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`UW- PHARMACY LIBE—Afi‘f
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`Comm-"rs
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`Tramatlol Compared with Dielofenae in Traumalit‘
`Musculoskeletal Pain—L. Foghorn. S. Tomago. J. Mommas-it).
`G. Prado. W. Albisetfr'. G. Thane; and C. Ferrari
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`An Open-Label. Noneomparative. Multicenler Evaluation
`of Flueonazole with or without Urea Nail Pedicure for
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`Treatment of OnyehomyeosisfiJ. E. Frfr'ki. H. T. Heikt‘ril‘u,
`M. 0. Kerr}. K. E. Kaokkmten. R. 0. Diurnal]. I T. Raamnen.
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`Bioavailahility of Once—Daily Venlat‘axine Extended Release
`Compared with the Immediate—Release Formulation in Healthy
`Adult Volunteers—S. M. Tim: C. Dilea. P. T. Martin.
`A. 5. Rose”, R. J. Ft'miemo. and S. T. CMung
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`492
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`Pharmacokinetics of Once-Daily Venlafttxine Extended
`Release in Healthy Volunteers—S. M. Titty. C. Dilea.
`P. T. Martin. C. A. Leism: R. J. Ft'mtt‘iHn. and S. T. Chimig
`
`Effect of Dobtttamine on Serum Bile Acid Levels in Patients
`with Cirrhosis—T. Kmart), K. Twin. um! K. Akanmtsu
`
`Effects of Eieosapentaenoic Acid on Blood Rheology in
`Rats with Fatty Liver— i": Kitt'iliarti. M. Akimoto. M. Triicht'ytt.
`H. Hm-hinmto. H. Ixhigitm. A. Niimi. A. Meade. M. Shigemmo.
`K. thmshito. f. Ynkoyamrt. S. Kaxliima. and Y. Kikut'ht'
`
`Stleralfate Prevents Bile Acid—Induced Retardation of
`Gastric Epithelial Repair in 3 Rabbit Cultured Cell
`Model—X-E. thg, S. Wmmlabe. M. Himse. A. Mii‘ozoki.
`and N. Sam
`
`Comparative. Study of the In Vitro Dose Deliver).r and
`Particle Size Distribution Characteristics of art Azmacort
`Metered—Dose Inhaler in Combination with Four Different
`
`Spacer Devices—A. K. mm. C. L. Ryan. and F Debtct‘iu
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`504
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`IPR2015—00410
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`University of Texas
`Houston, Texas
`Gastroenterology
`Richard Day, MD.
`St. Vincent’s Hospital
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`CURRENT
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`Clinical and Experimental
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`CURRENT THERAPEUTIC RESEARCH ® VOL. 58, NO. 8, AUGUST 1997 BIOAVAILABILITY OF ONCE-DAILY VENLAFAXINE EXTENDED RELEASE COMPARED WITH THE IMMEDIATE-RELEASE FORMULATION IN HEALTHY ADULT VOLUNTEERS STEVEN M. TROY, 1 CLIFFORD DILEA, I PATRICK T. MARTIN, I AMY S. ROSEN, I RICHARD J. FRUNCILLO, 2 AND SOONG T. CHIANG I 1Wyeth-Ayerst Research, Philadelphia, and 2Wyeth-Ayerst Research Clinical Pharmacology Unit, Graduate Hospital, Philadelphia, Pennsylvania ABSTRACT Two open-label, randomized, crossover studies, one single- and one multiple-dose, were conducted to assess the relative bioavailability of two formulations of once-dally venlafaxine extended release (XR) 75 and 150 mg compared with the immediate-release (IR) for- mulation of venlafaxine. Healthy adults (12 men, 12 women) aged 18 to 45 years were enrolled in each study. Frequent blood samples were taken for determination of the plasma concentrations of ven- lafaxine and its active metabolite, O-desmethylvenlafaxine (ODV). In the single-dose study, the 2 x 75-mg XR formulation and the 150- mg XR formulation were bioequivalent with respect to the rate and extent of absorption of venlafaxine and the formation of ODV, and the area under the plasma concentration-time curve (AUC) of both XR formulations and the AUC of the IR formulation also were bio- equivalent after normalization for dose. In the multiple-dose study, the three XR formulations were also bioequivalent with respect to the rate and extent of absorption of venlafaxine and formation of ODV, and the AUC of all three XR formulations compared with the AUC of the IR formulation also showed bioequivalence. Overall, the once-daily venlafaxine XR formulations provided the same total ex- posure (measured by AUC) to both venlafaxine and ODV. Thus it can be predicted that patients will obtain the same response with the XR formulations as with the IR fomulations. Key words: veulafaxine, bioavallability, extended release, healthy volunteers. INTRODUCTION Venlafaxine hydrochloride (hereafter referred to as venlafaxine) is a unique antidepressant that differs structurally from other currently avail- able antidepressants. 1 Venlafaxine and its active metabolite, O- desmethylvenlafaxine (ODV), inhibit the neuronal uptake of norepineph- rine, serotonin, and, to a lesser degree, dopamine, 2'3 but have no monoamine oxidase inhibitory activity and a low affinity for brain musca- Address correspondence to: Steven M. Troy, MS, Wyeth-Ayerst Research, P.O. Box 42528, Philadelphia, PA 19101. Received for publication on May I, 1997. Printed in the U.S.A. Reproduction in whole or part is not permitted. 492 0011-393X/97/$3.50
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`S. M. TROY ET AL. rinic, cholinergic, histaminergic, or alpha-adrenergic receptors. 4'5 Venla- faxine has an established tolerability and efficacy profile for the treatment of depressive disorders, s-l° Venlafaxine pharmacokinetics have been studied previously in healthy subjects receiving single oral doses ranging from 10 to 250 mg. 11'12 Venlafaxine is well absorbed after oral administration, and metabolism of venlafaxine occurs primarily via O-demethylation. About 5% of an admin- istered dose is excreted in the urine as unchanged drug, with less than 30% excreted as ODV. 13 Metabolism has been reported to be linear at venla- faxine doses up to 225 mg/d. 14 The steady-state half-lives of verdafaxine and ODV are approximately 5 and 11 hours, respectively, necessitating administration two or three times daily to maintain adequate plasma lev- els of drug. 15 A microencapsulated formulation of venlafaxine has been developed as an extended-release (XR) capsule, which allows for once-daily adminis- tration. This paper describes the results from single- and multiple-dose studies comparing the relative bioavailability of once-dally venlafaxine XR 75-rag and 150-mg formulations with each other and with the immediate- release (IR) formulation. SUBJECTS AND METHODS The single-dose study was conducted at Medeval Ltd., Manchester, En- gland, and the multiple-dose study was conducted at the Wyeth-Ayerst Research Clinical Pharmacology Unit, Philadelphia, Pennsylvania. All protocols and consent forms received institutional review board approval before study initiation, and all study subjects provided written informed consent before enrollment. Subjects had a screening assessment that included a medical history, physical examination, clinical laboratory tests, and an electrocardiogram (ECG) within 2 weeks before taking the study medication to determine eligibility for the study. Eligible subjects were physically and mentally healthy adults between 18 and 45 years of age who were within 15% of ideal body weight for height, frame, and sex according to the 1983 Metro- politan Height and Weight Tables (Society of Actuaries and Association of Life Insurance Medical Directors of America, 1980). In addition, subjects were to have no clinically significant abnormalities as judged a priori by the sponsor's medical monitor in complete blood count; serum chemistry panel; liver function tests; tests for hepatitis-B surface antigen; urinalysis, including urine drug screen; urine pregnancy test; and 12-lead ECG. Exclusion criteria included a history of any clinically significant medi- cal or psychiatric disease as judged by the investigator within 2 years of study entry, including any condition that might interfere with the absorp- 493
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`BIOAVAILABILITY OF ONCE-DAILY VENIJ~AX1NE EXTENDED RELEASE tion, distribution, metabolism, or excretion of any drug; a positive serologic test for human immunodeficiency virus; a history of clinically significant allergies or hypersensitivity to any drug; a history of alcohol abuse or history of habitual or clinically diagnosed illicit drug use within the pre- vious 2 years; use of any recreational or investigational drug within 3 months, any prescription drug within 30 days, or any over-the-counter drug (except for the occasional use of acetaminophen and vitamins ~< 100% of the USDA Recommended Daily Allowance [RDA]) within 14 days before study entry; consumption of any alcoholic beverages within 24 hours or caffeine-containing products within 12 hours before study entry; and the use of any nicotine-containing products within 3 months before study entry. Subjects also could not have any acute illness within 1 week before study entry or a weight loss or gain exceeding 10% of total body weight within 30 days before study entry, or be pregnant or breast-feeding. Subjects were not allowed to take any concomitant medication during the study period except for low-dose estrogens, progestin, or estrogen- progestin combination treatment in women, vitamins (~<100% RDA), and acetaminophen. The use of nicotine-containing products, caffeine- containing products, or alcohol was prohibited during the study period. Complete vital signs (temperature, respiratory rate, sitting blood pres- sure, and heart rate) were taken and clinical laboratory tests (complete blood count, serum chemistry, urinalysis) were performed on a routine basis throughout the study periods. A physical examination and an ECG were performed at scheduled intervals during each study period and at the end of the study. The tolerability of the study medication was assessed by tracking any adverse events that occurred during the study period. Blood samples (7 mL) were collected via venipuncture in heparinized blood tubes and centrifuged at 2500 rpm for 15 minutes. The separated plasma was then transferred to plastic tubes supplied by the sponsor and frozen at -20 °C. Plasma samples were assayed for venlafaxine and ODV concentrations by using high-performance liquid chromatography with ul- traviolet detection. 16 Single-Dose Study This was an open-label, randomized, three-period crossover study in healthy volunteers. Each subject received the three treatments in separate study periods according to a predetermined randomization schedule. The three treatments consisted of two venlafaxine 75-rag XR capsules (encap- sulated at Wyeth-Ayerst Laboratories, Rouses Point, New York), one ven- lafaxine 150-mg XR capsule (encapsulated at Ayerst-Wyeth Pharmaceuti- cals, Inc., Guayama, Puerto Rico), and one venlafaxine 50-mg IR capsule (manufactured at Ayerst-Wyeth Pharmaceuticals, Inc., Guayama). In each study period, subjects reported to the study center the evening 494
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`S. M, TROY ET AL. before administration of the study drug and remained in the study center for 3 days. The washout period between treatments was at least 5 days. Blood samples were obtained for determination of venlafaxine and ODV plasma concentrations before and at 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 14, 16, 20, 24, 28, 36, 48, and 72 hours after drug administration. Multiple-Dose Study This was an open-label, randomized, four-period crossover study con- ducted in healthy volunteers. Subjects reported to the study center the evening before administration of the first dose of venlafaxine. Subjects then began a 3-day dose titration period with venlafaxine 37.5-mg IR ad- ministered every 12 hours, and were subsequently randomized to receive the following 4-day regimens in four separate study periods without a washout phase between study periods. The four treatment regimens con- sisted of one venlafaxine 75-rag IR capsule twice daily (PR [encapsulated at the Puerto Rico facility]), two venlafaxine 75-mg XR capsules once daily (NY [encapsulated at the New York facility]), two venlafaxine 75-mg XR capsules once daily (PR), and one venlafaxine 150-rag XR capsule once daily (PR). Subjects remained in the study center for the duration of the study (titration period plus all four treatment periods). On the third day of each treatment period, blood samples were obtained before the morning dose of venlafaxine for determination of venlafaxine and ODV plasma concentra- tions. On the fourth day of each treatment period, blood samples were also obtained before the morning dose and at 1, 2, 4, 6, 8, 10, 12, 14, 16, 20, and 24 hours thereafter for the XR formulations, or before the morning dose and at 0.5, 1, 2, 4, 6, 8, 12, 12.5, 13, 14, 16, 18, 20, and 24 hours thereafter for the IR formulation. Tolerability assessment was based on adverse events elicited from spontaneous reports by subjects or by the investigator, or from results of routine physical examination or laboratory determinations. Serious ad- verse events were reviewed by the sponsor's medical monitor. Statistical Analysis Venlafaxine and ODV plasma concentration data for each subject were analyzed by using empirical, model-independent methods. 17 Thus the peak plasma concentration (Cm~x), the time to reach Cm~ (Tmax), and the trough or minimum plasma concentration (Cmi n) were directly taken from the observed plasma concentration data. The terminal-phase elimination half- life (tl/2) was estimated by Ln(2)/k Z, where kz was determined from a log- linear regression of the last three to five plasma concentration values. For the single-dose study, the log-trapezoidal method was used to calculate the 495
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`BIOAVAILABILITY OF ONCE-DAILY VENLAFAXINE EXTENDED RELEASE empirical area under the plasma concentration-time curve (AUC) to the last observable plasma concentration at time T (AUCT) , which was extrap- olated to the total AUC (AUC = AUC w + CT/kz). For the multiple-dose study, the log-trapezoidal method was used to calculate the AUC over one 24-hour steady-state interval (AUC24h). Additionally, Rf, the steady-state fluctuation ratio (Cm~ - CmiJCmean), and Cme~, the mean daily plasma concentration (AUC24h/24), were also estimated for the multiple-dose study. For the single-dose study, the Wagner-Nelson deconvolution method is was used to assess the cumulative fraction ofvenlafaxine absorbed as well as the cumulative amount of ODV formed at each time point. Additionally, the modified Wagner-Nelson deconvolution method 19 was applied to the multiple-dose data. Statistical comparisons of mean plasma concentrations at each sam- pling time and estimates of the pharmacokinetic variables were made by using an analysis of variance for a crossover design. Calculations of statistical power were based on detecting a 20% difference in log- transformed pharmacokinetic variables between treatments at the 0.05 significance level. 2° In addition, the two one-sided tests bioequivalence procedure for log-transformed data was applied. 21 The SAS statistical soft- ware package (SAS Institute, Inc., Cary, North Carolina) was used for statistical analyses. RESULTS Single-Dose Study A total of 24 healthy subjects (12 men and 12 women) were enrolled in the study, and 22 subjects completed the study (1 subject discontinued because of headaches on day 1 and 1 subject withdrew for medical rea- sons). All subjects were white, the women had a mean age of 24 + 4 years and a mean body weight of 58 + 6 kg, and the men had a mean age of 27 + 6 years and a mean body weight of 74 + 11 kg. Pharmacokinetic variables for venlafaxine and ODV are shown in Table I. Except for Tma~, there were no statistically significant differences between men and women in any of the venlafaxine or ODV pharmacoki- netic variables. The comparisons of Cm~, AUCT, and AUC for venlafaxine and ODV between the two XR formulations indicated bioequivalence (Table II). In addition, the mean fraction absorbed for venlafaxine and ODV was almost identical between these two formulations at all time points. The pharmacokinetic values were adjusted (dose-normalized) for differences in the dose between formulations. Comparisons of the dose- normalized AUC w and AUC among the IR and the two XR formulations indicated bioequivalence for both venlafaxine and ODV. However, the 496
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`S. M. TROY ETAL. Table I. Pharmacokinetic variables for venlafaxine and O-desmethylvenlafaxine following single-dose administration of venlafaxine extended release (XR) and venlafaxine immediate release (IR) to 22 healthy subjects. Values are expressed as mean ± SD. Cma x Tm= x tl/2 AUG T AUG Treatment (ng/mL) (h) (h) (ng• h/mL) (ng• h/mL) Venlafaxine 2 x 75 mg XR 107+42 6.1 ±1.5 11.8+6.9 1587+1165 1775±1206 1 x 150 mg XR 101 +36 5.7+1.5 10.3+4.4 1621 ±1253 1777±1423 1 x 50 mg IR 82 ± 28 3.0 ± 1.4 5.0 ± 3.2 571 ± 442 625 ± 470 0-desmethylvenlafaxine 2x75mgXR 163±53 10.5±3.0 13.2±3.3 4132±1491 4516±1523 1 x 150 mg XR 167±49 12.3±9.2 14.6±4.2 4268±1293 4787±1551 1 x 50 mg IR 120±30 5.5±3.4 9.6±2.5 1558±465 1758±494 Cmax = maximum plasma concentration; Tma x = time to reach Cm~; tl/2 = elimination half-life; AUG T = area under the plasma concentration-time curve at the last observable time. dose-normalized Cn~x for venlafaxine and ODV was lower for the XR for- mulations compared with the IR formulation (Figure 1). A total of 16 subjects experienced at least one adverse event, including three classified as severe. One subject during the IR treatment period developed a severe migraine headache; 1 subject had nausea and fainted during the 150-mg XR treatment period; and 1 subject developed a severe frontal headache during the 2 × 75-mg XR treatment period. Multiple-Dose Study Twenty-four healthy subjects (12 men and 12 women) were enrolled and completed the study. Twenty subjects were white, 2 were Hispanic, and 2 were black. The mean age of the women was 29 ± 9 years, and the Table II. Bioequivalence test results for venlafaxine and O-desmethylvenlafaxine (ODV) fol- lowing administration of a single dose of two formulations of venlafaxine extended release (XR) or venlafaxine immediate release (IR) in 22 healthy subjects. Geometric Mean Relative Bioavailability (%) and 90% Confidence Interval Venlafaxine ODV Test/Relerence Cma x AUCT AUC Cma x AUG T AUC 1 x 150 mg XR/ 2 x 75 mg XR 95 (87-104) 98 (92-105) 95 (89-103) 103 (86-123) 102 (97-107) 102 (97-108) 2 x 75 m0 XR/ 1 x 50 mg IR 42 (38-46) 92 (87-99) 94 (87-101) 43 (36-51) 88 (84-92) 88 (84-93) 1 x 150 mg XR/ 1 x 50 mg IR 40 (36-44) 91 (85-97) 90 (83-96) 45 (37-53) 90 (85-94) 90 (86-95) Cr.~ = maximum plasma concentration; AUCT = area under the plasma concentration-time curve at the last observable time. 497
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`BIOAVAILABILITY OF ONCE-DAILY VENLAFAXINE EXTENDED RELEASE 100 - ~o~ 80- i 60- 8 40- 2o- o J Venlafaxine J --0- 2 × 75 mg XR capsules --0- 1 x 150 mg XR capsule "PIIII I II II II II II II II II II I 0 6 12 18 24 30 36 42 48 Time (hours) B. I O-Desmethylvenlafaxine I ~, 160- E ~ 140- 120- ~ 100- 80- ~ 60- ~- 40- :~ 20- @ 2 x 75 mg XR capsules --0.- 1 x 150 mg XR capsule =P i i i I i I i I i I i i i i i i i f i i i i i T 6 12 18 24 30 36 42 48 Time (hours) Figure 1. Mean plasma concentrations for (A) venlafaxine and (B) O-desmethylvenlafaxine among 22 subjects receiving single doses of venlafaxine extended release (XR) or immediate release (IR). mean body weight was 62 + 8 kg. The mean age of the men was 27 ± 7 years, and the mean body weight was 78 ± 8 kg. Pharmacokinetic variables for venlafaxine and ODV are listed in Table III. There were no statistically significant differences between men and women for any of the venlafaxine and ODV pharmacokinetic variables. All three XR formulations produced a longer Tm~ than the IR capsule. In 498
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`S. M. TROY ET AL. Table III. Pharmacokinetic variables for venlafaxine and O-desmethylvenlafaxine following multiple-dose administration of venlafaxine extended release (XR) and venlafax- ine immediate release (IR) in 24 healthy subjects. Values are expressed as mean ± SD. Cma x Tmax tl,? AUC-lr Treatment (ng/mL) (h) (h) (ng • h/mL) Rt Venlafaxine 75 mg IR q12h 225 + 86 2.0 ± 0.7 50 ± 35 2604 ± 1325 1.86 ± 0.68 2 x 75 mg XR q24h (NY) 155±71 5.4±1.4 51 ±37 2246±1216 1.23±0.40 2 x 75 mg XR q24h (PR) 157 +71 5.8±1.6 50.37 2240±1218 1.27 + 0.34 1 x 150 mg XR q24h (PR) 149±79 5.4±1.1 41 ±44 2222±1403 1.21 ±0.35 O-desmethylvenlafaxine 75 mg IR q12h 290±117 3.1 ±1.5 167±69 5402-2131 0.54±0.20 2 x 75 mg XR q24h (NY) 256±108 7.8±2.4 148±61 5036±2115 0.50±0.14 2 x 75 mg XR q24h (PR) 266 _+ 105 9.2 ± 23 144 ± 65 5019 ± 2055 0.57 + 0.22 1 x 150 mg XR q24h (PR) 260±109 9.0*2.6 150±62 5052±2087 0.51 ±0.14 Cm~x = maximum plasma concentration; Tma x = time to reach Cmax; tl/2 = elimination half-life; AUC T = area under the plasma concentration time curve at the last observable time; Rf = steady-state fluctuation ratio (Cmax - CmJCmean); qnh = every n hours; NY = capsules formulated at Wyeth-Ayerst Laboratories, Rouses Point, New York; PR = capsules formulated at Ayerst-Wyeth Pharmaceuticals, Inc., Guayama, Puerto Rico. addition, the mean Wagner-Nelson deconvolution profile of venlafaxine was very similar for all three XR formulations. The Cma ~ was lower (Figure 2), the Tma x was longer, and the Rf was lower for the three XR treatments compared with the IR treatment. The venlafaxine and ODV C~, Cmin, AUC24h, and R~ all indicated bioequivalence for comparisons among the three XR formulations (Table IV). The venlafaxine and ODV AUC24 h also indicated bioequivalence for comparisons between the IR treatment and the three XR treatments. Ad- ditionally, the venlafaxine Cmi n indicated bioequivalence for comparisons between the IR treatment and two of the three XR treatments, and the ODV Cma ~ indicated bioequivalence for comparisons between the IR treat- ment and the three XR treatments. A total of 19 subjects experienced at least one adverse event; however, the majority of adverse events were considered to be mild. The most com- mon adverse events were nausea (13 subjects), dizziness (7), pharyngitis (7), and vomiting (6). DISCUSSION AND CONCLUSION Results from these single- and multiple-dose studies showed that the 75- and 150-mg XR formulations were bioequivalent when administered at a common dose. Furthermore, although the Cm~ was lower with the XR than with the IR formulation, the total exposure (single-dose AUC or multiple- dose AUC24 h) of subjects to both venlafaxine and ODV was similar when comparing the XR and IR formulations. In addition, there was less fluc- tuation from Cm~ to Cmi n for the XR formulations compared with venla- 499
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`BIOAVAILABILITY OF ONCE-DAILY VENLAFAXINE EXTENDED RELEASE 8 B. 250- 200- 150- t ,oolL 0 --O-- 2 × 75 mg XR (NY) --o- 2 x 75 mg XR (PR) 1 × 150 mg XR (PR) I I I I I ! 1 I I I I I I I I I I I I I I I I 4 8 12 16 20 24 Time (hours) 300 ~_ 200 "~ 150 0 t-- 0 o 100 o~ E 0~ ~- 50 t,- ID ~ 0 2 × 75 mg XR (NY) • -o-. 2 × 75 mg XR (PR) 1 x 150 mg XR (PR) --e.-- 75 mg q12h IR I I l I I I I I I I I I I I I I I I I I I I I I I 0 3 6 9 12 15 18 21 24 Time (hours) Figure 2. Mean plasma concentrations for (A) venlafaxine and (B) O-desmethylvenlafaxine among 24 subjects receiving multiple doses of venlafaxine extended release (XR, capsules formulated in New York [NY] or Puerto Rico [PR]), or immediate release (IR). faxine IR. Based on the results of these studies, a switch from the conven- tional venlafaxine formulation to the once-daily venlafaxine XR formulation will not produce a change in the subject's total daily exposure to venlafaxine or ODV. Previously, venlafaxine IR has been shown to be well absorbed after oral administration, and administration with food had no effect on its 500
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`S. M. TROY ET AL. Table IV. Bioequivalence test results for venlafaxine and O-desmethylvenlafaxine (ODV) following administration of a single dose of two formulations of venlafaxine ex- tended release (XR) or venlafaxine immediate release (IR) in 24 healthy subjects. Geomefric Mean Relative Bioavailabllity (%) and 90% Confidence Interval Venlafaxine ODV Cmax Groin AUCz4h Cmax Groin AUC24h Reference: 2 x 75 mo XR (NY) 2 x 75 mg XR (PR) 101 (94-108) 95 (88-103) 98 (93-103) 104 (99-109) 97 (91-103) 100 (97-103) 1 x 150 mg XR(PR) 94(88-101) 93(86-101) 96(91-101) 101(97-106) 101(95-107) 100(97-103) Reference: 75 mg IR q12h 2 x 75 mg XR (NY) 66 (61-70) 92 (85-100) 90 (86-95) 97 (93-102) 81 (76-86) 98 (96-101) 2 x 75 mg XR (PR) 66 (61-70) 88 (81-95) 89 (85-93) 101 (96-106) 76 (73-83) 98 (96-101) 1 x 150 mg XR (PR) 62 (58--66) 86 (79-93) 87 (82-91) 98 (94-103) 81 (76-87) 99 (96-102) Crnax = maximum plasma concentration; Cmi n = minimum plasma concentration; AUC24 = 24-hour area under the plasma concentration-time curve; NY = capsules formulated at Wyeth-Ayerst Laboratories, Rouses Point, New York; PR = capsules formulated at Ayerst-Wyeth Pharmaceuticals, Inc., Guayama, Puerto Rico. pharmacokinetic disposition. 1 Peak plasma concentrations were reached in 2 hours for venlafaxine and 2.8 hours for ODV. After doses of 25 to 150 mg three times daily the mean peak plasma concentration of venlafaxine ranged from 53 to 393 ng/mL, and the mean peak plasma concentration of ODV ranged from 148 to 686 ng/mL. 14 Plasma concentrations of ODV are two to three times higher than those ofvenlafaxine. The combined AUC for venlafaxine and ODV is linear over the dose range 75 to 450 mg/d. 14 The XR formulation of venlafaxine differs from the standard formu- lation in that venlafaxine is released much more slowly into the gastroin- testinal tract, which slows the absorption of venlafaxine into the systemic circulation. Consequently, peak plasma concentrations are reached at approximately 6.3 hours after administration, although the extent of venlafaxine absorption and formation of ODV are similar with the XR and IR formulations. However, values for Cm~ and AUC with venlafaxine XR reported here were similar to those previously reported with the IR formulation. 14,15 Patients being treated with venlafaxine IR administered twice daily who are switched to treatment with venlafaxine XR once daily will have the same total daily exposure to both venlafaxine and its active metabolite ODV. Therefore, it is possible, from a pharmacokinetic point of view, that patients may not experience any loss of efficacy when switched from treat- ment with venlafaxine IR to once-daily venlafaxine XR. In addition, use of the venlafaxine XR formulation may diminish side effects that are related to the rapid rise in the plasma concentrations of venlafaxine following IR 501
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`Page 14
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`BIOAVAILABILITY OF ONCE-DAILY VENLAFAXINE EXTENDBD RELEASE administration because the venlafaxine XR capsules provide a slower ab- sorption profile than IR treatment. Acknowledgment This study was supported by grants from Wyeth-Ayerst Research, Phila- delphia, Pennsylvania. References: 1. Holliday SM, Benfield P. Venlafaxine. A review of its pharmacology and therapeutic potential in depression. Drugs. 1995;49:280-294. 2. Haskins JT, Moyer JA, Muth EA, Sigg EB. Inhibition of noradrenergic neuronal activity by the novel bicyclic compounds, WY-45,030 and WY-45,881. Soc Neurosci Abstracts. 1984;10:262. Abstract. 3. Muth EA, Moyer JA, Haskins JT, et al. Biochemical, neurephysiological, and behavioral effects of WY-45,233, its enantiomers, and other identified metabolites of the antidepres- sant venlafaxine. Drug Dev Res. 1991;23:191-199. 4. Cusack B, Nelson A, Richelson E. Binding of antidepressants to human brain receptors: Focus on newer generation compounds. Psychopharmacology. 1994;114:559--