Evaluation of the antiplatelet effect of generic ticagrelor 90 mg (ticaspan®) alone and in combination with aspirin 75 mg as compared to ticagrelor (innovator): An in vitro study.

Objective: To evaluate an in vitro antiplatelet effect of generic ticagrelor 90 mg (ticaspan) alone and in combination with aspirin 75 mg as compared to the innovator formulation of ticagrelor alone and in combination with aspirin among healthy Indian volunteers. Methods: 18 volunteers were enrolled and platelet viability was tested using lactate dehydrogenase (LDH) assay in six of 18 volunteers. In 12 volunteers, maximum platelet aggregation (MPA) and percentage inhibition of platelet aggregation (PI) were assessed using a platelet aggregometer in six study groups. Results: There was no significant increase in LDH levels when platelets were incubated with an innovator or generic drug alone and in combination with aspirin as compared to the dimethyl sulfoxide [DMSO] group. All five study groups showed a significant reduction in the MPA values compared to the DMSO group (P < 0.01). The extent of decrease in MPA observed with the generic drug was not significantly different from the innovator drug (P = 0.325). Similarly, the MPA observed with the two combination groups did not differ from each other (P = 1.000), but it was significantly different from the MPA observed with aspirin (P = 0.039, each). The PI of platelet aggregation was significantly more in four study groups [generic drug alone; innovator alone; generic drug + aspirin; and innovator drug + aspirin] (P < 0.01) as compared to the aspirin group. Conclusion: The generic ticagrelor and its combination with aspirin demonstrated an antiplatelet effect equivalent to the innovator drug and its combination with aspirin.

Effect of Withania somnifera (L.) Dunal aqueous root extract on reinstatement using conditioned place preference and brain GABA and dopamine levels in alcohol dependent animals.

ETHNOPHARMACOLOGICAL RELEVANCE: Withania somnifera (L.) Dunal (WS), a known'Rasayana' (rejuvenating agent) as per Ayurveda is prescribed to promote health, to increase longevity and to hasten recovery in disease convalescent stages. WS has demonstrated protective effect on alcohol dependence and withdrawal anxiety in previous experimental studies. AIM OF THE STUDY: To evaluate effect of WS on conditioned place behavioral paradigm (model of relapse) and on GABA and dopamine levels in critical brain areas in alcohol dependent animals. METHODOLOGY: Following Animal Ethics Committee permission, the mice (n = 24) were divided into the following study groups for experiment 1: 1 -distilled water (vehicle control), 2 -WS and 3 -Naltrexone. They were conditioned on conditioned place preference (CPP) using alcohol (2 gm/kg)/saline (1 ml) administered intraperitoneally for 8 days. WS and Naltrexone were administered during the period of extinction (6-8 days). Effect of WS (650 mg/kg) on reinstating behaviour of mice (time spent in alcohol paired compartment) primed with alcohol injection was noted. In experiment 2, effect of WS (450 mg/kg/) on GABA and dopamine levels in the midbrain, striatum and cortex (ng/gm) were measured in alcohol dependent rats (n = 24) following the first phase of standardisation assay (n = 36). The rats were made alcohol dependent for 15 days (intermittent access model) and WS was administered concurrently. GABA and dopamine levels were measured on Day 16. RESULTS: WS group showed decrease in time spent in alcohol paired compartment alike Naltrexone and it differed significantly compared to the distilled water control group (p < 0.05) Alcohol-dependent rats showed significant decrease in GABA and increase in dopamine levels vs distilled water in the midbrain, striatum and cortex. WS and Naltrexone administration showed rise in GABA and fall in dopamine in all the isolated brain parts in the respective groups (p < 0.05 vs alcohol treated group). CONCLUSION: Withania somnifera protected animals from relapse and showed beneficial effects on the brain neurotransmitters involved in alcohol dependence. The study provides substantial evidence for its potential application in alcohol use disorder.

Development of miniaturized trigatron switch and experimental investigation of its switching performance.

There is an increasing interest in synchronization of multiple spark gap switches while maintaining compact geometry, less-complex circuit, and low jitter switching performances. A study of the effect of electrical parameters on switching performances is necessary for the operation of a large number of simultaneous switches. A miniaturized trigatron switch assembly (Outer diameter: 35 mm and thickness: 5 mm) is developed and experimentally investigated for switching performance. A polyether ether ketone insulator and brass conductor electrodes are utilized due to their high insulation and solderable properties, respectively. Important switching parameters, delay time, switch time delay, jitter in delay time, discharging peak current, trigger break down time, and trigger break down voltage, are studied under four typical conditions. These four conditions are: (a) a fast trigger (FT) with normal circuit inductance (10 ns, 20 nH); (b) a fast trigger with higher circuit inductance (10 ns and 500 nH); (c) a slow trigger (ST) with normal circuit inductance (250 ns and 20 nH) and (d) a slow trigger with higher circuit inductance (250 ns and 500 nH). Subsequently, three trigatron spark gaps (4 kV, 5 kA, >100 shots, 4 nH, and 20 mΩ) are simultaneously switched within 5 ns time. Many experimental results are the first of their kind in terms of compact switch development, switching performance, and single electrical trigger based synchronization. This paper will also add a good value to presently available knowledge through systematically implementing the simultaneous switching condition for the generation of 5 kA, 50 ns current pulses. These low cost (US$40) trigatron switches can be utilized in low energy, compact pulsed power applications.

Over-the-counter medicines: Global perspective and Indian scenario.

Patients often approach a pharmacist instead of visiting a doctor for minor ailments such as cough, cold, allergies, pain, fever, acidity, diarrhea, and skin-related conditions. Purchase of specific medicines over the counter is legally recognized in most countries. 'Over-the-Counter (OTC) Medicines' means drugs which are legally allowed to be sold by pharmacists without need for a prescription. The term does not have a legal definition in India. Technically, drugs are OTC unless they are specifically stated as prescription only drugs. OTC drugs allow faster and cheaper access to healthcare; however, their misuse and adverse health effects cause concerns. This article describes concept of OTC medicines and practices in India against the background of globally prevalent regulations and practices. A recognized category of OTC medicines by law, patient awareness programs, and support of pharmacists and pharmaceutical companies are required to optimize the use of OTC medicines in India.

Effects of oral nutritional supplementation in the management of malnutrition in hospital and post-hospital discharged patients in India: a randomised, open-label, controlled trial.

BACKGROUND: Hospital malnutrition is a significant problem that still remains under-recognised and under-treated in India. The present study assessed the effects of oral nutritional supplementation (ONS) in conjunction with dietary counselling versus dietary counselling (control) alone in malnourished patients when given in hospital and post-hospital discharge. METHODS: The present study was conducted in nine private and four public hospitals. Patients from various medical wards were screened for malnutrition using modified Subjective Global Assessment (mSGA) and randomised to control (n = 106) or ONS (n = 106) for 12 weeks. Two servings (460 mL) of ONS were prescribed daily, providing 432 kcal, 16 g of protein and 28 micronutrients. The primary outcome was weight gain over 12 weeks. Other outcomes included change in body mass index (BMI), serum pre-albumin, albumin and C-reactive protein levels, energy and nutrient intakes, and handgrip strength at weeks 4, 8 and 12, as well as mSGA score at week 12. RESULTS: The mean age of patients was 39 years. Fifty-five percent were males and 90.3% were moderately malnourished (mSGA score B) at baseline. At week 12, ONS significantly improved certain parameters compared to control: weight (2.0 versus 0.9 kg; P < 0.001), BMI (0.76 versus 0.37 kg m(-2) ; P < 0.001) and energy intake per day (560 versus 230 kcal; P < 0.05). There were no differences in biochemical parameters and mSGA score between groups. Additionally, patients on ONS who were more functionally impaired at baseline had significantly greater weight gain and improved handgrip strength scores than controls. CONCLUSIONS: ONS use throughout hospital stay and post-hospital discharge significantly improved energy intake and weight in malnourished Indian patients. Those patients with poorer functional status at baseline demonstrated the most benefit.

Projects not initiated by investigators: a retrospective analysis of the queries raised by the institutional ethics committees of a teaching hospital.

BACKGROUND: Some investigators on receiving queries from Institutional Ethics Committee (IEC), either leave the queries unanswered or withdraw their studies. The present study was conducted to assess the queries raised by two IECs after reviewing studies that were not initiated and to identify reasons for the same. Clinical Trials Registry-India (CTRI) website was checked to review approval status of these studies at other sites. MATERIALS AND METHODS: A retrospective analysis of studies (submitted between January 2006 and December 2011) not initiated by investigators on receiving queries from IECs were identified. The nature of of these studies: whether sponsored (pharmaceutical industry (pharma)/government/investigator initiated), single-centre/multi-centric, and queries raised were analyzed. Status of multi-centric trials; not initiated at our site was checked at CTRI. Data was analyzed using descriptive statistics. RESULTS: A total of 219/2075 (11%) studies were not initiated. The proportions in pharma sponsored, investigator initiated, and government sponsored were 33%. 7.4%, and 8%, respectively. Out of a total of 1676 queries, the maximum queries were related to ethics (42%) and the least were administrative (7%). The largest proportion of queries in the pharma studies was ethical (47%), whereas majority were scientific queries (45.5%) for the investigator initiated studies. Twenty-one of the 94 multi-centric studies not initiated at our site were found registered at the CTRI and were ongoing or completed at 2-55 sites. CONCLUSION: Inability of investigators to defend studies due to lack of good clinical research practice (GCP) and research methodology training or unwillingness of sponsors to comply with local IEC requirements could be potential reasons for studies remaining uninitiated. Continued GCP training of investigators and IEC members and development of uniform ethical review standards across IECs are strongly recommended.

1-Aminobenzotriazole, a known cytochrome P450 inhibitor, is a substrate and inhibitor of N-acetyltransferase.

1-Aminobenzotriazole (ABT) has been used widely as a nonselective in vitro and in vivo inhibitor of cytochrome P450 enzymes. To date, however, it has not been evaluated as an inhibitor of UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and N-acetyltransferase (NAT). In the present study, ABT was shown not to inhibit UGT and SULT activity (acetaminophen and 7-hydroxycoumarin as substrates) in rat liver microsomes and rat liver 9000 g supernatant fraction (RLS9), respectively. However, it did inhibit the RLS9-catalyzed N-acetylation of procainamide (IC(50) ∼ 30 µM), and no preincubation time dependence was evident. In agreement, oral ABT (100 mg/kg, 2 h predose) decreased the clearance of intravenous procainamide (45%) in rats, accompanied by a decreased N-acetylprocainamide-to-procainamide ratio in urine (0.74 versus 0.21) and plasma (area under the curve ratio 0.59 versus 0.11). Additional studies with human forms of NAT (hNAT1 and hNAT2) revealed that ABT is a more potent inhibitor of hNAT2 compared with hNAT1 (IC(50) 158 µM versus > 1 mM). Consistent with the IC(50) estimate, formal inhibition studies revealed that inhibition of hNAT2 was competitive with an inhibition constant of 67 µM. In accordance with the competitive inhibition, ABT was shown to undergo N-acetylation in the presence of both human NAT forms, with hNAT1 exhibiting less activity under the same assay conditions (∼40% of hNAT2). In summary, the results described herein indicate that ABT is a substrate and inhibitor of NAT. Such an interaction should be considered when using ABT as a nonselective inhibitor of P450, especially when NAT-dependent metabolism is also involved.

Prodrug design to improve pharmacokinetic and drug delivery properties: challenges to the discovery scientists.

The prodrug design is a versatile, powerful method that can be applied to a wide range of parent drug molecules, administration routes, and formulations. Clinically, the majority of prodrugs are used with the aim of enhancing drug permeation by increasing lipophilicity, or by improving aqueous solubility. Prodrug design may improve the bioavailability of parent molecule, and thus can be integrated into the iterative process of lead optimization, rather than employing it as a post-hoc approach. The purpose of this review is to provide an update of advances and progress in the knowledge of current strategic approaches of prodrug design, along with their real-world utility in drug discovery and development. The review covers the type of prodrugs and functional groups that are amenable to prodrug design. Various prodrug approaches for improving oral drug delivery are discussed, with numerous examples of marketed prodrugs, including improved aqueous solubility, improved lipophilicity, transporter-mediated absorption, and prodrug design to achieve site-specific delivery. Tools employed for prodrug screening, and specific challenges in prodrug research and development are also elaborated. This article is intended to encourage discovery scientists to be creative and consider a rationally designed prodrug approach during the lead optimization phase of drug discovery programs, when the structure activity relationship (SAR) for the drug target is incompatible with pharmacokinetic or biopharmaceutical objectives.

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.

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.

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.

Effect of altered gastric emptying and gastrointestinal motility on metformin absorption.

AIMS: The purpose of this in vivo human study was to assess the effect of altered gastric emptying and gastrointestinal motility on the absorption of metformin in healthy subjects. METHODS: An open-label, three treatment, three period crossover study was conducted in 11 healthy volunteers. Each subject received 550 mg metformin hydrochloride in solution alone; 5 min after a 10 mg i.v. dose of metoclopramide; and 30 min after a 30 mg oral dose of propantheline. Metformin solution was radiolabeled by the addition of 99mTc-DTPA. The gastrointestinal transit of the solution was monitored by gamma scintigraphy and the pharmacokinetic data were correlated with the scintigraphic findings. RESULTS: Scintigraphic data indicated that pretreatment with metoclopramide decreased gastric emptying time and increased gastrointestinal motility while pretreatment with propantheline had the opposite effect. The systemic disposition of metformin was not altered by pretreatment with metoclopramide and propantheline, as judged by unchanged renal clearance and elimination half-life of metformin. Extent of metformin absorption was essentially unchanged after pretreatment with metoclopramide. However, AUC(0,infinity) and % UR (percent dose excreted unchanged in urine) generally increased with increase in gastric emptying time and small intestinal transit times. GI overlay plots showed that the absorption phase of metformin plasma profile always coincided with gastric emptying and the beginning of decline of metformin plasma concentrations was usually associated with the colon arrival. Only in cases where the intestinal transit was drastically prolonged by propantheline pretreatment, was a decline in plasma levels observed prior to colon arrival. CONCLUSIONS: Metformin is primarily absorbed from the small intestine. The extent of metformin absorption is improved when the gastrointestinal motility is slowed. These findings have significant implications in the design of a metformin modified release dosage form.

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.

Nefazodone pharmacokinetics in depressed children and adolescents.

OBJECTIVE: To describe the pharmacokinetics and safety of nefazodone (NFZ) in depressed children and adolescents. METHOD: Depressed youths aged 7 to 17 years were eligible to participate. Intensive sampling for pharmacokinetic analyses of NFZ and 3 of its active metabolites was performed after single and multiple dose administration. Treatment was continued for 6 more weeks and titrated to maximize clinical response. RESULTS: Twenty-eight patients were enrolled. Systemic exposure to NFZ and 3 metabolites was generally higher in children than adolescents. NFZ and metabolite disposition profiles showed high intra- and interpatient variability. Compared to published data in adults, the half-life of NFZ and 2 of its metabolites appears shorter in children and adolescents. Meta-chlorphenylpiperazine pharmacokinetic parameters were different in 5 patients determined to be poor metabolizers of cytochrome P450 2D6 (CYP2D6). NFZ was well tolerated, and administration was associated with significant reductions (p < .001) in depressive symptoms. CONCLUSIONS: The pharmacokinetics of NFZ in pediatric patients is highly variable. NFZ appears to be safe in this small, short-term study. Pediatric patients who are poor metabolizers of CYP2D6 do not appear to be at increased risk for NFZ-associated adverse events. Open-label treatment of NFZ is associated with reductions in depressive symptoms.

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.

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.

In vivo evaluation of the absorption and gastrointestinal transit of avitriptan in fed and fasted subjects using gamma scintigraphy.

The study was conducted to assess the bioavailability of avitriptan after a standard high fat meal, in relation to gastrointestinal transit. Six healthy male subjects were enrolled in a four-period study with a partial replicate design where each was administered 150-mg avitriptan capsule (i) after an overnight fast, (ii) 5 min after a standard high-fat breakfast, and (iii) 4 hr after a standard high fat breakfast. The treatment administered in Period 3 was repeated in Period 4 to assess intrasubject variations in pharmacokinetics and gastrointestinal (GI) transit. Avitriptan capsules were specially formulated with nonradioactive samarium chloride hexahydrate which was neutron-activated to gamma-emitting samarium before dosing. Serial blood samples were collected for analysis of avitriptan up to 24-hr postdose, and serial scintigraphic images were obtained to assess the plasma concentration-time profile in relation to the GI transit of the avitriptan capsule contents. Bioavailability of avitriptan was reduced when administered in the fed condition but only the decrease in AUC(INF) was statistically significant. Tmax was significantly delayed between the fed conditions and the fasted condition. Qualitative appearance of plasma concentration-time profiles for avitriptan could be related to the manner in which the drug emptied from the stomach. It was also apparent that avitriptan exerted a secondary pharmacologic effect that temporarily suspended gastric emptying in the fasted treatment. Thus, when gastric emptying was interrupted and then resumed, the net result was a double peak in some of the individual plasma concentration profiles. Scintigraphic analysis also demonstrated that upon emptying from the stomach, avitriptan was rapidly absorbed from the upper small intestine. In the fed state, gastric emptying was slow and continuous resulting in extended absorption and a lower occurrence of double peaks. Qualitatively, the intrasubject variability in Cmax and AUC could be explained by the intrasubject variability in gastric emptying in both fasted and fed conditions.

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.

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.