1998 ECC-2/8IC0N-7
`Industry-Sponsored Symposium
`
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`A New Class of Antibiotics
`
`Tuesday, May 12,1998
`Hamburg, Germany
`PhD - Chair
`Jan Verhoef, MD,
`
`from Pharmacia & Upjohn
`Supported by an educational grant
`
`0001
`
`MYLAN - EXHIBIT 1017
`
`

`
`Linezolid Pharmacokinetics
`Dennis Stalker, PhD
`
`fasting condiiion was 23% higher than for the fed condi­
`tion. This difference doe.s noi influence the efficacy of
`linezolid and therefore linezolid may be administered
`without regard to meals. Systemic clearance after oral
`dosing (CLpo) was similar to CL following IV adminis­
`tration. and CLr and CL™ following oral administration
`were sinular to those following FV administration,' !
`
`The pharmacokinetics of linezolid have been described in
`healthy male and female volunteers participating in the
`phase I safety tolerance trials following both oral and
`intravenous (JV) dosing, Pharmacokinetic studies have
`been conducted to assess dose proportionality, absolute
`bioavailability, and the effect of food and formulation
`variables on bioavailability. The following doses have
`been studied; single oral doses (bulk drug in capsule) of
`50 mg to 500 mg;' multiple oral doses of 100 mg to 750
`mg even' 8 hours for up to 10 days;' muliiplc oral doses
`of 375 mg to 625 mg every 12 hours for 14 days;5 single
`IV doses (30-mmute infusion) of 250 mg to 750 mg;x
`multiple IV doses of 250 mg to 500 mg every 8 hours for
`up to 7 days;1 and multiple IV doses of 500 mg and 625
`ma every 12 hours for 7 days.'
`
`After single or multiple IV doses, the total systemic elim­
`ination clearance (CL) averaged about 125 mL/ratn-
`Aboui 30% of the dose is eliminated unchanged in the
`urine Renal clearance (CLt) averaged about 40 mL/min,
`Linezolid exhibits low binding to plasma proteins (about
`31% bound), and CLi for free drug (about 59 mL/min)
`suggests net tubular reabsorpikm. The nonrenal clear­
`ance (CLm), calculated as the difference between CL and
`CLr. averaged about 100 mL/min and was more variable
`than CLr. The distribution of linezolid appears to be lim
`ited to the volume of total body water (sicady-siatc
`volume of distribution, Vv., averaged about 50 L ) The
`elimination half-life averaged about 5 to 7 hours.'J
`Neithet CL nor Vu. estimated from single-dose data in
`parallel groups, appears to differ significamly with
`increasing dose;;
`
`Linezolid is rapidly and extensively absorbed after oral
`dosing. Maximum concentxations (Cm«) are reached
`within two hours of dosing. 5 and the average absolute
`bioavailability' is 103%, Therefore, linc/olid maj be giv­
`en orally without dose adjustment in patients who are
`able to receive oral medication There was no significant
`difference in the AUC values when linezolid was admin
`istered while fasting or after a high-fat breakfa-st. The
`average Cw value for linezolid administered under the
`
`0002
`
`

`
`Linezolid Pharmacokinetics
`
`The dose propurtionality of orally adminisiered linezolid
`was assessed for single dose and sicady sutc adndmstra-
`tion of 125 mg, 375 mg. and 625 mg doses in a cross­
`over study. The results of this study indicate that there is
`a small degree of nonhneant) with higher doses of line­
`zolid. The total clearance for the 625 mg dose is about
`30% lower than would be predicted from the 125 mg
`dose. The decrease in CL was accounted for by decreas­
`es in both CLr and CLnr. This dose dependency was
`observed after single and multiple doses. The perceni of
`the dose that appeared in the urine as linezolid remained
`constant at about 35% across ail dose levels for both sin
`gle- and multiple-dose administnition. Although the
`pharmacokinetics of linezolid have been shown to be sta­
`tistically dependent upon dose, the degree of nonlinearity
`is small relative to the overall variability among subjects,
`such that dose adjustments in the clinical use of linezolid
`are not considered necessary
`
`administered alone or together.* Simjlarh. there was no
`difference in ihc plasma concentration profiles of line/ol­
`id or gentarrucin when given separately or together.'
`Therefore, either aztreonam or gentamictn may be given
`concurrently with linezolid with no change in dosage for
`either drug
`
`Linezolid is neither a substrate nor an inhibitor of the
`major human cytochrome P 450 isofoims (CYP1A2,
`CYF2C9, CYP2C19. CYP2D6, CYP2E1, and CYF3A4)
`Therefow, it is anticipated that the metabolism of line­
`zolid wjfTl be unaffected by inhibitors or inducers of
`cytochrome P-450 and linezolid will not inhibit the
`metabolism of compounds cleared by cytochrome P-A'Sf)
`enzymes. Induction studies of cytochrome P-450
`enzymes CYP1A2, CYP2B. CYP2C. CYP2E. CYP3A
`and CYP4A in rats indicate that linezolid does not
`induce any of these isoforms.
`
`REFERENCES
`I Paw^cvSU. Daky-Y»l«PT.Waj%rraikCP. SaJkeDJ C I 00766 st'c
`ty. loleratkifj X'ld ptiarmjKokjnetiCS a fir I oral and
`Atlir.1
`u™
`tn Ptoprm and atwacu. European CnnfWM ol Ajuimicrobij;
`OienHNhfrapy. 19%
`tolerance and
`2, Sulkcr DJ V jpjiiut CP. BMSS Dli Linewitiri
`pfcjrniacotiixtKi folkwmf nrtl ilos4ng twice dah for 14 days In;
`Proceed •nys uf [tic J7ih InierscienM Coiifrn-nrr o; Aaumjcmhial
`and Chernotheripy; Sfp'-nntwi 2S-October 1. IW" Timwio. CajiAdi
`AlBtiati
`3. Stalker D) Wajisciuk CP. Batu DH UiwioJid ia-'cty. iclerantr ind
`pharnvKofcineijc^ after mcr^vetvocs dosinf twkr di^y for 7.5 days
`In Krpceedjiigs of (he <7ih Jnirrscience Confcfea.* or Anunucnjbial
`AgenL'. itni Chcrvjtheupy, SejMemtw 28-OaobeT ;. 19"}7 Turemio.
`Can»dl AlrMra* i
`Jungtluih C-L La^hn Siiwri 1. Hopkins NK. Kiierse! TJ. Bunon NK
`Donjid\iin KM unczolii! and tvtiutmicin or asm?urr: a ptiarmaeok;:.
`euc c\«lLll;on of mcmvsDOUl <04dinini"i»aiioii ts kithy volunteen
`In Propros snc atrsuacu of flic ^Sih annual irwe^-f of xtv Ipforuotts
`l>M!as<s Society of Amrnca September H-S^fKrcwr 16. 1997 5ai.
`rranc isi <5. Ci Abiuaci
`
`•<
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`j
`
`tTU3t
`
`The average minimum concentrauon (Cmm) values for
`oral administration of 200 mg or 400 mg of linezolid
`every 8 hours for 10 days were 3.57 ji/mL and 7.62
`li/mL, respectively, and the corresponding average C
`values were 8.28 jiAnL and 15.37 ji/mL. respectively.1
`The average Cmm values for oral adnunistration of 375
`mg or 625 mg of linezolid every 12 hours for 14.5 days
`were 3.90 p/mL and 8.01 n/mL. respectively, and the
`corresponding average C™ values were 13.1 \xlrr\, and
`1S.8 n/mL, respectively.7 Together, the results of these
`two studies indicate that for these dose regimens the Cmin
`values arc near or above the highest MICW (4 ji/mLj for
`the most resistant susceptible target pathogens, and bid
`dosing provides average plasma lineaolid concentrations
`comparable to rid dosing. Therefore, tw ice daily and
`three times daily dosing should provide comparable effi­
`cacy for the same total daily dose.1-2
`
`Linezolid has linle or no coverage for gram-negative
`bacteria the re tore, a eompar.iun antimicrobial agent may
`be used in infections with a mixture of gram-positive and
`gram-negative organisms Aztteonam and gentamicin
`are two probable companion drugs to provide gram-neg
`ative coverage. Drug interaction studies have been
`conducted for linezolid administered with aztreonam and
`with genUunicin.' There is no change in the plasma con­
`centration profiles of linezolid or aztrconam when
`
`0003
`
`

`
`Dennis Stalker, PhD
`
`Pharmacokinetic Characteristics
`
`Pharmacokinetic Characteristics
`
`Ora' bioavailability
`
`100%
`
`Metabolism
`
`Food effect
`
`Slight decrease ri rate, but
`no etlect on exlent ol absorption
`
`Volume of distribution 40 to 50 L
`
`Protein binding
`
`31%
`
`Elimination half-lite
`
`5 to 7 hours
`
`• Not metabolized by C>P-4S0
`- No inhiOiiior of major cvp-450 isoforms
`- MetaOoMes Oc not caotrtbui«
`antibaaenal acwtty
`
`100 to 200 mL/mm
`30 la SO miVmin
`70 10 150 mUmin
`
`Clearance
`.Total
`- Renal
`Nonrenal
`
`^0
`Pa^pnt of drug dose excreted
`in utine as parent compound
`
`30% to 35%
`
`Average Steady-State Plasma Unezolld Concentrations
`After Oral Administration of 375 or 625 mg
`Given Two Times a Day for 14 Days
`
`Average Steady-State Plasma Unazolid Concentration
`After Administration of a Single 375 mg Dose
`Given as Oral Tablets or IV Infusion
`
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`

`
`Linezotid Pharmacokinetics
`
`Average SteacJy-Slate Plasma Unezolid Concentralions
`After Admtristralion of a Single 375 mg Dose
`Given as Oral Tablets With or Without Food
`
`Linezolid Metabolism
`
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`• Nol metabolized by cytochrome P450 enzymes
`
`» Morpholane ring susceptible to Chemical oxjdalran
`
`• Does not inhibit the catalytic activity ot the major
`human P450 drug metabolizing enzymes
`v
`• Otses nal induce P'JSO enzymes in ihe rat
`
`Monoamine Oxidase Inhibition
`
`Drug Interactions
`
`• Inhibition of catecholamine metabolism
`- Tyramne or sympaEhorrnmetic effect
`MAO-A inhibilion associated with
`elevation ot blood pressure
`• Inhibition ot serotonin metabolism
`- Serotonin syndrome
`- MAO-B inhibition associated with
`hyperthermia, CNS alteration
`
`In Phase I studies, mild to moderaie changes
`in diastolic and systolic btaod pressure were
`seen in normal healthy volunteers given
`conconiitani
`
`• Phenylpropanolamine
`v f '
`. * PseudocchGdnjne_—
`Cj_* Tyramne
`
`.
`
`i
`
`0005
`
`

`
`Dennis Stalker, PhD
`
`Drug Interactions
`
`Monoamine Oxidase Inhibition
`
`In a Phase I study designed lo detect
`ar. MAO-B ettecl, there yvas ng iniernrtiQn in
`norma! healthy volunteers given concomitant
`
`- Dextromethorphan
`
`• Enzyme kmetic parametefS tndicatc a miid,
`revensible, and competitive inhibition of both
`MAO-A and MAO-B enzymes by linczolid
`
`* MAO-A preferentially deaminatcs.
`noradrenaline
`
`^ MAO-S prelerentialiy deaminates dopamine
`
`PK Studies Completed
`
`PK Studies Proposed or Ongoing
`
`• Absolute bioavailability
`• Effect of tood on oral bioavailability
`* Dose proportionality
`• Drug interactions, arrreonam
`*
`•1C - AO M E: angle ocse steady state aose
`* MAOI" pilot ainj
`chaNervgc.
`pseuOoeoheonoe. phe'Tytpropanolamine
`Mxlfo netfitMpfian
`
`• Demographic studies
`Sex, age, race
`
`£ fjenal and hepatic funciion studjes^
`
`• Dru^nteratifon studies
`T
`J
`^
`- Warfarin as a marker for CYP 2C9
`
`0006
`
`

`
`Linezolid Pharmacokinetics
`
`PK Studies Proposed or Ongoing
`
`• Tissue penetration studies
`- Skin blislef, CSF. tuie, pulmonary Secreliont
`
`• PK/PD relationship
`- With dincal outcome, populatton PK methods
`
`• Pediatrics
`— PK asscssmetit in pediatric paiienls
`— Population PK assessment In phase Il/lll studies
`— Support ot oral suspension dosage form
`
`A
`
`•
`
`L
`
`v
`
`0007