A pharmacokinetic interaction study of avitriptan and propranolol.

OBJECTIVE: To assess whether a clinically significant change in the pharmacokinetics of avitriptan and propranolol is observed in healthy subjects after coadministration of the two drugs. METHODS: The pharmacokinetics of avitriptan and propranolol were investigated when the two drugs administered separately and when two 150 mg doses of avitriptan 2 hours apart were added to a steady-state regimen (80 mg twice a day) of propranolol. The pharmacokinetics of metabolites of avitriptan (N-desmethylavitriptan, methoxypyrimidinyl piperazine, and O-desmethylavitriptan) and the pharmacokinetics of 4-hydroxypropranolol were also assessed. RESULTS: Administration of avitriptan alone and together with propranolol resulted in small increases in mean blood pressure and small decreases in heart rate. Administration of propranolol resulted in lowering of blood pressure and heart rate consistent with the beta-blocking actions of propranolol. There were no changes in the pharmacokinetics of avitriptan after coadministration with propranolol. However, area under the plasma concentration-time curve (AUC) of propranolol showed a 20% increase after coadministration with avitriptan, whereas the AUC of 4-hydroxypropranolol significantly decreased. Avitriptan therefore appeared to affect the metabolism of propranolol to 4-hydroxypropranolol. The peak plasma concentration and AUC for N-desmethylavitriptan and the AUC for methoxypyrimidinyl piperazine also showed statistically significant increases (about 25%) when avitriptan was coadministered with propranolol. CONCLUSIONS: Considering the wide safety margin of propranolol, the increase in the exposure is not clinically significant. The increase in the exposure to the metabolites of avitriptan is also not considered to be clinically significant because the metabolite contribution to the pharmacologic activity or side effects is expected to be minimal. Based on these findings, avitriptan may be added to a steady-state regimen of propranolol as an abortive antimigraine therapy.

The use of radiolabeled compounds for ADME studies in discovery and exploratory development.

Radiolabeled compounds are excellent investigative tools and widely used to carry out ADME studies during drug discovery and development stages. The most commonly used radioisotopes are 14C and 3H. 3H materials are generally easier to synthesize than 14C materials. Therefore, a variety of probes and substrates used in in vitro assays are labeled with 3H. Since synthesis of 14C material requires intensive resources, it is usually not available until after a molecule is considered for potential development or after the molecule enters the development phase. Improvement in the technology in radiochemistry has enabled the use of radiolabeled compounds earlier in pre-clinical and clinical development to address mechanistic issues. For in vitro studies, radiolabeled probes are utilized to test affinity with various transporters, to perform metabolism comparison among species and to assess possible formation of reactive metabolites. For in vivo studies, radiolabeled compounds are employed to identify and elucidate metabolites formed, to investigate the extent of absorption, bioavailability, tissue distribution, mass balance, routes of excretion, and pre-systemic metabolism. Due to the significant impact of radiolabeled studies on drug development, these studies will be performed earlier than have been in the past and will continue to be an integral part of drug discovery and development.

Pharmacokinetics and bioavailability of a metformin/glyburide tablet administered alone and with food.

Two randomized crossover studies were conducted to evaluate the pharmacokinetics (including food effect) of fixed-combination metformin/glyburide tablets. Pharmacokinetics and bioavailability of two strengths (500 mg/2.5 mg and 500 mg/5 mg) of metformin/glyburide tablets were assessed relative to coadministered metformin and glyburide tablets in study 1. The effect of a high-fat meal on the bioavailability of a metformin/glyburide (500 mg/5 mg) tablet was assessed relative to the fasted condition in study 2. The fixed combination metformin/glyburide tablets showed bioequivalence for the metformin component with the reference metformin tablet and comparable bioavailability for the glyburide component with the reference glyburide tablet. Food does not appear to affect the bioavailability of either component to an appreciable extent.

The effects of age and gender on the single dose pharmacokinetics of avitriptan administered to healthy volunteers.

The effects of age and gender on the single dose pharmacokinetics of avitriptan and its three metabolites were assessed in 15 young men, 15 young women, 15 elderly men and 15 elderly women. Avitriptan was administered as a 150-mg capsule after a 10-hour fast and serial plasma and urine samples were collected up to 36 hours after the dose. Plasma samples were analyzed for avitriptan and its metabolites, N-desmethyl avitriptan (ND048), O-desmethyl avitriptan (OD048), and methoxypyrimidinyl piperazine (MPP). Urine samples were analyzed for only avitriptan and MPP. Avitriptan was well tolerated in all four groups. The drug was rapidly absorbed with a median time to maximum plasma concentration (tmax) between 0.5 and 1.5 hours. No significant gender-related differences were found in the maximum plasma concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUC0-infinity) of avitriptan. Renal clearance of avitriptan was significantly smaller in young women compared with young men, but this is clinically not relevant because only 2% to 3% of the total dose is excreted unchanged. Compared with the young volunteers, mean Cmax was approximately 50% higher in the elderly but there was no difference in the AUC0-infinity between the 2 age groups. Plasma concentrations of ND048, OD048, and MPP were each 50 to 100 fold lower than those of avitriptan. Hence some age- and gender-related differences found in the pharmacokinetics of avitriptan metabolites are probably not relevant in the assessment of overall safety and efficacy of avitriptan. Based on the pharmacokinetics and tolerability, no age or gender-related dose adjustment is necessary for avitriptan.

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.

Pharmacokinetic and pharmacodynamic evaluation during coadministration of nefazodone and propranolol in healthy men.

Potential interactions between nefazodone (200 mg every 12 hours) and propranolol (40 mg every 12 hours) were assessed in 18 healthy male volunteers in an open-label, randomized, three-way crossover study. The nature, frequency, and severity of adverse events during coadministration of nefazodone and propranolol were similar to those observed with either treatment alone. There were no clinically significant effects on vital signs, electrocardiographic results, or laboratory parameters. With coadministration, the maximum peak concentration (Cmax) and area under the concentration-time curve over the dosing interval (AUC tau) of propranolol decreased 29% and 14%, respectively; Cmax and AUC tau of 4-hydroxy-propranolol decreased 15% and 21%, respectively. Despite decreased plasma concentrations of the beta-antagonists, the reduction in exercise-induced tachycardia and post-exercise double product was slightly greater with coadministration than with propranolol alone. Administration of nefazodone alone did not significantly affect either pharmacologic parameter. The pharmacokinetics of nefazodone and its metabolites were largely unaffected during coadministration. Coadministration of propranolol and nefazodone results in modest pharmacokinetic inequivalencies, but no clinically significant alterations of the pharmacodynamics of propranolol.

In vitro-in vivo correlation (IVIVC) models for metformin after administration of modified-release (MR) oral dosage forms to healthy human volunteers.

The objective of the current study was to develop and evaluate the internal predictability for level C and A in vitro-in vivo correlation (IVIVC) models for prototype modified-release (MR) dosage forms of metformin. In vitro dissolution data for metformin were collected for 22 h using a USP II (paddle) method. In vivo plasma concentration data were obtained from 8 healthy volunteers after administration of immediate-release (IR) and MR dosage forms of metformin. Linear level C IVIVC models were developed using dissolution data at 2.0 and 4.0 h and in vitro mean dissolution time (MDT). A deconvolution-based level A model was attempted through a correlation of percent in vivo input obtained through deconvolution and percent in vitro dissolution obtained experimentally. Further, basic and extended convolution level A IVIVC models were attempted for metformin. Internal predictability for the IVIVC models was assessed by comparing observed and predicted values for C(max) and AUC(INF). The results suggest that highly predictive level C models with prediction errors (%PE) of <5% could be developed. Mean percent in vivo input for metformin was incomplete from all formulations and did not exceed 35% of dose. The deconvolution-based level A models for all MR formulations were curvilinear. However, a unique IVIVC model applicable to all MR formulations could not be developed using the deconvolution approach. The basic convolution level A model, which used in vitro dissolution as the in vivo input, had %PE values as high as 103%. Using an extended convolution approach, which modeled the absorption of metformin using a Hill function, a level A IVIVC model with %PE as low as 11% was developed. In conclusion, the current work indicates that level C and A IVIVC models with good internal predictability may be developed for a permeability- and absorption window-limited drug such as metformin.

In-vitro in-vivo correlation models for glibenclamide after administration of metformin/glibenclamide tablets to healthy human volunteers.

In this study, level C and A in-vitro in-vivo correlation (IVIVC) models were developed for glibenclamide. In-vitro dissolution data were collected for the glibenclamide component of three metformin/glibenclamide tablets using a USP Type II apparatus. In-vivo plasma concentration data were obtained after administration of the prototype formulations to 24 healthy volunteers and subject to deconvolution analysis to obtain percentage in-vivo absorbed profiles. Multiple linear level C models were developed for CMAX and AUC(0-48) using percentage in-vitro dissolved data at 10, 45 and 120 min. Initially, the level A model was constructed for the first 2 h only, based on availability of in-vitro data. Another level A model was attempted using a time-scaled approach, with percentage in-vivo absorbed at time t and percentage in-vitro dissolved at time t/I as the correlating data. Internal predictability was evaluated for the level C and time-scaled level A models. For all level C approaches, linear regression models with r2 > 0.99 were determined. The prediction errors (% PE) for Cmax and AUC(0-48) were less than 1% for all formulations at all three chosen time points. The deconvolution analysis indicated biphasic absorption for glibenclamide, with one phase occurring at 2-3h and another at 6-12h after dose administration. The level A model using 2-h data was not unique for all formulations and was therefore not developed. The time-scaling factor I correlated highly (r2 = 0.99) with in vitro mean dissolution time (MDT). A linear regression time scaled model (r2 = 0.97) was successfully developed using in-vitro and in-vivo data from all 3 formulations. However, the internal predictability of the time-scaled model was poor, with % PE values for Cmax and AUC(0-48) being as much as 30.5% and 18.7%, respectively. The results indicate that level C models have good internal predictability. Though a time-scaled level A IVIVC model was successfully developed, the model was found to have poor internal predictability.

Pharmacokinetics of buspirone following oral administration to rhesus monkeys.

Pharmacokinetics of buspirone and its active metabolite, 1-pyrimidinyl piperazine (1-PP) following oral administration were assessed in rhesus monkeys at doses used in chronic toxicology studies. The study was conducted over four periods in three male and three female rhesus monkeys. In the first three periods, buspirone hydrochloride solution was administered in a randomized manner by oral gavage at doses (expressed as buspirone free base) of 12.5, 25 and 50 mg kg(-1) once a day on days 1 and 7 and twice a day on days 2-6. In the last period, all monkeys received 25 mg kg(-1) buspirone as a single daily dose for 7 days. Serial plasma samples were collected for analysis of buspirone and 1-PP on days 1 and 7 in the first three periods and on day 7 in the last period for assessment of single dose and steady-state pharmacokinetics. Inter-animal variability in the pharmacokinetics of buspirone was high. Examination of Cmin vs time plots revealed that the steady state was attained by day 7 except for one monkey who demonstrated much higher Cmin values. For buspirone, dose proportionality was concluded for both Cmax and AUC on day 1 but not on day 7. The accumulation factor on day 7 for buspirone was nearly 5 for Cmax and 7 for AUC when compared with day 1. For 1-PP, dose proportionality was concluded except for Cmax in male monkeys on day 7. In contrast to buspirone, 1-PP showed less than 2-fold accumulation in Cmax and AUC values on day 7 compared with those on day 1. Exposure at a dose of 25 mg kg(-1) once daily was in between the 125 mg kg(-1) and 25 mg kg(-1) twice-a-day regimens. These results document dose-dependency in the steady-state pharmacokinetics of buspirone in rhesus monkeys.

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.

Development of an in vivo rat screen model to predict pharmacokinetic interactions of CYP3A4 substrates.

With the advent of polytherapy, drug interactions have become a common clinical problem. Although in vitro data are routinely used for the prediction of drug interactions, in vitro systems are not dynamic and sometimes fail to predict drug interactions. We sought to use the rat as an in vivo screening model to predict pharmacokinetic interactions with ketoconazole. The pharmacokinetic studies were conducted following an oral dose of CYP3A substrates and an optimized oral regimen of ketoconazole. In vitro reaction phenotyping was conducted using individual human and rat cDNA-expressed CYP enzymes and human or rat liver microsomes in the presence of ketoconazole. The in vitro experiments indicated that the test compounds were largely metabolized by CYP3A in both human and rat. The compounds could be rank-ordered with respect to the increase in C(max) and area under the curve (AUC) values relative to midazolam in the presence of ketoconazole. The degree of pharmacokinetic interaction with ketoconazole was dependent, in part, upon their in vitro metabolism in the presence of rat CYP3A1/3A2 and in rat and human microsomes, co-incubated with ketoconazole, and on their fraction metabolized (f(m)) in the rat relative to other disposition pathways. Based on the rank-order of interaction, the compounds could be prioritized for further preclinical development.

Metabolic kinetics of pseudoracemic propranolol in human liver microsomes. Enantioselectivity and quinidine inhibition.

The enantioselective formation kinetics of 4-hydroxypropranolol (4-HOP), 5-hydroxypropranolol (5-HOP), and desisopropylpropranolol (DIP) were characterized over a wide substrate concentration range (1-1000 microM) in human liver microsomes using deuterium-labeled pseudoracemic propranolol. Existing data suggest that several microsomal cytochrome P-450 enzymes are involved in the oxidative metabolism of propranolol in humans. Biphasic kinetics were observed in the formation of all three metabolites, indicating the involvement of at least two enzymes in each pathway. The R/S ratios for the formation of all three metabolites varied with respect to the substrate concentration, lending further support to the contribution of two or more enzymes with differing KM's and enantioselectivity. The high-affinity 4-hydroxylation process showed a strong R-enantioselectivity. The low-affinity component of 4-hydroxylation also exhibited a preference for R-(+)-propranolol, although to a lesser degree than the high-affinity component. A similar pattern of enantioselectivity was observed for 5-hydroxylation, except that R/S ratio showed an initial increase followed by a decrease as the propranolol concentration increased beyond 200 microM. Formation of DIP was R-enantioselective at low substrate concentrations, whereas an opposite enantioselectivity was observed at high propranolol concentrations. The metabolism of propranolol in the presence of nanomolar concentrations of quinidine (a selective inhibitor of P-450 2D6) was studied at concentrations of pseudoracemic propranolol in the high- and low-affinity regions. A significant inhibition of 4- and 5-hydroxylation was observed, whereas N-dealkylation was not affected by quinidine. The inhibition of 4-hydroxylation was slightly enantioselective toward R-enantiomer. Quinidine had no significant effect on the low-affinity component for 4-hydroxylation. Although the inhibition of 4- and 5-hydroxylation at the high-affinity site was extensive, complete inhibition was not achieved even at the highest quinidine concentration (10 microM). Data could be fitted to a mixed-type inhibition kinetics resulting from multiple high-affinity hydroxylases. Our in vitro results indicate that formation of 4-HOP and 5-HOP is mediated by more than one P-450 enzyme with major contribution from P-450 2D6, whereas the formation of DIP is catalyzed by two or more P-450 enzymes other than 2D6.

Disposition of [14C]avitriptan in rats and humans.

Avitriptan is a new 5-HT1-like agonist with abortive antimigraine properties. The study was conducted to characterize the pharmacokinetics, absolute bioavailability, and disposition of avitriptan after intravenous (iv) and oral administrations of [14C]avitriptan in rats and oral administration of [14C]avitriptan in humans. The doses used were 20 mg/kg iv and oral in the rat, 10 mg iv in humans, and 50 mg oral in humans. The drug was rapidly absorbed after oral administration, with peak plasma concentrations occurring at 0.5 hr postdose. Absolute bioavailability was 19.3% in rats and 17.2% in humans. Renal excretion was a minor route of elimination in both species, with the majority of the dose being excreted in the feces. After a single oral dose, urinary excretion accounted for 10% of the administered dose in rats and 18% of the administered dose in humans, with the remainder excreted in the feces. Extensive biliary excretion was observed in rats. Avitriptan was extensively metabolized after oral administration, with the unchanged drug accounting for 32% and 22% of the total radioactivity in plasma in rats and humans, respectively. Plasma terminal elimination half-life was approximately 1 hr in rats and approximately 5 hr in humans. The drug was extensively distributed in rat tissues, with a tendency to accumulate in the pigmented tissues of the eye.

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)

Effect of serum protein binding on the entry of lidocaine into brain and cerebrospinal fluid in dogs.

To test the hypothesis that lidocaine passage into the central nervous system is a function of free rather than total lidocaine concentration, we examined the effect of serum protein binding on the distribution of lidocaine into brain and cerebrospinal fluid (CSF) in dogs. Six of the 13 dogs studied were pretreated with rifampin to induce a 4-fold increase (P = 0.019) in serum concentration of alpha 1-acid glycoprotein, which is a major binding protein for lidocaine. The dogs were anesthetized and prepared surgically to obtain samples of cortical brain tissue or CSF from the cisterna magna. Lidocaine at a dose of 3 mg/kg was infused intravenously over 15 s. Arterial blood and brain cortex or CSF were sampled serially during a 60-min interval and analyzed for lidocaine content. Unbound or free fraction of lidocaine in serum was measured by equilibrium dialysis. Rifampin pretreatment led to a significant decrease in average serum free fraction of lidocaine, from 0.24 +/- 0.08 to 0.080 +/- 0.030 (P less than 0.001). Total lidocaine concentration in serum was higher, but free lidocaine concentration was lower in the rifampin group. Equilibration of lidocaine between serum and brain or CSF was reached by 10 min after lidocaine administration. Rifampin-pretreated dogs had consistently lower partition ratios of lidocaine between brain and serum or between CSF and serum. A strong and positive correlation between time-averaged brain to serum or CSF to serum ratios and serum free fractions were observed (r = 0.92, P less than 0.001 for brain; r = 0.90, P less than 0.01 for CSF).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the steady-state pharmacokinetics of nefazodone after administration of 200 mg twice daily or 400 mg once daily in the morning or evening.

1. The steady-state pharmacokinetics of nefazodone, an antidepressant drug with non-linear pharmacokinetics, were determined in a multiple-dose, three-period crossover study in 24 male volunteers to evaluate whether administration of the same total daily dose of nefazodone by different dosing schedules has an effect on systemic exposure to the drug and its metabolites. 2. Three treatments administered were: a 400 mg dose once daily in the a.m. (treatment 1) or in the p.m. (treatment 2) for 5 days or a 200 mg twice daily (every 12 h, a.m. and p.m.) dose daily for 7 days (treatment 3). Prior to the administration of the 400 mg once daily dose, the subjects were administered 200 mg nefazodone once daily (a.m. or p.m.) for 2 days. There was a 7 day washout between treatments. 3. Serial blood samples were collected up to 72 h post dose for treatment 1 and treatment 2 and up to 84 h post a.m. dose for treatment 3 on day 7 for determination of pharmacokinetic parameters. Blood samples for trough (Cmin) plasma concentrations were also obtained on days 5, 6 and 7 of each treatment to assess attainment of steady state. Plasma samples were assayed for nefazodone and its metabolites, hydroxynefazodone, m-chlorophenylpiperazine and triazoledione by a validated h.p.l.c./u.v. assay. 4. The Cmin data indicated that nefazodone and its metabolites reached steady state by study day 5 of each treatment period. 5. Mean steady-state pharmacokinetic parameter values were similar among treatments. Statistical analyses indicated that, as reflected by AUC(0,24 h) and the ratios of individual nefazodone metabolite AUCs to nefazodone AUC over a dosing interval, there were no differences in steady-state exposure to nefazodone and its metabolites among treatments. For NEF, AUC(0,24 h) (point estimate and 90% CI) values were 102% (86%, 119%) for 400 mg a.m. and 91% (76%, 105%) for 400 mg p.m. when compared with the 200 mg twice daily. 6. Although there were some small differences in mean pharmacokinetic parameter values after a.m. and p.m. administration, no consistent diurnal variation was observed in the pharmacokinetics of nefazodone or its metabolites. 7. There were no serious or unexpected adverse events noted in the study. 8. It is concluded that despite the nonlinearity in the pharmacokinetics of nefazodone, the exposure to nefazodone and its metabolites is comparable for the once daily (400 mg) and twice daily (200 mg) treatments.

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.

Evaluation of the effect of food on the pharmacokinetics of avitriptan.

Bioavailability of avitriptan was found to decrease significantly when administered 5 min after a standard high fat meal. The studies described herein were carried out to gain insight into the mechanism of this food effect. A series of studies were conducted in humans to assess the effect of timing of meal, type of meal, gastric pH, change in the formulation and dose on the bioavailability of avitriptan. Avitriptan was administered as a 50 mg capsule under fasted condition and at 30 min, 1, 2 and 4 h after a standard high fat meal. The reduction in avitriptan bioavailability persisted even at 4 h post high fat meal, although as the time interval between the meal and dose increased, the effect of meal tended to decrease. Bioavailability of avitriptan also decreased significantly when the drug was administered after a high protein and a high carbohydrate meal. Elevation in gastric pH caused by food was not found to be responsible for the food-related decrease in bioavailability of avitriptan since ranitidine pretreatment did not lead to a decrease in bioavailability. When administered as a 50 mg 14C-labeled solution after a standard high fat meal, bioavailability of avitriptan decreased although the decrease was less compared with that observed for a capsule dosage form. Plasma concentrations and cumulative urinary excretion of total radioactivity also decreased in the fed condition, indicating the absorption of avitriptan was affected. The decrease in avitriptan AUC was somewhat more pronounced than the decrease in the exposure to the total radioactivity suggesting a food-related increase in the first-pass metabolism of avitriptan. Effect of the standard high fat meal on avitriptan administered as a 150 mg capsule was similar to that observed at the 50 mg dose. Overall, the results indicate that bioavailability of avitriptan is significantly reduced irrespective of the type of meal, dose and dosage form and the effect persists for as long as 4 h post meal. Thus, it appears that avitriptan absorption and bioavailability are highly sensitive to presence of food in the stomach and any food-related changes in gastric emptying time and gastrointestinal motility.

Assessment of effect of food, gender, and intra-subject variability in the pharmacokinetics of avitriptan.

The objectives of this study were to assess the effect of food and gender on the pharmacokinetics of avitripan. A group of 12 healthy men and 12 healthy women was administered a single 50 mg dose of avitriptan capsule under fasting conditions and 5 min after a high-fat breakfast. The two treatments were repeated in a replicate design to assess the intra-subject variability in the pharmacokinetics of avitriptan under fasted and fed conditions. There was a 1 week washout between treatments. Serial blood samples were collected over 24 h after dosing and analyzed by a validated HPLC method for avitriptan. The mean (SD) peak concentrations (Cmax) were 168 (86.4) ng mL-1 in the fasted condition and 57.3 (34.8) ng mL-1 in the fed condition in males and females combined. The corresponding areas under the plasma concentration curve (AUC) were 335 (162) and 185 (64.5) ng h mL-1, respectively. Both Cmax and AUC were significantly reduced in the fed condition. In addition, the time to peak concentration (tmax) was significantly delayed from a median of 45 min to 2 h after the high-fat breakfast. The clinical significance of this food effect is unclear at the present time. There were no gender differences nor a gender by food interaction in the pharmacokinetics of avitriptan. The intra- and inter-subject variability (%CV) in the Cmax and AUC of avitriptan in the fasted and fed conditions ranged from 10 to 60% in male and female subjects.