Pharmacokinetic profile of levofloxacin following once-daily 500-milligram oral or intravenous doses.

The pharmacokinetics of once-daily oral levofloxacin (study A) or intravenous levofloxacin (study B) in 40 healthy male volunteers were investigated in two separate randomized, double-blind, parallel-design, placebo-controlled studies. Levofloxacin at 500 mg or placebo was administered orally or intravenously as a single dose on day 1; daily oral or intravenous dosing resumed on days 4 to 10. In a third study (study C), the comparability of the bioavailabilities of two oral and one intravenous levofloxacin formulations were investigated with 24 healthy male subjects in an open-label, randomized, three-way crossover study. Levofloxacin at 500 mg as a single tablet or an intravenous infusion was administered on day 1; following a 1-week washout period, subjects received the second regimen (i.e., the other oral formulation or the intravenous infusion); the third and final regimen was administered following a 1-week washout period. The concentrations of drug in plasma and urine were measured by validated high-pressure liquid chromatography methods. Pharmacokinetic parameters were estimated by noncompartmental methods. In both study A (oral levofloxacin) and study B (intravenous levofloxacin), steady state was attained within 48 h after the start of the multiple dosing on day 4. Levofloxacin pharmacokinetics were linear and predictable for the single and multiple 500-mg, once-daily oral and intravenous dosing regimens, and the values of the pharmacokinetic parameters for the oral and intravenous administrations were similar. Study C indicated that levofloxacin was rapidly and completely absorbed from the oral tablets, with mean times to the maximum concentration of drug in serum of approximately 1.5 h and mean absolute bioavailability of > or =99%. These results support the interchangeability of the oral and intravenous routes of levofloxacin administration.     

Effect of a nutritional supplement on posaconazole pharmacokinetics following oral administration to healthy volunteers

We conducted a randomized, crossover study in healthy adults to examine the effects of a nutritional supplement (Boost Plus) on posaconazole pharmacokinetics. In this study, coadministration of posaconazole with Boost Plus increased the maximum concentration of posaconazole in serum and area under the concentration-time curve from 0 to 72 h values 3.4- and 2.6-fold, respectively, compared to those for the fasted state.     

Pharmacokinetics of flunitrazepam following single dose oral administration in liver disease patients compared with healthy volunteers

The pharmacokinetic behaviour of flunitrazepam and its main active metabolite, N-desmethyl flunitrazepam, was investigated in 12 patients with liver disease (cirrhosis or hepatitis) compared to 6 healthy volunteers. A gas-liquid chromatographic method allowing for simultaneous determination of flunitrazepam and N-desmethyl flunitrazepam in plasma samples was developed. The accuracy and the precision near the quantification limit of ca. 1 ng/ml were better than 5%. Plasma levels of flunitrazepam were not significantly altered by hepatic failure, whereas plasma levels of N-desmethyl flunitrazepam were lower in patients than in healthy subjects. Pharmacokinetic parameters did not differ significantly between healthy subjects and liver disease patients: the oral clearance was 3.5 +/- 0.8, 3.5 +/- 1.9 and 4.0 +/- 1.2 ml/min/kg, respectively in healthy subjects, patients with hepatitis and patients with cirrhosis. The apparent elimination half-life was 22 +/- 5 h in healthy subjects, 25 +/- 10 h in patients with hepatitis and 20 +/- 6 h in patients with cirrhosis. However, the expected increase of the drug free fraction during liver disease could decrease the therapeutic and toxic ranges of flunitrazepam in these patients.     

Pharmacokinetics of oritavancin in plasma and skin blister fluid following administration of a 200-milligram dose for 3 days or a single 800-milligram dose

Oritavancin is a novel glycopeptide currently being developed for the treatment of complicated skin and skin structure infections (cSSSI), including those caused by multidrug resistant gram-positive pathogens. The disposition of oritavancin in skin structures was investigated using a cantharide-induced blister fluid model. Seventeen healthy male subjects received oritavancin, but only 16 subjects were evaluated after one subject discontinued study drug. Each subject (eight per dose group) received 200 mg of oritavancin once a day for 3 days (group A) or 800 mg as one single dose (group B). Group A plasma samples and exudates from blister fluid were collected on days 3, 4, 7, 9, and 12 and on days 3, 4, 7, and 9, respectively. Group B samples and exudates were collected on days 1, 2, 5, 7, and 10 and on days 1, 2, 5, and 7, respectively. Drug concentrations were determined using a liquid chromatography-tandem mass spectrometry assay and, subsequently, pharmacokinetic analysis was performed. Differences between treatment groups in ratios for area under the concentration-time curve for blister fluid and plasma (AUC(blister fluid)/AUC(plasma) ratios) were evaluated using a t test (alpha = 0.05). Mean maximum concentration of drug in plasma or blister fluid was approximately 8-fold and 11-fold higher in plasma than in blister fluid following the 200- or 800-mg doses of oritavancin, respectively. Mean AUC(blister fluid)/AUC(plasma) ratios at 24 h were 0.190 (standard deviation [SD], 0.052) and 0.182 (SD, 0.062) for groups A and B, respectively (P = 0.791). To place these results in a clinical context, mean drug concentrations in blister fluid exceed the oritavancin MIC at which 90% of strains are inhibited of Staphylococcus aureus (2 microg/ml) by approximately 2- to 5.5-fold at 12 h and 1.5- to 3-fold at 24 h following administration of both dosing regimens. These results support the potential use of oritavancin for the treatment of cSSSI.     

Absolute oral bioavailability of rosuvastatin in healthy white adult male volunteers

BACKGROUND: Rosuvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitor developed for the treatment of dyslipidemia. The results of clinical trials suggest that it is effective and well tolerated. OBJECTIVES: The goals of this study were to determine the absolute bioavailability of an oral dose of rosuvastatin and to describe the intravenous pharmacokinetics of rosuvastatin in healthy volunteers. METHODS: This was a randomized, open-label, 2-way crossover study consisting of 2 trial days separated by a > or =7-day washout period. Healthy male adult volunteers were given a single oral dose of rosuvastatin 40 mg on one trial day and an intravenous infusion of rosuvastatin 8 mg over 4 hours on the other. Pharmacokinetic and tolerability assessments were conducted up to 96 hours after dosing. A 3-compartment pharmacokinetic model was fitted to the plasma concentration-time profiles obtained for each volunteer after intravenous dosing. RESULTS: Ten white male volunteers entered and completed the trial. Their mean age was 35.7 years (range, 21-51 years), their mean height was 177 cm (range, 169-182 cm), and their mean body weight was 77.6 kg (range, 68-85 kg). The absolute oral bioavailability of rosuvastatin was estimated to be 20.1%,and the hepatic extraction ratio was estimated to be 0.63. The mean volume of distribution at steady state was 134 L. Renal clearance accounted for approximately 28% of total plasma clearance (48.9 L/h). Single oral and intravenous doses of rosuvastatin were well tolerated in this small number of healthy male volunteers. CONCLUSIONS: The absolute oral bioavailability of rosuvastatin in these 10 healthy volunteers was approximately 20%, and absorption was estimated to be 50%. The volume of distribution at steady state was consistent with extensive distribution of rosuvastatin to the tissues. The modest absolute oral bioavailability and high hepatic extraction of rosuvastatin are consistent with first-pass uptake into the liver after oral dosing. Rosuvastatin was cleared by both renal and nonrenal routes; tubular secretion was the predominant renal process.     

Pharmacokinetics of itraconazole following oral administration to normal volunteers.

The pharmacokinetics of itraconazole, an orally effective, broad-spectrum, systemic antifungal agent, were evaluated in five healthy male volunteers. Each subject was studied on days 1 and 15 at the following dosages: 100 mg once daily (regimen A), 200 mg once daily (regimen B), and 200 mg twice daily (regimen C). On each study day, itraconazole was administered with a standardized meal. Plasma samples were collected for 72 h postdose, and 24-h urine specimens were obtained. On day 1 of regimen C, plasma samples were collected following the second dose. Samples were assayed for itraconazole by a sensitive, reverse-phase, high-performance liquid chromatography method. Wide intersubject variations in itraconazole concentration in plasma versus time profiles were observed on all study days. Absorption appeared to be slow, with day 1 mean peak itraconazole concentrations in plasma of 110 ng/ml at 2.8 h (regimen A), 272 ng/ml at 3.0 h (regimen B), and 553 ng/ml at 3.4 h (regimen C). Mean peak itraconazole concentrations in plasma on day 15 were 412 ng/ml at 3.0 h (regimen A), 1,070 ng/ml at 4.4 h (regimen B), and 1,980 ng/ml at 6.0 h (regimen C). The steady state was achieved by day 13. Respective elimination half-lives on days 1 and 15 were 15 and 34 h (regimen A), 20.7, and 36.5 h (regimen B), and 25 and 41.7 h (regimen C), respectively. The areas under the plasma concentration versus time curves (0 to infinity) on day 1 were 1,320 (regimen A), 4,160 (regimen B), and 12,600 ng.h/ml (regimen C). With the exception of one patient on day 15 of regimen C, itraconazole was not detected in the urine. All data support dose-dependent pharmacokinetic behavior for itraconazole.     

Pharmacokinetics and bactericidal activities of one 800-milligram dose versus two 400-milligram doses of intravenously administered pefloxacin in healthy volunteers.

Pefloxacin pharmacokinetics and serum bactericidal activities (SBA) against Escherichia coli and Staphylococcus aureus were compared after intravenous infusion of either a single 800-mg dose or twice-daily 400-mg doses into 16 healthy volunteers. Plasma pefloxacin concentrations were measured for up to 60 h, and SBAs were determined 1, 12, and 24 h after the start of the infusion. The mean areas under the concentration-versus-time curve for plasma were not different (138 versus 136 h.mg/liter). The mean clearances, volumes of distribution, and half-lives were also comparable. The mean (+/- standard deviation) maximal concentration after the 800-mg infusion was 12.11 +/- 1.35 versus 6.51 +/- 0.73 mg/liter after the first 400-mg infusion and 7.42 +/- 0.76 mg/liter after the second 400-mg infusion. Mean trough concentrations at 24 h were significantly different: 2.77 +/- 0.63 (800 mg) versus 1.93 +/- 0.49 (400 mg twice) mg/liter (P = 0.0007). Mean SBAs against E. coli after 800 mg of pefloxacin were higher than 1/128 (1 h), 1/32 (12 h), and 1/16 (24 h). Mean SBAs against S. aureus under the same conditions were higher than 1/64 (1 h), 1/16 (12 h), and 1/8 (24 h). Mean SBAs at 1 and 12 h were significantly higher after the 800-mg infusion than after the 400-mg infusion but were similar at 24 h for both regimens. Comparison of SBAs according to National Committee for Clinical Laboratory Standards criteria showed a similar adequacy at 24 h for both regimens against both strains. Administration of 800 mg of pefloxacin once a day is bioequivalent to 400 mg twice a day, and bactericidal activity of the 800-mg infusion is not less than that of two 400-mg infusions.     

Disposition of posaconazole following single-dose oral administration in healthy subjects

Posaconazole is a potent, broad-spectrum triazole antifungal agent currently in clinical development for the treatment of refractory invasive fungal infections. Eight healthy male subjects received a single 399-mg (81.7 microCi) oral dose of [(14)C]posaconazole after consuming a high-fat breakfast. Urine, feces, and blood samples were collected for up to 336 h postdose and assayed for total radioactivity; plasma and urine samples were also assayed for parent drug. Posaconazole was orally bioavailable, with a median maximum posaconazole concentration in plasma achieved by 10 h postdose. Thereafter, posaconazole was slowly eliminated, with a mean half-life of 20 h. The greatest peak in the radioactivity profile of pooled plasma extracts was due to posaconazole, with smaller peaks due to a monoglucuronide, a diglucuronide, and a smaller fragment of the molecule. The mean total amount of radioactivity recovered was 91.1%; the cumulative excretion of radioactivity in feces and in urine was 76.9 and 14.0% of the dose, respectively. Most of the fecal radioactivity was associated with posaconazole, which accounted for 66.3% of the administered dose; however, urine contained only trace amounts of unchanged posaconazole. The radioactivity profile of pooled urine extracts included two monoglucuronide conjugates and a diglucuronide conjugate of posaconazole. These observations suggest that oxidative (phase 1) metabolism by cytochrome P450 isoforms represents only a minor route of elimination for posaconazole, and therefore cytochrome P450-mediated drug interactions should have a limited potential to impact posaconazole pharmacokinetics.     

Pharmacokinetics of [14C]FCE 22891, a penem antibiotic, following oral administration to healthy volunteers.

FCE 22891 is a prodrug of the penem antibiotic FCE 22101 and is suitable for oral administration. The pharmacokinetics of FCE 22891 were investigated in four healthy male volunteers following the oral administration of 500 mg of [14C]FCE 22891. Levels of radioactivity in plasma were always higher and persisted for longer than those of FCE 22101. The time to the maximum concentration of radioactivity in plasma generally coincided with that of FCE 22101. The respective values for the maximum concentrations of radioactivity in plasma were, on average, 8.57 +/- 2.95 micrograms equivalent/ml and 2.97 +/- 2.05 micrograms/ml. Over a 5-day period, mean urinary and fecal recovery of radioactivity accounted for 53.2 and 41.0% of the dose, respectively. The average amount of FCE 22101 excreted in urine and feces corresponded to 9.0 and 1.6% of the dose, respectively. The urinary recovery of the open-ring metabolite P1 and of its 5-S epimer P2 accounted for about 6.5 and 1.2% of the dose, respectively. Other chromatographic peaks corresponding to nonidentified compounds accounted for about 14.0% (polar metabolite fraction; peak P), 3.7% (less polar fraction; peak X), and 15.4% (least polar fraction) of the dose. Elimination of radioactivity and FCE 22101 in urine was rapid. Intersubject variability in the kinetics of total radioactivity in plasma was far less than that observed for FCE 22101. The results of the present study support suggestions that presystemic metabolism of FCE 22101 and/or transformation of the prodrug to compounds other than FCE 22101 are the main cause of intersubject variability in the kinetics of FCE 22101 produced in plasma following oral administration of its prodrug.     

Multiple-dose pharmacokinetics and excretion balance of gatifloxacin,a new fluoroquinolone antibiotic,following oral administration to healthy Caucasian volunteers

The multiple-dose pharmacokinetics and excretion balance of gatifloxacin were evaluated in 42 healthy Caucasian volunteers. Following multiple oral doses of 400 and 600 mg, the pharmacokinetics of gatifloxacin were similar on days 1 and 15, suggesting no therapeutically relevant time-dependent changes in the pharmacokinetics of gatifloxacin at the doses and duration of dosing studied. Gatifloxacin was rapidly absorbed and a favourable elimination half-life of 7-8 h was evaluated. Saliva concentrations were similar to plasma concentrations. The main route of excretion is the urine. After a single dose of 400 mg of gatifloxacin, the recovery in urine was 83% and 5.2% in faeces. Following multiple doses of 400 or 600 mg, the renal excretion was 80 and 77%, respectively. The drug was well tolerated.     

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.     

Serum concentration and cardiovascular effects of salbutamol after oral and rectal administration in healthy volunteers

In order to evaluate rectal administration of salbutamol (SB), five healthy volunteers were dosed orally and rectally with racemic SB (0–1 mg/kg) solution. Compared with the oral SB, the rectal SB gave significantly higher serum SB concentration immediately after dosing but slightly lower levels in the elimination phase. The C_BMX following rectal administration was 17–9 ng/ml (17–0 ng/ml for oral administration), the t_max 0–67 h (1–5 h for oral administration) and the AUC 98–2 ng/ml/h (100 ng/ml/h for oral administration). Heart rate also rose more rapidly to a maximum of 70% above baseline values after rectal dosing. The rate continued to be twice larger than after oral dosing for up to 5 h. The concentration versus response curves indicated that rectal SB was more effective than oral SB at increasing heart rate at the same SB concentration in serum. A plausible explanation for this phenomenon might be a difference in the stereo–selective first–pass metabolism of the two enantiomers. Therefore, the rectal dose of SB administered as a suppository for prophylactic treatment of asthma should be lower than that used orally.     

Bioequivalence of oral and intravenous ofloxacin after multiple-dose administration to healthy male volunteers.

The bioequivalence of oral and intravenous ofloxacin was investigated after the administration of multiple doses of 400 mg every 12 h to 20 healthy male volunteers in a randomized, crossover, open-label study. Ofloxacin concentrations in plasma were evaluated after 4 days of oral or intravenous (1-h infusion) dosing with a 3-day wash-out period between regimens. As expected, delivery to the systemic circulation took slightly longer after the oral dosing (time to maximum concentration of drug in serum of 1.7 h) relative to the 1-h intravenous infusion, but the systemic availabilities of ofloxacin by the two routes of administration were equivalent (area under the concentration-time curve from 0 to 12 h ratio of 95%). Since previous studies have not demonstrated any change in the bioavailability of ofloxacin in infectious disease patients, this study supports the interchangeability of these dosing regimens.     

Measurement of cation transport in vivo in healthy volunteers after the oral administration of lithium carbonate

1. We have measured cation transport in vivo in seven healthy volunteers under control conditions and after they had taken lithium carbonate for 21 days in doses which maintained the serum lithium concentration in the range 0.6-0.8 mmol/l. 2. We have measured cation transport in vivo after the administration of an oral load of rubidium chloride, and have found that, although intra-erythrocytic concentrations of rubidium were significantly lower 1 h after the administration of rubidium when the subjects were taking lithium, there was a significant increase in the rate of uptake of rubidium into the erythrocytes over the subsequent period of the test, suggesting a direct stimulation of sodium, potassium-activated adenosine triphosphatase by lithium. 3. Lithium administration did not affect the plasma concentration versus time profile of rubidium after the rubidium load, implying that the lithium-stimulated uptake of rubidium which occurs in erythrocytes does not necessarily occur in other cell types. 4. These results suggest that previous studies of cation transport using peripheral cells and assay systems in vitro do not necessarily reflect changes in cation transport in vivo in excitable tissues.     

Pharmacokinetics of imipenem in healthy volunteers following administration by 2 h or 0.5 h infusion

OBJECTIVES: The aim of this study was to demonstrate the t > MIC of 0.5 and 1 g of imipenem when administered by 2 h infusion every 6 h compared with 0.5 g of imipenem when administered by 0.5 h infusion every 6 h. METHODS: The study was a randomized three-way crossover study with a 30 h wash-out period in eight healthy volunteers. Each subject received imipenem in three regimens: (i) a 0.5 h infusion of 0.5 g every 6 h for three doses; (ii) a 2 h infusion of 0.5 g every 6 h for three doses; and (iii) a 2 h infusion of 1 g every 6 h for three doses. RESULTS: Following 0.5 h infusion of 0.5 g, the percentages of time above four times an MIC of 4, 2 and 1 mg/L were 21.5 +/- 2.2%, 38.6 +/- 3.5% and 57.5 +/- 4% of a 6 h interval, respectively. For the 2 h infusion of 0.5 g, the percentages of time above four times an MIC of 4, 2 and 1 mg/L were 26.9 +/- 8.5%, 48.0 +/- 3.5% and 65.4 +/- 3.2% of a 6 h interval, respectively. For the 2 h infusion of 1 g, the percentages of time above four times an MIC of 4, 2 and 1 mg/L were 51.6 +/- 5.4%, 67.8 +/- 4.5% and 87.8 +/- 5.6% of a 6 h interval, respectively. CONCLUSIONS: A 2 h infusion resulted in a greater t > MIC than those after a 0.5 h infusion and intermittent infusion may be a useful mode of administration of imipenem in tropical countries.     

Clinical pharmacology of 1,4-butanediol and gamma-hydroxybutyrate after oral 1,4-butanediol administration to healthy volunteers

1,4-Butanediol (BD) is converted to gamma-hydroxybutyrate (GHB) after ingestion, and is associated with cases of dependence, coma, and death. The pharmacology of BD after oral ingestion has not been described in humans. Eight healthy volunteers (five men) were administered 25 mg/kg BD in a single oral dose after an overnight fast in a double-blinded, placebo-controlled, crossover study. Vital signs were monitored, and serial blood samples collected over 24 h for gas chromatography-mass spectrometry analysis of BD and GHB levels. Subjective mood and symptoms responses were assessed by visual analog scale. All subjects completed the study without significant adverse effects. BD was quickly absorbed and cleared, with time to maximal plasma concentration of 24+/-12 min, and elimination half-life (T(1/2)) of 39.3+/-11 min. BD was extensively converted to GHB, with a mean maximum GHB concentration of 45.6+/-19.7 mg/l reached 39.4+/-11.2 min after BD ingestion. GHB T(1/2) averaged 32.3+/-6.6 min. Some subjects exhibited slow oral clearance of BD, which tended to correlate with a variant haplotype of the alcohol dehydrogenase gene ADH-IB G143A. Mean CL/F was 151.5+/-176.5 ml/min kg for four subjects with variant haplotype versus 598.8+/-446.6 ml/min kg for four wild-type subjects (P=0.061). Subjects reported feeling less awake and alert, less able to concentrate, and more lightheaded in the first 90 min after BD ingestion. Pulse oximetry readings were lower 45 min after BD dosing with a mean oxygen saturation of 98.5% with BD versus 99.6% with placebo (P=0.031). Transient increases in mean systolic and diastolic blood pressure were observed, but other vital signs remained unchanged. BD was extensively converted to GHB after oral administration, but significant inter-individual variability in the rate of metabolism, possibly related to variants in ADH-IB, was observed. At the modest dose studied, significant clinical effects were not seen.     

Zanamivir pharmacokinetics and pulmonary penetration into epithelial lining fluid following intravenous or oral inhaled administration to healthy adult subjects

Zanamivir serum and pulmonary pharmacokinetics were characterized following intravenous (i.v.) or oral inhaled administration. I.v. zanamivir was given as intermittent doses of 100 mg, 200 mg, and 600 mg every 12 h (q12h) for two doses or as a continuous infusion (6-mg loading dose followed by 3 mg/h for 12 h). Oral inhaled zanamivir (two 5-mg inhalations q12h for two doses) was evaluated as well. Each zanamivir regimen was administered to six healthy subjects with serial pharmacokinetic sampling. In addition, a single bronchoalveolar lavage (BAL) fluid sample was collected at various time points and used to calculate epithelial lining fluid (ELF) drug concentrations for each subject. For intermittent i.v. administration of 100 mg, 200 mg, and 600 mg zanamivir, the median zanamivir concentrations in ELF collected 12 h after dosing were 74, 146, and 419 ng/ml, respectively, each higher than the historic mean 50% inhibitory concentrations for the neuraminidases of wild-type strains of influenza A and B viruses. Median ELF/serum zanamivir concentration ratios ranged from 55 to 79% for intermittent i.v. administration (when sampled 12 h after the last dose) and 43 to 45% for continuous infusion (when sampled 6 to 12 h after the start of the infusion). For oral inhaled zanamivir, the median zanamivir concentrations in ELF were 891 ng/ml for the first BAL fluid collection and 326 ng/ml for subsequent BAL fluid collections (when sampled 12 h after the last dose); corresponding serum drug concentrations were undetectable. This study demonstrates zanamivir's penetration into the human pulmonary compartment and supports the doses selected for the continuing development of i.v. zanamivir in clinical studies of influenza.