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`
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`BRIMOCHOLcarbachol Cmax 144% higher, AUC 101% higherin ICB than BRIMOCHOLF
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`BRIMOCHOLcarbachol Cmax 81% higher, AUC 133% higherin AH than BRIMOCHOLF
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`
`
`t
`
`—
`
`Pap ee
`:
`
`°
`
`1000
`
`I pel
`0
`2
`4
`6
`8
`2
`
`ern
`0
`2
`4
`6
`8
`0
`12
`
`TimePoint(hr post-dose)
`
`Time Point (hr post-dose)
`
`po VTF-004
`Carbachol
`
`VTF-010
`
`VTF-011
`
`2.75% SM 2.75%
`
`

`

`Aqueous Humor-Brimonidine vie010,011) (n=4/group)
`et Hae
`=pee-B
`
`
`+ VIF rn
`2.75%
`
`Aqueous Humor(Median + Range) - Brimonidine
`
`- VTF-004
`
`+ VIF-010
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`Time Point (hr post-dose)
`
`Time Point(hr post-dose)
`
`po VTF-004
`
`Carbachol
`
`2.75%
`
`VTF-010
`
`VTF-011
`
`BRIMOCHOL brimonidine Cmax 39.5% lower, AUC 36.8% lowerin AH than carbacholalone
`_sw
`NicaOE
`
`
`Aqueous Humor(Meant SEM)- Brimonidine
`
`i» \VTF-004
`
`> VIF-010
`- VIF-OH
`
`’
`|
`
`i.
`
`\ |
`
`nf 8
`
`

`

`.
`
`ng/ml
`
`- VTF-004
`
`ve VIF-010
`
`we VIF-O11
`
`Median ICB (Median + Range}- Carbachol
`
`“#- VTF-004
`
`sw VIF-010
`
`“ss VIF-011
`
`BRIMOCHOL carbachol Cmax 53% higher, AUC 47% higherin ICB than carbachol alone
`
`CB-Carbachol=n010,011)(n=4/eroup}
`ne a
` ICB (Meant SEM) - Carbachol
`2.75%
`
`We a
`
`Feeepee
`2
`4
`6
`8
`0
`2
`
`0
`
`Time Point(hr post-dose)
`
`rn
`8
`0
`2
`
`6
`
`TimePoint(hr post-dose)
`
`po VTF-004
`
`Carbachol
`
`2.75%
`
`VTF-010
`
`VTF-011
`
`

`

`Aqueous Humor- Carbachol(VTF-004, 010, 011} (n=4/eroup|
`
`BRIMOCHOLcarbachol Cmax 58% higher, AUC 47% higherin AH than carbacholalone
`
`
`
`
`Aqueous Humor (Median + Range) - Carbachol
`
`“8 VITF-004
`
`“x VIF-010
`
`oe VIFLOM
`
`LO
`
`MA
`
`“e- VTF-004
`
`oy \VIF-010
`
`se VFO
`
`Aqueous Humor (Meant SEM)- Carbachol
`
`ng/ml
`
`t\
`: B
`
`iN
`
`
`2.75%
`
`0
`
`2
`
`4
`
`6
`
`8
`
`0
`
`2
`
`0
`
`2
`
`4
`
`6
`
`8
`
`0
`
`2k
`
`Time Point(hr post-dose)
`
`TimePoint (hrpost-dose)
`
`po VTF-004
`
`Carbachol
`
`2.75%
`
`VTF-010
`
`VTF-011
`
`

`

`Summary of PK Study Following Single Dose
`Administration in Rabbits
`
`* BRIMOCHOL vs BRIMOCHOL F- The effect of BAK:
`
`* As expected, brimonidine with both formulationsis rapidly cleared from plasma, mostly by 1 hr
`* Carbachol plasma levels remain detectable for 12 hrs
`*
`ICB concentrations of carbachol with BAK in BRIMOCHOLare 104% higher than without BAK in BRIMOCHOLF. ICB
`concentrations are stable over 12 hrs. These results are consistent with the PD and priorclinicaldata
`|CB concentrations of brimonidine are high in the ICB (~2000ng/ml) and 39% higherin the presence of BAKin
`BRIMOCHOL than without BAKin BRIMOCHOL F
`
`*
`
`* As previously published by Acheompong (“160hrs), brimonidine has an extendedhalf-life in the iris/ciliary body
`presumably due to pigment binding and is well-above EC.» (0.45nM)}
`* The clearance of brimonidine from the AH is much morerapid, thoughstill detectable at 12 hrs
`
`* BRIMOCHOL vs Carbachol alone- Contribution of Elements:
`
`* The presenceof brimonidineincreases the bioavailability of carbachol, which is more apparentat earlier timepoints
`* The Cmaxfor carbachol with BRIMOCHOLin the ICB is 53% higher, AUC 47% higher, than with carbacholalone. The
`results are similar for carbachol in the AH (ICB: 58%; AH: 47%), These results are consistent with the PD andprior
`clinical data
`
`ICB concentrations of carbachol appear stable over 12 hrs
`*
`* The presence of carbachol may decreasethe bioavailability of brimonidine in the AH (~40%)
`Acheompong AA etal. Comparative ocular pharmacokineticsof brimonidine after a single dose application to the eyesof albino and pigmented
`rabbits. Drug Metab Dispos 1995 Jul:23(7):708-12
`
`

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