`

`662 Greenblatt et al.
`
`CLINICAL PHARMACOLOGY & THERAPEUTICS
`DECEMBER 1998
`
`Pharmacokinetic drug interactions involving inhibition
`of cytochrome P450 activity have received considerable
`recent attention. Antifungal agents of the azole class are
`of importance as inhibitors of human cytochrome P450-
`3A isoforms.10,l1 Coadministration of 3A substrate drugs
`with azole derivatives such as ketoconazole, itraconazole,
`and fluconazole can result in impairment of clearance of
`such drugs which, in some cases, can be quantitatively
`large and clinically important. This is particularly true for
`high-extraction compounds given orally, since the azoles
`may inhibit both the gastrointestinal and hepatic compo(cid:173)
`nents of presystemic extractionp,13 In the case of orally
`administered triazolam and midazolam (both relatively
`"pure" substrates for P450-3A 14-16), their oral clearance
`may be impaired by 85% or more when given together
`with ketoconazole I6-19; significant, although somewhat
`smaller, interactions are caused by itraconazole and flu(cid:173)
`conazole.17,18,20-22
`Since zolpidem is metabolized partially, but not exclu(cid:173)
`sively, by P450-3A isoforms, the possibility exists that
`azole antifungal agents have a lesser inhibiting effect on
`zolpidem clearance in vivo, resulting in a smaller clini(cid:173)
`cal interaction, compared with their effect on triazolam
`or midazolam clearance. In studies of human liver micro(cid:173)
`somes in vitro, ketoconazole inhibition constants (KD in
`the low nanomolar range were observed for inhibition of
`midazolam or triazolam hydroxylation. 15,16 In this study
`we compared the susceptibility of zolpidem hydroxyla(cid:173)
`tion and triazolam hydroxylation to inhibition by keto(cid:173)
`conazole in vitro. Possible interactions of zolpidem with
`ketoconazole, as well as with itraconazole and flucona(cid:173)
`zole, were tested in a controlled clinical pharmacoki(cid:173)
`netic-pharmacodynamic study.
`
`METHODS
`In vitro studies. Procedures for acquisition and stor(cid:173)
`age of human liver tissue samples and for preparation of
`microsomal fractions have been described previ(cid:173)
`ously.15,16,23,24 Zolpidem and its principal hydroxylated
`metabolite (termed the M-3 metabolite)8 were provided
`by SyntMlabo Recherche, Bagneux, France. Triazolam
`and its principal hydroxylated metabolites (a-hydroxy(cid:173)
`triazolam and 4-hydroxytriazolam)J6,25 were kindly
`provided by Pharmacia and Upjohn Co, Kalamazoo,
`Mich. Other chemical reagents and drug entities were
`purchased from commercial sources.
`Zolpidem and triazolam were prepared in methanol
`solution. Aliquots were added to incubation tubes to pro(cid:173)
`duce a final concentration of 10 f.1mollL zolpidem in one
`series, and 100 f.1mollL triazolam in another series. For
`zolpidem, 10 f.1mollL is below the concentration (Km) cor(cid:173)
`responding to 50% of the maximum velocity of M-3
`
`metabolite formation; for triazolam, 100 f.1mollL is
`slightly above the Km for a-hydroxytriazolam formation
`and below the Km for 4-hydroxytriazolam formation.
`Ketoconazole in methanol solution was co-added to incu(cid:173)
`bation tubes to yield final concentrations ranging from 0
`to 2.5 f.1mollL. The solvent was evaporated to dryness at
`40°C under mild vacuum. To each tube was then added
`incubation buffer, appropriate cofactors, and an NADPH(cid:173)
`regenerating system as described previously. 15,16,23,24 The
`mixture was heated to 3rC, and reactions initiated by
`addition of microsomal protein (up to 0.5 mglmL). After
`20 minutes at 37°C, reactions were stopped by cooling
`on ice and addition of acetonitrile. Internal standard was
`added, the mixtures centrifuged, and supernatants trans(cid:173)
`ferred to autosampling vials for HPLC analysis. All indi(cid:173)
`vidual incubations were done in duplicate. Studies of
`zolpidem and triazolam each were performed using
`microsomal preparations from 4 human liver samples.
`The HPLC mobile phase consisted of acetonitrile,
`methanol, and 50 f.1mollL phosphate buffer. For analy(cid:173)
`sis of the M-3 metabolite of zolpidem, mobile phase
`component proportions were 30:10:60, the analytical
`column was C18 Bondapak (30 cm x 3.9 mm), and the
`ultraviolet absorbance wavelength was 242 nm. For
`analysis of a-hydroxytriazolam and 4-hydroxytriazo(cid:173)
`lam, mobile phase proportions were 22.5:10:67.5, the
`column was C I8 NovaPak (15 cm x 3.9 mm), and ultra(cid:173)
`violet absorbance was at 220 nm.
`Design of clinical study. The protocol was reviewed
`and approved by the Human Investigation Review
`Committee serving Tufts University School of Medi(cid:173)
`cine and New England Medical Center Hospital.
`Twelve healthy volunteers (8 men and 4 women), aged
`20 to 40 years, participated after giving written
`informed consent. All were active ambulatory non(cid:173)
`smoking adults, with no evidence of medical disease
`and taking no other medications. Female subjects were
`not taking oral contraceptives and did not have contra(cid:173)
`ceptive implants.
`The study had a double-blind, randomized, 5-way
`crossover design, with at least 7 days elapsing between
`treatments. Medications were separately and identically
`packaged in opaque capsules and administered orally.
`The 5 treatments were as follows:
`A. Zolpidem placebo plus azole placebo
`B. Zolpidem (5 mg) plus azole placebo
`C. Zolpidem (5 mg) plus ketoconazole, 200 mg
`twice daily
`D. Zolpidem (5 mg) plus itraconazole, 100 mg twice
`daily
`E. ZoIpidem (5 mg) plus fluconazole, 100 mg twice
`daily
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2054, Page 2
`
`

`

`lLl:--lIC'I1 I'IHR.\I.'lCOI.[)t;y & TIIEll\I',.L'TICS
`VOl.l'ME M, Nl'MBFl,,,
`
`Greenblatt et al. 663
`
`Table I. Summary of analytical methods for analysis of azole antifungal agents in plasma
`
`Ketoconazole
`
`ltraconazolelhydroxyitraconaz.ole
`
`Fluconazole
`
`Dextromethorphan
`Ethyl acetate/isoamyl alcohol
`(98.5:1.5)
`CH3CN/CH30HJSO mmollL
`NH4H2P04 (40:5:55)
`1.5 mL/min
`C IH JlBondaPak*(30 em
`length, 10 /-lm particle size)
`220nm
`0.05-0.1 Jlg/mL
`<10%: <10%
`
`Clotrimazole
`Ethyl acetate
`
`Phenacetin
`Ethyl acetate
`
`CH3CNliO mmoIlL
`KH2P04 (50:50)
`1.5 mLimin
`CIS NovaPak* (15 em length,
`5 Jlm particle size)
`263 nm
`0.03-0.05 Jlg/mL
`<9%; <18%
`
`CH30HIIO mmol/L
`Na ~cetate (40:60)
`I.n mLimin
`CIS JlBondaPak* (30 em
`length, 10 Jlm particle size)
`261 nm
`0.1 Jlg/mL
`<7%; <3%
`
`Internal standard
`Extraction solvent
`
`Mobile phase composition
`
`Mobile phase t10w rate
`Analytical column
`
`Ultraviolet absorbance wavelength
`Lower limit of quantitation
`Assay variance (%CV) within-day;
`between-day
`
`CV, Coefficient of variance.
`*Waters A~sociates, Milford. Muss.
`
`Doses and dosage schedules for the azoles were cho(cid:173)
`sen based on recommendations in approved labeling.
`Procedures. At 8 AM on study day I, subjects entered
`the outpatient Clinical Psychopharmacology Research
`Unit where they received the initial dose of azole (or
`placebo) and remained under observation for 30 min(cid:173)
`utes. Subjects took a second dose of azole (or placebo)
`at home at 4 PM on day I. On the morning of day 2,
`after ingesting a standardized light breakfast with no
`caffeine-containing food or beverages and no grapefruit
`juice, they returned to the Research Unit at approxi(cid:173)
`mately 7:30 AM. They fasted until 12 noon, after which
`they resumed a normal diet (without grapefruit juice or
`caffeine-containing food or beverages). The third dose
`of azole (or placebo) was given at 8 AM, and the single
`dose of zolpidem or placebo was given at 9 AM. A final
`azole (or placebo) dose was given at 5 PM.
`Venous blood samples were drawn from an
`indwelling cannula into heparinized tubes before zolpi(cid:173)
`dem or placebo dosage and at the following postdosage
`times: Ye, L lYe, 2, 2Ye, 3, 4, 5, 6, 8, and 24 hours. Sam(cid:173)
`ples were centrifuged, and the plasma separated and
`frozen until the time of assay.
`The electroencephalogram (EEG) was recorded
`using a 6-electrode montage, with instrumentation and
`methodology described previously. 16.19,26-28 At 2 pre(cid:173)
`dosage times and during 8 hours after dosage at times
`corresponding to blood sampling, the EEG was quanti(cid:173)
`fied in 4-second epochs for as long as necessary to
`ensure at least 2 minutes of artifact-free recording. Data
`were digitized over the power spectrum from 4.0 to
`31.75 cycles per second (Hz), then fast-Fourier trans(cid:173)
`formed to determine activity over the 4.0 to 31.75 Hz
`spectrum, and in the "beta" (13.0 to 31.75 Hz) band.
`Subjects' self-ratings of sedative effects and mood
`
`state were obtained on a series of 100-mm visual ana(cid:173)
`log scales. 16, 19.26-30 Ratings of sedation were also per(cid:173)
`formed by trained observers, using the same rating
`instrument, without knowledge of the treatment condi(cid:173)
`tion. Self- and observer-ratings were obtained twice
`before medication administration and at postdosage
`times indicated above.
`The digit symbol substitution test (DSST) was
`administered twice before dosing and at times corre(cid:173)
`sponding to rating scales. 16,19,26-30 Subjects were asked
`to make as many correct symbol-for-digit substitutions
`as possible within a 2-minute period. Subjects com(cid:173)
`pleted equivalent DSST variants, with no individual
`taking the same test more than once.
`Acquisition and recall of information were evaluated
`using a word-list free recall procedure I6.19,26-31 that was
`administered at I y, hours after zolpidem or placebo
`administration. Sixteen words, taken from 4 different
`categories, were read in random order in "shopping(cid:173)
`list" fashion. Recall was tested immediately after pre(cid:173)
`sentation of each list. Subjects wrote down items imme(cid:173)
`diately after lists were presented in random order. List
`presentation and recall were repeated a total of 6 times
`at 1 V, hours after dosage. At 24 hours after dosing, sub(cid:173)
`jects were asked to remember as many words as possi(cid:173)
`ble from the previous day's list (delayed or "free"
`recall). Thereafter, the same lists were read in the same
`sequence in which they were presented on the previous
`day, to assess whether residual effects of drug admin(cid:173)
`istration on immediate recall were detectable.
`Analysis of data. In vitro rates of formation of
`metabolites of zolpidem or triazolam with coaddition
`of ketoconazole were expressed as a percentage ratio
`versus the control velocity with no inhibitor present.
`The relation of ketoconazole concentration to velocity
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2054, Page 3
`
`

`

`664 Greenblatt et al.
`
`CLINICAL PHARMACOLOGY & THERAPEUTICS
`DECEMBER 1998
`
`W
`I-C'
`~~ 100
`Z:C
`0.5
`i=5 80
`«0
`:E~
`ex: ~
`0- 60
`u.g
`W C
`I- 8
`:::J-
`o.:!
`III C
`« 8
`1-'-
`W 8.
`
`40
`
`20
`
`:E~
`
`'i
`
`"
`"
`"-{
`"'I-
`
`ZOLPIDEM M-3 METABOLITE
`/ " (ZOLPIDE~.10I'M)
`
`-I
`
`u..()H·TRIAZOLAM
`- - [rRIAZOLAM. 1001'M)
`
`o
`
`0.1
`
`0.2
`
`0.5
`
`2
`
`3
`
`KETOCONAZOLE (IlM)
`Figure 1. Rates of formation of the zolpidem M-3 hydrox(cid:173)
`ylated metabolite from zolpidem (10 JLmol/L) or of a-hydroxy(cid:173)
`triazolam (a-OH-triazolam) from triazolam (100 !.Lmol/L) by
`human liver microsomes in vitro. Reaction velocities with co(cid:173)
`addition of the inhibitor ketoconazole are expressed as a per(cid:173)
`centage ratio versus the control velocity with no ketocona(cid:173)
`zole present. Each point is the mean ± SE ratio from 4 sepa(cid:173)
`rate human liver microsomal preparations. Mean 50%
`inhibitory concentrations (ICso) for ketoconazole were 0.61
`!.LmollL versus the zolpidem M-3 metabolite and 0.053
`Ilmol/L versus ex-hydroxytriazolam. The ICso value versus 4-
`a-hydroxytriazolam (data not shown) was 0.046 !.Lmol/L.
`
`ratio was analyzed by nonlinear regression to detennine
`the ketoconazole concentration corresponding to a
`velocity ratio of 50% of the control value (IC50).19,32,33
`Plasma concentrations of zolpidem from the clinical
`study were detennined by HPLC with fluorescence detec(cid:173)
`tion.34 The sensitivity limit was 1 to 2 ng/mL, and the vari(cid:173)
`ance between replicate samples did not exceed 8%. The
`slope (beta) of the terminal log-linear phase of each zolpi(cid:173)
`dem plasma concentration versus time curve was deter(cid:173)
`mined by linear regression analysis. This slope was used
`to calculate the apparent elimination half-life. Area under
`the plasma concentration versus time curve from time zero
`until the last detectable concentration was detennined by
`the linear trapezoidal method. To this area was added the
`residual area extrapolated to infinity, calculated as the final
`concentration divided by beta, yielding the total area under
`the plasma concentration versus time curve (AUC). The
`peak plasma concentration and the time of peak concen(cid:173)
`tration represented the rate of appearance of drug in sys(cid:173)
`temic circulation. Apparent oral clearance was calculated
`as the administered dose divided by the total AVe.
`
`Plasma concentrations of ketoconazole, itraconazole
`(and its metabolite hydroxyitraconazole), or fluconazole
`were determined by HPLC (Table n.
`For self- and observer-ratings on visual analog
`scales, the 2 pre-dose baseline ratings were averaged,
`and post-dosage scores were expressed as the increment
`or decrement relative to the mean pre-dose value.
`Scores on the DSST were analyzed similarly. The word(cid:173)
`list memory test was analyzed as the mean absolute
`number of words correctly remembered for delayed
`recall and as mean number of words remembered after
`6 trials for immediate recall.
`For each EEG recording session, the relative beta
`amplitudes (beta divided by total, expressed as percent)
`were calculated, and values from the left and right
`frontotemporal leads were averaged. The means of the
`relative beta amplitudes in the pre-dose recordings were
`used as baseline, and all post-dosage values were
`expressed as the increment or decrement over that treat(cid:173)
`ment's mean pre-dose baseline value.
`For each pharmacodynamic variable, the area under
`the 4-hour plot of effect change score versus time was
`calculated to obtain a single integrated measure of phar(cid:173)
`macodynamic action during the period of greatest drug
`effect. Also evaluated were pharmacodynamic effects
`at individual time points.
`Statistical procedures included linear and nonlinear
`regression, ANOVA, the Student-Newman-Keuls pro(cid:173)
`cedure, and Dunnett's t test. One of the subjects did not
`ingest zolpidem as instructed during treatments D and
`E; accordingly mean values for treatments A, B, and C
`represent n = 12, and for treatments D and E, n = 11.
`For analysis of variance procedures, n = 11 was used
`throughout.
`
`RESULTS
`In vitro results. The mean ± SE (n = 4) IC50 value
`for ketoconazole versus formation of the M-3 metabo(cid:173)
`lite of zolpidem was 0.61 ± 0.27 Ilmol/L (Figure 1). In
`contrast, the ketoconazole IC50 was 0.053 ± 0.009
`).lmoUL versus ex-hydroxytriazolam formation, and
`0.046 ± 0.007 Ilmol/L versus 4-hydroxytriazolam for(cid:173)
`mation (Figure 1).
`Clinical study: Plasma concentrations of azoles.
`Plasma levels of the 3 azole derivatives were consistent
`with those anticipated during administration of usual
`therapeutic doses35 (Figure 2). As reported previ(cid:173)
`ously,36,37 plasma concentrations of hydroxyitracona(cid:173)
`zole exceeded those of itraconazole. Since values of
`elimination half-life for itraconazole and fluconazole
`generally exceed 20 hours,35 these 2 agents may not
`have actually reached steady state.
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2054, Page 4
`
`

`

`

`

`

`

`

`

`

`

`

`

`670 Greenblatt et at.
`
`CLINICAL PHARMACOLOGY & THERAl'EUTICS
`DECEMBER 1998
`
`Coadministration of triazolam with ketoconazole pro(cid:173)
`duces a very large decrement in triazolam clearance,
`increase in plasma triazolam concentrations, and
`enhancement of pharmacodynamic action.I6,17,19 Large
`and clinically important interactions of triazolam with
`itraconazole and fluconazole are also reported. 17,21 In
`contrast, ketoconazole produced a statistically significant
`but only quantitatively modest reduction in zolpidem
`clearance, with modest enhancement of pharmacody(cid:173)
`namic action. Zolpidem coadministered with itraconazole
`or fluconazole produced only small and nonsignificant
`changes in zolpidem kinetics and dynamics. The findings
`may have implications for choice of hypnotic drugs in
`patients receiving azole antifungal agents or other 3A
`inhibitors, such as the viral protease inhibitors including
`ritonavir,23,39 or the reverse transcriptase inhibitor delavir(cid:173)
`dine,4o,41 that may be administered to patients with
`human immunodeficiency virus infections.
`
`References
`1. Roth T, Puech AI, Paiva T. Zolpidem: place in therapy.
`In: Freeman H, Puech AJ, Roth T, editors. Zolpidem: an
`update of its pharmacological properties and thereapeu(cid:173)
`tic place in the management of insomnia. Paris: Elsevier;
`1996. p. 215-30.
`2. Langtry HD, Benfield P. Zolpidem: a review of its phar(cid:173)
`macodynamic and pharmacokinetic properties and thera(cid:173)
`peutic potential. Drugs 1990;40:291-313.
`3. Hoehns JD, Perry PJ. Zolpidem: a nonbenzodiazepine
`hypnotic for
`treatment of insomnia. Clin Pharm
`1993;12:814-28.
`4. Nowell PD, Mazumdar S, Buysse DJ, Dew MA, Reynolds
`CF, Kupfer DI. Benzodiazepines and zolpidem for
`chronic insomnia: a meta-analysis of treatment efficacy.
`lAMA 1997;278:2170-6.
`5. Sanger DJ, Benavides I, Perrault G, Morel E, Cohen C,
`Joly D, et al. Recent developments in the behavioral phar(cid:173)
`macology of benzodiazepine receptors: evidence for the
`functional significance of receptor subtypes. Neurosci
`Biobehav Rev 1994;18:355-72.
`6. Durand A, Thenot JP, Bianchetti G, MorseIIi PL. Compar(cid:173)
`ative pharmacokinetic profile of two imidazopyridine drugs:
`zolpidem and alpidem. Drug Metab Rev 1992;24:239-166.
`7. Salvli P, Costa I. Clinical pharmacokinetics and pharma(cid:173)
`codynamics of zolpidem: therapeutic implications. CIin
`Pharmacokinet 1995;29:142-53.
`8. Pichard L, Gillet G, Bonfils C, Domergue I, Thenot JP,
`Maurel P. Oxidative metabolism of zolpidem by human
`liver Cytochrome P450s. Drug Metab Dispos
`1995 ;23: 1253-62.
`9. Greenblatt DJ, von Moltke LL, Harmatz IS, Counihan M,
`Graf JA, Mertzanis P, et al. Interaction of zolpidem with
`ketoconazole, itraconazole, and fluconazole: kinetic and
`dynamic consequences [abstract]. J Clin Pharmacol
`1998;38:865.
`
`10. Bert RJ, Granneman GR. Vse of in vitro and in vivo data
`to estimate the likelihood of metabolic pharmacokinetic
`interactions. Clin Pharmacokinet 1997;32:210-58.
`I I. von Moltke LL, Greenblatt DJ, Schmider J, Wright CE, Har(cid:173)
`matz IS, Shader RI. In vitro approaches to predicting drug
`interactions in vivo. Biochem PharmacoI1998;55:113-22.
`12. Thummel KE, Kunze KL, Shen DD. Enzyme-catalyzed
`processes of first-pass hepatic and intestinal drug extrac(cid:173)
`tion. Adv Drug Deliv Rev 1997;27:99-127.
`13. Wilkinson GR. Cytochrome P4503A (CYP3A) metabo(cid:173)
`lism: prediction of in vivo activity in humans. J Pharma(cid:173)
`cokinet Biopharm 1996;24:475-90.
`14. Kronbach T, Mathys D, Vmeno M, Gonzalez FJ, Meyer
`VA. Oxidation of midazolam and triazolam by human liver
`cytochrome P450IIlA4. Mol Pharmacol 1989;36:89-96.
`15. von Moltke LL, Greenblatt DJ, Schmider J, Duan SX,
`Wright CE, Harmatz JS, et al. Midazolam hydroxylation
`by human liver microsomes in inhibition by fluoxetine,
`norfluoxetine, and by azole antifungal agents. I Clin Phar(cid:173)
`macoI1996;36:783-91.
`16. von Moltke LL, Greenblatt DI, Harmatz IS, Duan SX,
`Harrel LM, Cotreau-Bibbo MM, et al. Triazolam bio(cid:173)
`transformation by human liver microsomes in vitro:
`effects of metabolic inhibitors, and clinical confirmation
`of a predicted interaction with ketoconazole. J Pharma(cid:173)
`col Exp Ther 1996;276:370-9.
`17. Varhe A, OIkkola KT, Neuvonen PJ. Oral triazolam is
`potentially hazardous to patients receiving systemic
`antimycotics ketoconazole or itraconazole. Clin Pharma(cid:173)
`col Ther 1994;56:601-7.
`18. Olkkola KT, Backman JT, Neuvinen PI. Midazolam
`should be avoided in patients receiving the systemic
`antimycotics ketoconazole or itraconazole. Clin Pharma(cid:173)
`col Ther 1994;55:481-5.
`19. Greenblatt DJ, Wright CE, von Moltke LL, Harmatz IS,
`Ehrenberg BL, Harrel LM. Ketoconazole inhibition oftri(cid:173)
`azolam and alprazolam clearance: differential kinetic and
`dynamic
`consequences. Clin
`Pharmacol Ther
`1998;64:237-47.
`20. Olkkola K, Ahonen I, Neuvonen P. The effect of the sys(cid:173)
`temic antimycotics, itraconazole and fluconazole, on the
`pharmacokinetics and pharmacodynamics of intravenous
`and oral midazolam. Anesth Analg 1996;82:511-6.
`21. Varhe A, Olkkola KT, Neuvonen PI. Fluconazole, but not
`terbinafine, enhances the effects of triazolam by inhibit(cid:173)
`ing its metabolism. Br J Clin PharmacoI1996;41:319-23.
`22. Ahonen I, Olkkola K, Neuvonen P. Effect of itraconazole
`and terbinafine on the pharmacokinetics and pharmaco(cid:173)
`dynamics of midazolam in healthy volunteers. Br J Clin
`Pharmacol 1995;40:270-2.
`23. von Moltke LL, Greenblatt DJ, Grassi 1M, Granda BW,
`Duan SX, Fogelman SM, et al. Protease inhibitors as
`inhibitors of human cytochromes P450: high risk associ(cid:173)
`ated with ritonavir. J Clin Pharmacol 1998;38: 106-11.
`24. von Moltke LL, Greenblatt DI, Cotreau-Bibbo MM, Duan
`SX, Harmatz IS, Shader RI. Inhibition of desipramine
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2054, Page 10
`
`

`

`CLINICAL I'IHRMACOU)(;Y & rHEll~PECTiCS
`VOLlI,\lE 64, NCMBER 6
`
`Greenblatt et al. 671
`
`hydroxylation in vitro by serotonin-reuptake-inhibitor
`antidepressants, and by quinidine and ketoconazole: a
`model system to predict drug interactions in vivo. J Phar(cid:173)
`macal Exp Ther 1994;268: 1278-83.
`25. von Moltke LL, Greenblatt DJ, Duan SX, Harmatz JS,
`Shader Rl. Inhibition of triazolam hydroxylation by keto(cid:173)
`conazole, itraconazole, hydroxyitraconazole and flucona(cid:173)
`zole in vitro. Pharm Phannacol Commun 1998;4:443-5.
`26. Greenblatt DJ, Harmatz JS, Gouthro TA, Locke J, Shader
`Rl. Distinguishing a benzodiazepine agonist (triazo]am)
`from a non-agonist anxiolytic (buspirone) by electroen(cid:173)
`cephalography: kinetic-dynamic studies. Clin Pharmacol
`Ther 1994;56: I 00-1 I.
`27. Kaplan GB, Greenblatt Dl, Ehrenberg BL, Goddard JE,
`Cotreau-Bibbo MM, Harmatz 15, et a!. Dose-dependent
`pharmacokinetics and psychomotor effects of caffeine in
`humans. j Clin PharmacoI1997;37:693-703.
`28, Greenblatt DJ, von Moltke LL, Harmatz JS, Counihan M,
`Graf J, Durol ALB, et a!. Inhibition of triazolam clear(cid:173)
`ance by macrolide antimicrobial agents: in vitro corre(cid:173)
`lates and dynamic consequences. Clin Pharmacol Ther
`1998;64:278-85.
`29. Greenblatt DJ, Harmatz 15, Shapiro L, Engelhardt N,
`Gouthro TA, Shader RI. Sensitivity to triazolam in the
`elderly, N Engl 1 Med 1991 :324: 1691-8.
`30. Scavone M, Greenblatt DJ, Harmatz JS, Engelhardt N,
`Shader Rl. Kinetics and dynamics of diphenhydramine
`25 mg in young and elderly volunteers, J Clin Pharmacol
`1998;38:603-9.
`31. Shader Rl. Dreyfuss D, Gerrein JR, Harmatz JS. Allison
`SJ, Greenblatt DJ. Sedative effects and impaired learning
`and recall following single oral doses of lorazepam. Clin
`Pharmacol Ther 1986;39:526-9.
`32. Venkatakrishnan K, Greenblatt DJ, von Moltke LL,
`Schmider J, Harmatz JS, Shader Rl. Five distinct human
`cytochromes mediate amitriptyline N-demethylation in
`vitro: dominance of CYP 2C 19 and 3A4. J Clin Pharma(cid:173)
`col 1998:38: 112-21.
`
`33. Venkatakrishnan K, von Moltke LL, Duan SX.
`Fleishaker lC, Shader RI, Greenblatt DJ. Kinetic char(cid:173)
`acterization and identification of the enzymes responsi(cid:173)
`ble for the hepatic biotransformation of adinazolam and
`N-desmethyladinazolam. J Pharm Pharmacol 1998:
`50:265-74.
`34. Durol ALB, Greenblatt DJ. Analysis of zolpidem in
`human plasma by high-performance liquid chromatogra(cid:173)
`phy with fluorescence detection: application to single(cid:173)
`dose pharmacokinetic studies. J Anal Toxieol 1997;21:
`388-92.
`35. Como lA, Dismukes WE. Oral azole drugs as systemic
`antifungal therapy. N Eng1 J Med 1994;330:263-72.
`36. Barone JA, Koh lG, Bierman RH, Colaizzi lL. Swanson
`KA, Gaffar MC, et al. Food interaction and steady-state
`pharmacokinetics of itraconazole capsules in healthy
`male volunteers. Antimicrob Agents Chemother 1993:
`37:778-84.
`37. Luurila H, KivistO KT, Neuvonen PJ. Effect of itracona(cid:173)
`zole on the pharmacokinetics and pharmacodynamics of
`zolpidem. Eur J Clin Pharmacol 1998;54:336-40.
`38. Fahey JM, Pritchard GA, von Moltke LL. Pratt lS. Grassi
`JM, Shader RI, et al. The effects of ketoconazole on tria(cid:173)
`zolam pharmacokinetics, pharmacodynamics and benzo(cid:173)
`diazepine receptor binding in mice. J Pharmacol Exp Ther
`1998:285:27 J -6.
`39. Men-y C, Barry MG, Mulcahy F. Ryan M, Heavey J, Tjia
`JF. et al. Saquinavir pharmacokinetics alone and in com(cid:173)
`bination with ritonavir in HIV-infected patients. AIDS
`1997;II:F29-33.
`40. Cheng CL, Smith DE, Carver PL, Cox SR, Watkins PB,
`Blake DS, et al. Steady-state pharmacokinetics of delavir(cid:173)
`dine in HIV-positive patients: effect on erythromycin
`breath test. Clin Pharmacol Ther 1997;61:531-43.
`41. Ferry JJ, Herman BD, Carel BJ, Carlson GF, Batts DH.
`Pharmacokinetic drug-drug interaction study of delavir(cid:173)
`dine and indinavir in healthy volunteers. J Acquir Immune
`Defic Syndr Hum Retrovirol 1998; 18:252-9.
`
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
`Corcept Ex. 2054, Page 11
`
`