CURRENT
`THERAPEUTIC
`RESEARCH0
`VOL. 56, NO. 9, SEPTEMBER 1995
`
`CLINICAL PHARMACOKINETICS OF ALPRAZOLAM EXTENDED
`
`RELEASE: A SUMMARY
`
`C. EUGENE WRIGHT
`
`The Upjohn Company, Kalamazoo, Michigan
`
`ABSTRACT
`
`A new extended-release formulation of alprazolam (alprazolam XR)
`has been developed to facilitate less-frequent dosing than is required
`with the conventional formulation (alprazolam compressed tablet
`[CT]). During a study involving chronic dosing of alprazolam KB 6 mg
`once daily and alprazolam CT 1.5 mg four times daily, the extent of
`absorption and peak concentrations were comparable, whereas the
`trough concentration was higher with the latter formulation. During
`chronic dosing of alprazolam KB 3 mg twice daily and alprazolam CT
`1.5 mg four times daily, the extent of absorption, peak concentrations,
`and trough concentrations were comparable. The administration of a
`high-fat meal in conjunction with alprazolam KB 1 or 3 mg did not
`affect the extent of absorption, but the peak concentration increased
`by 12% and 26%, respectively. A similar concentration profile was
`observed when alprazolam XR 3 mg was administered at night as op-
`posed to the morning. Mean maximum sedation scores on the Nurse
`Rated Sedation Scale (0—4) are comparable with a 3-mg dose of alpra-
`zolam XR (2.12 = 0.485) and a 1.5-mg dose of alprazolam CT (2.74 :t
`0.485). During chronic dosing, tolerance to sedation occurs to the
`same extent with both formulations. The only difference in pharma-
`cokinetic profiles is the slower absorption of alprazolam XR compared
`with alprazolam CT. In view of the fact that distribution, metabolism,
`and elimination are comparable, the half-life and extent of accumu-
`lation during chronic dosing are the same for both formulations.
`
`INTRODUCTION
`
`Alprazolam is a triazolobenzodiazepine compound that is metabolized to
`4-hydroxy and a-hydroxy metabolites (Figure 1). Although these metabo-
`lites have pharmacologic activity in in vitro and animal models}2 they are
`not important from a clinical standpoint because their combined concen-
`trations constitute <15% of the parent compound concentration.3'4 Only
`parent compound concentrations are important for evaluating alprazolam
`pharmacokinetics and pharmacodynamics.
`Relationships between drug concentration and therapeutic response
`are an important component of the assessment of clinical utility. In a
`double-blind, placebo-controlled, fixed-dose study, the probability of re-
`sponse to the conventional immediate-release formulation of alprazolam
`(alprazolam compressed tablet [CT]) was examined in 90 patients with
`
`947
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`MYLAN - EXHIBIT 1034
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`MYLAN - EXHIBIT 1034
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`CLINICAL PHARMACOKINETICS 0F ALPRAZOLAM KR
`
` Alprazolam
`
`Figure 1. Chemical structures of alprazolam and its metabolites.
`
`panic disorder.5 The patients were randomized to receive either placebo or
`alprazolam CT 2 or 6 mg/d in three or four divided doses. Major response
`was defined as a >75% reduction, moderate response as a 25% to 75%
`reduction, and no response as a <25% reduction in the number of panic
`attacks. During a 6~week treatment period, the probability of a patient
`being classified as a major responder increased with increasing alprazolam
`concentration—from approximately 5% at 15 ng/mL to approximately 75%
`at 48 ng/mL (Figure 2). In another double~blind, placebo-controlled study,
`alprazolam doses were adjusted to achieve maximum therapeutic benefit
`in 219 patients with panic disorder.6 Maximum improvement in the Ham-
`ilton Anxiety Rating Scale and the Hamilton Depression Rating Scale was
`observed at alprazolam CT concentrations of 20 to 39 ng/mL.
`Recently, an extended-release formulation of alprazolam (alprazolam
`XR) was developed to facilitate less-frequent dosing. The comparative
`pharmacokinetic and pharmacodynamic profiles of the extended-release
`and conventional formulations have important implications for the treat-
`ment of anxiety and panic disorder.
`
`PHARMACOKINETICS OF ALPRAZOLAM XR VERSUS ALPRAZOLAM CT
`
`Single-Dose Studies
`
`Figure 3 shows plasma concentration versus time profiles following a
`
`948
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`

`C. E. WRIGHT
`
`1 .0
`
`0.9
`
`0.8
`
`0.7
`
`0.6
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0.0
`
`Probability
`
`Moderate
`
`o 10 20 30 40 50 60 7o 80 90 100110120130140150160170180190200 210220
`
`Aiprazolam Concentration (ng/mL)
`
`Figure 2. Probability of a patient being classified as a major responder, moderate responder,
`or nonresponder as a function post distribution of alprazolam plasma concentration
`at the patient's last evaluation. (Reprinted with permission from Antal et al.5)
`
`single oral dose of alprazolam KB (3 mg) and alprazolam CT (1.5 mg) in 17
`healthy volunteers.7 With alprazolam XR, the rate of absorption was
`slower and the peak concentration was relatively flat, occurring 6 to 12
`hours after administration of the dose. The maximum concentration was
`
`slightly higher with alprazolam XR than with alprazolam CT, but it oc—
`curred much later.
`
`Table I provides details on the pharmacokinetic parameters underly-
`ing these observations. At the 3-mg dose of alprazolam XR, the area under
`the curve (AUC, or extent of absorption) was approximately twice that
`associated with the 1.5-mg dose of alprazolam CT. However, after correc—
`tion for dose (AUCD), the extent of absorption was similar, indicating that
`patients receiving either formulation would be exposed to comparable
`amounts of alprazolam. The difference between the maximum concentra-
`tions was only approximately 16%, even though the alprazolam XR dose
`was twice that of the conventional formulation. Clearance was the same
`
`with both formulations, indicating that the extended-release tablet did not
`alter drug metabolism or elimination. The difference between volumes of
`distribution (although statistically significant) was relatively small in
`magnitude, and both values were within the range associated with alpra-
`zolam CT tablets.8 The half-lives of the two formulations were similar.
`
`Overall, then, only the absorption rate was different with alprazolam XR
`
`949
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`

`

`CLINICAL PHARMACOKINETICS 0F ALPRAZOLAM KR
`
`—£}~— Aiprazolam X8 3 mg (one tablet)
`
`—0-- Alprazolam CT 1.5 mg
`(one 1-mg tablet and one 0.5-mg tablet}
`
`(mg/mi.)
`AlprazolamConcentration
`
`
`0
`
`8
`
`1 6
`
`24
`
`32
`
`40
`
`48
`
`Time (b)
`
`Figure 3. Mean alprazolam plasma concentrations following the administration of single oral
`doses of an immediate-release formulation of alprazolam (alprazolam compressed
`tablet [CT]) and an extendedqelease formulation of alprazolam (alprazolam XR) in
`17 healthy male and female volunteers (mean age, 32 years; mean weight, 71 kg).
`
`compared with alprazolam CT. Drug distribution and elimination were not
`altereé.
`
`Figure 4 shows the results of a study in which 21 healthy volunteers
`received alprazolam XR in single doses of 2, 4, 8, or 10 mg according to a
`
`
`
`Table I. Alprszolam pharmacokinetic parameters resulting from the administration of single
`oral doses of the conventional immediate-release formulation of alprazolam (alprsv
`zolam compressed tablet {0TB or the extended-release formulation of slprazolam
`(alprazolam XR) in 17 healthy volunteers. Values are expressed as mean 2: SD.
`
`Aipmalsm 0T
`Almzelam XB.
`
`Paramflsr
`1.5 mg
`3 my
`ANDVA P Value
`
`0.009!
`1'5? :1.- 421
`359 t 154
`AUG (ng x mm.
`0.9080
`3?8 z 210
`359 z 154
`11130., (no >< him )*
`00445
`25.1 r 6.89
`21.7 i 5.15
`cm, éng/mL)
`0.0001
`9.88 x 4.09
`1.82 'J: 1.0?
`T
`h)
`0.9632
`1.12 i 9.429
`1.12 1*: 0.37?
`c mUminikg)
`0.00135
`1.16 :t 0.162
`0.964 x 0.171
`v31 SL019)
`
`11,201
`10.0
`12.4
`-
`
`ANGVA = analysis of variance; AUG = area under the (concentration vs time) curve; AUCD = dose-cor-
`rected AUG; C
`: maximum conoentration; TW a t1meto_max1mum concentratron; 01., = apparent oral
`clearance; Vd =
`parent volume of distributron; 1.12 = elimination half-life, harmomc mean.
`* Narmaiized to 31. -mg (rose.
`
`950
`
`

`

`C. E. WRIGHT
`
`--x— Alprazolam XR 10 mg
`—-a— Alprazolam XR 8 mg
`—-l:l— Alprazolam XR 4 mg
`—0— Alprazolam XR 2 mg
`
`(ng/mL)
`AlprazolamConcentration
`
`
`0
`
`a
`
`16
`
`24
`
`32
`
`4o
`
`40
`
`Figure 4. Mean alprazolam plasma concentrations following the administration of single oral
`doses of an extended-release formulation of alprazolam (alprazolam KB) 2 to 10 mg
`in 21 healthy male volunteers (mean age, 28 years; mean weight, 77 kg).
`
`Time (h)
`
`four-treatment crossover design.7 The plasma concentration versus time
`profiles associated with these doses reflected the extended-release charac-
`teristics of the formulation and also demonstrated a proportional increase
`in concentration with increasing dose. Examination of the pharmacokinet—
`ic data in Table II revealed that the extent of absorption (AUC) and max-
`
`Table H. Alprazolam pharmacokinetic parameters resulting from the oral administration of
`four different single doses of extended—release alprazolam (alprazolam XR) tablets
`to 21 healthy volunteers. Values are expressed as mean x SD.
`
`Dose
`
`Parameter
`
`2 my
`
`4 my
`
`8 my
`
`10 mg
`
`AUC 119 x h/mL)*
`cm ng/mL)*
`n)
`CinhgmUmin/kg)
`Vii/ Sng)
`11,: (h
`
`443 1 190
`15.1 r 4.02
`11.0 2 3.50
`1.03 i 0.272
`1.19 I 0.196
`12.8
`
`920 z 475
`31.5 x 10.3
`9.76 t 3.13
`1.05 :1: 0.253
`1.22 1 0.175
`13.3
`
`1800 I 636
`62.8 r 11.1
`9.48 i 3.43
`1.05 i 0.276
`1.21 2 0.148
`13.1
`
`2142 1- 611
`70.5 t 13.2
`9.38 i 3.77
`1.07 x 0.246
`1.26 2: 0.111
`13.6
`
`ANDVA
`P Value
`
`0.0001
`0.0001
`0.4681
`0.6283
`0.2366
`—
`
`= maximum
`C
`ANOVA = anal1ysis at variance; AU!) = area under the (concentration vs time) curve;
`concentration;
`_
`= time to maximum concentration; C_|u = apparent oral clearance; WW = apparent
`volume of distriliniilion; 11,2 ‘2 elimination half-life, harmonic mean.
`* Means for all doses are Significantly different from one another.
`
`951
`
`

`

`CLINICAL PHARMACOKINETICS 0F ALPRAZOLAM XR
`
`imum concentration increased significantly as the dose increased (P =
`0.0001), but the time to maximum concentration, clearance, and volume of
`distribution did not change. Therefore, as in the case of alprazolam CT,‘”10
`the pharmacokinetics of alprazolam XR are linear up to a 10-mg dose.
`
`Once-Daily Dosing
`
`In light of the preceding data, one would predict that the degree of
`drug accumulation would be the same with a single daily dose of alprazo~
`1am XR as with multiple daily doses of alprazolam CT. This hypothesis was
`examined in a 6-day study involving 20 healthy volunteers who each re—
`ceived a total daily dose of 6 mg as either a single dose (two 3-mg tablets)
`of alprazolam XR or four divided doses (1.5 mg each) of alprazolam CT
`according to a two-treatment crossover design:7 When pharmacokinetics
`were assessed on day 6, the extent of absorption (AUC) and maximum
`concentration were similar for the two formulations (Table III, Figure 5).
`The mean steady-state plasma concentration (035) was 53.5 t 17.0 ng/mL,
`which is similar to the 48-ng/mL concentration reported to be associated
`with a 75% probability of a panic patient being classified as a major
`responder. The minimum concentration was significantly lower with al-
`prazolam XR than with alprazolam CT (P = 0.0001), but the absolute
`difference was only approximately 7 ng/mL. The fluctuation ratio (a
`measurement of the difference between peak and trough concentrations)
`was greater with alprazolam XR than with alprazolam CT. Again, how-
`ever, clearance and volume of distribution were similar with the two
`formulations.
`
`Table III. Steady-state (day 6) alprazolam pharmacokinetic parameters resulting from the
`administration of multiple oral doses of an immediate-release formulation of al-
`prazolam (alprazolam compressed tablet [CT]) or an extended-release formulation
`of (alprazolam XR) in 20 healthy volunteers. Values are expressed as mean : SD.
`
`Parameter
`
`AUC Enggx h/mL)
`cm ng/mL)
`Cmln (ng/mL)
`Fr
`(h)
`01" mUmin/kg)
`Vd/ Sng)
`
`11,, (h
`
`Alpmolam CT 1.5 mg
`Four Times Daily
`
`Alprazolam X8 6 mo
`Once Dally
`
`AHOVA P Value
`
`1298 + 442
`1285 i 407
`70.3 I 20.6
`70.9 + 17.7
`1.6 i 16. 4
`34. 3 17.5
`0. 560 i 0.129
`0.739 d: 0.240
`915 i 4. 58
`6.75 11.97
`1.11 1 03451.12 : 0.372
`1.10 : 0.1411.15 i 0.186
`
`11.4
`
`11.7
`
`0.6954
`0.8163
`0.0001
`0.0001
`0.1999
`0.7821
`0.1183
`
`-
`
`= _maximum
`ANOVA: analysis of variance; AUC = area under the (concentration vs time) curve; C
`—t—ime to
`concentration; cm... = minimum concentration; Fr = 0maxto Cm," fluctuation ratio;
`maximum concentration; GIp = apparent oral clearance; Vd/F= apparent volume oi‘xdlstribution/
`bioavaiiability; 11,2—— elimination half-life harmonic mean.
`
`952
`
`

`

`
`
`
`
`AlprazotamConcentration(ng/mL)
`
`C. E. WRIGHT
`
`(one 1-mg tablet and one 0.5-mg table qid)
`
`—o— Alprazolam XR 6 mg QD
`(two 3-mg tablets each morning)
`
`—D—— Alprazolam CT 1.5 mg QID
`
`0
`
`4
`
`8
`
`12
`
`16
`
`2O
`
`24
`
`Time (h)
`
`Figure 5. Mean steady—state alprazolam plasma concentrations after the administration of
`multiple doses of an immediate-release formulation of alprazolam (alprazolam
`compressed tablet [CT]) (1.5 mg QID) and an extended-release formulation of al-
`prazolam (alprazolam XR) (6 mg QB) in 20 healthy male volunteers (mean age, 34
`years; mean weight, 77 kg). QID = four times daily; QD = once daily.
`
`Twice-Daily Dosing
`
`Essentially the same study design was used to evaluate the pharma—
`cokinetics of alprazolam XR 3 mg twice daily versus alprazolam CT 1.5 mg
`four times daily in 17 healthy volunteers.7 On day 7, the mean steady-state
`plasma concentration of alprazolam XR was 65.2 ng/mL (Figure 6), which
`is again similar to the 48-ng/mL concentration that was associated with a
`75% probability of a patient being classified as a major responder. The
`extent of absorption (AUC), maximum and minimum concentrations, fluc-
`tuation ratio, distribution, and elimination of alprazolam were similar
`between the two formulations. The only difference was that alprazolam XR
`was absorbed more slowly, facilitating the use of less-frequent doses than
`with alprazolam CT.
`
`Efl'ects ofFood and Nighttime Dosing
`
`The potential effect of food on pharmacokinetics is an important con-
`sideration in the use of any extended-release medication. In a study of 21
`healthy volunteers, single l-mg doses of alprazolam XR and alprazolam
`
`953
`
`

`

`
`
`
`
`AlprazolamConcentration(ng/mL)
`
`CLINICAL PHARMACOKINETICS 0F ALPRAZOLAM XR
`
`—D— Alprazolam XR 3 mg BID
`(one 3-mg tablet BID)
`
`--0— Alprazolam CT 1.5 mg QID
`(one 1-mg tablet and one 0.5-mg tablet QID)
`
`
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`Time (h) ‘
`Figure 6. Mean steady-state alprazolam plasma concentrations following the administration
`of multiple doses of an immediate-release formulation of alprazolam (alprazolam
`compressed tablet [CT]) (1.5 mg QID) and alprazolam XR (3 mg BID) in 17 healthy
`male and female volunteers (mean age, 32 years; mean weight, 71 kg). QID = four
`times daily; BID = twice daily.
`
`CT were administered under fasting conditions, and 1 mg of the extended-
`release formulation was also administered after a high-fat (55 g) meal.11
`The extent of absorption (AUC) was the same in all three arms. Relative
`to alprazolam CT in the fasting state, the bioavailability of alprazolam XR
`was 100%. The peak plasma concentration of alprazolam XR was approx-
`imately 12% higher in the fed versus the fasting condition (9.2 t 17 vs 8.2
`i 10 ng/mL, respectively; P = 0.0001), but the times to peak concentra-
`tion were similar (approximately 7 hours). The terminal elimination rate
`constant, which determines half-life, did not differ significantly by treat-
`ment or fed/fasting state.
`Another study of 21 subjects used this same design to evaluate the
`impact of food on the pharmacokinetics of alprazolam XR in a dose of 3
`mg.7 The extent of absorption (AUC) was unaffected by food, but the max-
`imum plasma concentration was 26% higher when alprazolam XR was
`administered with food as opposed to the fasting state (27.4 t 4.83 vs 21.7
`t. 4.42 ng/mL, respectively; P = 0.0001). Corrected to a 1~mg dose, the
`maximum drug concentration was significantly lower with alprazolam XR
`in the fed or fasting state than with a l-mg dose of alprazolam CT in the
`fasted condition (9.15 t 1.61, 7.24 i 1.47, and 13.7 i 4.71 ng/mL, respec-
`
`954
`
`

`

`C. E. WRIGHT
`
`tively; P = 0.0001 for all comparisons). The clearance, volume of distri-
`bution, and half-life did not differ significantly among the three arms.
`Because once-daily therapy with alprazolam XR can be administered
`either during the day or at night, the effect of circadian rhythm on the
`pharmacokinetics of this formulation was evaluated in 23 healthy volun-
`teers.7 The extent of absorption (AUC) did not differ according to the time
`of dosing. The maximum plasma concentration was approximately 30%
`higher after administration of a single 3-mg dose at 10 PM versus 7 AM
`(31.1 i 5.05 vs 24.0 i 3.78 ng/mL, respectively; P < 0.05), but concentra-
`tions were similar 12 hours after dosing. The clearance, volume of distri-
`bution, and half-lives were comparable.
`The pharmacokinetic profile with nighttime administration of alpra-
`zolam XR was similar to that observed with food, possibly because gastro-
`intestinal transit time is reduced by both factors. Although the maximum
`drug concentration was approximately 26% higher in the presence of food
`and 30% higher with nighttime administration, the development of toler-
`ance is likely to render these increases clinically unimportant.
`
`Development of Tolerance
`
`Single—dose studies have shown that alprazolam XR produces less se-
`dation and psychomotor impairment than does alprazolam CT at equiva-
`lent doses.7 In a pharmacodynamic study, nurse-rated sedation scores were
`compared following the administration of single and multiple doses of
`alprazolam XR (3 mg) and alprazolam CT (1.5 mg) to 17 healthy volun-
`teers.7 The sedation of each subject was determined using a Nurse Rated
`Sedation Scale (NRSS).12 The degree of sedation was recorded by a blinded
`observer at each blood sampling time during the first 12 hours after a
`single dose and then again after the morning dose on the seventh day of
`multiple dosing. The following scale was used: 0 = wide awake; 1 = awake
`but lethargic; 2 = dozing, eyes closed but not asleep; 3 = sleeping soundly,
`but awakened by blood draw; 4 = sleeping soundly, not awakened by blood
`draw. The same observer rated the subjects’ sedation for the first 8 hours
`of each phase and another observer rated sedation between 8 and 12 hours.
`At double the dose of alprazolam CT, alprazolam XR was associated with
`comparable sedation. After multiple dosing, tolerance to sedation occurred
`to the same extent with both formulations at steady state.
`
`CONCLUSIONS
`
`The bioavailability, distribution, metabolism, and elimination of alprazo-
`lam are the same whether the drug is administered in an immediate-
`release or extended-release formulation. As one would predict from these
`observations, the half-life and extent of drug accumulation are the same
`
`955
`
`

`

`CLINICAL PHARMACOKINETICS 0F ALPRAZOLAM XR
`
`for alprazolam CT and alprazolam KB. The range of plasma drug concen-
`trations resulting from once- or twice-daily dosing of alprazolam XR is
`comparable to that resulting from three- or four-times—daily administra-
`tion of alprazolam CT. The only difference in pharmacokinetics between
`the two formulations isslower absorption of alprazolam XR. At twice the
`dose of alprazolam CT, alprazolam XR is associated with comparable se-
`dation. Sedative effects are important considerations only during initia-
`tion of treatment with alprazolam XR, because tolerance develops during
`chronic dosing.
`
`Acknowledgments
`
`The author wishes to express gratitude to the following individuals for
`assistance in carrying out the studies described in this report: T Lasher-
`Silson, J. H. Chambers, J. C. Fleishaker, and E. J. Antal.
`
`References:
`
`1. Gall M, Kamdar BV, Collins RJ. Pharmacology of some metabolites of triazolam, alpra-
`2.01am, and diazepam prepared by a simple one-step oxidation of benzodiazepines. J Med
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`
`2. Sethy VH, Harris DW. Determination of biological activity of alprazolam, triazolam, and
`their metabolites. J Pharm Pharmacol. 1982;34:115—116.
`
`3. Smith RB, Kroboth PD. Influence of dosing regimen on alprazolam and metabolite serum
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`
`4. Kroboth PD, Smith RB, Erb RJ. Tolerance to alprazolam after intravenous bolus and
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`
`5. Antal EJ, Pyne DA, Starz KE, Smith RB. Probability models in pharmacodynamic anal-
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`
`6. Greenblatt DJ, Harmatz JS, Shader RI. Plasma alprazolam concentrations. Relation to
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`
`7. Data on file, The Upjohn Company, Kalamazoo, Michigan.
`
`8. Smith RB, Kroboth PD, Vanderlugt JT, et al. Pharmacokinetics and pharmacodynamics
`of alprazolam after oral and IV administration. Psychopharmacology 1984;84:452—456.
`
`9. Ciraulo DA, Antal EJ, Smith RB, et al. The relationship of alprazolam dose to steady—
`state plasma concentrations. J Clin Psychopharmacol. 1990;10:27—32.
`
`10. Ciraulo DA, Barnhill JG, Boxenbaum HG, et a1. Pharmacokinetics and clinical effects of
`alprazolam following single and multiple oral doses in patients with panic disorder. J
`Clin Pharmacol. 1986;26:292—298.
`
`11. Eller MG, Della-Coletta AA. Absence of effect of food on alprazolam absorption from
`sustained-release tablets. Biopharm Drug Dispos. 1990;11:31—37.
`
`12. Smith RB, Kroboth PD, Varner P0. Pharmacodynamics of triazolam after intravenous
`administration. J Clin Pharmacol. 1987 ;27:971—979.
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`956
`
`