Cyclosporins Past, Present, and Future
`
`J. Mason
`
`I T HAS taken more than a decade of using Sand immune
`
`in daily clinical practice to understand its limitations
`and identify those properties that are amenable to im(cid:173)
`provement. First and foremost, the full potential of this
`impressive immunosuppressant could not be exploited
`because of the occurrence of side elfects. Secondly, vari(cid:173)
`able drug exposure has resulted from poor and unpredict(cid:173)
`able intestinal absorption. Thirdly, the need for hepatic
`metabolism before excretion has made bioavailability vary
`with liver function and has resulted in a large quantity and
`number of metabolites that have made blood level moni(cid:173)
`toring complex.
`It has been these drawbacks that have motivated the
`search for new cyclosporins with an improved drug profile.
`Clearly, only clinical trials can determine with certainty
`how any new drug performs in humans. Yet laboratory
`experiments, in which new cyclosporins are compared to
`those older cyclosporins that have already been tested in
`humans, have guided the search for improved immunosup(cid:173)
`pressants. In addition to Sandimmune or cyclosporin A
`(CyA) , cyclosporin G and cyclosporin dihydro D have
`also been tested in clinical trials. Based on laboratory
`comparisons to them, the new cyclosporine, SDZ IMM
`125, has been selected for clinical development, as a
`potential successor to Sandimmune.
`
`THERAPEUTIC DOSE RANGE
`Today, there are few problems in identifying cyclosporins
`with good immunosuppressive properties. As a modern
`alternative to the mixed lymphocyte reaction for general
`screening purposes, the introduction of a state-of-the-art
`reporter gene assay has provided an easy and reliable
`system for quantifying immunosuppressive potency in a
`human-derived T-Iymphocyte cell line. Using this in vitro
`system to determine the concentration giving half maximal
`inliibition, the ICso, it is now quite clear that cyclosporin
`dihydro D is a very weak immunosuppressant, that cyclo(cid:173)
`sporin G is of similar potency to CyA, and that SDZ IMM
`125 is marginally more potent than the others.
`However, this information is of little value in assessing
`how cyclosporins will perform in vivo, when absorption,
`distribution, and metabolism determine therapeutic effi(cid:173)
`cacy, and dosage is frequently limited by side effects.
`Correspondingly, as depicted in Fig 1, a more appropriate
`test of potential clinical usefulness is to define the thera(cid:173)
`peutic dose range that separates the effective dose from the
`toxic ?ose. Here, etlicacy is inverted and expressed as a
`percentage of the maximum· response, and toxicity is
`expressed as the factor by which any parameter, has
`changed, relative to the control values.
`The therapeutic dose range for Cy A in rats is illustrated
`
`0
`
`50
`
`Efficacy
`(%)
`
`100
`
`3
`
`Toxicity
`(factor)
`
`2
`
`full
`efficacy
`
`beginning
`toxicity
`
`1
`1
`
`6 0
`
`3
`
`30
`
`100
`
`10
`Dose
`Fig 1. Schematic representation of the therapeutic dose range,
`with efficacy, inverted and given in percent of maximum response,
`and toxicity, given as a factor relative to control values, both plotted
`as a function of log dose.
`
`in Fig 2. Efficacy was assessed in heart and kidney
`transplantation and graft-vs-host-disease. Toxicity was
`evaluated from the rise in plasma creatinine, urea or
`bilirubin, and the fall in plasma magnesium, relative to
`untreated control animals. A factor of 2 indicates a dou(cid:173)
`bling if the parameters rise or a halving if they fall. What is
`important is the dose range that separates efficacy, on the
`left, from toxicity, on the right, and whether this dose
`range is widened compared to that of CyA.
`When the efficacy and toxicity relationship for cyclospo(cid:173)
`rin dihydro D is compared to that for CyA, it becomes
`obvious that cyclosporine dihydro D, although much less
`toxic, is also much less potent, giving no indication for an
`increase in clinical utility. The same comparison of cyclo(cid:173)
`sporin G with CyA shows little difference in the thera(cid:173)
`peutic dose range between both compounds. However, the
`therapeutic dose range for SDZ IMM 125, shown in Fig 2,
`is much wider than that of Cy A because therapeutic
`efficacy is maintained, despite a clear and sustained reduc(cid:173)
`tion in toxicity, that persists beyond the doses that are
`lethal with CyA,
`
`DRUG ABSORPTION
`
`Poor intestinal absorption and the large daily variations in
`bioavailability can lead to inconveniences with CyA. Re(cid:173)
`cently, the formulation of cyclosporins in vehicles that
`form microemulsions upon contact with digestive juices
`
`From Sandoz Pharma AG, Basle, Switzerland,
`Address reprint requests to June Mason MD, PhD, Sandoz
`Pharrra AG 386/722, CH-4002 Basle, Switzerland.
`© 1.992 by Appleton & Lange
`0041-1345/921$3,001+0
`
`Transplantation Proceedings, Vol 24, No 4, SuppJ 2 (August), 1992: pp 61-63
`
`61
`
`NOVARTIS EXHIBIT 2001
`Par v Novartis, IPR 2016-00084
`Page 1 of 3
`
`

`

`MASON
`
`CyA
`mllrketed form
`
`1200
`
`CyA
`mlcroemuls!on
`
`3
`
`1200
`
`Toxicity
`(factor)
`
`Cone.
`(nglml)
`
`2
`
`12
`
`24
`
`1200
`
`CyA
`mlcroemulslon
`
`1200
`
`Cone,
`(nglml)
`
`62
`
`o
`
`50
`
`Efficacy
`(%)
`
`100
`
`6 0
`
`a
`
`o
`
`50
`
`Efficacy
`(%)
`
`100
`
`3
`
`10
`
`30
`
`100
`
`Dose (mg/kg p.o.)
`
`SDZ IMM 125
`
`3
`
`Toxicity
`(factor)
`
`2
`
`nme (h)
`
`Fig 3. The blood levels of CyA or SOZ IMM 125 measured in
`dogs after a single oral dose, given as the oil-based marketed form
`or as a glycofurol-containing preconcentrate that forms a micro(cid:173)
`emulsion.
`
`DRUG DISTRIBUTION
`
`Drug distribution is another important component that
`determines both drug efficacy and drug toxicity. Cyclo(cid:173)
`sporins show large differences in distribution within the
`blood stream, as shown in Fig 5, where their concentration
`in erythrocytes, relative to that in plasma, indicates the
`degree of targeting to the cellular space, their site of action.
`For cyclosporin dihydro D and cyclosporin 0, less drug is
`found in the cells than in plasma. For CyA, more drug is
`found in the cells than in plasma. However, for SDZ IMM
`125, much more drug is targeted to the cellular space than
`to the plasma. Cyc\osporins also distribute quite differ(cid:173)
`ently into two tissues clearly not involved in immunosup(cid:173)
`pression as shown in Fig 6. In rats, CyA accumulates in fat
`and to a lesser extent in muscle in accordance with its high
`lipophilicity. SDZ IMM 125, in contrast, shows no accu(cid:173)
`mulation in fat and distributes little into muscle.
`
`10
`
`CyAorCyG
`
`SDZ IMM 125
`
`%of
`j,v. dose
`in urine
`
`%01
`I.v. dose
`In bile
`
`0"'"'--__
`
`25
`
`CyAorCyG
`
`, Fig 4. The eX9retion of un metabolized parent drug in urine or bile
`after IV administration of CyA, cyclosporin G, or SOZ IMM 125 to
`rats.
`
`b6F:.:.--, ----"'~~~
`
`3
`
`10
`
`30
`
`100
`
`o
`
`Dose (mg/kg p.o.)
`Fig 2. The therapeutic dose range for CyA (a) and SOZ IMM 125
`(b), as measured after oral dosing in Wi star rats. The efficacy
`parameters are: •
`for kidney transplantation, A for heart trans(cid:173)
`plantation, • for graft-vs-host disease. The toxicity parameters are
`for
`plasma concentrations of: ... for bilirubin, A for urea, •
`creatinine and. for magnesium.
`
`has greatly improved their intestinal absorption. As shown
`in Fig 3, a comparison of the blood concentration profile
`achieved in dogs after oral administration of CyA shows
`absorption with a micro emulsion formulation to be much
`improved compared to that of the marketed form. How(cid:173)
`ever, a comparison ofCyA and SDZ IMM 125, applied in
`the same microemulsion formulation, shows an even more
`dramatic improvement in bioavailability of SDZ IMM 125
`compared to CyA.
`
`DRUG METABOLISM
`
`Drug metabolism is an essential prereqUISIte for drug
`excretion with all of the older cyclosporins. This makes
`bioavailability vary with liver function and results in the
`presence of not only active parent drug but also many
`largely inactive, chemically similar, metabolites in blood.
`As shown in Fig 4, virtually no unmetabolized drug is
`excreted either in the urine or in the bile of rats after IV
`administration, of CyA or cyclosporin G. In contrast,
`however, a considerable amount of SDZ IMM 125 can be
`excreted as unmetabolized parent drug in the bile and a
`smaller but not insignificant amount can even be excreted
`unmetabolized in the urine.
`
`NOVARTIS EXHIBIT 2001
`Par v Novartis, IPR 2016-00084
`Page 2 of 3
`
`

`

`CYCLOSPORINES
`
`40
`
`20
`
`[ ery[
`TPiT
`
`CyA
`
`40
`
`20
`
`SOZIMM 125
`
`CyA
`
`25.
`
`SOZfMM 125
`
`[fat)
`[blood [
`
`63
`
`CyG
`
`CydhO
`
`20
`
`]
`
`]L---Il!l""m'%""TI=-_
`
`[ muscle]
`[blood]
`
`[ery )
`
`0
`
`IPfT L-_--"== __
`
`Fig 5. The steady-state red cell to plasma concentration ratio
`measured in human blood at 3rC after addition of 200 ng/mL of
`CyA, cyclosporin G, cyclosporin dihydro D, or SDZ IMM 125.
`
`SUMMARY AND CONCLUSIONS
`Hence, to summarize, it is now easy to identify cyclospo(cid:173)
`rins with high immunosuppressive potency in vitro. What
`has not been so easy is to establish the relationship
`between immunosuppression and toxicity in vivo. Now it
`is possible to identify cyclosporins with a convincing
`improvement in the therapeutic dose range that promise to
`be safer clinically. The low intcstinal absorption of cyclo(cid:173)
`sporins has been overcome using new galenical formula(cid:173)
`tions that provide high bioavailability. Newer cyclosporins
`have been identified that need less metabolism before
`elimination and arc better targeted towards the blood cells
`and away from the bodily tissues and fluids not involved in
`immunosuppression.
`Thus, to conclude and list our cxpectations for the
`cyclosporines of the future, including a potential successor
`to Sandimmune, SDZ IMM 125, we anticipate an immu(cid:173)
`nosuppression that is equal or superior to that of Sandim-
`
`0
`
`2.5
`
`0
`
`o
`
`l~
`
`CyA
`
`2.5.
`
`SOZ fMM 125
`
`0"",-__
`
`Fig 6. The tissue to blood concentration ratio seen in fat or
`muscle after application of radiolabelled CyA or SDZ IMM 125 to
`rats.
`
`mune. We want a much wider therapeutic dose range than
`for Sandimmune. We can guarantee better absorption with
`less variability than with Sandimmune. We can achieve an
`excretion of parent drug in both bile and urine. We are
`confident that there will be less metabolites in peripheral
`blood. We are encouraged by the lesser distribution into
`peripheral body tissues. We are optimistic about the im(cid:173)
`proved targeting to the cells of the blood stream. Thus, the
`cyclosporins are not just drugs of the past but are also
`drugs that have a great future ahead of them.
`
`ACKNOWLEDGMENTS
`
`I am deeply indebted to my colleagues in the departments of
`immunology, toxicology, biopharmaceuticals, galenics, and drug
`delivery for allowing me to present their data. My grateful thanks
`to Jean Borel, Peter Hiestand, Peter Donatsch, Michele Lemaire,
`Ulrich Posanski, Armin Meinzer, and Jacky Vonderscher.
`
`NOVARTIS EXHIBIT 2001
`Par v Novartis, IPR 2016-00084
`Page 3 of 3
`
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