CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICATION NUMBER:
`
`' 22-3 87
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTIC S REVIEW! S 1
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
`
`NDA: 22-387
`
`Submission Dates: 06/27/08 and 08/25/08
`
`Relevant IND
`
`70,362
`
`Submission Type; Code
`
`Original NDA; N-OOO
`
`PDUFA Goal Date
`
`Brand Name
`
`Generic Name
`
`Formulation; Strength
`
`Indication
`
`Applicant
`
`Reviewer
`
`Secondary Reviewer
`
`OCP Division
`
`0ND Division
`
`Briefing Date
`
`,
`
`_
`
`April 24, 2009
`
`TYVASOTM
`
`Treprostinil sodium
`
`Solution for inhalation; 0.6 mg/mL
`
`Pulmonary Arterial Hypertension
`
`United Therapeutics Corporation
`
`Robert O. Kumi, Ph.D.
`
`Angelica Dorantes, Ph.D.
`
`DCPl
`
`Cardiovascular and Renal Products
`
`March 23, 2009
`
`Briefing Attendees: A..Dorantes, M. Mehta, D. Brum, R. Uppoor, K. Reynolds; S.
`Schrieber, J. Cho, I. Younis, D. Menon-Andersen, S. Brar, M. Pacanowski, T. Qng, J.
`Park, A. Karkowsky, S. Berkman, R.. Kumi
`
`Page 1 of 88
`
`~~--—-—-——~
`
`hi4)
`
`

`

`Table of Contents
`
`Table of Contents ................................................................................................................ 2
`1 Executive Summary ................................................................................................... 3
`1.1 Recommendation ................................................................................................................ 3
`1.2 Phase IV Commitments .............._........................................................................................ 4
`1.3 Key Clinical Pharmacology and Biopharmaceutics Findings ............................................. 4
`2 Question Based Review ............................................................................................ 6
`2.1 What are the general attributes of treprostinil sodium? ...................................................... 6
`2.2 What are the general clinical pharmacology characteristics of treprostinil? ...................... 7
`2.3 What intrinsic factors affect treprostinil exposure? .......................................................... 11
`2.4 What extrinsic factors affect treprostinil exposure? ......................................................... 11
`2.5 What are the biopharrnaceutic characteristics of treprostinil solution for inhalation?...... 14
`2.6 What assay was used to measure treprostinil plasma concentrations in clinical
`pharmacology studies? ............................................................................................................ l4
`3 Detailed Labeling Recommendations.............................................................. 15
`4 Appendices................................................................................................................ 16
`4.1 Proposed Labeling ............................................................................................................ 17
`4.2 Individual Study Reviews ................................................................................................. 32
`4.2.1 An open-label, randomized, three-period crossover comparative pharmacokinetics and
`steady state absolute bioavailability study of treprostinil sodium for inhalation administration
`of Remodulin® by continuous infusion to normal healthy volunteers (LRX-TRIUMPH
`BA.001)................................................................................................................................... 33
`4.2.2 A randomized, double—blind, placebo—controlled, single dose, phase 1 dose-escalating
`study to determine the maximum tolerated dose of inhaled treprostinil sodium in healthy
`volunteers (RlN-PH-102)......................-.................................................................................. 38
`4.2.3 A double blind randomized parallel group trial to define the ECG effects of inhaled
`treprostinil sodium using a clinical and supratherapeutic dose compared to placebo and
`moxifloxacin (a positive control) in healthy men and women: A thorough ECG trial (RIN-
`PH-103)................................................................................................................................... 42
`4.2.4 Effect of an evaluation ofthe steady state pharmacokinetics ofUT—15C SR (treprostinil
`diethanolamine) with Tracleer® (bosentan) following oral co-administration in healthy adult
`volunteers (TDE—PH-IOS)....................................................................................................... 47
`4.2.5 An Evaluation of the steady state pharrnacokinetics of UT-l 5C SR (Treprostinil
`Diethanolamine) and RevatioTM (Sildenafil Citrate) following oral co-administration in
`healthy adult volunteers (TDE-PH—106) ................................................................................. 55
`4.2.6 An Evaluation of single oral dose UT-15C SR (treprostinil diethanolamine)
`pharmacokinetics following repeated dosing with prototypical cytochrome P450 2C8 and
`2C9 enzyme inducer rifampin in healthy adult volunteers (TDE-PH—109) ............................ 62
`4.2.7 An Evaluation of single oral dose UT-15C SR (Treprostinil Diethanolamine)
`pharmacokinetics following repeated dosing with oral prototypical cytochrome P450 2C8
`(Gemfibrozil) and 2C9 (Fluconazole) inhibitors in healthy adult volunteers (TDE—PH-l 10) 67
`4.2.8 Evaluation of CYP450 induction by UT-15C using primary cultures of human
`hepatocytes (7049-122)........................................................................................................... 74
`4.2.9 Reaction phenotyping of the metabolism of UT-15C by human hepatic microsomal
`cytochrome P450 (49251) ....................................................................................................... 77
`4.3 Information Request Letter to Sponsor: Review Team’s Comments regarding Nebulizer
`(inhalation Device).................................................................................................................. 80
`4.4 NDA filing and Review Form/Refusal to File Criteria ..................................................... 85
`
`Page 2 of 88
`
`RN rim
`
`

`

`1 Executive Summary
`
`Introduction
`
`In NDA 22-3 87, TYVASOTM (treprostinil sodium) inhalation solution is proposed for the
`indication of Pulmonary Arterial Hypertension (WHO Group 1) in patients with New York Heart
`Association Class III ‘ \ymptoms. Treprostinil is currently approved for the same indication
`as Remodulin injection for subcutaneous and intravenous administration (NDA 21-272). The
`applicant, United Therapeutics, was granted orphan designation for the stated indication in 1999.
`
`M4)
`
`Treprostinil is a stable, synthetic analog of prostacyclin. The major pharmacological effects of
`treprostinil are vasodilatation, inhibition of platelet aggregation and inhibition of smooth muscle
`cell proliferation. Tyvaso will be supplied in 2.9 mL ampoules containing 0.6 mg treprostinil per
`milliliter and is intended for oral inhalation use with a nebulizer (Optineb). The proposed product
`will be closed in four separate inhalation sessions per day, during the waking hours. Each breath
`is expected to deliver a dose of 6 ug. Initial therapy should begin with three breaths (18 pg
`treprostinil) and the maximal target dose per session is 54 pg (9 breaths).
`
`The clinical development program for NDA 22-3 87 includes approximately 20 studies involving
`the assessment of pharrnacokinetics (PK) of inhaled treprostinil, drug interactions with oral
`treprostinil, and in vitro metabolism. The PK studies were conducted to characterize the
`bioavailability of the new formulation, whereas the latter sets of studies were conducted to
`supplement existing information on approved or investigational treprostinil products. Nine of the
`20 studies were reviewed as they are most relevant to the current application. The remaining
`studies submitted in NDA 22-3 87, including investigator sponsored studies were not reviewed as
`they did not provide pertinent information.
`
`1.1 Recommendation
`
`The Office of Clinical Pharmacology and Biopharrnaceutics (OCPB) has reviewed the
`information submitted to NDA 22-387. The clinical pharmacology and biopharrnaceutics
`information provided in NDA 22—3 87 is acceptable, pending confirmation from the CDRH
`consultant that the inhalation device accurately delivered the dose reported in the
`pharmacokinetic (PK) studies. Without this confirmation, the reliability PK information is
`unclear and renders the PK information related to inhalation unacceptable. OCP has the
`following comments:
`
`General Comments
`
`1.
`
`2.
`
`If CDRH does not confirm the precision/accuracy of the delivery system, the applicant will
`need to conduct a bioavailability (PK) assessment of inhaled treprostinil using the to-be-
`marketed formulation and device.
`
`In multiple studies, some subjects (one or more) had undetectable or low treprostinil
`exposure compared to other subjects. The reason for these low exposures is unclear but may
`be related to the failure of the inhalation device (nebulizer) or factors intrinsic (e.g. CYP2C8
`polymorphism) to the patients. In this reviewer’s opinion, the low drug exposure is more
`likely due to issues related to the drug delivery device, and should be addressed by the
`Applicant.
`
`

`

`Labeling Comments
`Overall, the labeling proposed by the Applicant is acceptable; the majority of information is
`obtained from the labeling for NDA 21-272 (Remodulin). There should be minor modifications
`to the pharmacokinetics section: 1) statements regarding the linear range following inhaled
`treprostinil administration and 2) general editorial changes to the pharmacokinetic section to
`make the information clearer.
`
`1.2 Phase IV Commitments
`None
`
`1.3 Key Clinical Pharmacology and Biopharmaceutics Findings
`
`General Treprostinil Pharmacokinetics Following Inhalation
`The following estimates for PK measures (healthy volunteers) were obtained for inhaled
`treprostinil (single dose) for doses ranging from 18 to 90 pg:
`0 Tmax range = 0.12 — 0.25 hr (three studies)
`- T1/2 range = 0.46 — 0.62 hr (three studies)
`0 Vz/F range = 45 - 64 L (two studies); 0.78 — 1.00 L/kg (one study)
`- CL/F range = 60 - 77 L/hr (two studies); 1.01 — 1.45 L/hr/kg (one study)
`\/ Absolute Bioavailability
`The absolute bioavailability (F) estimations for inhaled treprostinil are summarized in the
`following table; F appeared to depend on dose.
`
`Table 1: Statistical Analysis in treprostinil absolute bioavailability* study (11 = 18, per group)
`
`
`
`_ Three Breaths = 18
`;
`Six Breaths = 36
`;
`— Bioavailabilit
`(F %
`
`Mean CV %
`
`
`
`
`
`61.52 29.68
`740542123)
`
`
`Median (Ran_e)
`60.84 (13.08— 90.69)
`70.27 (52.36 — 115.99)
`
`
`* IV dose = single 15 ng/kg/min infusion for 60 minutes
`
`
`
`
`
`
`PK Linearity (Dose Proportionality)
`Based on pooled plasma exposure data from three studies, treprostinil exposure was dose
`proportional over the 18 to 90 ug range following single dose administration.
`
`Intersubj ect variability
`The intersubject variability in pharmacokinetic measures ranged form approximately 20 to 67 %.
`In some instances, subjects had low or undetectable concentrations; the source of the variability
`is not clear, but is likely associated with the lack of reproducibility of the inhalation device
`(uncertainty of the administered dose).
`
`In Vitro Metabolism
`
`' The metabolism of treprostinil was evaluated in two in vitro studies. The results showed that;
`o CYP Substrate Status: Treprostinil is metabolized primarily by CYP2C8 followed by
`CYP2C9 to a minor extent; other CYP enzymes do not play a role in treprostinil metabolism.»
`
`

`

`o CYP Induction Potential: Treprostinil (2 and 10‘ MM) does not appear to induce the enzymatic
`activity of CYP1A2, CYP2B6, CYP2C9, CYP2C19, or CYP3A4 isoforms in human
`hepatocytes.
`'
`
`Bosentan
`
`Sildenafil
`
`
`
`
`
`
`
`
`Drug-Drug Interaction Studies with Oral Treprostinil
`The table below summarizes the drug interaction findings, where oral treprostinil (1 mg BID)
`was administered with other drugs (administered at clinically relevant dosages).
`Table 2: Drug-Drug Interaction Information for Orally Administered Treprostinil
`
`
`
`Basis for conductin
`
`
`
`
`Used in PAH as background
`
`No PK effect on either compound or bosentan metabolite;
`
`therapy and CYP inducer,
`possible increase in adverse events (AE3) for dual therapy
`
`
`
`(er A licant
`nossible PK/PD
`No PK effect on either compound or sildenafil metabolite;
`Used in PAH as background
`
`thera- , .ossible PD
`
`nossible increase in AEs for dual thera
`Per A n licant)
`
` Probe CYP inducer
`-
`Treprostinil AUC decreases by about 30 %
`
`
`
`o
`Treprostinil Cmax decreases numerically by 20 %, but
`
`
`
`the decrease is not statisticall si ificant
`
`
`CYP2C8 inhibitor expected to-_
`Treprostinil AUC and Cmax increased approximately 2-fold
`
`
`-—
`Treprostinil AUC decreased by approximately 14 %
`No effect on Cmax '
`
`
`
`QT Prolongation
`Inhaled treprostinil did not prolong the QT interval when administered as a single dose of 54 pg
`(target dose per inhalation session) or 84 ug (supra-therapeutic dose).
`
`O o
`
`Gemfibrozil
`
`Fluconazole
`
`CYP2C9 inhibitor expected to
`
`Formulation and Delivery Device
`Tyvaso will be supplied in 2.9 mL ampoules containing 0.6 mg treprostinil per milliliter and is
`intended for oral inhalation use with a nebulizer (Optineb-ir).
`
`Signatures
`
`Primary Clinical Pharmacology Reviewer
`
`Robert O. Kumi
`
`Acting Team Leader
`
`Angelica Dorantes
`
`CC:
`
`NDA 22-387; Dorantes Uppoor Mehta RKumi (HFD 860)
`
`

`

`Question Based Review
`2
`This clinical pharmacology and biopharmaceutical (CPB) review for NDA 22-3 87 employs an
`abridged version of the ‘Question Based Review’ (QBR) since most QBR elements were
`addressed in the original CPB review for treprostinil sodium for injection (NDA 21—272). Please
`refer to NDA 21—272 for information on human pharmacokinetics and bioavailability of
`treprostinil. The QBR elements addressed in detail in this Clinical Pharmacology Review are
`Clinical Pharmacology and Extrinsic Factors. In all, nine studies were reviewed.
`
`2.1 What are the general attributes of treprostinil sodium?
`Regulatogy Histog
`o NDA 21-272, Remodulin (treprostinil sodium) solution for injection (IV or SC) was approved
`in May 2002 for the treatment of pulmonary arterial hypertension in patients with NYHA
`Class III or IV symptoms to diminish symptoms associated with exercise.
`'
`0 The Applicant informed the Agency that the inhaled treprostinil NDA would include the
`’
`Optineb nebulizer device,
`'
`‘
`‘ K; "
`‘ “
`' “ ‘
`during the NDA review. CDRH is responsible for reviewing the suitability of the nebulizer
`devices.(Pre-NDA meeting held on May 16, 2008 for IND 70,362)
`0 The Applicant agreed to provide the missing drug interaction information for Remodulin; it
`was agreed that drug interaction information with oral treprostinil and a few selected
`compounds would be acceptable for this purpose (EOPl meeting held on November 9, 2005
`for IND 71,537, oral treprostinil)
`
`M4)
`
`Highlights of the chemistlgy and physical—chemical progerties of the drug substance and the
`formulation
`
`Please refer to the Clinical Pharmacology Review of NDA 21—272 (treprostinil sodium solution for
`injection) for detailed information on the chemistry and physical-chemical characteristics of
`treprostinil. The only difference between the formulation in NDA 22-3 87 for inhaled treprostinil
`sodium (TYVASOTM) and NDA 21—272 is the abSence \ in the
`product for inhalation. Tyvaso is supplied in 2.9 mL ampoules containing 0.6 mg treprostinil per
`milliliter. The product is to be administered undiluted, as supplied, using the Optineb-ir.
`
`M4)
`
`Proposed therapeutic indication and mechanism of action
`TYVASO will be indicated for the treatment of pulmonary arterial hypertension (WHO Group 1)
`in patients with NYHA Class III x. symptoms.
`
`We)
`
`The major pharmacologic actions of treprostinil are direct vasodilation of pulmonary and systemic
`arterial vascular beds, inhibition of platelet aggregation and inhibition of smooth muscle cell
`proliferation.
`
`Progosed route of administration and dosage
`Tyvasowill be delivered via inhalation using a nebulizer, Optineb-ir. The dosage instructions
`follow:
`
`General Dosage Recommendations (per label)
`TYVASO is dosed in four separate inhalation sessions per day, during waking hours. The
`inhalation sessions should be at least 4 hours apart.
`
`

`

`Initial Therapy
`0 Therapy should begin with three breaths of TYVASO (18 pg of treprostinil), per inhalation
`session given four times per day
`If three breaths per session are not tolerated, the dose may be reduced to one or two breaths
`and subsequently increased to three breaths, as tolerated.
`
`0
`
`Maintenance Therapy
`0 Dosage should be increased to six breaths per inhalation session given four times daily, and
`subsequently increased to the target maintenance dose of nine breaths (54 pg of treprostinil)
`per inhalation session given four times daily, as tolerated.
`If adverse effects preclude titration to this target dose, TYVASO should be continued at the
`highest dose that is tolerated by the patient.
`
`o
`
`The label also notes the following additional two points:
`0 The maximum dose used in clinical studies was 12 breaths (72 ug of treprostinil), per
`inhalation session.
`
`0
`
`If a scheduled inhalation session is missed or interrupted, therapy should be resumed as soon
`as possible.
`
`2.2 What are the general clinical pharmacology characteristics of
`treprostinil?
`
`Design Features of Clinical Study
`One pivotal clinical efficacy study, TRIUMPH I ('I‘Reprostinil sodium Inhalation Used in the
`Management of Pulmonary arterial Hypertension), was conducted. Some features of the
`TRIUMPH study are tabulated below.
`
`Table 3: Design features of pivotal clinical study
`
`
`
`Duration/number of subjects
`Description
`
`
`
`
`Background therapy
`
`Dosage in blinded phase
`
`'
`
`
` Dosae in men label extension
`
`12-week / 235
`Randomized, double-blind, placebo--controlled multi—
`center stud
`
`PAH patients who are clinically stable, WHO Group 1,
`NYHA Class III and IV s m toms
`
`approved therapy for PAH: bosentan (Tracleer) or
`sildenafil (Revatio); patients on these for at least three
`months urior to stud initiation
`
`
`
`
`
`
`
`
`
`anticoagulants, other vasodilators (e.g., calcium channel
`
`blockers), diuretics, oxygen, and digitalis, but not
`
`rostac clin or its analo_ues.
`
`four daily inhalation sessions with a target dose of 9
`
`breaths (54 mcg) per session over the course of the 12-
`
`week stud .
`
`
`maximum dose of 12 breaths (72 me; ner session.
`
`
`
`Clinical Response Endpoints
`The primary efficacy endpoint of the trial was the change in six-minute walk distance at 12 weeks
`measured at peak exposure (between 10 and 60 minutes after dosing), relative to baseline. This
`endpoint has been used in previous PAH clinical trials and is considered acceptable. Secondary
`endpoints included the following: Changes in Borg dyspnea score, PAH signs and symptoms, and
`NYHA functional class from Baseline to Week 12; there was also a quality of life assessment via a
`questionnaire.
`
`

`

`2.2.1 Are the active moieties in the plasma appropriately identified and measured
`to assess PK parameters and exposure response relationships?
`Yes, please refer to 2.6, Analytical Section.
`
`2.2.2. What are the characteristics of the exposure-response relationships for
`effectiveness and safety?
`No specific exposure-response data or quantitative analysis were collected or conducted for
`inhaled treprostinil; however, some useful empirical information was obtained from the various
`individual studies. Pharmacokinetic exposure data were not collected in the pivotal clinical trial.
`
`Exposure-Effectiveness Information
`Exposure-effectiveness data were not collected in the pivotal clinical trial. However, plasma
`exposure associated with the initial proposed dose, 18 pg, the targeted dose, 54 pg, and the
`maximum daily dose in clinical studies, 72 pg, (per inhalation session) are available. It should be
`noted that these data were obtained in healthy volunteers, rather than patients.
`
`Exposure-Safety Information
`In the single dose safety and tolerability study, the sponsor concluded that the maximum tolerated
`dose was 84 pg; the 90 pg dose Was considered intolerable and was associated with chest pain,
`chest discomfort, nausea and vomiting. The plasma concentrations associated with 84 and 90 pg
`single doses are available from healthy volunteers. It should be noted that in the pivotal clinical
`trial, the maximum inhaled dose per session was 72 pg given on multiple occasions.
`
`Evaluation of QT or QTc interval prolongation
`Tyvaso does not prolong the QT interval. Following a single dose of 54 pg (recommended clinical
`dose) and 84 pg (supratherapeutic dose), treprostinil had no effect on cardiac conduction.
`
`Suitabilifl of the sponsor’s selected dose, dosing regimen, and delivery device
`The proposed initial and maintenance dosing appear reasonable from a clinical pharmacology
`perspective; however, it is should be noted that
`a)
`there18 no definitive exposure (dose)-response information
`b) concern remains regarding the utility of the nebulizer with respect to its ability to reliably
`deliver the planned dose
`
`The first concern is somewhat alleviated by the fact that the clinical trials demonstrated that the
`product is effective (satisfied primary endpoint) at the proposed dose range. In all three studies,
`where exposure data were collected, there were one or more patients who had no or low drug
`exposure, suggesting that treprostinil was not delivered correctly via device or absorbed
`appropriately. CDRH and other CDER consulting staff have raised questions concerning the
`suitability of the device due to the somewhat complex nature of how the device must be operated.
`Please refer to attached document in Appendix 4.3. It should be noted that treprostinil is a
`substrate of CYP2C8 that exhibits genetic polymorphism; this can lead to differential exposure
`levels among subjects. The treprostinil development program did not include phenotyping or
`genotyping, thus the role of CYP2C8, if any, cannot be evaluated.
`
`The Clinical Reviewer, Abraham Karkowsky, MD, has also noted the following issues regarding
`the suitability of the proposed dosing regimen:
`
`

`

`0 There is no demonstration of effect over the inter-dosing interval (time between inhalation
`sessions and during sleeping hours): walk distance was evaluated at 10 minutes and 60
`minutes post inhalation
`0 There is no demonstration of an effect for a period greater than a year: this is a concern since
`there is evidence with Remodulin that “tolerance” appears to develop over time
`
`2.2.3 What are the pharmacokinetics (PK) of treprostinil following inhalation?
`Following inhalation, the PK of only parent drug, treprostinil, were determined; following
`subcutaneous and intravenous administration, five metabolites have been described (HUI to HUS)
`but the biological activity and metabolic fate of these metabolites is unknown.
`
`The accuracy of the PK information hinges on the reliability of the dose delivered via the
`nebulizer. In the following sections, the doses are assumed to be accurate and reflect the actual
`delivered dose.
`
`Single dose PK measures (Studies LRX-TRIUMPH BA.001, RIN-PH-IOZ, and RIV-PH-409)
`The following table summarizes the single dose PK data obtained from three studies.
`
`
`
`Table 4: Summary of PK measures for inhaled treprostinil*
`PK Measure
`Value
`Tmax (hr)
`0.12 — 0.25
`T1/2 (hr)
`0.46 — 0.62
`Ava (L)
`45 — 70
`"CL/F (L/hr)
`6O — 101
`* data from three studies have been recorded in the same units for ease of interpretation; where necessary, the
`assumed body weight was 70 kg
`A data were reported in a dose normalized fashion for one study
`
`The inhaled treprostinil doses ranged from 18 to 90 ug and data were consistent in all three
`studies. A representative mean plasma concentration-time profile (QT study) following single
`dose administration is depicted in the figure below.
`
`Figure 1: Treprostinil plasma concentration-time profile following inhalation of treprostinil
`1000010
`
`
`
`
`
`Cnnrrnlrzulnn(pg/mL)
`
`“100,0
`
`1.0
`
`9.1
`
`0
`
`r»
`
`.
`I
`
`x
`
`r
`4
`
`r
`
`I
`
`I
`
`U
`r1
`I
`~
`~r——n-
`f"“"l‘
`1
`1— "
`[3
`26
`I4
`‘2
`10
`8
`6
`
`Time (hours)
`-—0—- Treatment C: Inhaled Trcprosu'nil Sodium 54 meg
`_- - D ‘ Jazmin! D: Inhaled Trtamsu'nllsmimn unacL
`
`r
`
`1-
`
`r— )1
`10
`
`1
`D
`
`r
`
`24
`
`_ _
`
`

`

`Drug absorption
`Following inhalation, treprostinil was absorbed in a rapid manner with maximum concentrations
`achieved within 15 minutes. The absolute bioavailability was approximately 68 % (data flom two
`dose levels). The studies in this NDA did not evaluate the effect of swallowing the solution vs.
`Inhalation*. It is unclear if any of the data 'may have been altered by subjects inadvertently or
`intentionally swallowing the formulation.
`* the label (Overdose Section) indicates that a patient accidentally swallowed an unknown quantity of Tyvaso
`
`Drug Distribution
`The apparent volume of distribution ranged from 45 to 70 L
`
`Dose proportionalifl of treprostinil following inhalation
`Treprostinil exhibited dose-proportional increases in exposure over the 18 to 90 pg dose range.
`Figure 2: Evaluation of PK linearity* (dose proportionality) following inhaled treprostinil administration
`(Cmax vs. Dose, left panel and AUC vs. Dose, right panel: Reviewer Generated)
`
`Cm vs. Dnsnwnol M add)
`
`R’=o.sasa
`y=|szsn
`
`o Cm
`._.me (em)
`
`AUC vs. Dose (Linear Model)
`‘
`y=15.977x
`R2 = 0.9507
`
`—|
`
`1600
`
`.
`
`0 AUG
`
`A
`
`— Linear (AUC)
`
`
`0
`
`20
`
`40
`
`60
`
`80
`
`100
`
`TThe power model yielded the same conclusion regarding dose proportionality (not included)
`
`PK in healthy volunteers vs. patients
`PK data were obtained only in healthy volunteers, thus no comparison with patients is possible.
`Treprostinil is administered via a nebulizer with inherent complexity in usage that may pose some
`challenges for people who have breathing difficulty, such as patients with PAH. Consequently, it
`is unclear if patients and healthy volunteers will have similar PK following the inhalation of
`treprostinil.
`
`Intersubiect variability of PK parameters in volunteers
`Following inhalation of treprostinil, intersubject variability in CL/F and Vz/F ranged from 25 to
`120 %; as expected the highest variability was associated with cohorts with a small number of
`subjects (n = 6 was smallest size). However, even with n = 60 in the QT study, CV for the PK
`parameters was 42 to 62 %. This finding indicates that the absorption or delivery of treprostinil
`following inhalation is highly variable.
`
`The variability of exposure is further highlighted in the following table that provides a summary of
`treprostinil concentrations at given dose levels and time points.
`
`10
`
`

`

`Table 5: Example of intersubject variability in concentrations at the same point (Reviewer Generated)*
`
`Concentration
`Min
`Max
`Mean
`Standard Dev.
`
`n = 59
`T1
`262.00
`2210.00
`1324.00
`407.00
`
`CV (%)
`Ratio (Max/Min)
`
`30.74
`8.44
`
`T2
`143.00
`1177.00
`777.00
`186.00
`
`23.94
`8.23
`
`Dose = 54 microgram
`T3
`18.00
`356.00
`153.00
`64.00
`
`41.83
`19.78
`
`L1
`34.00
`473.00
`250.00
`179.00
`
`71.60
`13.91
`
`1616.00
`845.00
`542.00
`
`64.14
`12.06
`
`
`
`Concentration
`Min
`Max
`Mean
`Standard Dev.
`
`n = 60 ’
`T1
`331.00
`3589.00
`1776.00
`652.00
`
`T2
`331.00
`1722.00
`1042.00
`289.00
`
`Dose = 84 microgram
`T3
`50.00
`209.00
`467.00
`82.00
`
`L1
`179.00
`1011.00
`529.00
`347.00
`
`n = 6
`L2
`820.00
`2508.00
`1619.00
`739.00
`
`L3
`649.00
`1142.00
`846.00
`185.00
`
`.
`
`21.87
`45.65
`65.60
`17.56
`27.74
`36.71
`CV (%)
`1.76
`3.06
`5.65
`4.18
`5.20
`10.84
`Ratio (Max/Min)
`* T1 and L1 represent time point with first measurable concentration; T2 and L2 represent intermediate time
`point; T3 and L3 represent terminal time point (last time point with measurable concentration)
`
`Overall, the concentration data suggest that at any given time there is a great variation in the
`concentrations among patients. It should be noted that one subject in the 54 pg cohort (n = 59) did
`not have any detectable concentrations. This finding may pose clinical concern because a priori
`one could not determine which subjects would have inadequate exposure to treprostinil;
`consequently, it is possible that some subjects receiving Tyvaso may not receive a therapeutic
`dose and be unresponsive to treprostinil therapy.
`
`2.3 What intrinsic factors affect treprostinil exposure?
`
`The effect of intrinsic factors on treprostinil exposure was not evaluated in NDA 22-3 87.
`However, the intrinsic factors that were identified for Remodulin should be applicable to Tyvaso,
`as they contain the same active, major circulating moieties.
`
`2.4 What extrinsic factors affect treprostinil exposure?
`
`Extrinsic factors related to metabolic drug interactions were found to alter treprostinil exposure
`following oral administration; these factors in addition to those identified previously for
`Remodulin will be applicable to treprostinil exposure resulting from Tyvaso administration.
`
`In vitro metabolism
`
`CYP Substrate Status (Study 49251)
`Treprostinil was metabolized primarily by CYP2C8 and CYP2C9 to a lesser extent. The other
`evaluated CYP enzymes CYP1A2, 2A6, 2C19, 2D6, 3A4 and 4A11 do not metabolize treprostinil
`to a significant extent.
`
`ll
`
`

`

`Studies conducted with microsomes confirmed CYP involvement in treprostinil metabolism.
`Subsequently, studies with c-DNA enzymes identified two main enzymes, CYP2C8 and CYP2C9,
`as being primarily responsible for treprostinil metabolism (Table 6). CYP2C8 was confirmed as
`the main metabolic. pathway for treprostinil using two specific chemical inhibitors: quercetin
`(CYP2C8 — prevented treprostinil metabolism) and sulfaphenazole (CYP2C9 -— 35 % of
`treprostinil was metabolized.)
`
`Table 6: Treprostinil metabolism with c-DNA expressed enzymes
`
`
`
`
`_~ .
`
`% Remaining
`lsozyme
`0 min
`15 mln
`Average %CV Average
`sscv
`932467
`9.57
`1056000
`4.27
`1132000
`0.81
`1169867
`6.18
`
`1061700
`9.74
`54550
`12.27
`
`
`733500
`10.29
`570100
`19.90
`
`1098333
`7.19
`1143000
`7.89
`
`
`
`1282333
`4.21
`1142667
`6.18
`
`
`1135333
`10.13
`1180667
`10.44
`
`
`
`1286687
`4.00
`1364333
`6.35
`
`
`
`
`711266
`7.68
`781767
`4.42
`
`
`% Remaining = Peak Area at 15 min I Peak Area at 0 min
`Note: Vamas greater than 100% o! Trepmsllnli Remaining are not fign‘xfimnlly different 1mm five
`negative control values
`
`CYP Induction Potential (Study 7049-122)
`Treprostinil (2 and 10 uM) does not appear to induce the enzymatic activity of CYP1A2,
`CYP2B6, CYP2C9, CYP2C19, or CYP3A4 isoforms in human hepatocytes (in vitro). This finding
`suggests that clinically, treprostinil will not alter the exposure of substrates for these enzymes.
`
`12
`
`

`

`In vivo Drug Interaction Studies
`Orally administered treprostinil underwent a drug interaction when coadministered with
`gemfibrozil (CYP2C8 inhibitor) and rifampin (CYP inducer); whereas there was no clinically
`significant interaction with sildenafil, bosentan or fluconazole.
`
`The following figures depict treprostinil exposure changes with gemfibrozil and rifampin.
`Figure 3: Plasma concentration time profiles of treprostinil in drug interaction studies (gemfibrozil,
`left panel and rifampin, right panel)
`
`05
`
`0
`
`0.4
`
`am:ngm.
`
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`
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`
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`30
`40
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`
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`
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`
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`
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`
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`
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`
`of
`The following table summarizes the findings in the treprostinil drug interaction studies:
`coadministration of oral treprostinil (1 mg BID) with probe compounds (administered at
`clinically relevant dosages).
`
`
`
`Table 7: Treprostinil drug interaction profile (pharmacokinetic/PK and pharmacodynamic/PD)
`
`
`
`
`Finding
`Study/Drug
`Basis for conducti_ng_ study
`
`
`No adjustment
`No PK effect on either compound or
`TDE-PH—l 05/
`Used in PAH as
`
`
`
`
`Bosentan
`background therapy and
`bosentan metabolite; possible increase in
`needed for either
`
`
`
`CYP inducer; possible
`compound
`adverse events (AE5) for dual therapy (per
`
`
`PK/PD
`'
`
`A - nlicant
`
`TDE-PH-106/
`
`
`
`
`
`Used in PAH as
`No PK effect on either compound or
`No adjustment
`Sildenafil
`needed for either
`
`
`background therap)’;
`sildenafil metabolite; possible increase in
`
`
`
`
`comnound
`
`
`nossible PD
`AEs for dual theran (er A a nlicant)
`
`In presence of
`Probe CYP inducer that
`Treprostinil AUC decreases by about 30 %
`TDE-PH-109/
`
`
`
`
`rifampin Treprostinil
`Rifampin
`can decrease treprostinil
`Treprostinil Cmax decreases numerically
`
`
`
`
`may not be as
`exposure
`by 20 %, but the decrease is not statistically
`
`
`
`significant
`
`effective as in
`absence of rifam nin
`
`
`
`TDE-PH-l 10/
`Probe CYP2C8 inhibitor
`
`
`Treprostinil plasma AUC and Cmax
`
`
`Treprostinil dose
`
`
`Gemfibrozil
`expected to inhibit
`should be reduced to
`increased approximately 2-fold
`
`
`
`
`
`trenrostinil metabolism
`
`
`
`avoid high ex osure
`
`
`
`TDE-PH-l 1 0/
`