`
`
`'_:-."_V<'§"_'l_mfie"4'8=,
`
`Numberfi
`November 1999
`
`‘
`
`l
`
`‘
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`‘
`
`‘
`
`.
`
`'
`
`ISSN 0306-5251
`
`
`
`British Journal
`of Clinical
`‘
`Pharmacology
`
`
`
`
`
`I
`
`'An Inteméitional Journal
`-'ofHuman:Pharma0010gy
`and Theropeutics
`Published for tlle
`British Pharmacological Society
`
`
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`
`
`
`‘
`
`:1
`
`3
`
`'
`
`;
`
`
`
`
`
`Blackwell
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`'
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`WWW.blackwell-science.comlbc -
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`Neumayer 1999
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`Science
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`

`
`British journal of- Clinical Pharmacology Contents
`Volume 48, Number 5, November I999
`"
`
`643
`
`649
`
`655
`
`663
`
`669
`
`678
`
`688
`
`694
`
`RevieWS
`
`The UK Prospective Diabetes Study (UKPDS): clinical and
`therapeutic implications for type 2 diabetes: P. King,
`I. Peacock Ed R. Damzelly
`Therapeutic drug monitoring in a developing country: an
`overview: N. J. Gogtay, N. A. Kshirsagar {Er S. S. Dalw'
`
`Drug disposition
`Efi'ect of chronic magnesium supplementation on
`magnesium distribution in healthy volunteers evaluated by
`3lP-NMRS and ion selective electrodes; C. Wary,
`C. Brillault-Salvat, G. Bloch, A. Leroy-Willig, D. Roumerwiz,
`].-M'. Gregoire]. H. Lctlerr 8 P. G. Carli'er
`Tacrine is not an ideal probe drug for measuring CYP1A2
`activity in vivazj. T. Larsen, L. L..I-Iause11 E: K. Brass”
`
`Pharmacokinetics
`
`A mechanism—based pharmacokinetic-cnzyine model for
`cyclophosp‘hamide autoinduction in breast cancer patients:
`.M. Hanan, U. S. H. Svenssoa, P. Ljrmgman, .B. ch'iriestmud,
`H. Olsson,
`.M. Bi'elensreiiz,
`il/I. Abdel-Rehim, C. Nilsson,
`M. Joliamson G'M. O. Karisson
`Clinical pharmacoltinetics of doxazosin in a controlled—
`release gastrointestinal therapeutic system (GITS)
`formulation: M. Chung, V. Vaslii, ]. Fuentes, M. Swaency 5'
`P. Meredith
`‘
`.
`_
`Population pharmacokinetics of enterally administered
`cisapiide in youn‘g infants with galstrowesophageal reflux
`disease: Y. Preethagaun, B. Charles, V. Piotmusleij,
`T. Donovan G'A. Van Petr
`‘
`Entry—into—hurnan study with the novel
`immunosuppressant SDZ RAD in stable renal transplant
`recipients: H.-H. Neamayer, K. Paradis, A. Kern, C. jean,
`L. Fu'tsclie, K. Buckie, M. Wr'zzleier, V. Kiiem, R. Pi'rhlmayr,
`I. A. Hauser, K. Brirlthamlt, A.-E. Li'son, I. Bamdt Sr
`8'. Appel-Dingemanse
`
`704
`
`Pharmacokinetics in HIV infection
`Pharmacokinetics of rifabutin in P11V~infected patients
`with or without wasting syndrome: G. Card, A. Di Biagio,
`C. R. De Pastalis, M. Guen'a, M. Bassetti EirD. Bassctir'
`
`716
`
`728
`
`733
`
`743
`
`750
`
`756
`
`,
`
`761
`
`Phannacokinetics of efavirenz (EFV) alone and'in
`combination therapy with nelfinavir (NFV) in HIV-1
`infected patients: P. Villam', M.-B. Regazzi, F: Gasteflr',
`'P. Vials, C. Terri, E. Scminan' Fa R._Maserritr'
`
`.
`
`.
`_
`_
`-
`'
`‘
`>
`- Drug interactions
`CYPBA4 drug interactions: correlation oin in ilitm probe
`substrates: K. E. Keniuorthy, ]. C. Bloomer. S. E; Clarke 5'
`j. B. Houston
`'
`-‘
`_
`-
`.
`-
`-
`Impact of gastric emptying 0n the phannacolcin'etics
`of ethanol as influenced by 'cisapride: S. Kethagias,
`K.-A._]t'l'nssan GA. W.Janes _
`_
`'
`Effects of cytochrome P450indu'cers on 170!—
`ethinyloestracliol (EE2} conjugation by primary human
`hepatocytes: A. P. Li, N. R. Hartman, C. Lu, j.f-M. Cami-25
`<94]. AM. Strong
`'
`'
`.
`'
`.
`'
`'
`
`.
`
`.
`Pharmacokineticslpharmacodynarfiics
`Myocardial region (right er'.lefi"véntri_cle) and aetiology of '
`heart failure can-influence the inotr'opic eff'ecthf ouabain
`in failing human myocardium: R. 'Paiiiifli, M.Panfili,
`G. Maguoif, D; Played, D. Casamtta- 8‘ 11/1. «Ferran'
`.
`__
`.
`Rapid development of toleranceto dipyridamoIe—associated
`headaches]. G. W. Tl:ef_s,‘G._DeithseIIS‘S.'Marshall:
`‘
`
`_
`
`_
`..
`.
`,.
`,
`_
`._
`.
`_
`_
`Short reports
`Raised aldosterone to renin ratio predicts antihypertensiye
`efficacy of spironolscton'e: a" prospectiye cohort'folloW—up
`study: P. O. Lint, R. T jimg {527? M. M'atDonald- 7'
`Population frequency, mutation linkage andanaiyticai .
`methodology for the ArgléGly, 'Gln'27Giu'and' Thr164lle '
`polymorphisms in the flzradrenergic receptor among“
`'
`Turks: A. S. Aynatiogla, I.._Cascarbi,_K. Gangs}, M.; Ozkiir,
`IV. Belex‘r, I, Roots 8']. Brotkmo'iler '
`'
`-
`'
`
`-
`
`765
`
`_
`Book review
`A Guide to Training inClinical Pharmacology in Europe:
`D. N. Batemnn
`'
`'
`.
`-
`'
`'
`
`'
`, Proceedings
`7661’ Proceedings of the Dutch Society for Clinical -
`Pharmacology and Biopharrnacy, EEO-April 1999
`
`Citations. This journai is covered by CABS (Current
`Awareness in Biological Sciences), Chemical Abstracts, Current
`Contents®fClinical Medicine, Science Citation Index®, Sci
`Search®, Research Alert®, Current Conten.ts®/Life Sciences
`and Reference Update®.
`
`Information on this journai can be accessed at
`http:/ / wwwblackwelbscience.com/hep
`
`1
`
`ill
`
`ill llll
`
`|ll
`
`lillllll
`
`Typeset, Printed and Bound by The Charlesworth Group,
`Huddersfield, UK, 01484 517077
`
`Blackwell
`Science
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`s3 05f525w339t5i/iérlci éifiiiriibsg
`Nieumayer 1999
`age
`
`West-Ward Exhibit 1009
`Neumayer 1999
`Page 002
`
`

`

`Entry-into-human study with the novel immunosuppressant SDZ RAD
`in stable renal transplant recipients
`
`H.-H. Neumayer,1 K. Paradis,2 A. Korn,3 C. Jean,2 L. Fritsche,1 K. Budde,1 M. Winkler,4 V. Kliem,5
`R. Pichlmayr,4† I. A. Hauser,6 K. Burkhardt,7 A.-E. Lison,8 I. Barndt8 & S. Appel-Dingemanse2
`1Nephrology Section, University Hospital Charite´, Berlin, Germany, 2Clinical Research/Clinical Pharmacology, Novartis Pharma AG, Basel,
`Switzerland, 3Clinical Research, Novartis Pharma AG, Nuremberg, Germany, 4Department of Surgery, 5Department of Nephrology, Center for Internal
`Medicine, Medical School, Hanover, Germany, 6Department of Internal Medicine, Nephrology Section, University Hospital Frankfurt/Main, Frankfurt,
`Germany, 7Department of Nephrology, University Hospital, Erlangen–Nuremberg, Germany and 8Department of Internal Medicine, Central Hospital,
`Bremen, Germany
`
`Aims To evaluate the tolerability of single oral SDZ RAD doses in stable renal
`transplant recipients and the pharmacokinetics of ascending SDZ RAD doses when
`coadministered with steady-state cyclosporin A microemulsion (Neoral).
`study
`Methods This
`randomized, double-blind, placebo-controlled,
`sequential
`involved 54 patients in six treatment groups; a different SDZ RAD dose (0.25,
`0.75, 2.5, 7.5, 15, 25 mg) was assessed in each group. Patients received a single oral
`dose of SDZ RAD (n=6) or placebo (n=3) with their usual Neoral dose. SDZ
`RAD and cyclosporin A pharmacokinetic parameters were determined.
`Results All SDZ RAD doses were well tolerated, with no discontinuations due to
`adverse events, serious adverse events, or deaths. Similar proportions of patients
`receiving SDZ RAD and placebo had at least one adverse event (44% and 50%,
`respectively). Mean changes in laboratory variables (baseline to endpoint) showed
`no clinically meaningful differences between SDZ RAD and placebo groups. SDZ
`RAD was absorbed rapidly and showed dose-proportional pharmacokinetics (dose:
`2.5–25 mg), based on systemic exposure. Multiple postabsorptive phases in the
`pharmacokinetic profile indicate tissue distribution. The elimination half-life ranged
`from 24 to 35 h across the five highest dose groups. Pharmacokinetics were similar
`in men and women. Co-administration of escalating single oral SDZ RAD doses
`did not affect steady-state cyclosporin A pharmacokinetics.
`Conclusions SDZ RAD was well tolerated; safety profiles of SDZ RAD and placebo
`were similar. SDZ RAD pharmacokinetics were dose-proportional across the range
`2.5–25 mg in conjunction with cyclosporin A-based therapy, according to systemic
`exposure. Cyclosporin A pharmacokinetics were not affected by coadministration of
`single oral doses of 0.25–25 mg SDZ RAD.
`
`Keywords: cyclosporin A, immunosuppressant, pharmacokinetics, safety, SDZ RAD,
`transplantation
`
`Introduction
`
`The immunosuppressive properties of rapamycin have
`been known for more than 15 years [1, 2], but the
`clinical development of
`the drug has been hampered
`by its
`limited oral bioavailability. A novel
`immuno-
`suppressant, SDZ RAD, has recently been developed.
`SDZ RAD is a derivative of rapamycin but differs
`structurally by having a 2-hydroxyethyl chain at position
`
`Correspondence: Dr Silke Appel-Dingemanse, Department of Clinical Pharma-
`cology, Novartis Pharma AG, 4002 Basel, Switzerland.
`Received 30 November 1998, accepted 13 August 1999.
`† Deceased
`
`40. This modification allowed the development of a solid
`dosage formulation that is more convenient to administer
`than rapamycin, which must be prepared from a
`refrigerated stock solution just before use. SDZ RAD has
`a mechanism of action similar to that of rapamycin:
`inhibition of growth factor-driven proliferation of T cells
`and fibroblasts. SDZ RAD prevents graft rejection in rat
`models of allotransplantation (kidney, heart) [3]. SDZ
`RAD and cyclosporin A show synergism in immuno-
`suppression both in vitro and in vivo [4].
`The aim of the present study was to evaluate the safety
`and tolerability of single doses of SDZ RAD (0.25–25 mg)
`in stable renal
`transplant
`recipients and thereby to
`
`694
`
`© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 694–703
`
`West-Ward Exhibit 1009
`Neumayer 1999
`Page 003
`
`

`

`Novel immunosuppressant SDZ RAD
`
`studies
`large-scale clinical
`further
`determine whether
`are justified. Other objectives were to determine the
`pharmacokinetics of ascending single oral doses of SDZ
`RAD during steady-state dosing with the microemulsion
`formulation of cyclosporin A (Neoral) and to assess the
`effect of
`single-dose SDZ RAD on the steady-state
`pharmacokinetic profile of cyclosporin A.
`the American
`This study was presented in part at
`Society of Transplant Physicians’ Sixteenth Annual
`Meeting, 10–14 May, 1997, Chicago, Illinois.
`
`formulation; liver, heart, or autonomic dysfunction; illness
`defined as significant by the investigator within 2 weeks
`before the study; and the use of any drug known to
`potentiate cyclosporin A nephrotoxicity or to interfere
`with cyclosporin A pharmacokinetics within 2 weeks
`before the study (with the exception of calcium antagon-
`ists if
`the dose regimen had been stable for at
`least
`8 weeks before the start of the study). Azathioprine had
`to have been discontinued at least 4 weeks before the
`baseline assessment.
`
`Methods
`
`Study design
`
`This was a phase-I, multicentre, randomized, double-
`blind, placebo-controlled, ascending-dose study of the
`tolerability and pharmacokinetics of SDZ RAD. The
`study was approved by the local Ethics Committee and
`patients gave written informed consent to participate in
`the study. Patients (n=54) were allocated to six groups.
`In each group, six patients were randomized to the same
`single dose of SDZ RAD (0.25, 0.75, 2.5, 7.5, 15, or
`25 mg), and three patients
`randomized to placebo.
`Patients received study medication under fasting con-
`ditions, together with their usual, individually selected
`Neoral dose. The SDZ RAD doses were evaluated in
`ascending order, starting with the 0.25 mg dose. Each
`subsequent dose was not assessed until the safety and
`tolerability of the previous dose had been evaluated for
`at least 11 days.
`
`Participants
`
`Tolerability
`
`Adverse events were reported spontaneously by the
`patient or discovered from general questioning by the
`investigator, or after physical examination at any time, as
`required, up to 4 weeks after receiving SDZ RAD. The
`severity of the adverse events (mild, moderate, or severe),
`their relationship to study medication, and the occurrence
`of death, nonfatal
`serious adverse events, or adverse
`events resulting in the discontinuation of medication
`were recorded.
`Patients underwent a general physical examination
`with ophthalmic assessment, echo- and electrocardio-
`graphy, vital-signs assessment (blood pressure, pulse, body
`temperature), haematology, prothrombin time/partial
`thromboplastin time, blood biochemistry (including creat-
`inine clearance), endocrinology, urinalysis, and markers
`of
`inflammation
`(fibrinogen, C-reactive
`protein,
`c-globulin, and a1–, a2–, and b–proteins). The first
`laboratory assessment was made between 3 and 90 days
`before the start of the study (screening); patients returned
`for subsequent laboratory assessments up to 2 days before
`drug administration (baseline), on the day of drug
`administration (day 1), daily until day 7, and then on
`days 9 and 11.
`
`Pharmacokinetic assessments
`
`Men and women, aged 18–65 years, were included in
`the study if they were recipients of a primary cadaveric
`renal transplant, had undergone transplantation at least
`6 months before the start of
`the study, and were
`considered to be clinically stable at the start of the study.
`Their serum creatinine concentration had to be less than
`−1, with a creatinine clearance of at
`207 mmol l
`least Whole blood samples (3.5 ml) were collected by means
`40 ml min−1 estimated on the basis of the Cockcroft-
`of a catheter inserted into a forearm vein. Samples for
`the determination of cyclosporin A concentrations were
`Gault formula [5]. Whole blood trough cyclosporin A
`−1.
`concentrations had to be between 80 and 200 ng ml
`taken over one dosing interval ( just before and up to
`12 h after drug administration) one day before adminis-
`Patients had to be receiving twice-daily Neoral at a dose
`tration of SDZ RAD or placebo (day −1). After
`that had been stable for at least 3 weeks before screening,
`concomitant intake of Neoral with SDZ RAD or placebo,
`combined with prednisone
`at
`a dose of up to
`15 mg day−1, for at least 3 months.
`concentrations of cyclosporin A were again determined
`over one complete dosing interval
`(day 1) and,
`in
`Exclusion criteria included the following: graft rejection
`or continued tapering of corticosteroids from previous
`addition, just before each morning dose of Neoral until
`11 days after SDZ RAD or placebo intake. Samples for
`rejection therapy within 2 months before screening;
`use of other investigational immunosuppressants within
`the determination of SDZ RAD concentrations were
`collected just before and up to 192 h after drug
`4 months or other investigational drugs within 4 weeks
`before screening; hypersensitivity to drugs of the same
`administration. Samples were immediately stored below
`class as SDZ RAD or to components of the SDZ RAD −20° C pending analysis.
`
`© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 694–703
`
`695
`
`West-Ward Exhibit 1009
`Neumayer 1999
`Page 004
`
`

`

`H.-H. Neumayer et al.
`
`Cyclosporin A concentrations in whole blood were
`measured using a commercially available radioimmuno-
`assay
`(Cyclo-Trac,
`INCSTAR Corp.,
`Stillwater,
`Minnesota, USA). The limit of quantification (LOQ)
`−1. Precision and accuracy were 5.7–17.7%
`was 15 ng ml
`and −1.7 to +3.5%, respectively, at concentrations of
`quality control samples between 15 and 2540 ng ml−1.
`SDZ RAD concentrations in whole blood were quantified
`by means of a high-performance liquid chromatography/
`atmospheric pressure chemical
`ionization/mass
`spec-
`trometry method [6]. The LOQ was 0.75 ng ml−1. For
`the
`three quality control
`samples
`(0.75, 10,
`and
`−1) precision and accuracy ranged between 9
`125 ng ml
`and 11% and −12 to −7%, respectively.
`Pharmacokinetic parameters were determined for both
`SDZ RAD and cyclosporin A using noncompartmental
`methods [7].
`For cyclosporin A ratios of tmaxss, Cmaxss, Cminss, and
`AUCtss with and without coadministration of SDZ RAD
`or placebo were also calculated.
`
`Statistical analysis
`
`Because of the small number of patients in the study and
`within each group, data from the 18 patients receiving
`placebo were pooled for analysis. Data from the 36
`patients receiving SDZ RAD (n=6 per group) were
`analysed by dose level and also as a pooled SDZ RAD
`group (n=36). Patients failing to provide data at any visit
`were excluded from the analysis for that visit and data
`were not carried forward to subsequent time points. For
`each patient, the endpoint was taken as the last observation
`after baseline.
`For the tolerability analysis, the number of patients
`experiencing an adverse event was recorded and summar-
`ized by treatment group. The incidence rates of all
`adverse events were summarized by body system, severity,
`and treatment group. Changes in vital signs, laboratory
`data, electrocardiography, and physical examination data
`were summarized by treatment group, and any clinically
`significant abnormalities were recorded.
`For pharmacokinetic analyses, the dose proportionality
`of Cmax and AUC for SDZ RAD was assessed using
`linear regression on non-normalized data and one-factor
`analysis of variance (anova) on logarithmically trans-
`formed dose-normalized data with least-squares compari-
`sons between pairs of cohorts. The Kruskal–Wallis test
`(the nonparametric equivalent of anova) was performed
`on dose-normalized data. The relationships of the dose-
`normalized Cmax and AUC with body weight were also
`explored. For cyclosporin A, a two-factor anova with
`dose, time, and the interaction term (time · dose) as
`sources of variation including estimate statements was
`determined to assess the dose level of SDZ RAD at
`
`which a pharmacokinetic interaction with cyclosporin A
`occurred. Potential changes in morning predose cyclospo-
`rin A concentrations (Cminss) were investigated over time
`(11 days) after coadministration of single oral doses of
`SDZ RAD (0.25–25 mg) or placebo, using Hotelling’s
`T2 test
`(SAS 6.08, SAS Institute Inc., Cary, North
`Carolina, USA).
`
`Results
`
`All 54 patients completed the study, although 16 patients
`in the SDZ RAD groups (44%) and 10 patients in the
`placebo group (56%) violated an entry criterion (mainly
`−1, use of azathio-
`serum creatinine level ≥207 mmol l
`prine within 4 weeks of baseline, use of Neoral
`for
`<3 months before study, or <150 000 platelets/mm3).
`However, these were judged, on a case-by-case basis, to
`be minor deviations that did not necessitate exclusion
`from the trial.
`Baseline patient characteristics and concomitant medi-
`cations are shown in Table 1. Age, weight, and height in
`the SDZ RAD and placebo groups were similar; the
`absolute number/proportion of women in the SDZ RAD
`group was higher than in the placebo group (8/22% vs
`2/11%, respectively). Differences at baseline between the
`SDZ RAD and placebo groups were noted for the
`incidences of hyperparathyroidism (4/11% vs 5/28%),
`gastrointestinal disorders (7/19% vs 10/56%), hyperlipida-
`emia (10/28% vs 2/11%), hyperuricaemia (9/25% vs
`(7/19% vs 2/11%), cataract
`8/44%), polycythaemia
`(5/14% vs 1/6%). Most of the patients in the SDZ RAD
`and placebo groups (32/89% and 17/94%, respectively)
`had hypertension at baseline. This was reflected by the
`relatively high proportions of patients receiving antihyper-
`tensive medication concomitantly with study medication.
`
`Tolerability
`
`incidence of adverse events is shown in
`The overall
`Table 2. No deaths, serious adverse events, or events that
`led to discontinuation of study medication were reported.
`No adverse event was considered to be definitely related
`to the study medication. The most frequently reported
`adverse events were headache in the SDZ RAD group
`(11% of patients) and dizziness in the placebo group (22%).
`Most adverse events (26/43 in the SDZ RAD group and
`8/13 in the placebo group) were classified as mild; the
`remainder were classified as moderate. Adverse events in
`the SDZ RAD group were more diverse than those in
`the placebo group; a total of 36 adverse events occurred
`in the 36 patients in the SDZ RAD group (i.e. mean: 1
`event per patient), with at least one adverse event in
`each of the 16 body systems considered. This compared
`with a total of 13 adverse events occurring in the 18
`
`696
`
`© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 694–703
`
`West-Ward Exhibit 1009
`Neumayer 1999
`Page 005
`
`

`

`Novel immunosuppressant SDZ RAD
`
`18
`7(39)
`18(100)
`
`5(28)
`
`5(28)
`17(94)
`
`8(44)
`
`9(50)
`
`3(17)
`
`36
`10(28)
`36(100)
`
`9(25)
`
`14(39)
`34(94)
`
`21(58)
`
`14(39)
`
`12(33)
`
`6
`
`2(33)
`6(100)
`
`0
`
`4(67)
`4(67)
`
`2(33)
`
`2(33)
`
`2(33)
`
`6
`
`1(17)
`6(100)
`
`3(50)
`
`2(33)
`6(100)
`
`3(50)
`
`1(17)
`
`3(50)
`
`6
`
`2(33)
`6(100)
`
`4(67)
`
`2(33)
`6(100)
`
`3(50)
`
`2(33)
`
`4(67)
`
`6
`
`2(33)
`6(100)
`
`0
`
`1(17)
`6(100)
`
`5(83)
`
`4(67)
`
`0
`
`0
`
`6
`
`6(100)
`
`1(17)
`
`2(33)
`6(100)
`
`3(50)
`
`2(33)
`
`1(17)
`
`6
`
`3(50)
`6(100)
`
`1(17)
`
`3(50)
`6(100)
`
`5(83)
`
`3(50)
`
`2(33)
`
`172.8±8.9
`75.1±13.5
`1652
`46.8±10.3
`
`(n=18)
`Placebo
`
`173.6±10.5
`76.1±14.0
`2858
`48.4±11.3
`
`(n=36)
`
`total
`
`SDZRAD
`
`170.5±10.6
`76.8±15.4
`353
`50.0±7.1
`
`(n=6)
`
`25
`
`173.3±9.0
`74.8±15.1
`452
`57.0±6.8
`
`(n=6)
`
`15
`
`177.0±9.3
`78.1±12.2
`650
`45.2±12.5
`
`167.3±14.8
`68.3±11.6
`452
`49.2±12.9
`
`(n=6)
`(n=6)
`2.5
`7.5
`SDZRADdose(mg)
`
`174.8±10.6
`69.4±11.1
`551
`42.5±15.3
`
`(n=6)
`0.75
`
`178.7±7.0
`89.4±12.6
`650
`46.7±9.5
`
`(n=6)
`0.25
`
`Whereapplicable,dataaremeans±s.d.
`
`Anymedication
`Sulphonamides,plain
`CyclosporinA
`
`acidproduction/excretion
`Preparationsmodifyinguric
`
`inhibitors
`
`HMGCoA-reductase
`Glucocorticoids
`
`derivatives
`
`Dihydropyridine
`
`blockers,selective
`
`b-adrenoceptor
`
`enzymeinhibitors
`
`Angiotensin-converting
`Concomitantmedication,n(%):
`
`Height(cm)
`Bodymass(kg)
`Male5femaleratio(n)
`Age(years)
`
`Table1Baselinepatientcharacteristicsandconcomitantmedications.
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`H.-H. Neumayer et al.
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`Table 2 Adverse events.
`
`SDZ RAD dose
`(mg )
`
`Patients experiencing
`≥1 adverse event
`(n [%])
`
`Patients with possibly or probably
`drug-related adverse events
`(n [%])
`
`0.25
`0.75
`2.5
`
`7.5
`
`15
`
`25
`SDZ RAD (total)
`Placebo
`
`2 (33)
`3 (50)
`4 (67)
`
`2 (33)
`
`3 (50)
`
`2 (33)
`16 (44)
`9 (50)
`
`0
`1 (17)
`3 (50)
`
`2 (33)
`
`2 (33)
`
`1 (17)
`9 (25)
`5 (28)
`
`Description of adverse events per patient
`
`Abdominal pain
`Dizziness, chest pain, dyspnea
`Arrhythmia
`Fever (×2), headache (×2)
`Malaise (×2), asthenia, hypotension, dizziness,
`paresthesia (×2), vertigo, dry mouth, acne
`Hot flushes, headache, erythematous rush, taste
`perversion, thrombophlebitis
`Chest pain
`Paresthesia
`Thrombocytopaenia, leucopaenia, pharyngitis
`
`Hot flushes
`Dizziness
`Dizziness
`Dizziness, headache
`Headache
`
`Normal at baseline (n)
`
`SDZ RAD
`
`Placebo
`
`Post baseline (%)a
`
`Low
`SDZ RAD
`
`Placebo
`
`High
`SDZ RAD
`
`Placebo
`
`Table 3 Patients experiencing a shift in
`biochemical variables from normal
`baseline to abnormal postbaseline values.
`
`Creatinine
`ASAT
`ALAT
`Glucoseb
`Cholesterol
`Triglyceride
`Potassium
`Magnesium
`Amylase
`Lipase
`
`22
`35
`35
`33
`32
`24
`36
`31
`29
`26
`
`12
`17
`17
`18
`14
`14
`17
`15
`16
`9
`
`0
`0
`0
`12
`0
`0
`3
`3
`0
`0
`
`0
`0
`0
`6
`0
`0
`6
`13
`0
`0
`
`32
`9
`11
`15
`9
`42
`14
`0
`7
`8
`
`17
`0
`6
`22
`21
`50
`29
`0
`0
`33
`
`Data were pooled for the SDZ RAD groups (n=36) and for the placebo groups (n=18).
`aPercentages are based on the number of patients per group with normal values at baseline.
`b3% of SDZ RAD patients and 6% of placebo patients gave individual glucose values, some of
`which were higher and some lower than baseline, and therefore provided both high and low
`values, in addition to those tabulated.
`ASAT=aspartate aminotransferase, ALAT=alanine aminotransferase.
`
`patients in the placebo group (mean: 0.7 events per
`patient),
`involving six body systems
`(general cardio-
`vascular, nervous system, gastrointestinal system, musculo-
`skeletal system, skin and appendages, and general body as
`a whole).
`Mean values for systolic and diastolic blood pressure,
`pulse rate, body mass, and body temperature were similar
`in all
`treatment groups
`throughout
`the study. Echo-
`cardiograms (taken only at baseline) revealed abnormalities
`in 28% of patients in the SDZ RAD groups and in 39%
`
`of those in the placebo group (data not shown). No
`clinically significant differences in luteinizing hormone,
`follicle-stimulating hormone, or
`testosterone concen-
`trations were found between the SDZ RAD and
`placebo groups.
`The incidence of clinically significant haematologic
`and biochemical abnormalities
`(high or
`low values
`compared with baseline) was generally similar for the
`SDZ RAD and placebo groups (Table 3). However, a
`trend towards lower platelet counts was seen in patients
`
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`Novel immunosuppressant SDZ RAD
`
`day 9. Leucocyte counts also differed generally between
`SDZ RAD and placebo groups: 17% of patients receiving
`SDZ RAD who had normal leucocyte counts at baseline
`shifted to a low postbaseline count, compared with none
`on placebo (Figure 1c). One mild case of leucopaenia
`and one mild case of leucocytosis were also reported in
`patients receiving SDZ RAD. None of these haematol-
`ogic abnormalities had clinical sequelae.
`Relatively high proportions of patients in both the
`SDZ RAD and placebo groups experienced a shift from
`normal baseline to abnormal
`(either high or
`low)
`postbaseline values
`for certain biochemical variables.
`Serum creatinine increased to abnormal values (≥30%
`above baseline) in seven patients receiving SDZ RAD
`(Figure 1a); however, such an increase in serum creatinine
`is not unusual in renal allograft recipients. Although a
`higher proportion of patients in the SDZ RAD group
`(32%) than in the placebo group (17%) shifted to high
`postbaseline serum creatinine concentrations,
`the esti-
`mated creatinine clearance rate was similar for the SDZ
`RAD and placebo groups. In both groups, relatively high
`proportions of patients with normal baseline triglyceride
`levels had high postbaseline triglyceride levels (42% and
`50%, respectively). A lower proportion of patients in the
`SDZ RAD group than in the placebo group had normal
`baseline cholesterol and high postbaseline cholesterol
`(9% and 21%, respectively). Blood concentrations of
`markers of inflammation (fibrinogen, C-reactive protein,
`c-globulin, and a-1–, a-2–, and b–proteins) did not
`change significantly between baseline and the end of the
`study and did not differ significantly between SDZ RAD
`and placebo treatment groups. As
`in the case of
`haematologic abnormalities, none of
`the changes
`in
`laboratory variables had clinical sequelae.
`
`Pharmacokinetics
`
`Mean SDZ RAD whole blood concentration–time
`profiles after single doses of 0.25, 0.75, 2.5, 7.5, 15, and
`25 mg are shown in Figure 2. At a dose of 0.25 mg,
`maximum SDZ RAD concentrations were only just
`above the assay LOQ, and therefore pharmacokinetic
`characterization was not possible. The graph indicates
`reproducible pharmacokinetics within, and similar half-
`the different dose levels. The derived
`lives among,
`pharmacokinetic variables for SDZ RAD are shown in
`Table 4. SDZ RAD was absorbed rapidly; whole blood
`concentrations were measurable in most patients 30 min
`after the dose. Peak concentrations were reached on
`average 1.0–2.2 h after the dose. The increase in Cmax
`from the 0.25 mg dose to the 15 mg dose was not
`proportional to the dose over the entire range (Table 4).
`Dose-normalized AUC values were not
`significantly
`different for doses in the range 2.5–25 mg but were
`
`a
`
`0
`b
`
`0
`c
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10 11
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10 11
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`6
`7
`Visit (days)
`
`8
`
`9
`
`10 11
`
`20
`
`10
`
`0
`
`–10
`
`–20
`
`80
`70
`60
`50
`40
`30
`20
`10
`0
`–10
`–20
`–30
`–40
`
`2 1 0
`
`–1
`
`–2
`
`Creatinine (µmoll–1)
`
`Platelet count (109l–1)
`
`Leuccocytes (109l–1)
`
`Figure 1 Mean change from baseline over time for creatinine (a),
`platelet count (b), and leucocytes (c); n=6 for SDZ RAD doses
`(& 0.25 mg, % 0.75 mg, + 2.5 mg, 6 7.5 mg, $ 15 mg,
`# 25 mg) and n=18 for placebo (1).
`
`receiving SDZ RAD doses of 15 or 25 mg. This was
`most apparent in the 15 mg SDZ RAD treatment group,
`with the lowest mean counts on days 6 and 7 after dosing
`and recovery by day 11 after dosing (Figure 1b). The
`largest
`individual decrease in platelets occurred in a
`52-year-old woman who had received a 25 mg SDZ
`RAD dose and who had a platelet count of 133×109
`l−1 on day 9, compared with the lower limit of the
`−1. This patient
`expanded normal range of 149×109 l
`−1) on
`also had a decreased leucocyte count (2.1×109 l
`
`© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 694–703
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`699
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`Neumayer 1999
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`

`H.-H. Neumayer et al.
`
`a
`
`1000
`
`100
`
`10
`
`1
`
`0.1
`
`Blood concentration (ngml–1)
`
`b
`
`250
`
`200
`
`150
`
`100
`
`50
`
`0
`
`48
`
`96
`
`144
`
`0
`
`192
`0
`Time postdose (h)
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`Figure 2 Whole blood concentration–time profiles of SDZ RAD on (a) semilogarithmic and (b) linear scales (initial 12 h postdose time
`interval) after single oral administration of SDZ RAD. Data are means+s.d.; n=6 for each dose, & 0.25 mg, % 0.75 mg, + 2.5 mg,
`6 7.5 mg, $ 15 mg, # 25 mg.
`
`Table 4 Pharmacokinetic parameters of SDZ RAD after single oral administration.
`
`0.25
`
`0.75
`
`SDZ RAD dose (mg )
`7.5
`
`2.5
`
`15
`
`25
`
`tmax (h)
`−1)
`Cmax (ng ml
`−1 h)
`AUC(0,t) (ng ml
`−1 h)
`AUC (ng ml
`AUC/Dose (ng ml
`t1/2 (h)
`
`−1 mg
`
`−1 h)
`
`2.2±0.7
`2.3±0.8
`8±4
`—
`—
`—
`
`1.7±0.5
`14±2.7
`134±42
`171±50
`112±17
`35±14
`
`1.3±0.4
`45±21
`305±132
`344±141
`85±37
`25±6
`
`1.3±0.6
`85±16
`745±191
`783±191
`62±12
`26±4
`
`1.0±0.0
`173±37
`1428±237
`1468±238
`59±7
`24±7
`
`1.3±0.4
`179±24
`2358±601
`2400±608
`46±8
`30±5
`
`Data are means±s.d.; n=6 in each group.
`
`Table 5 Baseline predose cyclosporin A whole blood concentrations and daily Neoral dose.
`
`0.25
`(n=6)
`
`136±24
`223±52
`
`0.75
`(n=6)
`
`115±36
`230±53
`
`2.5
`(n=6)
`
`124±30
`218±50
`
`SDZ RAD dose (mg )
`7.5
`(n=6)
`
`15
`(n=6)
`
`114±24
`266±56
`
`116±44
`267±107
`
`25
`(n=6)
`
`115±17
`193±49
`
`Placebo
`(n=18)
`
`121±34
`215±60
`
`−1)
`Cyclosporine A C0 (ng ml
`−1)
`Neoral dose (mg day
`
`Data are means±s.d.
`
`(Table 4). Dose-
`the 0.75 mg dose level
`higher at
`normalized Cmax and AUC for 0.75 and 2.5 mg SDZ
`RAD tended to increase with low body weight. The
`elimination half-life was approximately 1 day (25 h) for
`the 2.5, 7.5, and 15 mg doses and somewhat longer for
`the 0.75 and 25 mg doses (difference not significant).
`Morning predose cyclosporin A whole blood concen-
`
`trations were similar across the six dose groups and were
`−1 (Table 5).
`well within the target range of 80–200 ng ml
`Table 5 also provides the respective daily Neoral doses.
`Similar doses of Neoral were given as capsule and
`solution, with means of 224±62 mg (n=42)
`and
`235±70 mg (n=12), respectively. Overlapping morn-
`ing trough-normalized (untransformed) whole blood
`
`700
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`

`Novel immunosuppressant SDZ RAD
`
`concentration–time profiles of cyclosporin A after admin-
`istration of Neoral alone or with a single oral dose of
`25 mg SDZ RAD or placebo are illustrated in Figure 3.
`tmaxss, Cmaxss,
`The means of
`the individual ratios of
`Cminss, and AUCtss for cyclosporin A (coadministration
`of Neoral with SDZ RAD or placebo on day 1/Neoral
`alone on day −1) are presented in Table 6. Individual
`results relative to the means of the ratios for Cmaxss and
`AUCtss are shown in Figure 4. No significant difference
`in these pharmacokinetic parameters was seen among the
`different groups, indicating no effect of single oral doses
`of 0.25–25 mg SDZ RAD on the steady-state pharmaco-
`kinetics of cyclosporin A.
`
`Discussion
`
`In this small group of stable primary renal transplant
`recipients, evaluations of
`adverse events,
`laboratory
`investigations, vital
`signs, and physical examinations
`indicated that single doses of SDZ RAD in the range
`0.25–25 mg were well tolerated. SDZ RAD also showed
`a favourable pharmacokinetic profile and had no effect
`on steady-state cyclosporin A pharmacokinetics when
`coadministered with the microemulsion formulation of
`cyclosporin A, Neoral.
`No overall difference was seen between the adverse
`event profiles of SDZ RAD and placebo. However, some
`
`a
`
`2000
`
`b
`
`2000
`
`1500
`
`1000
`
`500
`
`0
`
`1500
`
`1000
`
`500
`
`0
`
`Blood concentration (ngml–1)
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`0
`12
`Time postdose (h)
`Figure 3 Morning trough-normalized whole blood cyclosporin A concentration–time profiles after administration of Neoral alone (&,
`%) or coadministered with a single dose of (a) placebo ($) or (b) 25 mg SDZ RAD (#). Data are means + or − s.d.; n=18 for
`placebo; n=6 for SDZ RAD.
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`
`Table 6 Ratios (in percentage) of cyclosporin A steady-state pharmacokinetic variables with and without (baseline) coadministration of
`SDZ RAD.
`
`0.25
`(n=6)
`
`149±80
`90±17
`105±7
`98±7
`
`0.75
`(n=6)
`
`131±56
`129±45
`113±18
`110±26
`
`2.5
`(n=6)
`
`101±44
`114±40
`94±18
`99±21
`
`SDZ RAD dose (mg)
`7.5
`(n=6)
`
`113±25
`118±32
`106±25
`116±17
`
`15
`(n=6)
`
`83±47
`92±39
`103±21
`98±32
`
`25
`(n=6)
`
`91±32
`114±30
`105±11
`103±6
`
`tmaxss (h)
`−1)
`Cmaxss (ng ml
`−1)
`Cminss (ng ml
`−1 h)
`AUCtss (ng ml
`
`Data are means±s.d. percentages.
`
`© 1999 Blackwell Science Ltd Br J Clin Pharmacol, 48, 694–703
`
`Placebo
`(n=18)
`
`111±53
`132±35
`100±13
`104±14
`
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`

`H.-H. Neumayer et al.
`
`a
`
`b
`
`200
`
`180
`
`160
`
`140
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`Cyclosporin A AUC ratio (%)
`
`0
`
`5
`
`10
`
`15
`
`20
`
`0
`
`25
`30
`0
`SDZ RAD dose (mg)
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`200
`
`180
`
`160
`
`140
`
`120
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`Cyclosporin A Cmax ratio (%)
`
`Figure 4 Effect of single oral doses of SDZ RAD on steady-state cyclosporin A ratios for Cmax and AUC (coadministration on day
`1/Neoral alone on day −1); n=6 for each dose, & 0.25 mg, % 0.75 mg, + 2.5 mg, 6 7.5 mg, $