Investigation of pharmacokinetic and pharmacodynamic interactions after coadministration of nefazodone and haloperidol.

A double-blind, placebo-controlled study using 12 healthy men was designed to evaluate pharmacokinetic and pharmacodynamic interactions when nefazodone and haloperidol are coadministered. Two groups of six subjects each received a 5-mg oral dose of haloperidol or a placebo on study days 1 and 2. Nefazodone, 200 mg, was administered to all 12 subjects twice daily (every 12 hours) on study days 3 to 9; on study day 10, only the morning dose of nefazodone was administered. On study days 9 and 10, all subjects also received 5 mg of haloperidol or a placebo along with the morning dose of nefazodone. Serial blood samples for pharmacokinetic analysis were collected from each subject over a 12-hour period after the morning dose on study days 1, 2, 9, and 10. Plasma samples were assayed for haloperidol, reduced haloperidol, nefazodone, hydroxynefazodone and m-chlorophenylpiperazine by specific, validated high-performance liquid chromatogoraphy methods. Psychomotor performance tests to evaluate haloperidol pharmacodynamics were also performed on days 1, 2, 9, and 10. Reduced haloperidol in the majority of samples was below the limit of quantitation; therefore, the effect of nefazodone on the pharmacokinetics of reduced haloperidol could not be determined. The administration of 5 mg of haloperidol to subjects dosed with nefazodone to steady state led to a modest pharmacokinetic interaction, as indicated by a 36, 13, and 37% increase in mean area under the curve (AUC0-12), highest concentration, and 12-h concentration values for haloperidol, respectively; only the increase in AUC was statistically significant. In contrast, the steady-state pharmacokinetics of nefazodone, hydroxynefazodone, and m-chlorophenylpiperazine were not affected by the administration of haloperidol. Although there were significant differences observed in some psychomotor performance tests, the effects of nefazodone on the pharmacodynamics of haloperidol could not be consistently demonstrated. The results from this study suggest that nefazodone has only modest pharmacokinetic and pharmacodynamic interactions with haloperidol. Although no specific recommendations can be made, dosage adjustment may be necessary for haloperidol when coadministered with nefazodone.

Nefazodone pharmacokinetics: assessment of nonlinearity, intra-subject variability and time to attain steady-state plasma concentrations after dose escalation and de-escalation.

OBJECTIVE: The time required to reach steady-state plasma levels after an increase and a subsequent decrease in the dose of nefazodone, an antidepressant drug with nonlinear pharmacokinetics, was assessed in 24 healthy, male volunteers. METHODS: Each subject was administered 100 mg nefazodone hydrochloride b.i.d. (q 12 h) from study day 1 to 7, 200 mg b.i.d. from study day 8 to 14 and 100 mg b.i.d. from study day 15 to 21. Trough (Cmin blood samples were obtained just prior to the morning dose on days 4-7, 11-14 and 16-21 to evaluate the attainment of steady state. Serial blood samples were collected for 12 h after the morning dose on days 7, 14, 16, 18 and 21 for pharmacokinetic analysis of plasma levels of nefazodone (NEF) and its metabolites, hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP) and triazoledione (DIONE), which were determined by validated HPLC/UV assay methods. The Cmin results indicated that when nefazodone was administered at a dose of 100 mg b.i.d., steady-state plasma levels of parent compound and its metabolites were attained by the 4th day (i.e., after six doses) and when the dose was increased from 100 mg b.i.d. to 200 mg b.i.d. and then decreased back to 100 mg b.i.d., new steady-state plasma levels were also reached by the beginning of the 3rd or 4th day of each regimen. Consistent with the attainment of steady-state data, there were no statistically significant differences in Cmax or AUC values for nefazodone or its metabolites between study days 7, 18 and 21. Also consistent with the known nonlinear pharmacokinetics of nefazodone, the mean nefazodone steady-state Cmax and AUC values for the 200-mg dose were three fold and four fold greater, respectively, than those at the 100-mg dose level. Intrasubject variability (% cv) for NEF and its metabolites ranged from 13% to 24% for Cmax and AUC after 100 mg b.i.d.. Intersubject variability was considerably greater and ranged from 29% to 131% for Cmax and AUC after the same dose.

Absorption and presystemic metabolism of nefazodone administered at different regions in the gastrointestinal tract of humans.

PURPOSE: The absorption and disposition of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP) and triazole dione (dione) were assessed in 10 healthy subjects following infusion of NEF solution into the proximal and distal regions of the intestine vs administration of NEF solution orally by mouth. METHODS: NEF HCl (400 mg) was infused over 5 hours into the proximal or distal intestine through a nasogastric tube, or orally ingested in 10 divided doses over 4.5 hours. The three treatments in the three-period crossover design were separated by one week. RESULTS: The bioavailability of NEF, based on AUC(INF), from proximal and distal regions relative to that from oral administration was 97% and 106%, respectively. NEF was absorbed equally well from all three treatments with median Tmax of 5.0 hours which coincided with the duration of infusion. Mean Cmax of NEF was not different between proximal and oral administrations, however, mean Cmax after distal instillation was 40% lower than that after oral administration. Exposure to HO-NEF, mCPP and dione, following proximal instillation was also comparable to that after oral administration. AUC(INF) of HO-NEF and dione was significantly lower after distal instillation compared to that after oral administration but AUC(INF) of mCPP was not. Cmax of all metabolites was significantly lower after distal administration in comparison to oral treatment. Terminal half-life for NEF, HO-NEF and mCPP after distal administration was longer than the other two treatments. CONCLUSIONS: NEF is absorbed throughout the length of the gastro-intestinal tract which supports the development of an extended-release formulation of NEF. The exposure to the metabolites (relative to NEF) was lower from the distal intestinal site compared to the proximal and oral site which may be explained by a reduced first pass of NEF by the cytochrome P450 3A4 in the distal intestine.

Single- and multiple-dose pharmacokinetics of nefazodone in patients with hepatic cirrhosis.

OBJECTIVE: To compare the single- and multiple-dose pharmacokinetics of nefazodone and its three pharmacologically active metabolites, hydroxynefazodone, m-chlorophenylpiperazine, and triazoledione, in patients with biopsy-proven cirrhosis and age-, sex-, and weight-matched healthy volunteers. METHODS: Subjects received a single 100 mg dose of nefazodone on day 1 followed by 100 mg nefazodone every 12 hours on days 3 through 10. Serial blood samples were collected on days 1 and 10; blood samples for trough levels were also collected just before the morning doses on days 7, 8, and 9. Plasma samples were assayed for nefazodone and its metabolites by validated chromatographic methods. RESULTS: The blood samples for trough levels indicated that, regardless of hepatic function, steady state for nefazodone and its metabolites was achieved by the fourth day of every-12-hour dosing. Subjects with liver cirrhosis had about a two-fold greater systemic exposure to nefazodone and hydroxynefazodone compared with normal subjects after a single dose of nefazodone, the difference decreasing to approximately 25% at steady state. Exposure to m-chlorophenylpiperazine was twofold to threefold greater and exposure to triazoledione was similar in patients with cirrhosis after a single dose of nefazodone and at steady state. There were no serious or unexpected adverse events observed in this study. CONCLUSIONS: These findings indicate that, although no untoward accumulation is anticipated compared with patients with normal hepatic function, patients with hepatic impairment may be exposed to higher concentrations of nefazodone and its metabolites than would subjects with normal hepatic function. Consequently, a lower daily dose of nefazodone should be considered when treating patients with impairment of hepatic function.

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.

Coadministration of nefazodone and benzodiazepines: I. Pharmacodynamic assessment.

One hundred two healthy men were evaluated in one of three studies conducted to evaluate the coadministration of nefazodone, 200 mg twice daily, and three benzodiazepines: triazolam, 0.25 mg; alprazolam, 1 mg twice daily; or lorazepam, 2 mg twice daily. In the first study, psychomotor performance, memory, and sedation were assessed at 0, 0.5, 1.5, 2.5, and 9 hours after single doses of triazolam alone and again after 7 days of nefazodone. Data from 6 of 12 subjects in this study were evaluable because of a dosing error in the other 6 subjects. In the subsequent two parallel design studies, groups of 12 volunteers received 7 days of either placebo; nefazodone, 200 mg; alprazolam, 1 mg twice daily; or alprazolam plus nefazodone or, in the second study, either placebo; nefazodone; lorazepam, 2 mg twice daily; or lorazepam plus nefazodone; the studies were identical, double-dummy, double-blind designs. Psychomotor performance, memory, and sedation were assessed at 0, 1, 3, and 8 hours after the 8 a.m. dose on days 1, 3, 5, and 7 of the studies. In all studies, blood samples were also obtained at testing times so that effect/concentration comparisons could be made and so full pharmacokinetic analyses could be done for separate studies. Nefazodone had no effect on psychomotor performance, memory, or sedation relative to placebo in any study. The mean maximum observed effect (MaxOE) on psychomotor performance and sedation were increased when triazolam was given after 7 days of nefazodone (p < 0.05); also, triazolam concentration was 60% higher at this time. Alprazolam and lorazepam impaired performance on day 1 (mean MaxOE, 34 and 30%, respectively) relative to placebo and nefazodone. By day 7 of alprazolam or lorazepam, psychomotor impairment decreased, indicating the development of tolerance. Alprazolam plus nefazodone increased psychomotor impairment (MaxOE, approximately 50%) and sedation relative to alprazolam alone on days 3, 5, and 7 (p < 0.05). Higher alprazolam concentrations explained the increased impairment in the alprazolam plus nefazodone treatment group; however, it is also possible that there was a delay in the development of tolerance. There were no differences in psychomotor impairment, memory, sedation, or lorazepam concentration detected between the lorazepam alone and lorazepam plus nefazodone treatments. This is consistent with the absence of a pharmacokinetic interaction between nefazodone and lorazepam. These results indicate that if the coadministration of a benzodiazepine is required in patients receiving nefazodone therapy, clinically significant interactions would be less likely with those eliminated by conjugative metabolism such as lorazepam. In cases where a benzodiazepine eliminated by oxidative metabolism is required, a reduction in initial dosage and careful clinical evaluation for signs of psychomotor impairment may be appropriate.

Coadministration of nefazodone and benzodiazepines: II. A pharmacokinetic interaction study with triazolam.

This study was conducted to determine the potential for an interaction between nefazodone, a new antidepressant, and triazolam after a single dose of triazolam and multiple doses of nefazodone in a randomized, double-blind, placebo-controlled study in healthy male volunteers. The metabolism of triazolam is dependent on cytochrome P450 3A4, and because nefazodone has been shown in vitro to be an inhibitor of this isoenzyme, this study was conducted to assess the potential for an interaction between the two drugs. Twelve subjects were assigned to one of two groups and received an oral dose of either placebo or 0.25 mg of triazolam on days 1 and 2. Nefazodone (200 mg) was administered twice daily from the evening of day 2 to the morning of day 9. Subjects received either 0.25 mg of triazolam or placebo with the nefazodone dose on the mornings of days 8 and 9. Serial blood samples were collected on the mornings of days 1, 2, 8, and 9 for the analysis of triazolam by a validated gas chromatography/electron capture detection method and on days 8 and 9 for the analysis of nefazodone and its metabolites, hydroxynefazodone (HO-nefazodone) and m-chlorophenylpiperazine (mCPP), by a validated high-performance liquid chromatography/ultraviolet method. Noncompartmental pharmacokinetic analysis showed that there was no effect of triazolam on the pharmacokinetics of nefazodone, HO-nefazodone, or mCPP after the coadministration of triazolam and nefazodone. There was a significant effect of 200 mg of nefazodone twice daily on the pharmacokinetics of triazolam. Mean triazolam peak concentration values increased (p = 0.003) from 2.33 to 3.88 ng/ml when triazolam was administered alone and in combination with nefazodone, respectively. Corresponding mean triazolam area under the curve values increased (p < 0.001) from 8.14 to 31.74 ng.h/ml. The plasma protein binding of triazolam was approximately 85% when triazolam was given alone and when given concurrently with nefazodone. The increase in triazolam concentrations in plasma appears to be attributable to the inhibition of cytochrome P450 3A4 metabolism by nefazodone. If triazolam is coadministered with nefazodone, a reduction in the triazolam dosage is recommended; no dosage adjustment is required for nefazodone.

Nonlinear pharmacokinetics of nefazodone after escalating single and multiple oral doses.

The single- and multiple-dose pharmacokinetics of nefazodone and its metabolites, hydroxynefazodone, p-hydroxynefazodone, and m-chlorophenylpiperazine were investigated in two groups of 18 healthy male volunteers, employing three-period complete crossover designs. In one group, single 50-mg, 100-mg, and 200-mg oral doses of nefazodone hydrochloride were administered with a 1-week washout between treatments. In the other group, doses of 50 mg, 100 mg, and 200 mg were administered twice a day (every 12 hours) for 7.5 days (15 doses) with a 1-week washout between treatments. Serial plasma samples were obtained in both groups and assayed for nefazodone, hydroxynefazodone, m-chlorophenylpiperazine, and p-hydroxynefazodone. Cmax plasma levels of nefazodone and hydroxynefazodone were attained within 2 hours of administration of nefazodone; tmax for m-chlorophenylpiperazine was more delayed, and p-hydroxynefazodone levels were generally below the assay limit. On repeated twice-daily dosing of nefazodone, steady-state levels of the drug and its metabolites were reached within 3 days. Mean single-dose plasma half-life (t1/2) values for nefazodone increased from approximately 1 hour at a 50-mg dose to approximately 2 hours at a 200-mg dose; at steady state, t1/2 values increased from approximately 2 hours at 50 mg twice daily to approximately 3.7 hours at 200 mg twice daily. Whereas dose increased in the proportion of 1:2:4, mean single-dose AUC0-infinity for nefazodone increased in the proportion of 1:3.3:8.9 and mean steady-state AUC0-tau for nefazodone increased in the proportion of 1:4.2:16.8. Plasma levels of hydroxynefazodone paralleled those of nefazodone and were approximately 33% of nefazodone levels at each dose level. Plasma levels of m-chlorophenylpiperazine were only approximately 10% those of nefazodone. Within the dosage range of 50-200 mg of nefazodone hydrochloride, nefazodone and hydroxynefazodone exhibited nonlinear pharmacokinetics; m-chlorophenylpiperazine, a minor metabolite, appeared to exhibit linear pharmacokinetics.

Lack of interaction between nefazodone and cimetidine: a steady state pharmacokinetic study in humans.

The steady-state pharmacokinetic interaction between nefazodone and cimetidine was evaluated in a three-period crossover study consisting of three treatments of 1 week duration with a 1 week washout between treatments. The 18 healthy, male study subjects received: nefazodone hydrochloride 200 mg twice daily (every 12 h) for 6 days; cimetidine 300 mg four times daily for 6 days; and 200 mg nefazodone hydrochloride twice daily + 300 mg cimetidine four times daily for 6 days. On day 7 of each treatment, only the morning dose was administered. Serial blood samples were collected for pharmacokinetic analysis after drug administration on day 7 of each treatment; blood samples for trough levels (Cmin) to assess attainment of steady state, were also collected just prior to the morning doses on days 2-7 of each study period. Plasma samples were assayed for cimetidine, and nefazodone and its metabolites hydroxynefazodone and m-chlorophenylpiperazine by specific, validated h.p.l.c. methods. Statistical analyses of Cmin data indicated that, regardless of treatment, steady state was achieved for cimetidine by day 2 and for nefazodone and its metabolites by day 3 of multiple dosing, and that there were no significant differences in Cmin levels between treatments. When nefazodone and cimetidine were co-administered for 1 week, no change in steady-state pharmacokinetic parameters for cimetidine, nefazodone or hydroxynefazodone was observed compared with each drug dosed alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Single-dose pharmacokinetics of nefazodone in healthy young and elderly subjects and in subjects with renal or hepatic impairment.

The single-dose pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were examined in 12 healthy younger subjects < or = 55 years of age (YNG), 12 elderly subjects > or = 65 years of age (ELD), 12 patients with biopsy proven hepatic cirrhosis (HEP) and 12 patients with moderate renal impairment (REN), ClCR 20-60 ml.min-1. The study was of parallel group design, with each of the four subject groups receiving escalating single oral doses of 50, 100 and 200 mg of nefazodone at 1 week intervals. Serial blood samples for pharmacokinetic analysis were collected for 48 h following each dose and plasma samples were assayed for NEF, HO-NEF and mCPP by a validated HPLC method. Single oral doses up to 200 mg of nefazodone were well tolerated by all subjects. Maximum plasma levels of NEF and HO-NEF were generally attained within 1 h after administration of nefazodone. HO-NEF and mCPP plasma levels were about 1/3 and < 1/10 those of NEF, respectively. There were no apparent gender-related pharmacokinetic differences in any group of subjects. NEF and HO-NEF pharmacokinetics were dose dependent in all four subject groups; a superproportional increase in AUC and an increase in t1/2 with increasing dose was obtained, indicative of nonlinear pharmacokinetics. Relative to normal subjects, elderly and cirrhotic subjects exhibited increased systemic exposure to NEF and HO-NEF, as reflected by AUC, at all doses of nefazodone; subjects with moderate renal impairment did not. Elderly and cirrhotic patients may require lower doses of NEF to achieve and maintain therapeutic effectiveness.

Steady-state pharmacokinetics of nefazodone in subjects with normal and impaired renal function.

UNLABELLED: The steady-state pharmacokinetics of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were compared in subjects with normal and impaired renal function. PATIENTS: The Study was of parallel group design which included 7 subjects with normal (NOR) renal function, CLCR > or = 72 ml.min-1 x 1.73 m-2, 6 with moderate (MOD) renal impairment, CLCR 31-60 ml.min-1 x 1.73 m-2 and 9 with severe (SEV) renal impairment, CLCR < or = 30 ml.min-1 x 1.73 m-2. Subjects in each renal function group received a 100-mg oral dose of nefazodone hydrochloride BID for 7 days and a single morning dose on day 8. Starting 48 h after the last 100-mg dose, 200-mg doses were administered on a similar schedule to 3, 4 and 3 subjects from each renal function group (NOR, MOD and SEV, respectively). Single trough blood samples just prior to each morning dose (Cmin) and serial samples after the dose on day 8 were obtained at each dose level for pharmacokinetic analysis. Plasma samples were assayed by a specific HPLC method for NEF, HO-NEF and mCPP. The CMIN data indicated that steady state was attained by the third day of BID administration of both the 100- and 200-mg doses of nefazodone, regardless of degree of renal function. Both NEF and HO-NEF attained steady-state Cmax within 2 h after administration of nefazodone; tmax for mCPP was less defined and more delayed. HO-NEF and mCPP plasma levels were about 1/3 and < 1/10 those of NEF, respectively, regardless of the status of renal function. Steady-state systemic exposure of NEF and HO-NEF, as reflected by AUC and Cmax, and elimination t1/2 values did not differ significantly among renal function groups. CONCLUSION: The study results suggest that dose adjustments may not be necessary, but nefazodone should be used with caution in the presence of severe renal impairment.

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)

Absorption, disposition, and metabolism of [14C]didanosine in the beagle dog.

The absorption, disposition, and metabolism of didanosine were investigated in three adult male beagle dogs that received a single iv and po solution dose of 200 mg (ca. 20 mg/kg) of [14C]didanosine. The dog model was "humanized" by predosing with pentagastrin (6 micrograms/kg). The po dose was in buffer, as administered in man. The iv and po sessions were separated by 1 week. Plasma, urine, and feces were collected and assayed for total radioactivity; plasma and urine samples were also analyzed for intact didanosine using validated HPLC/UV assays. Metabolic profiles of [14C]didanosine were obtained in plasma and urine. After iv dose, 87% and 0.5% of the administered radioactivity were recovered in urine and feces within 6 days, respectively; the corresponding recoveries were 84% and 2.1% after po dose. Oral absorption of didanosine was rapid and complete; but due to first pass metabolism, the absolute bioavailability of didanosine was 44%. Mean renal clearance of didanosine (110 ml/min) accounted for about 43% of the total body clearance. The mean steady state volume of distribution of didanosine was 9.6 liters. The mean terminal half-life of didanosine was 0.8 hr after iv or po administration. Five putative metabolites, M1 (allantoin), M2, M3 (uric acid), M4 (hypoxanthine), and M5 (xanthine) of didanosine were observed in plasma and/or urine. The sum of the five metabolites plus unchanged drug accounted for virtually all of the radioactivity in plasma and urine. Allantoin represented the major metabolite in both plasma and urine. The extent of metabolism and the proportion of dose excreted as unchanged didanosine were markedly route dependent.(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)

A role for sigma binding in the antipsychotic profile of BMY 14802?

BMY 14802 was identified as a potential antipsychotic drug in traditional model systems, and this identification was confirmed in modern behavioral and electrophysiological systems. The drug appears to be atypical as an antipsychotic in its lack of activity in models predictive of the potential to produce extrapyramidal side effects and tardive dyskinesia. Indeed, this suggestion is corroborated by clinical findings to date. The atypical profile of BMY 14802 extends to its neurochemical actions and appears to find its basis in regionally selective, indirect modulation of the dopamine system. Furthermore, BMY 14802 exhibits interactions with sigma binding sites in vitro and in vivo, a notion supported by data from neurophysiological, behavioral, and biochemical investigations. BMY 14802 also appears to be neuroprotective in some model systems and may have utility in the treatment of stroke (Boissard et al. 1991). BMY 14802 appears to interact with 5-HT1A receptors, but this interaction does not seem to contribute significantly to the potential antipsychotic actions of the drug. Moreover, the formation of active metabolites of BMY 14802 does not appear to occur in animals or humans to an extent of physiological or behavioral relevance. If clinically efficacious, BMY 14802 may treat the symptoms of schizophrenia by a mechanism novel for antipsychotic drugs: regionally selective, indirect modulation of dopaminergic systems by specific interaction at sigma sites.

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.

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)

Population pharmacokinetic analysis of didanosine (2',3'-dideoxyinosine) plasma concentrations obtained in phase I clinical trials in patients with AIDS or AIDS-related complex.

Plasma didanosine concentration data from 36 patients receiving once-a-day therapy and from 33 patients receiving twice-a-day therapy were subject to population pharmacokinetic analysis with the computer program NONMEM. Once- or twice-a-day regimens of didanosine were administered intravenously (i.v.) (dose: 0.8-33 mg/kg) during the first 2 weeks of therapy, and orally (dose: 1.6-66 mg/kg) for the remaining 4 weeks of therapy. Plasma pharmacokinetics were determined after the first and last (steady-state) i.v. and oral doses. Population pharmacokinetic parameters for the combined i.v. and oral steady-state data were (mean [%CV]): systemic clearance, CL, 0.70 (5.2) L/h/kg; central compartment volume, Vc, 0.18 (32) L/kg; steady-state distribution volume, Vdss, 0.84 (6.8) L/kg; first-order absorption rate constant, Ka, 1.3 (9.5) hr-1; and bioavailable fraction, F, 0.34 (8.5). Interindividual variability (omega) was (%CV) 22.3 and 71.0 for CL and Vc, respectively. Intraindividual (residual) variability (sigma) in plasma concentrations (%CV) was 50.2. Body weight, sex, and age did not account for the variability in either CL or Vc, and the use of alternate pharmacokinetic models did not reduce the value of intraindividual variability. Population parameters for the combined i.v. and oral first-dose data were generally similar to those for the steady-state data. The parameters can be used to design dosing regimens in patients using the Bayesian feedback approach.

Simultaneous high-performance liquid chromatographic analysis of cefprozil diastereomers in a pharmacokinetic study.

Cefprozil, a new oral cephalosporin, consists of a 90:10 cis:trans isomer mixture. Sensitive, specific and reproducible high performance liquid chromatographic methods have been developed for the simultaneous quantification of the two stereoisomers of cefprozil in plasma and urine samples from human and rats. Cephalexin acted as the internal standard. Plasma protein was precipitated with acetonitrile and trichloracetic acid with subsequent extraction of acetonitrile. After vortexing and centrifuging, the aqueous phase was injected onto a reverse phase C8 column. Urine samples were acidified with sodium acetate buffer (pH 3.8) and then directly injected onto a reverse phase C18 column. The detector was set at 280 nm. These methods were applied to determine protein binding of both isomers in human and rat sera, and to perform a pharmacokinetic study in human. Results showed that both isomers bound moderately to serum proteins with no interference by the other isomer. The pharmacokinetic study in human indicated that cefprozil was well absorbed and the cis and trans isomers have similar pharmacokinetics.