Effect of ketoconazole on the pharmacokinetics and safety of telithromycin and clarithromycin in older subjects with renal impairment.

OBJECTIVE: The objective of this study was to determine the effect of multiple impairments in drug elimination on the pharmacokinetics and pharmacodynamics (effect on QTc interval), using clarithromycin as a comparator. METHODS: Thirty-two subjects aged > or = 60 years with renal impairment who were otherwise medically stable were recruited into this parallel-group study. Following stratification according to creatinine clearance (CL(CR)), subjects were randomized to a five-day treatment with ketoconazole (400 mg once daily) alone, or a five-day treatment with ketoconazole (400 mg once daily) and telithromycin (800 mg once daily) given concomitantly or a five-day treatment with ketoconazole (400 mg once daily) and clarithromycin (500 mg twice daily) given concomitantly. Steady-state pharmacokinetics and safety, including serial electrocardiograms, were assessed. RESULTS: In subjects with CL(CR) 30 - 80 ml/min, the mean maximal telithromycin concentration at steady state (C(max),ss) was 3.6 mg/l and the steady state area under the plasma concentration-time curve from time zero to 24 hours (AUC(0-24 h) ss) was 33.4 mg x h/l. The mean C(max), ss and AUC(0-12 h)ss for clarithromycin were 6.2 mg/l and 56.1 mg x h/l, respectively. The increases in telithromycin C(max) ss and AUC(0-24 h) ss compared to corresponding data for healthy young subjects were 1.6- and 2.7-fold, respectively, whereas corresponding increases for clarithromycin were 2.2- and 3.3-fold, respectively. In the telithromycin plus ketoconazole group deltaQTc values were equal or < 60 ms. All QTc values were equal or < 450 ms in males and equal or < 470 ms in females. CONCLUSIONS: The increase in telithromycin plasma concentrations during ketoconazole-mediated inhibition of CYP3A4 in subjects aged 60 years or older with renal impairment was similar to that for clarithromycin under the same conditions. Telithromycin was well tolerated and produced no clinically significant prolongations in the QTc interval.

Dose proportionality and comparison of single and multiple dose pharmacokinetics of fexofenadine (MDL 16455) and its enantiomers in healthy male volunteers.

The pharmacokinetics and dose proportionality of fexofenadine, a new non-sedating antihistamine, and its enantiomers were characterized after single and multiple-dose administration of its hydrochloride salt. A total of 24 healthy male volunteers (31 +/- 8 years) received oral doses of 20, 60, 120 and 240 mg fexofenadine HCl in a randomized, complete four-period cross-over design. Subjects received a single oral dose on day 1, and multiple oral doses every 12 h on day 3 through the morning on day 7. Treatments were separated by a 14-day washout period. Serial blood and urine samples were collected for up to 48 h following the first and last doses of fexofenadine HCl. Fexofenadine and its R(+) and S(-) enantiomers were analysed in plasma and urine by validated HPLC methods. Fexofenadine pharmacokinetics were linear across the 20-120 mg dose range, but a small disproportionate increase in area under the plasma concentration-time curve (AUC) (< 25%) was observed following the 240 mg dose. Single-dose pharmacokinetics of fexofenadine were predictive of steady-state pharmacokinetics. Urinary elimination of fexofenadine played a minor role (10%) in the disposition of this drug. A 63:37 steady-state ratio of R(+) and S(-) fexofenadine was observed in plasma. This ratio was essentially constant across time and dose. R(+) and S(-) fexofenadine were eliminated into urine in equal rates and quantities. All doses of fexofenadine HCl were well tolerated after single and multiple-dose administration.

Relative bioavailability of Cardizem CD and Tiazac controlled-release diltiazem dosage forms after single and multiple dosing in healthy volunteers.

The purpose of this study was to determine the relative bioavailability of Cardizem CD compared to Tiazac after single and multiple doses. Twenty-three healthy males were enrolled in this open-label, two-way, complete crossover investigation. During each of the two treatment periods, a single 240-mg dose of diltiazem HCl was given in the morning on study day 1, then once daily on days 3 through 9. Serial plasma samples were obtained and pharmacokinetic parameters were calculated from the single-dose and steady-state concentration-time profiles. After single doses, mean diltiazem maximum plasma concentration (Cmax ) was 46% higher with the Tiazac formulation compared with Cardizem CD, and the mean area under the plasma concentration-time profile (AUC) was 19% higher with Tiazac. At steady-state, similar Cmax and AUC for the 24-hour dosing interval were found for Cardizem CD and Tiazac. However, Tiazac produced a 21% lower diltiazem minimum plasma concentration, a 28% lower trough concentration (the concentration in the plasma sample obtained just before the daily dose was given), and a 1.5-times higher fluctuation in maximum to minimum diltiazem plasma concentration compared with Cardizem CD. The pharmacokinetic profiles of the two pharmacologically active diltiazem metabolites, desacetyldiltiazem and N-desmethyldiltiazem, followed that of parent drug after single and multiple doses of Cardizem CD and Tiazac. From these results, it is concluded that the pharmacokinetic profiles of Tiazac and Cardizem CD are significantly different.

Selection of doses for phase II clinical trials based on pharmacokinetic variability consideration.

Pharmacokinetic variability is an important component of the total variability in drug response, but Phase II dose-response trials frequently are designed without considering this important factor. Mixed-effects model simulation was performed to examine overlap of patient area under the concentration-time curve (AUC) values between doses for drugs with differing inter- and intrapatient pharmacokinetic variability. Based on the results of this simulation, a dose increment of at least threefold is needed to ensure that drug exposure does not overlap in at least 50% of the patient population for a drug that exhibits greater than 25% variability. In contrast, an increment factor of 2 is normally sufficient to produce the same degree of resolution when the variability is less than 25%. These results suggest that a more aggressive choice of administration increments could lead to a better separation in systemic drug exposure between doses. This needs to be balanced against the therapeutic window of an individual drug product.

Pharmacokinetics of MDL 26479, a novel benzodiazepine inverse agonist, in normal volunteers.

MDL 26479 is a new drug undergoing clinical evaluation for the treatment of depression and for memory loss associated with Alzheimer's disease. As part of a dose tolerance trial, the single- (SD) and multiple-dose (MD) pharmacokinetics of MDL 26479 were evaluated in healthy male volunteers. SDs ranging from 2 to 465 mg, and doses of 30, 60, and 120 mg administered twice daily for 28 d, were examined. Serial blood samples were collected for up to 48 h. Plasma MDL 26479 concentrations were determined by HPLC. Plasma MDL 26479 concentration versus time profiles increased rapidly, followed by multiexponential decline. Time to maximum plasma concentration increased over the 230-fold SD range from 0.5 to 3.8 h. Maximum concentrations and areas under the concentration versus time curves increased disproportionately with dose. Apparent oral clearance estimates decreased from 52.9 to 13.8 Lh-1. MD pharmacokinetic parameters for doses from 30 to 120 mg were consistent with those observed following SD, thus indicating that SD pharmacokinetics are predictive of MD. SD and MD terminal half-life estimates were similar and independent of dose.

An investigation of the dose proportionality of deflazacort pharmacokinetics.

The dose proportionality of deflazacort was assessed following single-dose oral administration at doses of 3, 6, and 36 mg to 24 healthy young adult volunteers. The active metabolite of deflazacort (21-desacetyl deflazacort) was monitored in plasma using a sensitive, semi-microbore liquid chromatographic method. Cmax averaged 10.4 +/- 5.0, 19.8 +/- 7.5, and 132.6 +/- 52.5 ng mL-1 for the 3, 6, and 36 mg doses, respectively. AUC(0-infinity) averaged 38.5 +/- 37.1, 64.9 +/- 20.8, and 411.7 +/- 148.5 ng h mL-1 for the same three doses, respectively. Elimination half-life ranged from 1.9 +/- 0.5 h at the 6 mg dose to 2.4 +/- 1.5 h at the 36 mg dose. Regression analyses of dose versus Cmax and AUC(0-infinity) yielded intercepts which were not significantly different from zero (p > 0.05) and slopes which were significant (p < 0.05). Regression analysis of dose versus apparent oral clearance yielded a slope which was not significantly different from zero (p > 0.05). These data indicate that deflazacort exhibits dose-proportional pharmacokinetics.

Percutaneous absorption of ketoprofen from different anatomical sites in man.

PURPOSE: The purpose of this study was to investigate the percutaneous absorption of ketoprofen applied topically to different anatomical sites on the body. METHODS: The study design was a randomized, four-way crossover in 24 healthy male subjects. One gram of ketoprofen 3% gel (30 mg dose) was applied every six hours for 25 doses over a 100 cm2 of the back, arm, and knee. A 0.5 ml of ketoprofen solution (60 mg/ml) was applied to the back as a reference treatment. Plasma and urine samples were obtained for the assay of racemic ketoprofen and ketoprofen enantiomers (S and R), respectively. RESULTS: The relative bioavailabilities of ketoprofen gel were 0.90 +/- 0.50, 1.08 +/- 0.63, and 0.74 +/- 0.38 when applied to the back, arm, and knee, respectively. The plasma ketoprofen C(max) for gel applied to the back and arm are similar (p > 0.05) but C(max) was lower when applied to the knee (p < 0.05). The time to C(max) ranged from 2.7 to 4.0 hours and was similar for gel treatments on the back and arm, but no longer for the knee treatment. The fraction of dose excreted in urine as total S and R enantiomers ranged from 5.41 to 9.10%. CONCLUSIONS: The percutaneous absorption of ketoprofen was similar when applied to either the back or arm but was lower when applied to the knee.

The relative bioavailability of two marketed controlled release diltiazem dosage forms at steady state in healthy volunteers.

This study was conducted to determine the relative bioavailability of Dilacor XR capsules compared to Cardizem CD capsules at both low (180 mg d-1) and high (540 mg d-1) dose levels. Trough and serial plasma samples were obtained and pharmacokinetic parameters were calculated from the steady state concentration-time profiles. Mean steady state plasma diltiazem concentrations (AUCss(0-24)) of Dilacor XR were 19% and 26% lower than those of Cardizem CD for the 180 mg d-1 and 540 mg d-1 dose levels, respectively. In addition, Dilacor XR had lower mean Cmax,ss, Tmax,ss, Cmin,ss, and trough values than Cardizem CD with percentage differences ranging from 17% to 29%. The variability (%CV) in the data from the Dilacor XR treatments was higher for each calculated pharmacokinetic parameter compared to the Cardizem CD treatments. The %CV for Dilacor XR ranged from 34% to 104% while the %CV for Cardizem CD ranged from 21% to 49%. From these results, it may be concluded that Dilacor XR is not bioequivalent to Cardizem CD at steady state doses of 180 mg d-1 and 540 mg d-1.

Population pharmacokinetics of teicoplanin in patients with endocarditis.

Teicoplanin is a new glycopeptide antibiotic, active against aerobic and anaerobic gram-positive bacteria. The drug is intended for the treatment of systemic infections including endocarditis. In two U.S. clinical safety and efficacy trials, loading doses of 6 to 30 mg/kg doses of teicoplanin were administered initially to 197 patients, followed by once-a-day treatment of approximately the same doses over several weeks. Blood samples were collected sporadically during the study to monitor serum teicoplanin concentrations either by FPIA or microbiological assay. Nonlinear mixed-effects modeling was performed on these data to characterize the population pharmacokinetics of teicoplanin that were best described by a two-compartment model. Patient body weight, concomitant gram-positive drug treatment, and serum creatinine had significant influences on systemic clearance (CL) of the glycopeptide. In addition, body weight affected the volume of distribution of the central compartment (Vc). Other demographic factors such as age, gender, etc., had no effects. The FPIA assay method was more precise than the microbiological assay.

A comparison of population and standard two-stage pharmacokinetic analyses of vigabatrin data.

Vigabatrin (VGB), an irreversible inhibitor of GABA, is being developed as an add-on therapy for uncontrolled complex partial seizure. A single-dose study was conducted in three groups of subjects with normal, mild-to-moderate, and moderate-to-severe renal impairment to examine the effect of renal function on the pharmacokinetics of VGB. Serial blood samples were collected up to 60 h following a single 750 mg oral dose of VGB for the quantitation of drug concentrations. The plasma VGB concentration-time data were analyzed by mixed-effects modeling to estimate population pharmacokinetic parameters and to identify any significant demographic covariates. The parameters of VGB were also calculated by standard two-stage techniques and then compared to the results obtained using the mixed-effects analysis. Population VGB plasma concentration-time profiles were best described by a two-compartment model with zero-order absorption. Creatinine clearance was observed to significantly affect the oral clearance of VGB (p < 0.05), i.e. a linear increasing relationship existed between the two variables. Other demographic factors had no influence on VGB pharmacokinetics. There were agreements in the oral clearance, apparent volume of distribution during elimination, and half-life estimates calculated by both methods. In addition, the conventional technique identified a linear relationship between oral and creatinine clearances. In summary, mixed-effects modeling of serial vigabatrin data validated results determined by the standard two-stage technique.

Single and multiple oral dose pharmacokinetics of clentiazem in normal volunteers.

This study was designed to determine the pharmacokinetics and dose proportionality of clentiazem (CLZ) after single doses (SD) of 20, 40, and 80 mg and multiple dose administration (SS) of 40, 80, and 160 mg/day for 5 days. The study was an open-label, randomized four-period complete crossover design. Twenty-four healthy male volunteers participated in the study, and blood samples were drawn over 48 hours after both SD and SS. Plasma samples were analyzed for CLZ and three metabolites by high-pressure liquid chromatography. After SD, the area under the plasma concentration-time curve (AUC0-infinity) and maximum concentration (Cmax) increased disproportionately with the increase in dose. At steady-state, a twofold increase in dose (20 to 40 mg twice daily and 40 to 80 mg twice daily) resulted in an increase in AUCss of 2.14- and 2.51-fold, respectively. Oral clearance of CLZ decreased (203.8 L/h at 40 mg/d to 140.2 L/h at 160 mg/d) and bioavailability increased (0.35 at 40 mg/d to 0.50 at 160 mg/d) with increasing doses. The terminal half-life of CLZ remained unchanged with increasing doses (13.7-15.5 hours). The ratios of AUCss to AUC0-infinity at SD ranged from 1.13 to 1.27, indicating no significant accumulation of CLZ (P > .05). The AUC ratio of N-desmethyl CLZ to that of CLZ remained constant after SD. On SS, however, there was a small decrease in this ratio with increasing dose (0.77 at 40 mg/d to 0.61 at 160 mg/d). These results indicate that the degree of nonlinearity observed with CLZ pharmacokinetics may largely be due to saturable first-pass metabolism.

Pharmacokinetics of clentiazem after intravenous and oral administration in healthy subjects.

This study characterized the pharmacokinetics of clentiazem (CLZ) after a single intravenous bolus (IV) and oral (PO) dose in humans. Twenty-four healthy male subjects (28.5 +/- 5.2 years; 77 +/- 8.2 kg) received IV (20 mg) and PO (80 mg) doses of CLZ as part of a four-way, randomized, complete crossover study. Serial blood samples were drawn up to 48 hours after administration of the drug. Plasma samples were analyzed for CLZ and three metabolites by a high-pressure liquid chromatography method. The values (mean [CV, %]) for systemic clearance, volume of distribution at steady-state, and half-life of CLZ were 63.6 L/hour (23.5), 756.1 L (19.1), and 10.6 hours (33.1), respectively, after IV administration. The peak plasma CLZ concentration (Cmax) and time to Cmax were 37.0 ng/mL (38.7) and 3.7 hours (22.9), respectively, with a lag time after PO administration. The absolute bioavailability of PO CLZ was 45% (30.7). The ratio of area under the curve of N-desmethyl CLZ to that of CLZ increased from 0.15 (57.0) after IV to 0.60 (21.4) after PO administration, suggesting a significant first-pass effect. The mean residence time and mean absorption time of CLZ were 12.3 hours (24.3) and 3.1 hours (88.1), respectively. The plasma concentration-time data of CLZ can be described by either a one- or two-compartment pharmacokinetic model.

Age-dependent changes in first-pass metabolism of acetaminophen in rats.

The contribution of gastrointestinal tract (GIT), liver, and lung towards the first-pass metabolism of acetaminophen was examined using 3-week-old, 10-week-old and 1-year-old rats after administration of 30 mg kg-1 doses by intra-arterial, intravenous, intraperitoneal, and oral routes. Plasma concentrations of acetaminophen and its two major metabolites, acetaminophen glucuronide and acetaminophen sulfate, were measured for about 5h after drug administration. Total oral extraction of acetaminophen was extensive in 10-week-old and 1-year-old rats (Eo = 0.46) and the major contribution to the overall first-pass metabolism was due to the GIT (Eg = 0.50-0.53). Oral extraction in 3-week-old rats was minimal (Eo = 0.10) and there did not appear to be an extraction by the GIT (Eg = 0.00). These results suggest that the ability of GIT to metabolize acetaminophen to glucuronide and sulfate is undeveloped in the infant rats. No changes in the contribution of different organs to the first-pass metabolism of acetaminophen was observed 10 weeks after birth. Pharmacokinetic parameters for acetaminophen in infant rats (3-week-old) and 10-week-old rats were similar after drug administration by the intra-arterial and intravenous routes.

[First-pass metabolism of acetaminophen in thyroxine treated rats].

The study on the first-pass metabolism of acetaminophen was carried out in normal and thyroxine-treated rats, administered 30 mg/kg by three routes of intravenous, intraperitoneal, and oral one. Unconjugated acetaminophen and two major metabolites, glucuronide and sulfate in the plasma and urine were then measured 5 and 24 h after the administration, respectively. It was found that there was no difference in total percentage of excreted amount, independent of the routes for administration, between normal and thyroxine-treated rats. This fact shows that acetaminophen is absorbed completely from the gastrointestinal tract. However, it was also found that the extraction ratio of gastrointestinal tract in thyroxine-treated rats became smaller, and that the volume of distribution and total body clearance became larger than those in normal rats. The first-pass metabolism of acetaminophen was found to be influenced by the continuous administration of thyroxine.

First-pass metabolism of acetaminophen in rats after low and high doses.

The first-pass metabolism of acetaminophen was examined in rats after the administration of 15, 30, 150, and 300 mg kg-1 doses by intra-arterial, intravenous, portal vein, and oral routes. Plasma concentrations of acetaminophen and its two major metabolites, acetaminophen glucuronide and acetaminophen sulfate, were measured for about 5 h after drug administration. The first-pass effect after oral administration (oral extraction) was extensive (Eo = 0.34-0.50) at all doses administered. Calculation of the relative contribution of the gastrointestinal tract, liver, and lung to the oral extraction of acetaminophen indicated that the major contribution was due to the gastrointestinal tract at all doses studied (Eg = 0.33-0.50). At higher doses (150 and 300 mg kg-1) clearance was lower possibly due to the saturation of acetaminophen sulfate formation. However, even at these high doses, the contribution of the gastrointestinal mucosa to the oral extraction remained unchanged. Therefore, it appears that the apparent dose-dependent characteristics of acetaminophen metabolism may be due to the saturation of acetaminophen sulfate formation in the liver.

Effect of an enteral nutrient formula on sustained-release theophylline absorption.

The effect of an enteral nutrient formula (Osmolite) on the absorption of a single oral dose of sustained-release theophylline (Slo-bid) was studied in healthy men. In a randomized, crossover design, subjects received the enteral nutrient diet (2,400 ml/day) or food diet (F) of similar caloric, fat, carbohydrate, protein, and sodium content for 7 days. On day 6 of each diet, volunteers received a single oral dose (600 mg) of sustained-release theophylline (SRT) after fasting or with hourly oral boluses (100 ml) of enteral nutrient formula (ENF). Serial blood samples were collected for 48 h and serum concentrations were analyzed by enzyme multiplied immunoassay. Slight differences (p less than 0.01; paired t test) in Cmax (7.1 +/- 1.2 versus 8.2 +/- 1.3 mg/L) and Tmax (10.7 +/- 2.4 vs. 7.1 +/- 1.1 h) were observed between the ENF and F diets, respectively. However, areas under the curve values were similar (215 +/- 72 versus 211 +/- 70 mg h/L). This study suggests that ENF does not affect the extent of absorption of SRT when administered as a single oral dose.

Gastrointestinal, liver, and lung extraction ratio of acetaminophen in the rat after high dose administration.

The pharmacokinetics of acetaminophen was examined in rats after administration of a single dose of 200 mg kg-1 by the intra-arterial, intravenous, portal vein, and oral routes. Levels of acetaminophen and its two major metabolites, acetaminophen-glucuronide and acetaminophen-sulfate, were quantitated in plasma at various time points for about 5 h after drug administration. The relative contribution of the gastrointestinal tract, liver, and lung to the oral extraction ratio (first-pass effect after oral absorption) was determined. A mean oral extraction ratio of 0.49 was obtained. The mean relative extraction ratio of the gastrointestinal tract, liver, and lung were 0.52, 0.07, and 0, respectively, indicating a major contribution due to the gastrointestinal tract. This is in contrast to earlier studies which have indicated negligible contribution by the gastrointestinal tract to the oral first-pass effect when lower doses were utilized. These results suggest that the relative contribution of the gastrointestinal tract and liver to the oral first-pass effect of acetaminophen may be dose-dependent.

Stability of galactose in aqueous solutions.

The stability of 5%-30% w/v galactose in sterile water for injection and acetate and phosphate buffers was studied. The concentration of galactose was determined after each sample was diluted to a nominal concentration of 0.5% (w/v); for purposes of data analysis, the concentration as measured in the diluted sample was multiplied by a dilution factor to obtain the true concentration in the sample. The concentrations were determined from the regression line obtained by plotting the peak-height ratios (for various concentrations of galactose and the internal standard cellobiose) versus the galactose concentrations. Triplicate samples were quantitatively analyzed for galactose content by high-performance liquid chromatography. The stability of the samples was then studied in relation to buffer concentration; pH; storage at 25, 45, and 65 degrees C for six weeks, and autoclaving at 121 degrees C for 30 minutes. Galactose degradation increased in relation to its concentration, increasing temperature, and buffer concentration. Galactose solutions in water and phosphate incurred less than 5% degradation on autoclaving; however, the 30% solutions in acetate buffers lost up to 21% of initial content. Yellow discoloration of solutions was associated with autoclaving and prolonged exposure at 65 degrees C and appeared in some solutions that did not exceed the USP XXI limit of 5-hydroxymethylfurfural and related compounds in dextrose injection. The estimated room temperature shelf-life of galactose in sterile water for injection sterilized by 0.45-micron-porosity membrane filtration is four and one-half months. Solutions may also be sterilized by autoclaving at 121 degrees C for 30 minutes; galactose solutions containing pH buffers should not be sterilized by autoclaving.