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INTERNATIONAL RESEARCH JOURNAL OF PHARMACY ISSN 2230 – 8407 Available online http://www.irjponline.com Research Article

PHARMACOKINETIC AND BIOEQUIVALENCE COMPARISON BETWEEN

EXTENDED RELEASE CAPSULES OF VENLAFAXINE HYDROCHLORIDE 150MG: AN OPEN LABEL, BALANCED, RANDOMIZED-SEQUENCE, SINGLE-DOSE, TWO-PERIOD

CROSSOVER STUDY IN HEALTHY INDIAN MALE VOLUNTEERS I.Sarath chandiran1*, K.N. Jayaveera2 and Raghunadha Reddy.S3

1Gokula Krishna College of Pharmacy, Sullurpet, Andhra Pradesh, India 2Jawaharlal Nehru Technological University, Anantapoor, Andhra Pradesh, India

3Clinical Research and Biosciences (I) Pvt. Ltd., Hyderabad, Andhra Pradesh, India

Article Received on: 20/01/2011 Revised on: 03/03/2011 Approved for publication: 10/03/2011 *CRABS (I) Pvt Ltd, Hyderabad-500017, India. E-mail: raghu_nathseelam@yahoo.co.in ABSTRACT This bioequivalence study was designed to determine the pharmacokinetic, bioavailability and bioequivalence of Venlafaxine HCl 150 mg Extended Release Capsules in comparison with Effexor®-XR 150mg Extended Release Capsules after single dose administration under fed conditions in 20 healthy adult male subjects. Therefore the design of an open label, balanced, randomized, two-sequence, single dose, two way crossover study with a washout period of at least 7 days was used. Each volunteer received a 150 mg capsule of the reference or test drug respectively. On the day of dosing, blood samples were collected before dosing and at various time points up to 72 hours after dosing. Analysis of venlafaxine and its metabolite O-Desmethylvenlafaxine concentrations was performed using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. The pharmacokinetic parameters including Cmax, AUC0-t, AUC0-inf, Tmax, t1/2 and Kel were analyzed using the non-compartmental model. Drug safety and tolerability were assessed. The pharmacokinetic parameters including Cmax, AUC0-t, AUC0-inf, Tmax, t1/2 and Kel were analyzed using the non-compartmental model. Drug safety and tolerability were assessed. The primary pharmacokinetic parameters (Cmax, AUC0-t and AUC0-inf) 90%CI were within the 80 to 125% interval required for bioequivalence as stipulated in the current regulations of the USFDA acceptance criteria. The geometric mean ratios (Test/Reference) between the two products of extended-release venlafaxine capsule under fed condition were 104.91% (92.86%-118.53%) and 114.41% (103.43%-124.55%) for Cmax ratios, 102.24% (95.95%-108.94%) and 105.27% (96.76%-114.53%) for AUC0-t ratios and 101.66% (95.73%-107.97%) and 104.71% (96.13%-114.05%) for AUC0-inf ratios of Venlafaxine and its metabolite O-Desmethylvenlafaxine (ODV) respectively. 20 volunteers had completed both treatment periods. There was no significant difference of the Tmax parameter between the two formulations (p >0.05). No serious adverse events related to the study drugs were found. This single dose study found that the test formulation Venlafaxine HCl Extended release capsules is bioequivalent to the reference formulation Effexor®-XR Extended Release Capsules the extent and the rate of absorption, of 150mg under fed condition in healthy adult male volunteers according to the USFDA regulatory guidance. KEYWORDS: Venlafaxine, O-Desmethylvenlafaxine, Bioavailability, Bioequivalence, Intrasubject Variability INTRODUCTION Depression and anxiety are two of the most important problems in psychiatry. They are of high prevalence and major world-wide public health problems. Venlafaxine1 is the first of a new class of antidepressants or atypical antidepressants2-9 that selectively inhibits the neuronal uptake pumps for both serotonin and noradrenaline (SNaRI). Venlafaxine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake10-12 and a weak inhibitor of dopamine reuptake. It has no significant affinity for muscarinic cholinergic, H1-histaminergic, or α1-adrenergic receptors in vitro. Whereas it has similar efficacy when compared with classical antidepressants,

it has better-tolerated adverse effects13-18 and is less likely to produce high cardiac toxicity of tricyclic antidepressant19-22 drugs and drug-drug interactions of nonselective monoamine oxidase inhibitors (MAOIs)23-

26. Venlafaxine hydrochloride27 is a structurally novel antidepressant. It is designated as (R/S)-1-[2-(dimethylamino)-1-(4-methoxyphenyl) ethyl] cyclohexanol hydrochloride or (±)-1-[α-[(dimethylamino) methyl]-p-methoxybenzyl] cyclohexanol hydrochloride and has the empirical formula of C17H27NO2 HCl and a molecular weight of 313.87 g/mol.

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O-Desmethylvenlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. It is designated as 4-[2-dimethylamino-1-(1-hydroxycyclohexyl) ethyl] phenol and has the empirical formula of C16H25NO2 and a molecular weight of 263.375 g/mol. The chemical structures of Venlafaxine hydrochloride and its metabolite O-Desmethylvenlafaxine has been given in Fig 1. Steady-state concentrations of venlafaxine and its major metabolite, O-Desmethylvenlafaxine (ODV), in plasma are attained within 3 days of oral multiple dose. Therefore, provides a slower rate of absorption28-30, but the same extent of absorption compared with the immediate release tablet31. The observed mean (SD) apparent steady state volume of distribution of 7.5 (3.7) and 5.7 (1.8) L/kg for venlafaxine and ODV, respectively, has been reported32-33. Metabolism of venlafaxine occurs primarily via CYP2D6 and CYP3A4 (cytochrome P-450 isozyme).Venlafaxine and ODV exhibit linear kinetics over the dose range of 75 to 450 mg/day. It has been shown that the mean (SD) values of steady-state plasma clearance of venlafaxine and ODV are 1.3 (0.6) and 0.4 (0.2) L/h/kg, respectively and the clearance decreases with cirrhosis, renal impairment and dialysis. Apparent elimination half-lives of venlafaxine and ODV are 5 ± 2 and 11 ± 2 hours, respectively. Approximately 87% of a venlafaxine dose is recovered in the urine within 48 hours as unchanged venlafaxine (5%), unconjugated ODV (29%), conjugated ODV (26%), or other minor inactive metabolites (27%). Renal elimination of venlafaxine and its metabolites is thus the primary route of excretion. The rationale of this present bioequivalence study34 for two formulations of 150mg venlafaxine hydrochloride extended release35 capsule was examined between generic drug Venlafaxine HCl ER Capsules as the test product and Effexor®-XR (Wyeth Pharmaceuticals Inc.)36 as the reference product. This bioequivalence study could give assurance when prescribing less expensive generic drugs as alternatives with similar efficacy and safety. The study objectives of this present study are to assess the single dose bioequivalence of Venlafaxine 150mg ER Capsules with Effexor®-XR (Wyeth Pharmaceuticals Inc.) in healthy, adult, human study participants under fed conditions and to monitor the clinical status, adverse events, laboratory investigations and assess relative safety and tolerance of Venlafaxine formulations under fed conditions.

MATERIALS AND METHODS According to the USFDA Regulatory individual product recommendations, two studies (Fed and Fed Sprinkle) to be done with 150mg venlafaxine HCl ER Capsules to obtain marketing authorization in USA. USFDA Waiver request of in-vivo testing: 37.5 mg and 75 mg based on (i) acceptable bioequivalence studies on the 150mg strength, (ii) proportional similarity of the formulations across all strengths and (iii) acceptable in vitro dissolution testing of all strengths. Study drugs Venlafaxine HCl (Batch no: 09G001, Mfg. Date: 07/2009) and Effexor®-XR (Batch no: D65167S, Exp. Date: 02/2012) from Wyeth Pharmaceuticals Inc. were used as the test and the reference products respectively. Both products were prepared as venlafaxine hydrochloride equivalent to venlafaxine 150 mg. Both the products were stored at controlled room temperature 25˚C (77 ˚F). Study population The study protocol was approved by the Ethics Committee. In addition, the protocol was performed in accordance with the Declaration of Helsinki Principles37 as outlined in the ICH-E6 Guidelines for Good Clinical Practice (GCP)38. All subjects were given a detailed description of the study and written informed consent was obtained prior to the enrollment. The sample size was estimated based on, Coefficient of variation (C.V.) of the drug, sufficient statistical power to detect 20% difference with the power of 0.8 in Cmax and AUC between the test and reference product, Regulatory requirements. Sample size was based on estimates obtained from reported literature and previous studies. Assuming a formulation ratio (T/R) ranging from 0.95-1.05 a sample of 20 subjects including dropouts would be sufficient to show bioequivalence between the two formulations with a power of at least 80%. Hence sample size of 20 subjects was enrolled in the study. Twenty healthy male volunteers between the ages of 18-45 years with a body mass index between 18.5 kg/m2 and 24.9 kg/m2, with body weight equal to or not less than 50 kg were assessed to be in good physical condition by a complete medical screening including a medical history, physical examination and laboratory screening test for hematologic and blood biochemistry parameters. Subjects with a history of hypersensitivity to any ingredients in the venlafaxine products and/or related drugs or its constituents or who were taking any medication or alcohol for a 21-day period prior to the study were excluded. Subjects who had a history of

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cardiovascular, hepatic, renal, gastrointestinal or hematologic disease were excluded from the study. Study design The study was an open-labeled, single-dose, study taken with food, two-treatment, two-period, two-sequence randomized two way crossover with at least one week washout period. Subjects were randomly allocated to two groups by the sequence of product administered [Test-Reference (TR) and Reference-Test (RT) group]. In each period, 1X150mg ER capsule of venlafaxine hydrochloride of the test or reference product was administered 30 minutes after starting a high fat, high calorie breakfast at the same time in the morning before dosing. Subjects were housed 12 hours prior to dosing in the clinical facility from a time adequate to ensure 10 hours supervised fasting before consuming high fat breakfast and were allowed to leave the facility after 24.00 hours post-dose sample in each period. The subjects received a standard meal at about 4.0, 9.0 and 13.0 hours after dosing in each period. During housing, all meal plans were identical for all the periods. Drinking water was not allowed from one hour before dosing till one hour post-dose (except for 240 ± 02 mL of drinking water given for dosing). Before and after that, drinking water was allowed at ad libitum. After a minimum of 1 week washout period, the subjects were crossed over to the next treatment following the same procedure as conducted in the 1st period. Sample collection During dosing day in each period, 23 blood samples (6 mL each) will be collected as per the following schedule: Pre dose sample(0.00 hr) within 02 hrs prior to drug administration and the others at 1.00, 2.00, 3.00, 4.00, 4.50, 5.00, 5.50, 6.00, 6.50, 7.00, 7.50, 8.00, 8.50, 9.00, 9.50, 10.00, 12.00, 16.00, 24.00, 36.00, 48.00 and 72.00 hours post dose. The total volume collected per study participant in this study will not exceed approximately 321 mL including up to 9 mL for screening, and 7-9 mL for post clinical assessment of lab parameters and 18 mL for discarded blood sample resulting from use of intravenous cannula for 12 hours and 2-9 mL was collected for repeat/additional lab tests, if required. For separating plasma, all blood samples were centrifuged at 3800rpm for 10 minutes at 4°C ± 2°C. Centrifugation of all samples was done as early as possible after each sample draw time point. After centrifugation, plasma samples were aliquoted into two sets in properly labeled polypropylene tubes and immediately stored at about -60°C or colder.

Venlafaxine and its metabolite analysis by LC-MS/MS 50 µL of Ticlopidine dilution (about 100ng/mL) was added to 100 µL of plasma sample and vortexed to mix. Added 2.5 mL of Extraction solvent (70:30 Diethyl ether: Dichloromethane), vortexed for 10min. Centrifuged the polypropylene tubes at 4,000 rpm and 10°C for 5 min, transferred approximately 2.0 mL of supernatant to Prelabelled glass tubes and evaporated till dryness. After completion of evaporation, reconstituted by using 0.250mL of mobile phase, vortexed for 30 seconds and transfer to pre-labeled HPLC vials, then to the auto sampler. HPLC39-41 was carried isocratically at room temperature using a Thermo BDS Hypersil C18 (4.6 x 50mm) column. The mobile phase consisted of 80:20, Acetonitrile: 10mM Ammonium formate Buffer. The flow-rate was 1 ml/min by using 40:60 splitter. The duration of the analytical time was 3 min. The analytical column effluent is directed through the divert valve to a thermo electron TSQ quantum discovery mass spectrometer. Source/gas parameters such as spray voltage was operated at 4500, sheath gas pressure, auxiliary gas and capillary temperature settings are maintained at 60 psi, 35 psi and 300 °C, respectively. Chromatograms were acquired on a TSQ tandem mass spectrometry (Thermo Finnegan, Sanjose, CA, USA) equipped with Electrospray ionization (ESI) and connected to a PC runs with the standard software Xcalibur 2.0.7 and LC Quan 2.5.6. Mass spectroscopic detection was performed on a Triple quadrapole instrument (Thermo, TSQ Quantum Discovery Max). Robotic liquid handling system is operated using the software package supplied from the cohesive technologies AriaTM. The calibration curve is constructed by weighted 1/x2 least-square linear regression analysis of the peak area ratio (drug/ISTD) vs. the concentration of drug and peak area ratio (metabolite/ISTD) vs. the concentration of metabolite. Pharmacokinetic and statistical analysis For the purpose of Average Bioequivalence analysis Cmax, AUC0-t and AUC0-inf were considered as the primary variables and Tmax, t1/2 and Kel were considered as the secondary variables. General Linear Model42-43 for analysis of variance (ANOVA) for crossover design was performed for log-transformed data and used to assess the effect of formulations, periods, sequences and subjects nested in sequence on these parameters. The difference between two related parameters was considered statistically significant for a p-value equal to or less than 0.05. 90% confidence interval (CI) for the ratios of geometric mean Test/Reference (T/R) for Cmax,

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AUC0-t and AUC0-inf was calculated based on least squares means from the ANOVA of log-transformed data. The 90% geometric CI of the ratio (T/R) of least squares means from the ANOVA of the log-transformed Cmax, AUC0-t and AUC0-inf should be within 80.00% to 125.00%. Tolerability assessment Physical examination and measurement of vital signs (Blood Pressure, Pulse Rate, and Oral Temperature) were examined at the time of Check-in, prior to administration of the each study drug (0.00 hr), 1.00, 3.00, 6.00, 12.00, 24.00, 36.00, 48.00, and 72.00 hours post dose and during the entire study period. Adverse events were monitored throughout the study and recorded by physicians. RESULTS Study population Twenty healthy male adults eligible for the study enrollment were randomly divided into 2 groups [Test-Reference (TR) and Reference-Test (RT)] according to the sequence of drug administration. All the subjects had completed both the periods. Thus, this study was balanced in each sequence and the results from 20 volunteers were used for pharmacokinetic and statistical analysis. Table 1 demonstrates the demographic characteristics of the volunteers. Bioanalysis and pharmacokinetics The Mass instrument was operated in the positive ion mode. The precursor ions at 279.848, 264.944 and 263.353m/z for Venlafaxine, ODV and Ticlopidine, respectively were selected by the first quadrupole (Q1). After collision-induced fragmentation in Q2, the product ions at 58.270, 58.170 and 124.824 m/z for Venlafaxine, ODV and Ticlopidine, respectively, were monitored in Q3. A resolution of one unit (at half peak height) was used for both Q1 and Q3. The method was fully validated using these Q1 and Q3 masses for both compounds with satisfactory results. Linear calibration curves were obtained with a coefficient of correlation (r2) usually higher than 0.995 in range of 1.00ng/mL to 300ng/mL. For each calibration standard level, the concentration was back calculated from the linear regression curve equation. No significant difference was observed in any of the analyzed pharmacokinetic parameters for Venlafaxine and its metabolite O-Desmethylvenlafaxine is shown in Table 2. Bioequivalence analysis Ninety percent confidence interval of geometric mean ratios of bioavailability parameters between the test and reference formulation are presented in Table 3. The

statistical analysis obtained from this study showed that the point estimate (90% CI) of the geometric mean ratio (GMR) (T/R) of Cmax, AUC0-t and AUC0-inf was entirely within the equivalence criteria (80.00-125.00%) which was 104.91% (92.86%-118.53%) and 114.41% (103.43%-124.55%) for Cmax ratios, 102.24% (95.95%-108.94%) and 105.27% (96.76%-114.53%) for AUC0-t ratios and 101.66% (95.73%-107.97%) and 104.71% (96.13%-114.05%) for AUC0-inf ratios of Venlafaxine and its metabolite O-Desmethylvenlafaxine (ODV) respectively. In addition, no significant difference of the Tmax parameter between the two studied formulations was observed (p >0.05). Therefore, it was concluded that the two extended-release capsule formulations of venlafaxine were bioequivalent in terms of rate and extent of absorption for the drug venlafaxine and the metabolite data has been given as supportive evidence. The mean plasma concentration vs. time profiles is given in Fig 2. Tolerability Almost all volunteers taking both venlafaxine formulations were noted for mild adverse events. Most common events were drowsiness, nausea and loss of appetite. However, no subject had any severe adverse event or withdrew from the study because of an adverse event. DISCUSSION A number of patients suffer from depression, which can cause a problem in quality of their lives and families. Venlafaxine, a selective SNaRI has similar efficacy and better tolerability when compared to classical antidepressants. An open-labeled, single-dose with food, two-treatment, two-period, two-sequence randomized two way crossover design in 20 healthy adult volunteers was considered appropriate and standard for bioequivalence evaluation of the generic and the reference products. The study simulates real life conditions including the influence of meals as well as circadian effects on the performance of the extended release product. For a safety reason, co-administration of the drug with food can reduce nausea, a common side effect of venlafaxine. In general, the pharmacokinetic parameters for both formulations were similar to the pharmacokinetic parameters of venlafaxine in previous published data. This study demonstrated that 90% CI of the logarithmic transformed of parameters Cmax, AUC0-t and AUC0-inf were contained in 80.00-125.00%. In addition, no significant differences of the Tmax values between the two formulations were observed (p>0.05). Therefore,

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the two extended-release capsule formulations of venlafaxine are considered bioequivalent in terms of the rate and extent of absorption. Moreover, both formulations were well tolerated. Hence, the test (Venlafaxine) and reference (Effexor®-XR) formulations of venlafaxine 150mg are bioequivalent. CONCLUSION This single dose study found that the test formulation Venlafaxine HCl Extended release capsules is bioequivalent to the reference formulation Effexor®-XR Extended Release Capsules the extent and the rate of absorption, of 150mg under fed condition in healthy adult male volunteers according to the USFDA regulatory guidance. REFERENCES 1. Rowbotham M, Goli V, Kunz N, Lei D. Venlafaxine extended

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Table 1: Demographic characteristics

Category Treatment Total Test (T) Reference (R)

Age (years)

Mean ± SD 23.84 ± 4.37 23.84 ± 4.00 23.84 ± 4.14

Range 18.0 – 35.0 19.0 – 36.0 18.0 – 36.0

Median 23.0 23.0 23.0

N 20 20 40

Age Groups

< 18 00 00 00

18 – 40 20 20 40

41 – 64 00 00 00

65 – 75 00 00 00

> 75 00 00 00

Gender Female 00 00 00

Male 20 20 40

Race

American 00 00 00

Hispanic 00 00 00

Caucasian 00 00 00

Asian 20 20 40

Height (cm)

Mean ± SD 164.12 ± 5.69 166.84 ± 4.89 165.48 ± 5.57

Range 155.0 – 175.0 159.0 – 176.0 155.0 – 176.0

Median 162.00 168.0 165.0

N 20 20 40

Weight (kg)

Mean ± SD 58.96 ± 6.24 61.56 ± 6.43 60.26 ± 6.41

Range 52.0 – 70.0 52.0 – 77.0 52.0 – 77.0

Median 58.0 59.0 59.0

N 20 20 40

BMI (kg/m2)

Mean ± SD 21.86 ± 1.46 22.10 ± 1.79 21.98 ± 1.62

Range 20.1 – 24.8 20.0 – 24.9 20.0 – 24.9

Median 22.00 21.60 21.80

N 20 20 40

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Table 2: Pharmacokinetic Parameters of Venlafaxine and its metabolite ODV for Both Formulations

Venlafaxine (Drug)

Parameters Test (T) Reference (R)

Mean ± SD CV (%) Mean ± SD CV (%)

Cmax (ng/mL) 168.77 ± 57.00 33.8 156.27 ± 47.84 30.6 AUCt (h.ng/mL)

2942.31 ± 1572.71 53.5 2823.34 ± 1436.89 50.9

AUCinf (h.ng/mL)

2973.54 ± 1592.76 53.6 2864.38 ± 1466.57 51.2

Tmax (hr) 7.33 ± 1.68 23.0 5.79 ± 1.16 20.0

t1/2 (hr) 7.37 ± 1.88 25.6 8.44 ± 2.27 26.9

kel(1/hr) 0.100 ± 0.025 25.0 0.087 ± 0.020 23.0

O-Desmethylvenlafaxine (Metabolite)

Cmax (ng/mL) 228.76 ± 76.64 33.5 190.07 ± 58.77 30.9 AUCt (h.ng/mL)

6065.66 ± 1951.72 32.2 5636.66 ± 1763.90 31.3

AUCinf (h.ng/mL)

6185.72 ± 1981.51 32.0 5776.86 ± 1808.23 31.3

Tmax (hr) 10.79 ± 1.95 18.0 9.38 ± 1.91 20.4

t1/2 (hr) 10.97 ± 1.29 11.8 11.57 ± 1.28 11.1

kel (1/hr) 0.064 ± 0.007 11.6 0.061 ± 0.006 10.7

Table 3: Bioequivalence Parameters for Venlafaxine and ODV

Parameter Venlafaxine O-Desmethylvenlafaxine

Cmax AUCt AUCinf Cmax AUCt AUCinf

90% CI Lower Limit 92.86 95.95 95.73 103.43 96.76 96.13

90% CI Upper Limit 118.53 108.94 107.97 124.55 114.53 114.05

T/R Ratio (%) 104.91 102.24 101.66 114.41 105.27 104.71

Power 0.92 1.00 1.00 0.97 0.99 0.99

Intra Subject Variability 12.34 6.40 6.06 8.26 8.50 8.62

Inter Subject Variability 29.88 54.04 53.94 30.85 29.35 29.31

ANOVA (p-Value)

Sequence 0.1229 0.1717 0.1686 0.1206 0.1669 0.1727

Period 0.8021 0.4122 0.3555 0.3100 0.5403 0.5313

Treatment 0.4924 0.5411 0.6296 0.0561 0.2950 0.3523

Fig.1.Chemical structures of Venlafaxine HCl and ODV

I.Sarath Chandiran et al. IRJP 2 (3) 2011 262-269

IRJP 2 (3) Mar 2011 Page 262-269

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Time vs Mean Plasma ConcentrationAnalyte : Venlafaxine

Fig 2: Time vs. Mean Plasma Concentration Graph of Venlafaxine and its metabolite ODV

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Time vs Mean Plasma ConcentrationAnalyte : O-Desmethylvenlafaxine

Source of support: Nil, Conflict of interest: None Declared