg oral dose of telithromycin maintains an effective concentration in plasma for the treatment of respiratory tract infections involving the key respiratory pathogens.

Absorption of angiotensin II antagonists in Ussing chambers, Caco-2, perfused jejunum loop and in vivo: importance of drug ionisation in the in vitro prediction of in vivo absorption.

The aims of this study were (i) to compare the absorption of three closely related inhibitors of angiotensin II, RU60018, RU60079 and HR720, in various in vitro and in vivo models, and (ii) to explain the differences in the results and to assess the importance of drug ionisation to predict absorption. Drug absorption was investigated in Ussing chambers, Caco-2 cell monolayers, perfused rat jejunum loops and in vivo after oral, intraduodenal or intravenous administration. In Ussing chambers, the analogues showed the same site-related absorption profile and a common mechanism involving the paracellular pathway. At pH 7.4 in Ussing chambers, perfused jejunum loop or Caco-2 transport studies, the three compounds exhibited low and comparable permeability values suggesting that a similar level of oral absorption may be expected for all three compounds. However, after oral or intraduodenal administration, only HR720 was significantly absorbed. The in vivo results can be explained by the ionic distribution profile which indicated that only HR720 possessed a significant amount of uncharged species at pH values close to that found in the upper part of intestinal tract. Hence, it is expected that in this part of the intestine, only HR720 absorption is favoured. This is supported by Caco-2 transport studies performed when the pH of the apical medium was lowered from 7.4 to 6.0, in which a dramatic increase in permeability was observed for HR720 compared to those of the other analogues. This study highlights the usefulness of different absorption models for drug screening and demonstrates that ionisation profiles must be carefully considered to avoid rejection of promising compounds.

Concentrations of cefpirome in cerebrospinal fluid of children with bacterial meningitis after a single intravenous dose.

A single intravenous dose of cefpirome, 50 mg/kg, was administered to 15 children with bacterial meningitis 24 to 48 h after initiation of standard antibiotic and steroid therapy. Cefpirome concentrations in serum and cerebrospinal fluid were determined at selected time intervals. The mean (standard deviation) peak concentration in cerebrospinal fluid (n = 5) was 10.8 (7.8) microg/ml. Drug concentrations in cerebrospinal fluid above the MIC for Streptococcus pneumoniae at which 90% of the isolates were inhibited were found 2, 4, and 8 h after the dose of cefpirome was given. The penetration of cefpirome into cerebrospinal fluid compares favorably with that of other extended-spectrum cephalosporins and suggests that this agent would be useful in the therapy of childhood meningitis, including cases caused by drug-resistant S. pneumoniae.

Concentrations of cefpodoxime in plasma, adenoid, and tonsillar tissue after repeated administrations of cefpodoxime proxetil in children.

Cefpodoxime proxetil was administered to 36 children undergoing tonsillectomy, adenoidectomy or both. It was very well tolerated. The detectable tissue concentrations of cefpodoxime were moderate but remained constant (approximately 0.05 mg/kg) 3, 6, and 12 h after the last dose of the drug, while the respective plasma concentrations were declining. This suggests the possibility of twice-daily administration. However, 30% of children did not have quantifiable concentrations in the tonsil and more than half the adenoids did not have quantifiable levels. Whether a higher dosage would lead to higher and more satisfactory tissue concentrations is a matter for further investigation.

Pharmacokinetics of cefodizime following single doses of 0.5, 1.0, 2.0, and 3.0 grams administered intravenously to healthy volunteers.

Cefodizime is a new expanded-spectrum cephalosporin for parenteral use which possesses a broad antibacterial spectrum and potent antibacterial activity and is stable against most beta-lactamases. The aim of this study was to assess the pharmacokinetics of cefodizime, administered intravenously, over the dose range of 0.5 to 3.0 g in healthy volunteers. Concentrations of cefodizime in the serum and urine were determined by high-performance liquid chromatography. The area under the concentration-time curve from 0 h to infinity and the amount of drug excreted in urine from 0 to 34 h increased in a linear, dose-dependent manner with increasing doses of antibiotic from 0.5 to 3.0 g. Mean concentrations of cefodizime in plasma at the end of infusion increased from 97 to 440 mg liter-1 over the dose range 0.5 to 3.0 g and displayed a slight deviation from linearity at doses in excess of 2.0 g. Total plasma clearance (3.11 liters h-1), volume of distribution at steady state (10.5 liters), terminal elimination half-life (3.3 h), and renal clearance (1.91 liters h-1) remained constant over the doses administered. Cefodizime was well tolerated in this study.

Trandolapril: pharmacokinetics of single oral doses in healthy male volunteers.

The pharmacokinetics and dose proportionality of trandolapril, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated in 12 healthy male volunteers in a four-way randomized crossover study over the therapeutic dose range, 0.5-4 mg. Trandolapril is rapidly absorbed, with a single elimination half-life (t1/2) of 0.72 h, irrespective of dose. Peak plasma levels (Cmax) occurred at 0.5 h and were proportional to the dose, as was the area under the plasma concentration-time curve (AUC). Concentration of the active metabolite (trandolaprilat) increased with increasing doses but in a nonlinear fashion, probably owing to saturable plasma ACE binding. However, the Cmax and AUC values for trandolaprilat were directly proportional to the highest doses, 2 and 4 mg, suggesting linear kinetics for the trandolaprilat, which is not bound to ACE. Trandolapril showed linear kinetics but trandolaprilat showed some features of nonlinear kinetics, particularly at low doses.

Pharmacokinetics and pharmacodynamics of trandolapril after repeated administration of 2 mg to patients with chronic renal failure and healthy control subjects.

A new, long-acting angiotensin-converting enzyme (ACE) inhibitor, trandolapril, was administered daily for 10 days to 13 patients with chronic renal failure [CRF; creatinine clearance (CLCR) 7-55 ml/min/1.73 m2) and 8 healthy volunteers (CLCR > 80 ml/min/1.73 m2)]. Plasma ACE inhibition parameters were the same, irrespective of the degree of renal insufficiency, although renal failure tended to prolong ACE inhibition. The pharmacokinetics of trandolapril were not affected by CRF; hence, no accumulation of trandolapril was detected. After single or repeated administration the active metabolite, trandolaprilat, showed an inverse correlation between maximal plasma concentrations (Cmax) and CLCR (r = -0.676 day 1 and r = -0.864 day 10) and area under the concentration-time curve (AUC) and CLCR (r = -0.635 day 1 and r = -0.794 day 10). The renal clearance of trandolaprilat showed significant linear correlation (r = > 0.885, p < 0.0001) with CLCR after single (r = 0.879) and repeated administration (r = 0.957). Significantly reduced excretion of trandolaprilat was seen only when the CLCR was < 30 ml/min/1.73 m2. A steady state had been achieved by 7 days in all patients, and extrapolation suggested that this was achieved in most cases after 4 days. The drug was well tolerated. The effect of CRF on the pharmacokinetics and pharmacodynamics of trandolaprilat is of significance only when CLCR is < 30 ml/min/1.73 m2. Hence, in these patients the standard dose should be reduced.

Pharmacokinetics and pharmacodynamics of trandolapril after repeated administration of 2 mg to young and elderly patients with mild-to-moderate hypertension.

The new angiotensin-converting enzyme (ACE) inhibitor trandolapril 2 mg was administered daily for 10 consecutive days to young (mean age +/- SEM 44.1 +/- 2.3 years; n = 10) and elderly (mean age +/- SEM 69.3 +/- 0.9 years; n = 14) patients with mild-to-moderate hypertension. All groups had similar baseline blood pressures: mean 164/100 mm Hg. Maximal plasma ACE inhibition on day 10 and residual inhibition 24 h after the last dose was the same, irrespective of age: young, 85.2 and 57.4%; elderly 89.1 and 59.8%, respectively. There was no difference between the results on day 1 for the young and elderly groups. The absorption of trandolapril was rapid (< 1 h in all groups). The peak plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) were slightly higher in the older group, but the elimination half-life (t1/2) was the same, with no accumulation after repeat dosing. A steady-state plasma concentration of the active metabolite of trandolapril, trandolaprilat, was reached after 4 days in the two groups, with similar accumulation ratios (young, 1.48; elderly, 1.49). At steady state, the Cmax and AUC 0-24 h for trandolaprilat were similar in the two groups: young, 7.49 +/- 0.98 ng/ml and 82.27 +/- 6.95 ng/ml/h; elderly, 8.35 +/- 0.67 ng/ml/h and 96.75 +/- 5.67 ng/ml/h. Maximal reductions in systolic/diastolic blood pressures (at 6 h postdose) were -14.1%/-16.1% in young patients and -14.6%/-17.5% for the elderly. Significant blood pressure reduction persisted for 48 h after the last dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Diffusion of cefpirome into the cerebrospinal fluid of patients with purulent meningitis.

We evaluated the diffusion of cefpirome into the cerebrospinal fluid (CSF) of 25 patients with bacterial meningitis or ventriculitis who were receiving conventional antibiotic treatment. A single cefpirome dose of 2 g was infused at day 2-3 after the onset of therapy. Concentrations of cefpirome in serum and CSF obtained at 2, 4, 8 or 12 h after the infusion were determined by high-performance liquid chromatography. The mean (+/- S.E.M.) concentrations of cefpirome in CSF ranged from 2.26 +/- 1.16 to 4.17 +/- 0.83 mg/L. These concentrations were higher than the MBCs for the pathogens usually responsible for bacterial meningitis.

Pharmacokinetics of cefpodoxime in young and elderly volunteers after single doses.

Three pharmacokinetic studies involving single oral doses of cefpodoxime proxetil in healthy volunteers are reported. The first study was to determine the absolute bioavailability of cefpodoxime, the second was to study the relationship between the oral dose of cefpodoxime proxetil and pharmacokinetic parameters of cefpodoxime, and the third was to compare the pharmacokinetics of cefpodoxime in healthy young and elderly volunteers. Half the dose of cefpodoxime orally administered as cefpodoxime proxetil in tablet form reaches the systemic circulation, while 80% of the cefpodoxime absorbed is excreted unchanged in urine. The volume of distribution is large (32.3 l). The pharmacokinetics of cefpodoxime were linear in young and elderly subjects after 100 and 200 mg oral doses, which are those used therapeutically. The Cmax was about 1.4 mg/l (after 100 mg) and 2.6 mg/l (after 200 mg). Deviation from linearity appeared at 400 mg and the effect was confirmed at 800 mg. The differences between young and elderly subjects were negligible, with the exception of the half-life which increased by only 14%, from 2.67 to 3 h. Dosage adjustment is therefore not necessary in the elderly.

Multiple dose pharmacokinetics of cefpodoxime in young adult and elderly patients.

Multiple dose pharmacokinetics of a new third-generation cephalosporin, cefpodoxime, were evaluated in adults (15, 18-60 years) and elderly adults (10, greater than or equal to 70 years), all out-patients suffering from acute lower respiratory tract infection. A dose of 200 mg cefpodoxime proxetil (expressed in mg cefpodoxime) was administered 12-hourly for seven to ten days and timed blood samples were evaluated on days 0, 3, 5, 6/7 and on the last day of treatment. Results showed that the pharmacokinetics in adult and elderly patients were comparable with those of healthy volunteers and with each other, with the exception of one elderly patient with severe renal impairment. Dosage adjustment of cefpodoxime proxetil does not therefore appear to be necessary in the elderly unless there is evidence of severe renal insufficiency.

Concentrations of cefpodoxime in plasma and lung tissue after a single oral dose of cefpodoxime proxetil.

Eighteen patients undergoing thoracotomy for suspected pulmonary neoplasia were given 200 mg cefpodoxime equivalent by mouth, before operation. Plasma samples were obtained before dose administration, and plasma and lung tissue samples were obtained at the time of operation which was 3, 6 or 12 h after the dose. All samples were assayed for cefpodoxime. The mean ratios for lung tissue/plasma concentrations were similar between 3 and 12 h after dose, suggesting that equilibrium between plasma and lung tissue concentrations was reached within 3 h of medication. The mean concentrations of cefpodoxime in lung tissue were 0.63 +/- 0.16, 0.52 +/- 0.09 and 0.19 +/- 0.02 mg/kg at 3, 6 and 12 h after administration, respectively. These observations indicate good, rapid and sustained penetration into lung tissue in concentrations greater than or equal to the MIC90 for most common micro-organisms found in community-acquired pneumonia.

Concentrations of cefpodoxime in plasma and pleural fluid after a single oral dose of cefpodoxime proxetil.

Eighteen patients of either sex with pleural effusions underwent aspiration 3, 6 or 12 h after receiving a single oral dose of cefpodoxime proxetil equivalent to 200 mg cefpodoxime. The mean concentrations of cefpodoxime in pleural fluid were, respectively, 0.62, 1.84 and 0.78 mg/l for these three time intervals, the corresponding ratios between pleural fluid and plasma concentrations being 0.24, 0.67 and 1.07. The findings indicate that there is good penetration of cefpodoxime into pleural fluid. Concentrations between 3 and 12 h after dosing were equal to or above the MIC90 for most of the organisms commonly found in lower respiratory tract infections.

Concentrations of cefpodoxime in plasma and tonsillar tissue after a single oral dose of cefpodoxime proxetil.

Seventeen patients undergoing tonsillectomy received cefpodoxime proxetil orally in a dose equivalent to 100 mg cefpodoxime 4, 7 or 12 h before operation. Plasma and tonsillar tissue concentrations of cefpodoxime were assayed by a microbiological method. Tonsillar tissue concentrations after 4 and 7 h were 0.24 and 0.09 mg/kg respectively--being 23% of the plasma concentration. The tonsillar tissue concentration after 12 h was less than 0.06 mg/kg. As the MIC for Streptococcus pyogenes is less than 0.06 mg/l, cefpodoxime proxetil may be of value in acute tonsillitis.

The pharmacokinetics of cefodizime following intravenous and intramuscular administration of a single dose of 1.0 g.

The pharmacokinetics and absolute bioavailability of cefodizime were determined after iv and im administration of a single 1.0 g dose in eight healthy volunteers. The absolute bioavailability of cefodizime after im injection of 1.0 g was 88% and 91% when determined by two different formulae.

Pharmacokinetics of cefodizime administered intravenously as a single-dose (1.0 and 2.0 g) to healthy adult volunteers.

Cefodizime is a new third generation cephalosporin for parenteral use. The purpose of this study was to define the pharmacokinetic profile of cefodizime after intravenous dosing with 1.0 and 2.0 g in healthy adult volunteers. Concentrations in plasma were determined over a period of 34 h and in urine over 48 h, using high-pressure liquid chromatographic procedures. Cefodizime displays a long elimination half-life (3.5-3.7 h). Mean total clearance was 2.63 +/- 0.19 l/h and mean renal clearance was 1.37 +/- 0.15 l/h. Areas under the curve were 422 +/- 43 mg.h/l and 757 +/- 39 mg.h/l for 1.0 and 2.0 g respectively. The apparent volumes of distribution were 12.8 +/- 1.81 and 14.3 +/- 1.11. After 1.0 g administration the residual concentrations were 3.94 +/- 0.79 mg/l and 0.38 +/- 0.10 mg/l at 12 and 24 h, respectively; after 2.0 g administration the residual concentrations were 6.80 +/- 1.40 mg/l and 0.65 +/- 0.18 mg/l, at 12 h and 24 h. Cefodizime is mainly eliminated via the kidneys. This profile supports once-daily administration of cefodizime, when indicated in non-life-threatening infections.

Pharmacokinetics of cefodizime in the elderly following single and repeated intravenous administration of 1 g.

In an open, crossover study of 12 patients of mean age 74 (range 64-88) who required perioperative prophylactic antibiotic therapy, cefodizime was administered as a single iv infusion of 1 g, and repeated infusions of 1 g twice daily for 4.5 days. Serum and urine concentrations of cefodizime were determined by high performance liquid chromatography. The following pharmacokinetic indices were estimated after single and repeated (values in brackets) dosing: C0.15h 269 (285) mg/l; C12h 8.7 (8.5) mg/l; AUC 557 (494) mg.h/l; Clt 1.93 (2.20) l/h; Vdss 8.62 (8.56) l; T1-2 4.06 (4.07) h; U0-36h: 569 (624) mg; and Clr0-12h 1.17 (1.39) l/h. No statistically significant differences in these values were found between single and repeated dose treatments. These results demonstrate a lack of accumulation and no changes in the pharmacokinetic profile of cefodizime during repeated dosing in the elderly. No modification of the dosage regimen of cefodizime would appear to be necessary in the elderly as compared with young healthy subjects.