Safety, tolerance, and preliminary pharmacokinetics of nefazodone after administration of single and multiple oral doses to healthy adult male volunteers: a double-blind, phase I study.

Safety, tolerance, and preliminary pharmacokinetics of nefazodone, a new antidepressant, were assessed in a randomized, double-blind, parallel group study carried out in two sequential segments: a single and a multiple daily dose segment. Nine subjects in the single daily dose segment were divided into three treatment groups and received nefazodone doses in a leapfrog fashion. Each day of treatment with nefazodone was followed by 2 days of placebo treatment and then administration of the next higher drug dose. Single doses ranged from 5-500 mg. 8 subjects enrolled in the multiple daily dose segment were divided into two treatment groups. In each group, 3 subjects received nefazodone and one received placebo 3 times a day. Each dosage level was administered for 2 days before proceeding to the next higher dose from 5 mg or 10 mg 3 times a day to a maximum of 500 mg 3 times a day. After the dose-escalation period, the subjects in the multiple daily dose segment underwent a 3-day washout, after which they received a single dose of nefazodone at the maximum tolerated level. Safety and tolerance assessment involved analyses of adverse events, laboratory tests, vital signs, ophthalmic examinations, and ECGs. Blood and urine samples were obtained only in the multiple daily dose segment and analyzed for nefazodone and its two pharmacologically active metabolites, hydroxynefazodone and mCPP. A single blood sample was collected on 8 different days for assessment of trough levels (Cmin) and serial samples were obtained on days 5, 9, and 22 of dosing for pharmacokinetic profiles. Additional serial samples were also obtained after the last single dose of 500 mg after a 3-day washout. Nefazodone was found to be safe and well-tolerated in total daily doses as high as 1350 mg (450 mg 3 times a day). Nefazodone was rapidly absorbed after oral administration and converted to hydroxynefazodone and mCPP. The pharmacokinetics of nefazodone, hydroxynefazodone, and mCPP were found to be dose-dependent, as evidenced by dose normalized values of Cmin, Cmax, and AUC0-8 that progressively increased with dose. Although exposure of normal subjects to nefazodone and its 2 pharmacologically active metabolites was disproportionately higher than the corresponding increase in dose, the safety and tolerance profiles did not show a parallel increase in adverse events. Nefazodone may be well-tolerated by patients receiving expected therapeutic doses from 200-600 mg per day when administered in divided doses every 8 to 12 hours.

Analysis of potential risk factors associated with the development of pancreatitis in phase I patients with AIDS or AIDS-related complex receiving didanosine.

Phase I dose-escalating trials of didanosine revealed dose-limiting toxicities, including pancreatitis, and established a total daily dose of 12.5 mg/kg/day as the maximum tolerated dose. Clinical and pharmacokinetic data of 61 patients from two trials were analyzed to further evaluate the risk of pancreatitis: 1 (6.3%) of 16 patients who received < 500 mg/day didanosine, 2 (13.3%) of 15 who received 500-750 mg/day, and 15 (50%) of 30 who received > 750 mg/day developed pancreatitis (P < .001). A relationship between risk of pancreatitis and steady-state plasma concentrations of didanosine and age was also observed, suggesting that knowledge of didanosine pharmacokinetics provided additional information regarding risk of toxicity. Further confirmation of these findings will be necessary to determine if the risk factors for pancreatitis remain the same at lower doses currently used.

High-performance liquid chromatographic method for the quantitative determination of butorphanol, hydroxybutorphanol, and norbutorphanol in human urine using fluorescence detection.

A sensitive, quantitative reversed-phase high-performance liquid chromatographic method has been established for the simultaneous determination of butorphanol, a synthetic opioid, and its metabolites, hydroxybutorphanol and norbutorphanol, in human urine samples. The method involved extraction of butorphanol, hydroxybutorphanol, and norbutorphanol from urine (1.0 ml), buffered with 0.1 ml of 1.0 M ammonium acetate (pH 6.0), onto 1-ml Cyano Bond Elut columns. The eluent was evaporated under nitrogen and low heat, and reconstituted with the HPLC mobile phase, acetonitrile-methanol-water (20:10:70, v/v/v), containing 10 mM ammonium acetate and 10 mM TMAH (pH 5.0). The samples were chromatographed on a reversed-phase octyl 5-microns column. The analysis was accomplished by detection of the fluorescence of the three analytes, at excitation and emission wavelengths of 200 nm and 325 nm, respectively. The retention times for hydroxybutorphanol, norbutorphanol, the internal standard, and butorphanol were 5.5, 9.0, 13.0, and 23.4 min respectively. The validated quantitation range of the method was 1-100 ng/ml for butorphanol and hydroxybutorphanol, and 2-200 ng/ml for norbutorphanol in urine. The observed recoveries for butorphanol, hydroxybutorphanol, and norbutorphanol were 93%, 72%, and 50%, respectively. Standard curve correlation coefficients of 0.995 or greater were obtained during validation experiments and analysis of study samples. The method was applied on study samples from a clinical study of butorphanol, providing a pharmacokinetic profiling of butorphanol.

The effects of age and sex on the systemic availability and pharmacokinetics of transnasal butorphanol.

We have studied the effects of age and sex on the pharmacokinetics and the systemic availability of transnasal butorphanol in a randomized, two-way, cross-over study of 48 subjects: young men and women, and elderly men and women. Each subject took a single 1 mg dose of intravenous and transnasal butorphanol tartrate on separate occasions with a one-week washout period. Blood samples were collected over 16 hours. Plasma butorphanol concentrations were determined using radioimmunoassay. The AUC of plasma butorphanol concentrations after an intravenous injection were higher in the elderly women than in the other groups. However, there were no significant differences in Cmax and AUC between the groups after transnasal administration. The mean systemic availability of transnasal butorphanol was about 70%, except for the elderly women (48%). After intravenous and transnasal administration, the half-life and mean residence time were greater in the elderly than the young. Clearance was lower in women than men. Apparent volume of distribution was higher for elderly men than the others. The age- and sex-related changes in the pharmacokinetics of transnasal butorphanol are not large enough to necessitate dosage differences.

Disposition kinetics of buspirone in patients with renal or hepatic impairment after administration of single and multiple doses.

The single dose and steady-state pharmacokinetics of buspirone and its metabolite 1-pyrimidinyl piperazine (1-PP) have been evaluated in normal volunteers and patients with renal or hepatic impairment, using a parallel group design, with assignment of patients to study group on the basis of the degree of renal (mild, moderate, severe) or hepatic (compensated or decompensated) impairment. Each healthy volunteer or patient received a single dose of 10 mg buspirone on Day 1 of the study, and starting 36 h after the first dose, healthy volunteers and patients received 10 mg doses of buspirone every 12 hours for 9 days. On the morning of Day 10 they received the last dose. Serial blood samples were collected on Days 1, 5 and 10 and plasma was analysed for buspirone and 1-PP. The plasma concentrations of buspirone and 1-PP were highly variable regardless of the renal or hepatic function. The peak concentrations (Cmax) and area under the curves (AUC) of buspirone and 1-PP on Days D5 and 10 were higher than on Day D1. The trough levels (Cmin) and AUCs (D5 and 10) of buspirone and 1-PP indicated, that, regardless of renal or hepatic function, steady state was reached after 3 to 5 days of dosing. At steady-state, patients with renal or hepatic impairment had significantly higher Cmax and AUC values of buspirone than in normal volunteers. However, the intensity and frequency of adverse experiences in patients with renal or hepatic impairment were not significantly different from those observed in normal volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of food on the bioavailability of gepirone in humans.

A randomized two-period crossover study was conducted in 20 healthy male volunteers to assess the effect of food on the pharmacokinetics of gepirone (BMY-13805) and its metabolite, 1-(2-pyrimidinyl)-piperazine (1-PP) after a single 20-mg dose of gepirone either after fasting or after consumption of a standard high-fat breakfast. There was a 1-week washout period between treatments. Plasma samples were obtained predose and at specified time points after dosing and analyzed for gepirone and 1-PP content by a specific gas chromatographic-mass spectrometric method. Food did not significantly affect gepirone maximum peak plasma concentration (Cmax) and half-life (t1/2). The mean gepirone Cmax was 16.98 +/- 8.12 ng/mL (fed) and 18.73 +/- 10.30 ng/mL (fasted), with mean t1/2 of 3.32 +/- 1.84 hours (fed) and 2.94 +/- 0.90 hours (fasted). Food significantly increased the mean area under the curveinf (AUCinf) from 55.26 +/- 35.74 ng.hour/mL (fasted) to 75.69 +/- 42.79 ng.hour/mL (fed), and the mean residence timeinf (MRTinf) from 4.31 +/- 0.78 hours (fasted) to 5.37 +/- 1.21 hours (fed). The median time to maximum plasma concentration (tmax) for gepirone was also significantly increased in the presence of food, 2.0 hours, versus 0.75 hours in the absence of food. For 1-PP, food had no affect on Cmax, t1/2, or AUCinf. Mean t1/2 for 1-PP in the presence and absence of food was 6.06 +/- 1.75 and 5.76 +/- 1.75 hours, respectively. MRTinf, however, was increased significantly from 9.32 +/- 2.68 hours (fasted) to 10.53 +/- 2.89 hours (fed).(ABSTRACT TRUNCATED AT 250 WORDS)

Biopharmaceutical evaluation of transnasal, sublingual, and buccal disk dosage forms of butorphanol.

A series of three-way crossover randomized studies were conducted to evaluate the absolute bioavailability of butorphanol, a potent agonist-antagonist analgesic, from transnasal, sublingual, and buccal disk formulations in order to identify a practical alternative to oral administration. In each study, healthy male volunteers received 2 mg doses of butorphanol tartrate intravenously and either transnasally, sublingually or buccally. Serial blood samples were collected over 12 h and butorphanol plasma concentrations were determined by radioimmunoassay. The plasma concentration data were subjected to non-compartmental pharmacokinetic analysis. The elimination half-life of butorphanol was about 3-5 h and was independent of the route of administration. Absorption of butorphanol following transnasal administration was faster than that observed following sublingual or buccal administration. Mean absolute bioavailabilities of sublingual tablet and buccal disk formulation were only 19 per cent and 29 per cent, respectively, but for transnasal administration the value rose significantly, to 70 per cent. Based on the results of these studies, transnasal dosage form of butorphanol was selected for further clinical trials of treatment of moderate to severe pain.

Multiple-dose phase I study of transnasal butorphanol.

The safety, tolerance, and pharmacokinetics of transnasal butorphanol were evaluated in a double-blind, multiple-dose phase I study. A total of 18 subjects received either placebo (n = 6) or a single transnasal dose of 2 mg butorphanol tartrate on the first day and 1, 2, and 4 mg doses of butorphanol tartrate every 6 hours on days 2 through 6, 7 through 11, and 12 through 16, respectively. Safety assessment was performed on days 7, 12, and 17. Serial blood samples were collected on days 1, 6, 11, and 16, and the plasma was analyzed for unchanged butorphanol by a validated and specific radioimmunoassay. Butorphanol was rapidly absorbed and peak levels in plasma were generally attained within 1 hour after the nasal administration. The values of maximum concentration, minimum concentration, and area under the concentration versus time curve from time zero to the dosing interval [AUC(0-tau)] increased as the administered dose increased in a dose-proportional manner. The values of AUC from time zero to infinity after a single dose of 2 mg butorphanol tartrate, 10.9 ng.hr/ml, were identical to the values of AUC(0-tau) after a multiple administration of 2 mg dose, 10.4 ng.hr/ml. Mean elimination half-life value was 5.45 hours. Steady state was reached in fewer than eight doses when given every 6 hours. Transnasal butorphanol was well tolerated by all subjects. After repeated administration of transnasal butorphanol, no significant changes were observed in the nasal examination, which included evaluation of color, wetness, and thickness of nostril membrane, air flow, airway patency, and general nasal conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics, absolute bioavailability, and disposition of [14C]nefazodone in the dog.

In a two-way crossover study, the pharmacokinetics and disposition of nefazodone (NEF) were investigated after intravenous (i.v.) infusion and oral (po) gavage of a solution of 10 mg/kg (5 microCi/kg) of [14C]NEF to four beagle dogs. Plasma was analyzed by HPLC for NEF, and its metabolites hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP), and p-hydroxynefazodone (p-HO-NEF). Plasma, urine, and feces were also analyzed for total radioactivity. Mean AUC(INF) values for NEF after po administration were about an order of magnitude lower compared with those after i.v. administration. Mean Cmax and AUC(INF) values for the metabolites after po administration were about as high or higher compared with those after i.v. administration. Mean (SD) total body clearance of NEF was 1.56 (0.34) liter/hr.kg-1, and mean (SD) steady-state volume of distribution of NEF was 3.24 (1.0) liter/kg. Mean (SD) absolute bioavailability of NEF after po administration was calculated to be 14.0 (4.2)%. The fraction of oral NEF eliminated presystemically was estimated to be 86%. Plasma concentration-time profiles for total radioactivity after i.v. and po administration were superimposable. The recovery of total radioactivity in urine and feces was similar after iv and po administration, indicating complete absorption of the drug after po administration. NEF, HO-NEF, and p-HO-NEF accounted for approximately 37% and 12% of the plasma AUC for total radioactivity following i.v. and po administration, respectively. The total urinary (28%) and fecal (61%) recovery after i.v. or po administration was approximately 90% of the dose within 7 days.(ABSTRACT TRUNCATED AT 250 WORDS)

The absolute bioavailability of transnasal butorphanol in patients experiencing rhinitis.

The absolute bioavailability (f) and pharmacokinetics of transnasal butorphanol were evaluated in patients experiencing rhinitis. In an open three-way crossover study, a single 2-mg dose of butorphanol tartrate was administered by intravenous bolus injection (Treatment A), by the transnasal route (Treatment B), or by the transnasal route with pretreatment of the vasoconstrictor, oxymetazoline (Treatment C). Plasma concentrations of butorphanol were determined using a drug specific radioimmunoassay. The pharmacokinetic parameters were derived using the noncompartmental methods. Butorphanol was rapidly absorbed after transnasal administration. The mean maximum concentrations (Cmax) for the transnasal treatment with and without pretreatment of oxymetazoline were 1.61 and 3.01 ng.ml-1, respectively. The corresponding mean absorption times (MAT) were 1.34 and 0.23 h. The mean half-life values were 5.95, 6.28, and 5.77 h, for treatments A, B, and C, respectively. The resulting mean area under the plasma concentration curve (AUC) values were 11.9, 8.6, and 8.07 ng.h.ml-1 for treatments A, B, and C, respectively. The estimates for absolute bioavailability (f) of transnasal butorphanol were 69% and 72% when administered with and without oxymetazoline, respectively. The mean CLT and Vss were 121 l.h-1 and 791 l, respectively, for the intravenous treatment. The pretreatment of oxymetazoline significantly lowered the Cmax and prolonged the absorption time of butorphanol. Although the rate of absorption of transnasal butorphanol was affected by oxymetazoline, the absolute bioavailability in rhinitis patients (72%) was similar to that found with the pretreatment of oxymetazoline (69%) and those reported in healthy volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of nefazodone in the dog following single oral administration.

The pharmacokinetics of nefazodone (NEF) and two of its pharmacologically active metabolites viz hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were determined following single oral administration of 100, 200 and 400 mg NEF to 6 beagle dogs in a three-way crossover study. Blood samples were collected for 48 h and plasma was analyzed for NEF, HO-NEF and mCPP by a validated HPLC assay. NEF was rapidly absorbed after oral administration. Cmax values for all three compounds and AUCinf values for HO-NEF and mCPP were dose-proportional; AUCinf values for NEF were dose-linear but not dose-proportional. The T1/2 values for NEF and HO-NEF following the 400 mg dose were significantly greater than those for the 100 mg dose. No differences in mCPP T1/2 were observed among the doses. The Cmax and AUCinf ratios for metabolite:NEF were about 2-fold lower for the 200 and 400 mg doses than those observed for the 100 mg dose. However, due to extensive variability, the ratios for three doses were not significantly different based on statistical analysis. Overall, these data suggest the pharmacokinetics of NEF are dose-dependent in the beagle dog. Statistical significance for dose-dependency for many of the pharmacokinetic parameters could not be demonstrated due to high variability associated with the plasma concentration vs time profiles.

Pharmacokinetics of nefazodone following multiple escalating oral doses in the dog.

The single and multiple dose pharmacokinetics of nefazodone (NEF) were investigated in a dose-escalating study in which 4 beagle dogs (weighing approximately 10 kg) were orally administered 100 mg nefazodone hydrochloride on days 1-7, 500 mg on days 8-14 and 1000 mg on days 15-20 once daily. Serial blood samples were collected over a 24 h period following administration of the first (day 1) and last (day 7) doses for the 100 mg/day dose and the last dose for the 500 (day 14) and 1000 mg/day (day 20) doses. Blood samples were also collected for trough level (Cmin) determination on the morning of the 5th, 6th and 7th day of 100 and 500 mg/day dosing regimens and the 3rd, 5th and 6th day of 1000 mg/day regimen. Plasma was analyzed for NEF and 3 metabolites [hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP) and p-hydroxynefazodone (p-HO-NEF)] by a validated HPLC assay. There were no significant differences between the 100 mg single and 100 mg/day multiple dose pharmacokinetic parameters for NEF, HO-NEF and mCPP. However, for p-HO-NEF, single dose elimination half life (T1/2) and area under the plasma concentration-time curve (AUC) extended to infinity were significantly smaller (P < or = 0.05) than the multiple dose T1/2 and AUCTAU, respectively. Based on Cmin data, steady state was reached by the 5th day of 500 mg/day and 1000 mg/day multiple dosing. Mean multiple dose AUCTAU values for NEF increased in a 1:9:26 ratio for a 1:5:10 increase in dose. Due to extensive variability and small number of animals used in the study, the statistical analysis indicated that AUCTAU values were dose-proportional. However, metabolite formation decreased significantly with increasing dose as indicated by AUCTAU ratios for metabolite:NEF. These data suggest that NEF exhibits nonlinear pharmacokinetics within 100-1000 mg/kg dose range in dogs.

Oral absolute bioavailability and intravenous dose-proportionality of cefprozil in humans.

The absolute bioavailability (F) and dose proportionality of cefprozil were investigated in a parallel design study with an embedded two-way crossover leg. Twenty-four healthy male subjects divided into 3 dosing groups received a single 250-, 500-, or 1000-mg dose of cefprozil by a 30-minute intravenous infusion. Subjects assigned to the 500-mg dose group also received a 500-mg oral dose of cefprozil in crossover manner with a wash-out period of 7 days between each treatment. Cefprozil consists of cis and trans isomers in an approximate 90:10 ratio. Serial blood and urine samples were collected and analyzed for the concentrations of the cis and trans isomers of the cephalosporin using high-pressure liquid chromatographic assay with UV detection methods. After the 250-, 500-, and 1000-mg intravenous administration of cefprozil, the peak concentrations were 13.2, 26.0, and 48.5 micrograms/mL, and area under the plasma concentration versus time profiles were 17.2, 31.4, and 58.1 micrograms.hour/mL, respectively, for the cis isomer increasing in a dose proportional manner. Total body clearance, renal clearance, and volume of distribution at steady state, adjusted for body weight, were not significantly different among all groups. Mean residence time, elimination half-life, and urinary recovery were invariant with the dose. Based on the plasma and urine data, the estimates of F were 89% and 94% for the cis isomer, respectively. The plasma concentrations of the trans isomer were about 1/10th of the cis isomer, and all parameters were similar to those observed for the cis isomer. In summary, cefprozil exhibits linear pharmacokinetics and is essentially completely absorbed after oral administration.

The site of gastrointestinal absorption of gepirone in humans.

This study was conducted in seven healthy male subjects and was performed over four sessions with a 1-week washout between sessions. It was designed to compare the bioavailability of an oral 20-mg gepirone dose (treatment 1) with that obtained after application of the same dose by gastric intubation to the distal (treatment 2) and proximal (treatment 3) regions of the small intestine, and after 4 consecutive 5-mg gepirone doses given orally at hourly intervals (treatment 4). Serial blood samples were taken over 24 hours after dose after each treatment. Plasma concentrations of gepirone and 1-(2-pyrimidinyl)-piperazine (1-PP), a metabolite of gepirone, were quantitated by gas chromatography-mass spectrometry. Mean gepirone time to reach peak concentration (tmax) after treatments 1, 2, and 3 ranged between 0.57 and 1.07 hours. There were no significant differences between sites and treatments for gepirone t1/2, which ranged between 2.8 and 3.3 hours. The mean gepirone maximum peak plasma concentration (Cmax) was significantly higher (P less than .05) after treatment 2 (12.92 +/- 7.24 ng/mL) compared with treatment 1 (6.79 +/- 3.54 ng/mL) or treatment 3 (6.33 +/- 2.26 ng/mL). Gepirone area under the curve (AUCinf) was also significantly higher (P less than .05) after treatment 2 (29.83 +/- 17.42 ng.h/mL) compared with treatment 1 (18.07 +/- 6.10 ng.h/mL) or treatment 3 (17.74 +/- 7.69 ng.h/mL). There were no significant differences in gepirone AUCinf between treatments 1 and 4.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic interactions of cefprozil with food, propantheline, metoclopramide, and probenecid in healthy volunteers.

Cefprozil, a new oral cephalosporin antibiotic, is composed of cis and trans isomers in an approximate 90:10 ratio. The objectives of this study were: (1) to assess the effects of alterations in gastrointestinal motility by metoclopramide and propantheline on the pharmacokinetics of cis and trans isomers of cefprozil, and to compare them with the effects of food on the pharmacokinetics of cefprozil; (2) to assess the effects of inhibition of renal tubular secretion by probenecid on the pharmacokinetics of cefprozil isomers. In this four-way crossover study, 15 healthy male volunteers received a 1000-mg dose of cefprozil after fasting, pretreatment with metoclopramide or propantheline, after breakfast, or after probenecid in an incomplete, balanced block design. There was a 1-week washout period between each treatment. Blood and urine samples collected over a 24-hour period were assayed for the cis and trans isomers. The concentrations of the trans isomers were generally 1/10 of the cis isomer. The means and variances of the pharmacokinetic parameters of the cis and trans isomers of cefprozil were similar in fasting subjects and were affected in a parallel manner by food, metoclopramide, propantheline, and probenecid. The pharmacokinetics of the cis isomer under the fasting condition were as follows: maximum peak plasma concentration (Cmax), 14.0 +/- 2.7 micrograms/mL; median time to reach Cmax (tmax), 1.5 (range, 1.0-3.5) hours; half-life (t1/2), 1.24 +/- 0.27 hours; area under the concentration (AUC0-infinity), 47.3 +/- 7.7 micrograms.hour/mL; mean residence time after oral administration (MRTpo), 2.9 +/- 0.4 hours; CLR, 219 +/- 60 mL/minute; and Xu% (percent cumulative urinary excretion in 0-24 hours), 68.1 +/- 12.5.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of pharmacokinetic interaction between cefepime and amikacin in humans.

The interaction potential between cefepime and amikacin was investigated in a steady-state pharmacokinetic study in 16 healthy male subjects. Eight subjects (group A) received a first course of 2,000 mg of cefepime; this was followed by a second course of 2,000 mg of cefepime with 300 mg of amikacin and a third course of 2,000 mg of cefepime. Eight other subjects (group B) received a first course of 300 mg of amikacin, a second course of 300 mg of amikacin with 2,000 mg of cefepime, and a third course of 300 mg of amikacin. Each course consisted of four consecutive doses administered every 8 h as 30-min intravenous infusions. Serial plasma and urine samples, which were collected after administration of the fourth dose of each course, were assayed for cefepime and/or amikacin by validated high-performance liquid chromatographic assays. Trough levels of cefepime and amikacin indicated that these antibiotics attained a steady state prior to administration of the fourth dose of each course. Key pharmacokinetic parameters for each antibiotic were determined by noncompartmental methods. The peak concentrations of cefepime and amikacin in plasma when the drugs were given alone were about 160 and 27 micrograms/ml, respectively. Levels of each antibiotic in plasma declined, with an apparent half-life of approximately 2.2 h. Urinary recovery of cefepime and amikacin accounted for more than 85% of the administered dose of each antibiotic. Mean renal clearances for cefepime and amikacin ranged from 79 to 95 ml/min and suggested that glomerular filtration is the primary excretion mechanism. The results of the statistical analyses indicated that the pharmacokinetic parameters of cefepime following the concurrent administration of amikacin and following the discontinuation of the amikacin following the concurrent administration of cefepime and following the discontinuation of the cefepime therapy were not significantly altered. Cefepime and amikacin can be coadministered to patients with normal renal function by using the standard recommended dosing regimens.

Pharmacokinetics of cefepime in patients undergoing continuous ambulatory peritoneal dialysis.

The pharmacokinetics of cefepime were studied in 10 male patients receiving continuous ambulatory peritoneal dialysis therapy. Five patients received a single 1,000-mg dose and the other five received a single 2,000-mg dose; all doses were given as 30-min intravenous infusions. Serial plasma, urine, and peritoneal dialysate samples were collected; and the concentrations of cefepime in these fluids were measured over 72 h by using a high-performance liquid chromatographic assay with UV detection. Pharmacokinetic parameters were calculated by noncompartmental methods. The peak concentrations in plasma and the areas under the plasma concentration-versus-time curve for the 2,000-mg dose group were twice as high as those observed for the 1,000-mg dose group. The elimination half-life of cefepime was about 18 h and was independent of the dose. The steady-state volume of distribution was about 22 liters, and values for the 1,000- and 2,000-mg doses were not significantly different. The values for total body clearance and peritoneal dialysis clearance were about 15 and 4 ml/min, respectively. No dose dependency was observed for the clearance estimates. Over the 72-h sampling period, about 26% of the dose was excreted intact into the peritoneal dialysis fluid. For 48 h postdose, mean concentrations of cefepime in dialysate at the end of each dialysis interval exceeded the reported MICs for 90% of the isolates (MIC90s) for bacteria which commonly cause peritonitis resulting from continuous peritoneal dialysis. A parenteral dose of 1,000 or 2,000 mg of cefepime every 48 h would maintain the antibiotic levels in plasma and peritoneal fluid above the MIC90s for the most susceptible bacteria for the treatment of systemic and intraperitoneal infections [corrected].

Effects of age and gender on pharmacokinetics of cefepime.

The effects of age and gender on the pharmacokinetics of cefepime were examined in 48 volunteers following administration of a single 1,000-mg intravenous dose. Male and female subjects were divided into four groups, each consisting of 12 subjects, according to their age and gender. The young subjects were between 20 and 40 years of age and elderly subjects were between 65 and 81 years of age. Serial blood and urine samples were collected from each subject and were analyzed for cefepime by validated high-pressure liquid chromatographic assays with UV detection. Key pharmacokinetic parameters were calculated by noncompartmental methods. There were no gender-related differences in elimination half-life (t1/2) and weight-normalized total body clearance (CLT), renal clearance (CLR), and steady-state volume of distribution (Vss). Statistically significant age-related effects were found for t1/2, CLT, CLR, and Vss parameters. In different study groups, Vss ranged from 0.21 to 0.24 liter/kg. The values for Vss were significant greater for elderly subjects than they were for young subjects. The cefepime t1/2 was significantly longer in elderly subjects (about 3 h) than that observed in young subjects (about 2.2 h). The mean values for CLT and CLR in the four study groups ranged from 1.11 to 1.56 and 0.99 to 1.44 ml/min/kg, respectively. In elderly subjects, the estimates for CLT and CLR were significantly lower than those observed in young subjects. Linear regression revealed good correlations between clearance values of cefepime and creatinine. The magnitude of age-related changes in the pharmacokinetics of cefepime is not significant enough to recommend dosage adjustment in elderly patients with kidney functions normal for their age.

Excretion of cefprozil into human breast milk.

The excretion of cefprozil into breast milk in nine healthy, lactating female subjects was investigated. Each subject received a single 1,000-mg oral dose of cefprozil consisting of cis and trans isomers in an approximately 90:10 ratio. Serial blood, urine, and breast milk samples were collected and analyzed for the concentrations of the cis and trans isomers by a specific high-pressure liquid chromatography-UV assay. The mean pharmacokinetic parameters for both isomers were essentially the same. The mean peak concentrations in plasma for the cis isomer were 14.8 micrograms/ml, and the area under the concentration curve was 54.8 micrograms.h/ml. The mean values of elimination half-life, renal clearance, and urinary excretion for the cis isomer were 1.69 h, 164 ml/min, and 60%, respectively. The mean concentrations in milk of the cis isomer over a 24-h period ranged from 0.25 to 3.36 micrograms/ml, with the maximum concentration appearing at 6 h after dosing. The average maximum concentration in milk of the trans isomer was less than 0.26 micrograms/ml. The concentrations of the trans isomer in plasma and in breast milk were about 1/10 of those for the cis isomer. Less than 0.3% of the dose was excreted in breast milk for both isomers of cefprozil. Even if one assumes that the concentration of cefprozil in milk remains constant at 3.36 micrograms/ml (the highest concentration of cefprozil observed in breast milk), an infant ingesting an average of 800 ml of milk per day will be exposed to a maximum amount of about 3 mg of cefprozil per day. This value represents about 0.3% of the maternal dose. Low excretion of cefprozil in breast milk and the excellent safety profile of cefprozil suggest that this cephalosporin may be administered to nursing mothers when indicated.

Effect of antacid on the bioavailability of cefprozil.

The effect of antacid on the bioavailability of cefprozil was investigated in a two-way crossover study. Eight healthy male subjects received a single 500-mg oral dose of cefprozil with and without coadministration of 30 ml of an antacid suspension containing magnesium hydroxide and aluminum hydroxide (Maalox). Cefprozil consists of cis and trans isomers in an approximate 90:10 ratio. When cefprozil was administered alone (treatment A), the mean maximum concentrations (Cmax) of the cis and trans isomers were 9.2 and 1.2 micrograms/ml, respectively. When cefprozil was coadministered with Maalox (treatment B), the Cmax values of the cis and trans isomers were 8.7 and 1.3 micrograms/ml, respectively. The mean values of the area under the curve from time zero to infinity (AUC0-infinity) were 27.7 and 3.5 micrograms.h/ml for treatment A and 27.5 and 3.5 micrograms.h/ml for treatment B for the cis and trans isomers, respectively. The other pharmacokinetic parameters, time to Cmax, elimination half-life, mean residence time, renal clearance, and percent urinary excretion, were essentially the same for the two isomers. The respective values of the elimination half-life for the cis and trans isomers were 1.36 and 1.32 h for treatment A and 1.36 and 1.42 h for treatment B. Mean urinary excretion was 63 and 60% for treatment A and 58 and 56% for treatment B for the cis and trans isomers, respectively. No significant differences between the two treatments were found for any of the pharmacokinetic parameters for either isomer. For the cis isomer, bioavailability point estimates (90% confidence intervals) of the mean Cmax and AUG0-infinity values for the Maalox treatment relative to those for the reference treatment were 95% (87%, 103%) and 99% (95%, 104%), respectively. For the trans isomer, the value were 109% (92%, 126%) for Cmax and 97% (88%, 106%) for AUC0-infinity. On the basis of the results of this study, it is concluded that the bioavailability of cefprozil is not affected by the coadministration of Maalox.