CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-2 72
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEWQSQ
`
`

`

`Office of Clinical Pharmacology and Biopharmaceutics
`New Dru A I lication Filin and Review Farm
`
`3 3.
`
`p
`
`3"
`
`a 0
`
`information
`
`NDA Number
`OCPB Division
`Medical Division
`OCPB Reviewer
`
`I! ll]
`
`OCPB Team Leader
`
`Date of Submission
`
`Estimated Due Date of OCPB Review
`PDUFA Due Date
`Division Due Date
`
`ardio-Ronal Dru Products
`. Nhl Nguyen a
`-
`-
`o Gobburu
`v lica Dorantes
`
`SW
`
`iiilllllllli
`
`§
`
`Brand Name
`Generic Name
`
`Indications)
`
`Dosae Form
`a5
`
`liilllllllii
`
`Route of Administration
`
`Priori Classification
`
`Information
`emodulin"
`re- stinol sodium UT-15
`nostac ‘ linanal no
`ulmonary artery
`aai”
`"
`
`1
`
`1.25 nglkg/min x 1 wk, then
`increase weekly by a
`maximum of 1.25 nglkf/min.
`After 4 wits, increase weekly
`by maximum of 2.5
`
`Continuous subcutaneous
`infusion
`United Tbera « utics Cor ~ .
`
`=<r
`
`Clin. Pharm. and Biopharm. Information
`“X” it included Number of
`at filing
`studies
`submitted
`
`Number of
`studios
`reviewed
`
`-
`
`Critical Comments if any
`
`STUDYTYPE
`Table of Contents present and
`
`sufficient to locate reports. tables. data. I
`
`Tabular Listin of All Human Studios
`
`V
`
`ll
`
`.
`
`,,
`
`,I
`
`all
`
`a
`
`‘
`
`I
`
`I a
`I
`
`l—
`
`[||
`
` g1“fig;-paiv:i
`
`Reference Bloanalytlcal and Analytical
`Methods
`I.‘ Clinical Pharmaco - -
`Mass balance:
`lsoz,
`e characterization:
`Blood! . lasma ratio:
`-:
`Plasma . otein bindi
`Pharmacoklnetics o.. Phasol -
`
`acute dose:
`
`-
`
`a...-—
`
`“.7
`
`‘-
`ii1'
`Illlll
`
`.s
`
`-
`
`t...
`
`-
`
`I
`
`Patients-
`
`Dose -
`
`-
`- onionali
`lasti
`- l non-fastin acute dose:
`ias'
`. InonJast
`- chronic dose:
`Dru 3 -dru- intonation studios -
`d -:
`ln—vivo efiectson dime
`ln~vivo effects of -
`a d :
`
`Sub -
`
`-
`
`~
`
`lotion studies -
`
`a;22%
`
`ethni
`
`.
`
`renal im - irrnen '
`he- atic im - airme
`
`X
`
`u.
`
`-... V -.,.I.-w..r q v. .Wo.r-,._., »._......._~_ Y- -.
`
`.- ., .
`
`.
`
`.
`
`. o
`
`PageiofHZ
`
`

`

`
`
`w,mmtmwtwxwew‘_=
`
`
`«fig—«,w‘smm:4:2fig“mm—Aw
`=7.»anamt,me;,twey;wnug=a%uk=ag
`
`3.5.]
`V
`II
`I
`_I ll
`——-_—
`————_
`MI ' II
`I
`II_
`m__l__
`—IZ_I_I__
`-_I II
`I
`II
`I
`_———_
`—:m———_
`_I II
`I
`II
`I
`_B'—____
`“I II
`I
`II
`I
`—_——_
`—_———
`-_I ll
`I
`II
`I
`—T_—_——
`M—___
`-—_———
`—_———
`M—__—
`_1'__—_—
`mm—__——
`_I II
`I
`II
`I
`m—_—_
`————__
`—:-::——_—_
`—_———
`_I “-1-—
`
` Fflab/lily and QBR comment:
`
`
`
`
`
`
`
`
`
`
`Application filablo ?
`
`Comments sent to firm 7
`
`QBR questions (key issues to be
`considered)
`
`
`
`
`
`Comments
`
`Reasons if the application jc, not filable (or an attachment if applicable)
`For example, is clinical formulation the same as the lobe-marketed one?
`
`Comments have been sent to firm (or attachment included). FDA letter date
`if applicable.
`
`
`
`1a. Ia there an exposure-response relationship?
`b. if yea, does tolerance develop to 01-15?
`2. Has the metabolism of UT-15 been adequately characterized?
`
`
`Other comments or information not
`
`
`included above
`
`
` Primary reviewer Signature and Date V
`Secondary reviewer Signature and Date Angelica Dorantea 3/05/01
`
`PM reviewer signature and Date
`
`B. Nhi Nguyen 3/05/01
`Jog-no Gobburu 3/05/01
`
`
`
`
`
`CC: NBA 21 -272, HFD-850(Electronic Entry or Lee), HFD-110(CSO), HFD-860(Dorantesa. Mehta),
`CDR (B. Murphy)
`
`-
`
`,
`
`-
`
`~
`
`-
`
`e —. A.; H‘ - \ "’"T""“*I—"‘””"'
`
`~
`
`-«,
`
`w;
`
`_
`
`»
`
`.,,
`
`PageZofllZ
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
`
`NDA:
`
`21-272
`
`1PV
`TYPE:
`RemodulinTM
`BRAND NAME:
`treprostinol sodium
`GENERIC NAME:
`ALTERNATE NAMES: UT-IS, uniprost, LRX-lS, 15AU81,
`BW Al 5AU, U-62,840
`DOSAGE STRENGTH: 1.0, 2.5, 5.0, 10.0 mg/mL injection
`SPONSOR:
`United Therapeutics Corp.
`
`DIVISION OF PHARMACEUTICAL EVALUATION: I
`
`PRIMARY REVIEWER: B. Nhi Nguyen, Pharm.D.
`PHARMACOMETRICS REVIEWER: Jogarao Gobburu, Ph.D.
`TEAM LEADER: Angelica Dorantes, Ph.D.
`
`TABLE OF CONTENTS
`
`SUBMISSION DATES
`
`Original NDA 10/16/00
`Original amendment N-BB 1/25/01
`Original amendment N-BB 2/28/01
`
`PAGE
`
`4
`RECOMMENDATION (COMMENTS To THE SPONSOR) ..........................................................................................
`COMMENTS To THE MEDICAL omctknnn» ........ 4
`EXECUTIVE SUMMARY ......... ..
`.....................................
`
`6 8
`
`18
`
`15
`
`APPENDIX 11: REVIEW OF INDIVIDUAL STUDIES.... 33
`IN- VITRO PLASMA PROTEIN BINDING STUDY
`
`Report 7049-106 In vitro protein binding of [”C]-UT-l 5 in human plasma ..................................
`IN- VITRO METABOLISM STUDY
`
`34
`
`- Report 749-100 Effect OfUT-l 5 on cytochrome P450 isozymes ..................................................
`
`37
`
`MASS BALANCE STUDY
`
`P01 :10 Mass balance, metabolite profiling and safety study of ["C] UT-lS following an 8-hour SQ
`infusion in healthy males ...................................................................................................................
`
`PHARMACOKINETICS
`
`P01 :02 Bioavailability of SQ vs. IV UT-l 5 in NYHA Class HI/IV patients with primary pulmonary
`hypertension (PPH) ............................................................................................................................
`P01 :07 Bioavailability of SQ vs. IV UT-lS in healthy volunteers ..................................................................
`P01 :09 Phamiacokinetics of chronic, escalating doses of continuous SQ UT-l 5 in healthy volunteers ........
`
`PHARMACOKINE'ncs & PHARMACODYNAMICS
`
`P01 :03 Safety and efficacy of chronic (8 weeks) SQ UT-lS plus conventional therapy vs. conventional
`therapy in severe PPH ........................................................................................................................
`P01 :04 and P0l:05 Safety and efficacy ofchronic (12 weeks) SQ UT-lS plus conventional therapy vs.
`conventional therapy in pulmonary artery hypeflension ....................................................................
`
`39
`
`47
`54
`59
`
`66
`
`72
`
`SPECIAL POPULATIONS
`
`P02:0l Pharmacokinetics in portopulmonary hypertension with mild and moderate hepatic insufficiency
`
`82
`
`DRUG INTERACTION STUDIES
`
`P01 :08 Effects of acetaminophen on the phannacokineties of UT-l 5 in healthy volunteers ......
`
`P01 :12 Effect of UT-l 5 on warfarin PK/PD in healthy volunteers .............................................
`APPENDIX 11]: PHARMACOMETRICSREVIEW ......................................................................................................
`
`86
`90
`95
`
`Page3 ofllz
`
`
`
`

`

`I
`
`' NDA 21-272, Remodulinm, UT-lS, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`RECOMMENDATIONS
`
`The Office of Clinical Pharmacology and Biopharmaceutics has reviewed NDA 21 -272 and find
`the clinical pharmacology and biopharrnaceutics section acceptable provided the following
`comments to the sponsor are addressed:
`
`PPR“?
`
`The sponsor should identify the enzymes responsible for the metabolism of UT-l 5.
`The sponsor should make every effort to identify the fifth metabolite (HUI).
`The sponsor should make every effort to determine the activity of all five metabolites.
`Labeling comments #1 - 7 should be adequately addressed if the medical officer also
`concurs.
`
`COMMENTS TO THE MEDICAL OFFICER
`
`I. Exposure-Response
`The PK/PD analysis performed on the P01:04/05 data shows that UT—l 5 has a statistically
`significant effect on the hemodynamic variables PAPm, CI, SVOz and PVRI, and dyspnea
`(BORG score). Additionally, the change in PAPm correlated with the distance walked in six
`minutes by the patients. Although these relationships were statistically significant, the slope of
`the relationship was very shallow. Based on the shallow slope and the EC50 derived fi'om in-
`vitro experiments, the data are probably in the lower part of the exposure - response curve.
`Although uncertain, crude analysis suggests a dose-dependent opiate (surrogate for injection site
`pain) use.
`
`2. Tolerance
`
`We were unable to assess if patients develop tolerance to UT-l 5 with respect to its effect on
`PAPm. Although uncertain, crude analysis suggests a dose-dependent opiate (surrogate for
`injection site pain) use. Both PAPm and injection site pain are biomarkers of puhnonary and
`systemic vasodilation. Tolerance implies that higher exposure of the drug not necessarily
`produces proportionally greater effects. The fact that the PAPm was measured once at baseline
`and once towards the end of the study will not permit explorations of whether tolerance develops
`to UT-l 5. The frequency of patients with pain is dependent on dose rate in the P01 :04/05
`studies. The percentage of patients receiving opiates did not decrease at higher dose rates.
`
`3. Dose adjustmentfor body size
`Analysis of studies P01:04/05 and P01 :09 data suggest that dosing adjusted for ideal body weight
`(IBW) is more appropriate than dosing based on total body weight. The volume of distribution
`at steady state is not very large (~50 L/kg in a 70 kg IBW person) implying that the drug is not
`distributed into deeper adipose tissues.
`
`4. Hepatic insufliciency (HI)
`The sponsor studied patients with mild and moderate H]. The sponsor found that patients with
`mild and moderate HI have 2x and 4x higher Cmax, respectively, and 3x and 5x higher AUC 0.in
`
`Page4 ofll2
`
`
`
`

`

`i
`
`NDA 21-272, Remodulin‘m, UT-l 5, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`‘ than healthy subjects. Clearance is decreased by ~60% in mild HI and 80% in moderate HI
`compared to healthy adults. Effect of UT-l 5 in severe HI has not been established.
`
`5. Renal insufi’iciency
`UT-lS has not been studied in patients with renal insufficiency. UT-l 5 forms five metabolites
`(activity unknown), all of which are excreted in the urine. One metabolite is unidentified, and
`the other four are products of phase I and phase II biotransformation reactions. It may be
`possible for the metabolites to accumulate in severe renal insufficiency. Additionally, the '1‘ V2 of
`UT-15 is between 2-4 hours, however in the radiolabeled study, the radioactive T '/2 was 65
`hours. A plausible reason for this long T 1/2 is a slowly cleared metabolite.
`
`6. Metabolism
`
`The sponsor has not identified the enzymes responsible for the metabolism of UT-lS.
`
`OCPB briefing held on March 9, 2001.
`(Lesko, Lee P, Karkowsky, Lazor, Malinowski, Mehta, Sahajwalla, Dorantes, Gobburu,
`Bonapace, Fetterly, Kim J, Sobel, Chou W, Collins, Hussain were present.)
`
`«1’
`
`B. Nhi Nguyen, PharmD.
`Division of Pharmaceutical Evaluation I
`
`Primary reviewer
`——
`
`m‘
`
`Jogarao Gobburu, Ph.D.
`Division of Pharmaceutical Evaluation I
`Pharmacometrics reviewer
`
`Initialed by Angelica Dorantes, Ph.D.
`FT
`CC list: HFD-l 10: NDA 21-272; HFD-860: (Nguyen, Gobburuj, Mehta); CDER Central
`Document Room
`
`Page 5 ofllZ
`
`

`

`‘ NéDA 21-272, Remodulin‘m, UT—15, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`EXECUTIVE SUMMARY
`
`United Therapeutics Corp. is seeking the approval of UT—l 5 for the long-term treatment of
`pulmonary arterial hypertension in NYHA Class II-IV patients. UT-15 for injection contains the
`active ingredient treprostinol sodium, a structural analogue of prostacyclin which vasodilates
`pulmonary and systemic vasculatures, thus reducing pulmonary and systemic pressures. It is
`administered as a continuous subcutaneous (SC) infusion. The proposed initial infusion is 1.25
`ng/kg/min to be increased weekly by a maximum of 1.25 ng/kg/min for the first 4 weeks.
`Thereafter, the dose may be increased weekly by a maximum of 2.5 ng/kg/min. The usual dose
`studied in pharmacokinetic studies ranged from 2.5 — 15 ng/kg/min.
`
`Section 6 of NBA 21-272 includes 12 studies. An additional warfarin drug interaction study was
`later submitted and is also included in this review. Of the 12 studies submitted with the original
`NDA, ten were reviewed. These include three pharmacokinetic studies (acute and chronic), two
`PK/PD studies (8 and 12 weeks duration), one mass balance study, one in—vitro metabolism
`study, one in-vitro plasma protein binding study, one hepatic insufficiency study and one drug
`interaction study. The remaining two studies not reviewed are animal studies.
`
`.UT-15 is at least 91% bound to human plasma proteins. Absorption of SC UT-15 is relatively
`rapid and complete with an absolute bioavailability of ~ 100%. The rate of absorption following
`a SC infiision is slower than the elimination rate after an IV infiJsion. UT-15 is largely
`metabolized in the liver with less than 4% excreted unchanged in the urine. Five metabolites of
`unknown activity are formed. Each metabolite comprises 10-16% of the dose and are excreted
`primarily in the urine. Approximately 78.6% of the dose is excreted in the urine and 13.4% is
`excreted in the feces. In-vitro human hepatic cytochrome P450 studies indicate that UT-15 does
`not inhibit CYP1A2, 2C9, 2Cl9, 2D6, 2E1 or 3A. The enzymes responsible for UT-15
`metabolism have not been identified.
`
`The pharmacokinetics of SC UT-15 are linear over the dose range of 1.25 -— 22.5 ng/kg/min (0.03
`—— 8 ug/L) and could be described by a two-compartment body model. The terminal half—life of
`UT-lS is ~2-4 hours. Clearance is ~ 30 L/hr/70 kg ideal body weight person. Volume of
`distribution of the central compartment is small, ~ 14 um kg ideal body weight person.
`According to our population PK analysis there were no differences in pharrnacokinetics with
`respect to gender, age or obesity. Patients with mild and moderate hepatic insufficiency have 2x
`and 4x higher Cmax, respectively, and 3x and 5x higher AUC (an than healthy subjects.
`Clearance is decreased ~60% and 80% in mild and moderate HI, respectively. The effect of
`renal insufficiency is unknown, but may be of concern since the metabolites are excreted in the
`urine. There is no significant drug interaction between UT-l 5 and warfarin or UT-15 and
`acetaminophen.
`
`In support of approval for this NDA, the sponsor conducted one large clinical efficacy trial
`which is actually two combined trials, P01 :04 and P01 :05. Based on the PK/PD analysis
`(nonlinear mixed effects modeling) performed on the P01 :04 / 05 data, UT-l 5 has a statistically
`significant effect on the hemodynamic variables mean pulmonary artery pressure (PAPm),
`cardiac index, mixed venous saturation, and pulmonary vascular resistance index, and dyspnea
`(BORG score). Further, the change in PAPm correlated with the distance walked in 6 min by the
`
`Page6ofll2
`
`

`

`I
`" NDA 21-272, Remodulinm, UT-lS, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`patients. The model predicted that PAPm changes ~l% (relative to the placebo group) with one
`unit change in concentration or dose, and the distance walked in 6 min changes ~2% with one
`unit change in PAPm. These results are consistent with the conventional statistical findings.
`Although these relationships were statistically significant the slope of the relationship was very
`shallow. Based on the shallow slope and the BCso derived from in-vitro experiments, the data
`are probably in the lower pan of the exposure - response curve. Although uncertain, crude
`analysis suggests a dose—dependent opiate (surrogate for injection site pain) use.
`
`The assay ,a—-—--‘ used to quantify UT-lS was precise and accurate, but insensitive with
`respect to the lower limit of quantitation. Thus, the sponsor was unable to measure UT-l 5
`concentrations for an adequate duration to appropriately assess the pharmacokinetics in several
`studies.
`
`APPEARS THIS WAY
`ON ORIGINAL
`
`APPEAE—ZS ms WAY
`
`0N ORiGll‘iAL
`
`APPEARS nus WAY
`0N GRlGINAL
`
`Page7ofll2
`
`r“,
`
`/\
`
`"
`‘
`
`
`
`

`

`I
`
`' NDA 21-272, RemodulinT", UT-l 5, treprostinol sodium for injection
`Oflice of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`1. INTRODUCTION
`
`QUESTION BASED REVIEW
`
`A. WHAT ARE THE HIGHLIGHTS OF THE CHEMISTRY, FORMULATION AND PHYSICAL-
`CHEMICAL PROPERTIES OF THE DRUG AND DRUG PRODUCT?
`
`STRUCTURE
`
`UT-l 5 is (lR,2R,3aS,9aS)-[[2,3,3a,4,9,9a-Hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H-
`benz[flinden-5-yl]oxy]acetic acid monosodium salt.
`
`on
`
`H _
`
`H
`
`ocnzco2
`
`Na+
`
`molecular formula: C23H33Na05
`
`molecular wei ght: 412.49
`
`FORMULA TION AND MANUFACTURING
`
`UT-l 5 for injection contains the active ingredient treprostinol sodium. It is a white to cream
`
`colored powder It will be packagedin
`and suppliedin 20 mL multi-use vials1n
`dosage strengths of 1.,0 2. 5, 5.0 and 10 mg/mL of UT-15. The to-be-marketed formulations for
`UT-lS (see table below) were usedin all of the studies reviewed.
`
`mg per mL
`2.5
`5.0
`6.3
`6.3
`
`10.0
`6.3
`
`1.0
`6.3
`
`Ingredient
`Treprostinol
`Sodium citrate, USP
`(dihydrate)
`Hydrochloric acid, NF (mg, W
`q.s. pH 6.3 to 6.5)
`3.0
`3.0
`3.0
`3.0
`Metacresol, USP
`__.__—..—————--
`Sodium hydroxide, NF/BP
`5.3
`5.3
`5.3
`4.0
`Sodium chloride, USP
`Water for injection, USP/EP 9s.
`93.
`9.5.
`9.3.
`
`Sodium hydroxide and hydrochloric acid are added to obtain a target pH of 6.4 (range 6.3-6.5).
`It is chemically stable at room temperature and neutral pH.
`
`UT-l 5 injection for commercial distn'bution will be manufactured, packaged, and labeled by
`M NDA demonstration batches and Phase 3
`
`
`clinical batches were manufactured by
`by.--——--———-————~
`
`,7
`
`UT-15lS manufactured
`
`Pagesofllz
`
`
`wMWmmmwmwmwmwmmmmwmmwvmmu
`
`

`

`' ' NBA 21-272, Remodulinm, UT-IS, trcprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`‘ ¢_;x"__gmfl_,.,,;mw’a=«-e—-
`
`..
`
`r‘lxyWo-snvmzimwryvu.{ Ax‘flhrflzvmw .. .u H, . . .
`
`.
`
`“Km“...ufi‘
`
`. mm.WWW”~MA«m-ylfiwm>.~a ‘fln—mwww" ’ “'"'
`
`”av
`
`.4”
`
`L-pew“
`
`B. WHAT IS THE PROPOSED MECHANISM OF ACTION AND THERAPEUTIC INDICATION?
`
`UT-l 5 is vasodilates pulmonary and systemic vasculatures and inhibits platelet aggregation.
`United Therapeutics Corporation is seeking the approval of UT-l 5 for the long-term treatment of
`pulmonary arterial hypertension (PAH) in NYHA Class II - IV patients. Thus, the sponsor is
`seeking approval to treat patients with primary and secondary pulmonary hypertension.
`
`C. WHAT Is THE PROPOSED DOSAGE AND ADMINISTRATION?
`
`The proposed initial infusion is 1.25 ng/kg/min to be given as a continuous subcutaneous (SC)
`infusion. If intolerable, the initial infusion can be reduced to 0.625 ng/kg/min. The infiision can
`be increased weekly by a maximum of 1.25 ng/kg/min for the first 4 weeks. Thereafier, the
`infusion can be increased weekly by a maximum of 2.5 ng/kg/min for the remaining duration of
`the infusion. This is the same dosing scheme used in the pivotal clinical study, P01 :04/05.
`
`AN ) positive pressure micro-infusion pump is used to infiIse UT-15
`subcutaneously via an abdominal site.
`
`II. CLINICAL PHARMACOLOGY
`
`A. WAS THERE REASONABLE BASIS FOR THE SELECTION OF THE CLINICAL ENDPOINTS,
`SURROGATE ENDPOINTS OR BIOMARKERS AND WERE THEY MEASURED PROPERLY TO ASSESS
`
`EFFICACY AND SAFETY IN CLINICAL PHARMACOLOGY STUDIES?
`
`The clinical endpoint measured was distance walked in 6 minutes. This is typically used
`clinically to assess exercise capacity in patients with PAH. This was assessed by standard
`methods (measuring the distance a patient walked in 6 minutes). The typical distances walked in
`6 minutes were 350, 323 and 251 meters for NYHA Class II, III and IV patients, respectively.
`
`The biomarkers measured are measurements used to assess improvement and deterioration in
`patients with PAH. They include the following:
`
`mean pulmonary artery pressure (PAPm)
`
`Page9of112
`
`

`

`s
`NDA 2 l —272, Remodulinm, UT-lS, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamccutics Review
`Nhi Nguyen and Joga Gobburu
`
`'
`mean right arterial pressure (RAPm)
`pulmonary vascular resistance index (PVRI)
`cardiac index (CI)
`mixed venous saturation (SvOz)
`BORG dyspnea score
`
`Hemodynamic parameters were measured by insertion of a pulmonary artery catheter into the
`proximal pulmonary artery, at standard technique. The BORG dyspnea score was also assessed
`by standard techniques.
`
`B. WERE THE CORRECT MOIETIES IDENTIFIED AND PROPERLY MEASURED TO ASSESS CLINICAL
`PHARMACOLOGY?
`
`UT-lS was the only substance measured in plasma. None of its five metabolites (activity
`unknown) were measured in any of the clinical or pharmacokinetic studies.
`
`ASSA Y VALIDA TION
`
`C. WHAT ARE THE EXPOSURE—RESPONSE RELATIONSHIPS FOR EFFICACY AND SAFETY?
`
`The PK of UT-lS are linear and could be described by a twmcompartment model. The PK/PD
`analysis performed on the P01:04/05 data shows that UT-IS concentrations have a statistically
`significant effect on the hemodynamic variables PAPm, CI, SvOz and PVRI, and dyspnea
`(BORG score). Additionally, the change in PAPm correlated with the distance walked in 6
`minutes by the patients. Although these relationships were statistically significant, the slope of
`the relationship was very shallow. Although uncertain, cmde analysis suggests a dosedependent
`opiate (surrogate for injection site pain) use.
`
`0 Do PK PARAMETERS CHANGE WITH TIME?
`
`Page 10 ofllZ
`
`

`

`I
`
`3 NBA 21—272, Remodulin'm, UT-lS, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`The sponsor claims that there are indications of diurnal variation in the systemic clearance.
`Neither the changes in clearance over the time of the day are obvious from the concentration —
`time data, nor is there any a priori expectation for such a behavior.
`
`0 HOW LONG T0 ONSET?
`
`The pivotal studies (POI :04/05) are not designed to answer this question.
`
`0 HOW LONG T0 OFFSET?
`
`The pivotal studies (POI :04/05) are not designed to answer this question.
`
`D. ARE THE PHARMACOKINETICS lN HEALTHY VOLUNTEERS SIMILAR To THAT IN PATIENTS?
`
`Yes, the pharmacokinetics of UT-lS in healthy subjects are similar to that in patients. The
`phannacokinetics of the metabolites are unknown.
`
`ABSORPTION
`
`Absorption of SC UT-15 is relatively rapid and complete in healthy volunteers and in patients
`with primary pulmonary hypertension. Absolute bioavailability/of UT-l 5 is ~ 100%. The
`pharmacokinetics are dosevproportional over the dose range of 2.5 — 15 ng/kg/min (0.025 - ~10
`ug/L). Absorption of SC UT-15 is slower than the elimination after IV infitsion such that a
`marginal flip—flop phenomenon is observed (see next figure) in the terminal slopes.
`
`Figure. Individual plasma concentrations ofIV UT-1 5 (darker circles) and SC UT-15 in healthy
`volunteersfollowing a 2.5 hour infusion.
`
`W
`
`DISTRIBUTION
`
`The volume of distribution of the central compartment is small, ~ 14 U70 kg ideal body weight
`person. In-vitro studies indicate that UT-l 5 is ~ 91% bound to human plasma protein over the
`
`Page ll ofllZ
`
`

`

`r
`’ NDA 2l-272, Remodulin‘m, UT~lS, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`concentration of 0.05 — 50 ug/L. It is expected that at physiologic concentrations, 0.025 ug/L to
`7 ug/L, UT-l 5 will be at least 91% bound.
`
`.
`METABOLISM
`UT-l 5 is primarily metabolized in the liver. The enzymes responsible for its metabolism are
`.unknown. Five metabolites (HUI , HUZ, HU3, HU4 and HUS) of unknown activity have been
`identified in the urine, and account for 64.4% of the dose. There is no major metabolite. Each
`metabolite accounts for 10-16% of the dose. HUl is unidentified. HU2 and HUS are products of
`oxidation of the 3-hydroxyloctyl side chain, HU4 is the product of oxidation of the 3-
`hydroxyloctyl side chain with an additional dehydration of the 3-hydroxyl group of that side
`chain, and HUS is the product of glucuronidation. See figure below for proposed metabolite
`structures.
`
`Mfim
`(1:I sum)
`
`0
`koo
`H
`‘
`-———'—’
`
`on
`
`on
`
`ur'5
`
`mm a
`
`(1.34:w‘ii)
`
`mum H03
`
`(15.5statue)
`
`on
`
`Io
`
`n
`
`m Hm
`(10.: 15am)
`
`no
`
`OH
`
`NO
`
`0
`QA/O
`
`0
`o/k/
`t
`
`H
`
`Hummus
`(1021mm)
`
`' Position of “c label.
`
`EXCRETION
`
`The elimination is biphasic. The mean terminal half-life of SC UT-15 is ~2-4 hours. The
`primary route of elimination is renal, accounting for 78.6% of an administered dose. Mostly
`
`Pagen ofllZ
`
`

`

`-' N‘DA 21—272, Remodulinm, UT-IS, trrprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`metabolites are cleared in the urine since less than 4% of the dose is excreted as unchanged drug.
`Approximately 13.4% of an administered dose is excreted in the feces. Clearance is ~ 30 L/hr/7O
`kg ideal body weight person.
`
`0 WHA TAKE THE VARIABILITIES or PK PARAMETERS IN VOLUNTEERS AND PA HENTS?
`
`The inter—individual variability between volunteers and patients was similar. After adjustment
`for ideal body weight, the unexplained variability in clearance and volume of distribution of the
`central compartment was 1] and 33%, respectively.
`
`E. WHAT ARE THE INTRINSIC FACTORS THAT INFLUENCE EXPOSURE OR RESPONSE? WHAT IS
`THEIR IMPACT ON EXPOSURE AND/OR RESPONSE? BASED UPON WHAT Is KNOWN ABOUT
`
`EXPOSURE—RESPONSE RELATIONSHIPS AND THEIR VARIAEILITY AND THE GROUPS STUDIED,
`WHAT DOSAGE REGIMEN ADJUSTMENTS, IF ANY, Do YOU RECOMMEND FOR EACH or THESE
`GROUPS!
`
`0 ELDERLY
`
`There were no differences in pharmacokinetics in patients 2 65 years old according to the
`population PK/PD analysis.
`
`0
`
`PEDIA TRIC PA TIENTS
`
`This patient population was not studied.
`
`0 GENDER
`
`There were no differences in pharmacokinetics between males and females according to the
`population PK/PD analysis.
`
`0 RACE
`
`Most subjects studied were Caucasian (85% in the pivotal P01:04/05 study). Differences in PK
`between race were not assessed.
`
`0 RENAL INSUFFICIENCY
`
`Mass balance studies suggest that renal elimination is not important for the parent drug, UT-15,
`since < 4% is excreted unchanged in the urine. However, all five metabolites are excreted in the
`urine and account for 64.4% of the dose. Of the 92.2% of the dose eliminated 224 hours afier the
`infusion is initiated, 78.6% is in the urine and 13.4% is in the feces. Thus, the metabolites may
`accumulate in severe renal insufficiency. Studies in patients with renal insufficiency were not
`conducted.
`
`0 HEPA TIC INSUFFICIENCY (HI)
`Patients with mild and moderate HI have 2x higher Cmax and 3x higher AUC 04,“— compared to
`healthy subjects. Patients with moderate HI have 4x higher Cmax and 5x higher AUC (Hut
`compared to healthy subjects. Apparent clearance was ~60% lower in mild HI and 80% lower in
`moderate HI compared to healthy subjects.
`
`0 OBESITY
`
`Page 13 ofllz
`
`
`
`

`

`' NDA 21-272, Remodulin'm, UT—lS, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`According to the population PK/PD analysis, obesity does not affect the clearance of UT-lS,
`afier adjusted for ideal body weight.
`
`E. WHAT ARE THE EXTRINSIC FACTORS THAT INFLUENCE EXPOSURE OR RESPONSE?
`
`0 DRUG-DRUG INTERACTIONS
`In-vitro
`
`The enzymes responsible for the metabolism of UT-15 have not been identified. In-vitro human
`hepatic cytochrome P450 studies indicate that UT-lS does not inhibit CYP1A2, 2C9, 2C19, 2D6,
`2E1 or 3A.
`
`In-vivo
`
`UT-15 does not affect the pharmacokinetics or pharmacodynamics of warfarin. The
`pharmacokinetics of R— and S-warfarin and the INR in healthy subjects given a single 25 mg
`dose of warfarin were unaffected by continuous SC UT-lS, 10 ng/kg/min. The effects of
`warfarin on UT-IS were not determined.
`
`Analgesic doses of acetaminophen do not affect the pharmacokinetics of UT-l 5.
`Acetaminophen 1000 mg every 6 hours for 7 doses was given to healthy volunteers receiving
`UT-15, 15 ng/kg/min. The pharmacokinetics of UT—l 5 with acetaminophen and without
`acetaminophen were similar. The 90% confidence intervals for UT-15 Cmax and AUC ratio in
`the presence and absence of acetaminophen was within the 80 — 125% equivalence interval, 92.7
`— 105.7% and 88.8 - 101.7%, respectively. The efi'ects of UT-IS on acetaminophen ‘
`pharmacokinetics were not determined.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`Page l4of112
`
`

`

`i page(S) of
`revised draft labeling.
`has been redacted
`
`from this portion of
`the review.
`
`

`

`I
`
`’ NDA 21-272, Remodulinm, UT-l 5, trcprostinol sodium for injection
`Office of Clinical Pharmacology 8: Biopharamccutics Review
`Nhi Nguyen and Joga Gobburu
`
`l
`
`APPENDIX I
`
`Page IS of112
`
`l
`
`Ii
`
`j i
`
`I \
`
`V
`
`
`
`E
`
`
`
`v?
`
`i
`
`2
`
`r’
`
`

`

`
`
`W page(s) of
`revised draft labeling
`has been redacted
`
`frOm this portion of
`the review.
`
`
`
`

`

`I
`NDA 21-272, Remodulinm, UT-lS, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`
`
`ll
`
`APPENDIX II
`
`Page 33 ofIIZ
`
`
`
`

`

`NUA 21472, Remodulinm, UT-l5, treprostinol sodium for injection
`'
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`STUDY TITLE: The in-vitro protein binding of [”C] UT-lS in human plasma
`
`STUDY NO: r_.__
`
`7049-106
`
`VOLUME: 2.14
`
`PAGES: 3956 to 3995
`
`PRINCIPAL INVESTIGATOR: Sheela PaiBir, PhD
`CLINICAL LABORATORY:
`
`H...”M
`
`CITATION: not applicable
`
`PROPOSED ANALYTICAL START DATE: February 4, 2000
`PROPOSED ANALYTICAL END DATE: March 28, 2000
`
`OBJECTIVES:
`
`0 To determine the extent Of protein binding of UT-lS in female human plasma in-vitro;
`0 To evaluate the potential for protein binding interactions of UT~15 with digoxin and with
`warfarin in female human plasma
`
`PROCEDURE: The in-vitro protein binding of UT-IS was assessed by i M Pooled
`female human plasma was fortified with [MC] UT—15 (0.33 and 10 ug/mL ) and filtered in
`
`triplicate. An aliquot of the remaining plasma in the reservoir portion Of the
`was analyzed by -- to assess the total radioactive recovery.
`
`, device
`
`The effect Of UT-l 5 on the protein binding Of digoxin and warfarin was evaluated in human
`plasma at four concentrations of UT—l 5 (0.05, 0.5, 5 and 50 ug/L) and at a single concentration
`of the ligand, [3H] digoxin 2 ug/L and [”C] warfarin 2.5 ug/mL.
`
`The following test materials and lots were used:
` Materials Lots
`
`[ C] UT-l 5
`CSL-994832-83-2o
`UT-is
`UT15 RP-981001
`
`[3H] digoxin
`digoxin
`[‘ C] warfarin
`warfarin
`
`3363-229
`98H0922
`B60
`H-l
`
`STATISTICAL ANALYSIS: Descriptive statistics were used where appropriate.
`
`RESULTS: Protein binding to human plasma protein
`[”C] UT-l 5 was highly bound to human plasma proteins in females at concentrations of 0.33
`and 10 pg/mL (330 and 10,000 [Ag/L). Mean protein binding was 91% at both concentrations.
`Mean recovery Of[”C] UT—l 5—derived radioactivity following 1
`-—~
`was 104% at 0.33
`pg UT-lS/mL and 103% at 10 ug UT-lS/mL.
`
`Protein binding of digoxin and warfarin
`UT-15 over a concentration range Of 0.05 to 50 ug/L did not significantly affect the in-vitro
`protein binding of [3H] digoxin and ["C] warfarin in pooled female human plasma. Binding of
`
`Page 34 of l l2
`
`

`

`N‘DA 21-272, Remodulinm, UT-IS, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biophararnceutics Review
`Nhi Nguyen and loga Gobburu
`
`digoxin averaged 33.4% and 35.7% in the presence and absence, respectively, of UT-l 5.
`Binding of warfarin was 98.9% and 99.1% in the presence and absence, respectively, of UT-IS.
`
`Radiopurity and stability
`Results should be interpreted cautiously because of the impurity of [MC] UT-l 5. Radiopurity of
`[”C] UT-l 5 was less than 90%; 87.5% at the beginning ofthe study and 86.3% at the end ofthe
`study. This implies that [“C] UT-lS was stable during the study, but the impurities will
`contribute to the free fi’action of ["C] UT-lS.
`
`The radiopurity of [3H] digoxin and [”C] warfarin were high; 98.6% and 98.9%, respectively.
`
`Nonspecific Binding
`Ultraflltration was an acceptable method for assessing the in-vitro plasma protein binding of
`[”C] UT—l 5, [3H] digoxin, and [“c1 warfarin because the non-specific binding to the
`
`\—-/
`device was minimal. The mean percent bound to the
`device and the
`mean percent recovered are shown in the table below.
`% of radioactivity
`Bound
`
`Recovered
`
`("c1 UT-lS 0.33 ug/ml.
`[”C]UT-15 10 ng/ml.
`[3H] digoxin
`["q warfarin
`
`5.95
`8.23
`6.14
`3.95
`
`92.8
`98.0
`97.9
`97.7
`
`SPONSOR’S COMMENTS: Because of the limit of detection due to the specific activity of [MC]
`UT-IS, the lowest concentration was ~ 6.6 to 66 fold higher than physiologic concentrations of
`UT-ls (5-50 ug/L).
`
`The plasma protein binding of [”C] UT-lS in females was independent of concentration,
`suggesting that binding of UT—l 5 to plasma proteins in females is concentration-independent at
`the physiologic concentrations of UT—l 5.
`
`SPONSOR’S CONCLUSION: UT-15 is ~ 91% bound to human plasma protein in-vitro.
`
`UT-l 5, over the concentration range of 0.05 to 50 ug/L, does not have a significant effect on the
`protein binding of digoxin or warfarin in-vitro.
`
`REVIEWER’S COMMENTS: UT—15 is at least 91% bound to human plasma protein. Assuming
`there is saturable protein binding, then more drug is free (less bound) at high concentrations
`compared to low concentrations. Thus, at the lower concentrations that were measured in studies
`m