NDA 21-272, Remodulinm, UT-l5, treprostinol sodium for injection
`’
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`Plasma clearance values for all of the four doses ranged from W
`”'"j'
`, supporting the linear kinetics over the dose range used. The terminal
`T '/2 determined afier termination of the 15 ng/kg/min infusion was 2.93 hours. Inter-subject
`variability of Css,CL and T '/2 ranged from 13.6 - 25.5%. The mean concentration-time data
`after the end of the infusion is shown below.
`
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`SPONSOR’S CONCLUSIONS: Over a 24-hour steady state period, plasma UT-15 concentrations
`achieved peak levels twice (at 1 am. and 10 a.m., respectively) and achieved trough levels twice
`(at 4 pm. and 7 a.m., respectively). The peak concentrations were approximately 20 to 30%
`higher than the trough concentrations.
`
`Pharmacokinetic linearity was demonstrated over the dose range of 2.5 to 15 ng/kg/min.
`
`The mean apparent elimination T '/2 of chronic SC UT-15 was ~3 hours with a CV of 26%.
`
`REVIEWER’S COMMENTS: PK linearity was observed in health volunteers over the dose range
`of2.5 — 15 ng/kg/minv—‘\___/-%<)pulation PK analysis ofthe
`data produced similar clearance values (40.8 L/hr/70 kg) to those obtained by the sponsor.
`
`It is not clearly evident that SC UT—l 5 produces two peaks and two troughs. The sponsor
`proposes that a peak occurs at l a.m., troughs 6 hours later at 7 a.m., peaks again 3 hours later at
`10 a.m., then troughs 6 hours later at 4 pm. Nine hours then separates the 4 pm. trough and 1
`am. peak. However, the sponsor did not measure concentrations at these times. Concentrations
`
`Page“ 01112
`
`

`

`NDA 21.272, Remodulin‘m, UT-lS, treprostinol sodium for injection
`'
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`during the 24-hour period were measured at 9 am, 12 noon, 3 p.m., 6 p.rn., 9 pm, midnight, 3
`am. and 9 am. Since peak concentrations we're generally 20-30% higher than trough
`concentrations, then the difference between peak and mean steady state concentration or trough
`and mean steady concentration is even less. Additionally, much of the fluctuations in
`concentrations can be explained by assay variability (CV ~20%). Afier all of this is considered,
`it seems unlikely that there is any significant fluctuation in steady state plasma concentrations of
`UT-l 5.
`
`Chronic SC UT—IS in healthy adult volunteers elicited vasodilatory adverse events. Chronic
`administration ofUT-l 5 also caused injection site pain with dose escalation every 7 days in 13 of
`14 volunteers. Eight subjects discontinued from the study early because of this adverse effect.
`Only 6 volunteers tolerated all 4 dose levels. SC UT-IS infusion at doses up to 10 ng/kg/min
`was well tolerated by 13 of 14 volunteers.
`
`The sponsor often used injection and infiision site pain interchangeably. It may be difficult to
`differentiate between the two. I am specifically referring to the 8 subjects that withdrew from
`the study. In one section it states that the subjects withdrew because of infusion site pain and in
`another section the sponsor states that the subjects withdrew because of injection site pain.
`
`,,
`
`APPEARS THIS WAY
`ON ORIGENAL
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`Page 65 of] l2
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`
`
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`

`

`’
`
`NpA 2l-272, Remodulin‘m, UT-lS, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`STUDY TITLE: A multicenter, double-blind, randomized, parallel comparison of the safety and
`efficacy of chronic subcutaneous UT—l 5 plus conventional therapy to conventional therapy in
`patients with severe primary pulmonary hypertension: an 8 week study
`
`STUDY P01:03
`
`VOLUME: 2.4
`
`PAGES: 350 — 555
`
`PRINCIPAL INVESTIGATOR: Sean Gaine, et al.
`CLINICAL LABORATORY: PPD Development
`706 Ben White Blvd, West
`Austin, TX 787044016
`
`CITATION: not" applicable
`
`FIRST SUBJECT SCREENED: April 23, 1998
`LAST SUBJECT COMPLETED: October 7, 1998
`
`OBJECTIVES: To characterize the pharmacokinetics of chronic, subcutaneous UT-l 5 in patients
`with primary pulmonary hypertension (PPH).
`
`STUDY DESIGN: multi-center, double-blind, randomized, parallel group
`DURATION: 8 weeks
`
`POPULATION: Twenty-six patients with severe symptomatic PPH (NYHA Class III-IV) who
`were not receiving Flolan or other intravenous, inhaled or oral prostaglandins were enrolled.
`
`PROCEDURE: After qualifying for the study, patients were randomized (2:1) to receive
`conventional therapy plus a continuous subcutaneous infusion of UT-l 5 or conventional therapy
`plus a continuous subcutaneous infusion of placebo. Blood was drawn for PK analysis and PD
`assessments (exercise capacity, clinical signs and symptoms of disease) were performed at weeks
`1, 4, and 8. After completion of this study, patients had the option of continuing with UT-lS
`treatment in an open continuation study under a separate protocol (P01 :06).
`
`Treatment All patients received conventional therapy. The UT-lS dose was based on clinical
`signs and symptoms of PPH and the occurrence of adverse events. UT-lS was initiated at 2.5 or
`5 ng/kg/min SC if tolerated. The dose was escalated in increments of 2.5 to 5 ng/kg/min at 24-
`hour intervals until a dose equivalent of 40 ng/kg/min was achieved. Dose escalation could be
`discontinued based on treatment-emergent safety signs or symptoms (e.g., hemodynamic
`changes, onset ofnausea, emesis, or persistent headache, etc.). The maximum allowable dose at
`the end of weeks 1 through 8 was 20, 25, 30, 35, 40, 45, SO, and 50 ng/kg/min, respectively.
`Once a non-tolerated does was determined in a patient, the infiision rate of the study drug was to
`be decreased to a maximum tolerated dose.
`
`
`A . ~ M pump was used to subcutaneously
`administer UT-lS. The SC catheter was placedIn the abdominal wall and could be moved, if
`needed, at the discretion of the investigator.
`
`.,
`
`Page 66 of l l2
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`

`

`nun z I '4 IL, Aculuuuflll'“, U 1 -i .7, lrcprosuncu soaium IOl’ injection
`3
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobbum
`
`Pharmacokinetics Serial plasma samples were collected at baseline, and at 0.5, l, 2, 4, and 6
`hours following drug initiation and immediately before each UT-l 5 dose change and at 0.5, l, 2,
`4, and 6 hours after each dose change. PK samples were to be collected at the end of weeks 1, 4,
`and 8.
`
`OTHER MEDICATIONS: Investigators were to maintain all patients on the same oral medications
`and doses as were used at baseline. However, doses of oral therapies could be adjusted and oral
`therapy added or discontinued based on clinical judgement. The following were not permitted:
`chronic (.>. 5 days) use of intravenous medications to treat PPH, chronic inhaled medications
`(other than oxygen), and other prostaglandins or prostaglandin analogues.
`
`FORMULATION: UT—lS was provided as a sterile solution whose formulation is summarized in
`the table below. Lot number Y7H0978A had a UT—l 5 concentration of 0.5 mg/mL and was
`provided in 2 mL vials. Lot number 800003 had a UT-15 concentration of 5 mg/mL and was
`provided in 20 mL vials. A central pharmacy prepared prefilled 3 mL syringes at three
`concentrations 1, 2.5, and 5 m- mL fiom lot 800003.
`
`Concentration of UT-lS Solution (mg/mL)
`
`Constituents
`
`UT-lS
`
`Sodium Chloride
`
`Metacresol
`
`Sodium Citrate, Dihydrate
`
`Citric Acid
`
`Sodium Hydroxide I
`
`The reference therapy was a placebo (citrate buffer vehicle) administered via subcutaneous
`infusion (Lot Number. 800001). The citrate buffer was supplied in 3 mL syringes or in 20 mL
`vials. Each mL of plaCebo contained 5.0 mg sodium citrate dihydrate, 1.8 mg citric acid, 3 mg
`metacresol and 6.2 mg sodium chloride.
`
`All materials were protected fiom light. Vials were stored at 15-30°C, and syringes were stored
`
`SSAY: W analyzed the plasma samples with a validated . N”...
`assay. Quality controls were analyzed at concentrations ofW
`
`A A
`
`Page 67 of 1 l2
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`

`

`NVDA 21-272, Remodulinm, UT-lS, trcprostinol sodium for injection
`'
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`Precision Interday CV was less than 15%. Intraday precision could not be calculated because
`multiple samples were not analyzed in the same day.
`
`Accuracy Interday accuracy was within 9%. Intraday accuracy could not be calculated because
`multiple samples were not analyzed in the same day.
`
`Sensitivity The LOQ was b—f—‘ffl
`
`‘ for a 1 mL aliquot of plasma.
`
`Linearity The assay was linear over a standard curve range ofM
`
`ANALYSIS: The planned sample size was considered sufficient to provide descriptive
`information on the safety of UT-lS, and was an initial step in the exploration of the safety,
`pharmacokinetics, and efficacy of UT-l 5.
`
`Pharmacokinetic Data The pharmacokinetic plasma drug concentration data were listed by
`patient and dose. Individual patient plasma UT-l 5 concentration versus time data were
`displayed graphically. Apparent plasma clearance (CL/F) was to be determined for each infusion
`rate from each C5,. Pharmacokinetic linearity was to be investigated based on individual patient
`plot of Css versus UT-l 5 dose.
`
`Pharmacodynamic Data Linear correlation analysis was performed on Week 8 steady-state
`plasma UT-l 5 concentrations versus selected hemodynamic variables or percentage change in
`hemodynamic variables (including pulmonary vascular resistance index [PVRI], cardiac index
`[CI], mean pulmonary arterial pressure [PAPm], right atrial pressure [RAP], mean systemic
`arterial pressure [SAPm], stroke index [SI], heart rate [HR], and mixed venous oxygen saturation
`[SV02D-
`
`RESULTS: Seventeen patients were randomized to receive UT-15 and nine were randomized to
`receive placebo. Of the patients that received UT-l 5, only 15 completed the study in its entirety.
`Two patients discontinued because of adverse effects. All patients that received UT-l 5 were
`Caucasian and 14 were females. Their ages ranged from 12 to 73 years with a median age of 34
`years. The median body weight was 74 kg.
`
`UT-l 5 dosing was not standardized. The initial UT-15 infusion rate was 1.25 ng/kg/min in one
`patient, 2.5 ng/kg/min in 15 patients and 5 ng/kg/min in one patient.
`
`PHARMACOKINETIC RESULTS: The PK results are based on data fiom 17 patients. The blood
`sample collections were reduced to four samples to be collected on study days 2 through 5,
`instead of 8 samples on study days 2 though 9. There were also some unscheduled plasma
`samples collected from selected patients. The sampling times and dates were not properly
`documented because these collections were unanticipated. The sponsor did not calculate plasma
`clearance values because of concern ofthe accuracy of the data. Also, because the timing of
`dose escalation was not standardized, the PK data lacked uniformity in terms of UT-15 doses and
`corresponding durations of infiision. Thus, it was not possible to summarize the PK data across
`patients by generating descriptive statistics.
`
`Page 68 of 112
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`

`

`NDA 21-272, Remodulin'", UT-l 5, treprostinol sodium for injection r
`'
`Office of Clinical Pharmacology & Biopharamccutics Review
`Nhi Nguyen and Joga Gobburu
`
`Data from five patients demonstrated PK linearity. The remaining patients did not have 3 or
`more steady state values documented over thef8 week study period.
`
`PHARMACODYNAMIC RESULTS: Correlation analysis of Week 8 plasma UT-l 5 concentration
`versus various hemodynamic variables failed to show any meaningful relationships. The
`coefficient of determination ranged from ---—-~ Visual inspection of the data suggests that
`a correlation exists with several of the hemodynamic parameters, but a better study will have to
`confirm these data.
`
`
`
`Page 69 of l l2
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`page(s) have been
`I
`removed because it
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`contains trade secret
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`-
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`and/or confidential
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`‘
`
`information that is not
`
`disclosable.
`
`’
`
`

`

`NPA 21472, Remodulin’", UT-lS, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biophammceutics Review
`Nhi Nguyen and Joga Gobburu
`
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`COMMENTS: Dose escalation and optimization were individualized and no two patients had
`exactly the same dosing regimen. From a PK perspective, non standardization of dose escalation
`and optimization made the summarization of PK outcome across patients an impossible task.
`
`CONCLUSION: The pharmacokinetics of UT—l S was linear in those patients with adequate data.
`There was no meaningful correlation between UT-l 5 plasma concentration and various
`hemodynarnic variables.
`
`REVIEWERS COMMENTS: Because of the problems identified with the design of this study, little
`meaningful information can be obtained from this study. It is unclear why some of the
`hemodynamic paramters trended in the wrong direction with higher concentrations of UT-l 5
`(e.g.CI, PVRI, RAP and SvOz). Perhaps the PD data would have shown a better correlation if
`more data were obtained and more subjects were studied.
`
`PPEARS ““5 W
`A mt GRlGlliM.
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`AY
`
`Page 7] of!”
`
`

`

`NBA 21 -272, Remodulin‘”, UT—lS, treprostinol sodium for injection
`'
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`STUDY TITLE: An international, multicenter, double-blind, randomized, parallel placebo-
`controlled comparison of the safety and efficacy of chronic-subcutaneous UT-l 5 plus
`conventional therapy to conventional therapy in patients with pulmonary hypertension: a 12
`week study
`
`STUDY P01:04 and P01:05 ' VOLUME: 211
`
`PAGES: 2942 to 3254
`
`PRINCIPAL INVESTIGATOR: Gaine S, et al.
`
`CLINICAL LABORATORY: Final PK report prepared by Allen Lai, PhD. of CPKD Solutions, PO
`Box 13822, Research Triangle Park, NC 27709
`
`CITATION: not applicable
`
`FIRST SUBJECT DOSED: November 11, 1998 (P01 :04), December 15, 1998 (POI :05)
`LAST SUBJECT COMPLETED: November 22, 1998 (P01204), February 3, 2000 (P01:05)
`
`OBJECTIVES: This study had two objectives. The primary Objective was to assess the effects of
`chronic UT-15 SC infusions compared to placebo on exercise capacity in an out-patient
`environment. The effects ofUT-l 5 on signs and symptoms of PAH, dyspnea-fatigue rating and
`time to discontinuation were used in this assessment. Secondary objectives included assessing
`the effects of quality of life, and assessing the effects of patient factors (gender, race, age and
`weight) on the disposition of UT-l 5 and to evaluate PK drug interactions.
`
`r“~
`
`This review will only focus on the assessment made on the effects ofpatient factors on the
`disposition ofUT-IS and the evaluation of PK drug interactions.
`
`STUDY DESIGN: multinational, multicenter, randomized, double-blind, placebo-controlled trial
`
`DURATION: 12 weeks
`
`POPULATION: The planned enrollment was 224 patients in each study (04 and 05) with
`clinically stable symptom-limited (NYHA Class II, III or IV) PAH despite use of chronic
`vasodilators for at least one month. These patients were also not receiving Flolan or other iv or
`inhaled prostaglandins or prostaglandin analogues. Patients were male and nonpregnant females
`between 8 and 75 years old. Study P01 :04 was conducted in North America, and study P01 :05
`was conducted in Europe, Israel and Australia, but also enrolled patients from the US and
`Canada.
`-
`
`PROCEDURE:
`
`Treatment The first weekly infusion was initiated at 1.25 ng/kg/min. If the initial dose was
`intolerable, the dose was reduced to 0.625 nykg/min. Patients were maintained on the first
`infusion during week 1. Dose changes during the next 11 weeks were based upon signs and
`symptoms of disease and ABS. There was no washout period between changes in UT-l 5
`infiision rates. The infusion was increased weekly if the drug was tolerated, and symptoms of
`pulmonary hypertension did not improve or if the patient’s clinical condition deteriorated and the
`patient became more symptomatic. From week 1 to week 4, doses could be increased by no
`
`Page 72 of 112
`
`

`

`NDA 21-272, Remodulinm, UT~15, trcprostinol sodium for injection
`'
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`more than 1.25 ng/kg/min per week. After week 4, doses could be increased by no more than 2.5
`ng/kg/min per week. Thus, the maximum aIIOWable dose was 5 ng/kg/min by week 4 and 22.5
`ng/kg/min by week 11. The infusion rate remained constant during weeks 11 and 12.
`
`If dose reductions were required, the infusion rate was to be decreased by no more than 2.5
`ng/kg/min every week until the symptom or sign precipitating the dose reduction was resolved.
`
`
`UT-15 solution was infused SC into the abdominal wall via aW
`,M pump. The SC catheter was changed every 3 days. The infusion site
`was moved, if necessary, every 24 hours.
`
`Pharmacokineti'cs Blood samples were collected from specified centers at baseline, week 1, 6
`and 12. Patients in the P01 :05 study did not have samples from week 1 and 6 analyzed, only
`samples at baseline and week 12 were reported. Blood samples collected from patients receiving
`placebo were not analyzed.
`
`FORMULATION: UT-lS was provided as a sterile solution in 20 mL vials in 1 mg/mL and 2.5
`mgme strengs. The tmbe-marketed formulation was used.
`Treatment
`Dose
`Formulation
`
`Lot numbers
`
`-
`
`UT-15 (SC)
`
`1.25 (or less) to 22.5 ng/kg/min
`
`1.0 mg /mL
`
`800412, 800504, 800506,
`800557, 800559
`
`2.5 mg/mL
`
`800413, 800505, 800560
`
`Placebo (citrate buffer vehicle)
`
`800348
`
`UT-15 was buffered with a citric acid/sodium citrate buffer. Hydrochloric acid or sodium
`hydroxide was used to adjust the pH ofthe 1.0 and 2.5 mg/mL formulations to 6.5. Drug in vials
`or syringes was stored at 36°F '. ,—- . drug in vials could be stored at controlled room
`temperature for up to 3 months to facilitate shipping and handling. The drug was protected from
`light and not exposed to extreme cold or heat.
`
`ASSAY: Plasma concentrations of UT-15 were determined with a validated . ’—-~ assay.
`Quantification was based on peak area ratios. The elution order was internal stande 4"“
`pal—m followed by UT-l 5. The concentration of quality control samples was 1 ~_.._\
`
`
`Precision
`
`L
`
`“
`
`The intraday and interday coefficient of variations were less than 7% for the P01 :04 study.
`The intraday and interday coefficient of variations were less than 17% for the low control and
`less than 12% for the other controls in the P01:05 study.
`
`Accuracy
`For the P01:04 study, intraday accuracy was within 5%. Interday accuracy was within 14, 8 and
`11% for low, medium and high controls, respectively. For the P01:05 study, intraday and
`interday accuracy was within 14, 6, and 5% for low, medium and high controls, respectively.
`
`Sensitivity The LOQ using a 25 11L injection volume was m
`
`Page 73 01'112
`
`

`

`r".
`
`'
`
`NPA 2l-272, Remodulinm, UT—l 5, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`Linearity The assay was linear within the tested range of \ W3“ The r2 2 0.9933
`for the P01 :04 standards and 2 0.9939 for the P01 :05 standards.
`
`ANALYSIS:
`
`Phamacokinetic Data Individual patient plasma UT-15 clearance values were determined from
`the ratio between the infusion rate and steady state UT-15 plasma concentrations at week 12.
`Univariate analyses (Kruskal-Wallace rank sum test followed by simple linear regression) were
`first performed to assess the relationship between UT—l 5 plasma clearance and individual patient
`covariates. Only significant univariate factors (p .<. 0.1) that had an R square (coefficient of
`determination) of at least 0.05 were selected for evaluation in the final backwards-stepwise
`regression model. The stepwise multivariate regression analysis was performed to identify the
`best predictors for plasma UT-15 clearance. This procedure accounted for confounding
`interactions. The patient covariates used in the final model were obesity, furosemide and serum
`creatinine.
`
`RESULTS: 236 patients received UT-15. Thirty-three dropped out prior to week 12. Of the
`remaining 203 patient, 17 patients did not have usable week 12 plasma samples (9 samples lost,
`4 samples not drawn, 1 sample drawn too late, and the infusion was changed in 3 patients less
`than 24 hours prior to blood sampling). Thus, 186 patients (87 in the P01 :04 and 99 in the
`P01 :05) were included in the PK analysis. Demographics are listed in the table below. The
`mean age was 45 i 15 years. The majority of patients were female and Caucasian. Patients
`mean weight were 71 i 20 kg.
`
`Age (yearS)
`
`2 65
`S 18
`17 to 64
`
`Female
`
`Race
`
`Caucasian
`Hispanic
`African American
`Asian
`Native American
`Multiracial
`
`Weight
`Normal
`Obese
`Overweight
`Underweight
`
`0 (Va)
`
`17 (9.1)
`9 (4.8)
`160 (86.0)
`
`157 (84.4)
`
`159 (85.5)
`12 (6.5)
`9 (4.8)
`4 (2.2)
`1 (0.5)
`1 (0.5)
`
`79 (42.3)
`48 (25.8)
`46 (24.3)
`14 (7.5)
`
`Page 74 of 112
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`

`

`NDA 21-272, Remodulinm, UT-ls, treprostinol sodium for injection
`’
`Office of Clinical Pharmacology & Biopharamccutics Review
`Nhi Nguyen and Joga Gobburu
`
`Semm creatinine was another covariate analyzed in this study. Two out of 186 patients had scr >
`2.5 mgdL. The remainder were divided into‘two groups: 176 with 'scr s 1.2 mg/dL (classified
`as normal) 8 with 1.2 < set S 1.5 mg/dL (classified as mild renal dysfunction).
`
`Another covariate was concomitant medicines. Ten medicines were included in this analysis:
`warfarin, furosemide, amlodipine, digoxin, levothyroxine, nifedipine, omeprazole, paracetamol
`(acetaminophen), prednisone and spironolactone. The most prevalent medication was warfan'n,
`with 57.5% of patients taking it.
`
`The doses at week 12 ranged from 0.62 to 22.5 ng/kg/min. The patient receiving-0.62 ng/kg/min
`was also on the lowest dose after adjustment for weight, 58.9 ng/min. Seven patients reached the
`highest allowed dose, 22.5 ng/kg/min. The highest weight adjusted dose was 1890 ng/min.
`
`PHARMACOKINETIC RESULTS: Mean i SD dose was 9.2 i 5.254 ng/kg/min. Plasma
`concentration was 1.892 :1: 1.294 ug/L (mean i SD). The range of plasma concentrations was
`from x /"‘“‘"
`
`Mean i SD clearance was 6.1 i 5.79 mL/min/kg. The distribution of clearance is shown in the
`figure below. Three patients were classified as outliers. These patients had clearances > 15
`ml/min/kg; 16.2, 22.1 and‘74.3 mL/min/kg. These patients were dropped during all regression
`analyses but were included in the nonparametric analyses.
`
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`
`Based on descriptive statistics the following observations were made about median steady state
`UT—IS Clearance:
`
`Page 75 ofll2
`
`

`

`NDA 21-272, Remodulin’”, UT-l 5, treprostinol sodium for injection
`‘
`Office of Clinical Pharmacology & Biophammceutics Review
`Nhi Nguyen and Joga Gobburu
`
`0 Clearance is 17% lower in males versus females,
`
`min—Ihhhu
`
`
`
`
`mam-ammuena-
`
`Page 76 on 12
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`

`

`NDA 2l-272, Remodulinm, UTJ 5, u-epmstinol sodium fot injection
`'
`Office of Clinical Pharmacology & Biopharamccutics Review
`Nhi Nguyen and Joga Gobburu
`
`l"
`
`0
`
`20% lower in patients 2 65 years old (eldefly) versus those < 65 years old,
`
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`Page77of112
`
`

`

`NDA 21-272, Remodulin‘m, UT-l 5, trcprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`(,
`
`0
`
`29% lower in obese than non-obese patients.
`
`mum-ammwm
`
`
`
`Page 78 of112
`
`
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`i
`
`
`
`

`

`NDA 21-272, Remodulin'“, UT-l S, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`Presence or absence of most medications did not affect the distribution of clearance. Based on
`univariate analysis, median UT-15 clearance Was affected by these three drugs:
`0
`22% lower in patients taking furosemide (43%) versus those not taking furosemide,
`o
`19% lower in patients taking levothyroxine (l 1%) versus those not taking levothyroxine, and
`0
`19% lower in patients taking spironolactone (16%) versus those not taking spironolactone.
`The graphs are shown below.
`F...
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`Page 79 of] l2
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`, NDA 21-272, Remodulinm, UT-IS, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
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`The results of simple linear regression analyses of covariates that were significant by univariate
`analysis (elderly, BMI, serum creatinine, furosemide, levothyroxine and spironolactone) showed
`that obesity (:2 = 0.119), defined as a BMI > 30.0 kg/mz, furosemide (:1 = 0.061) and serum
`creatinine (12 = 0.083) were significantly associated with steady state clearance of UT-lS. See
`scatterplot below of UT-l 5 clearance and serum creatinine.
`
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`Obesity, fiirosemide, serum creatinine and creatinine/obesity interaction jointly explained 26.2%
`of the variability in UT-l 5 clearance. Obesity was the best predictor of steady state clearance. It
`accounted for 12% of the observed inter-patient variability in clearance. Furosemide was also an
`important predictor of steady state clearance. It accounted for 6% of the variability.
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`Page 80 ofllz
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`NPA 21-272, Remodulin‘”, UT-l 5, ueprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobbum
`
`SPONSOR’S COMMENTS: Furosemide accounted for 6% of the inter-subject variability in plasma
`UT-l 5 clearance values. The sponsor offers a'possible mechanistic explanation for the drug
`interaction. The elimination of fiirosemide is mostly via glucuronidation of the carboxylate
`group. While UT—IS has two hydroxyl groups and one carboxylate group, only the carboxylate
`group undergoes glucuronidation. Approximately 14% of 3 SC dose of UT-IS is eliminated via
`this conjugation. It is speculated that furosemide might have prevented UT—l 5 from reaching the
`active site of the enzyme that facilitates glucuronidation.
`
`The sponsor acknowledges that the finding that serum creatinine was also an important predictor
`of steady state clearance is illogical since 98.9% of patients had serum creatinine from 0.5 to 1.4
`mg/dL and renal excretion of unchanged drug has a minor role in the elimination of UT-lS.
`
`SPONSOR’S CONCLUSION: The sponsor concludes that obesity was the best predictor of steady-
`state plasma UT-15 clearance. It accounted for ~12% of the observed inter-individual variability
`in plasma UT—IS clearance. Dosing of UT-l 5 chould be based on ideal body weight.
`
`Furosemide was an important predictor of plasma UT-15 clearance accounting for ~6% of the
`variability.
`
`Serum creatinine was also shown to be a significant predictor of plasma UT-15 clearance. The
`sponsor states the cause for this finding to be “happenstance”.
`
`REVIEWER’S COMMENTS: Dosing of UT-lS should be based on ideal body weight.
`
`The increase in UT-lS concentration caused by furosemide is of little clinical significance.
`Additionally, it was difficult to determine the sponsor’s definition of concomitant medication.
`
`We analyzed the data using a physiologic model and found no difference in pharmacokinetics
`with respect to age, gender or obesity. See the pharmacometrics review for further details.
`
`APPEARS THIS WAY
`0N OREGINAL
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`N'DA 21-272, Remodulinm, UT-IS, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`STUDY TITLE: A pharmacokinetic study of subcutaneous UT-l 5 in patients with secondary
`pulmonary hypertension a study in patients with portopulmonary hypertension
`
`STUDY P02:01
`
`VOLUME: 2.4
`
`PAGES: 555 - 602
`
`PRINCIPAL INVESTIGATOR:
`CLINICAL LABORATORY:
`
`-
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`a
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`7
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`-
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`CITATION: not applicable
`
`FIRST SUBJECT SCREENED: May 19, 2000
`LAST SUBJECT COMPLETED: July 26, 2000
`
`OBJECTIVES:
`
`Primary
`
`To characterize the pharmacokinetic profile of subcutaneous UT-l 5 in patients with
`mild to moderate hepatic dysfunction associated with portopulmonary hypertension.
`
`STUDY DESIGN: open label, single-dose
`DURATION: The study duration consisted of a 150 minute treatment phase and a 300 minute
`washOut phase.
`
`POPULATION: Five patients with mild hepatic dysfunction (Child Pugh Grade B) and four
`patients with moderate hepatic dysfunction (Child Pugh Grade A) associated with
`portopulmonary hypertension were studied. These patients were in NYHA Class II-III for PPH.
`Mean time since diagnosis of primary pulmonary hypertension was 6 months. Mean age was 49
`years. Patients were within 30% of ideal body weight. There were three females. All patients
`were Caucasian, except for one who was Black.
`
`PROCEDURE: Hepatic fimction status was determined using the Child Pugh Classification scale.
`During the Baseline/screening phase, all patients underwent right heart catheterization to
`determine baseline hemodynamic parameters. Cardioplumonary hemodynamics were also
`assessed every 15-30 minutes during the dose and washout periods.
`
`Treatment The treatment phase consisted of two phases; a dosing phase and a washout phase.
`Dosing phase: UT-l 5 10 ng/kg/min SC for 150 minutes.
`Washout phase: 300 minutes
`
`Pharmacokinetics Blood samples for determination of UT-l 5 were collected at Baseline and at
`the following times during the dosing phase: 15, 30, 60, 90, 120, and 150 minutes. During the
`washout phase blood samples were collected at 5, 10, 15, 30, 60, 90, 120, 180, 240, and 300
`minutes. One additional sample was obtained during the post-treatment phase.
`
`Fomumnon: UT-rs 0.5 mymL, lot number Y7H0978A was used.
`
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`, NDA 21-272, Remodulin’“, UT-lS, treprostinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`assay. The
`,—-———
`UT-IS ASSAY: The plasma samples were analyzed with a validated i
`lower LOQ was -""
`’ and the upper LOQ was "" No other details of the assay were
`submitted.
`
`ANALYSIS:
`
`Pharmacokinetic Data PK parameters fiom this study were compared to that obtained from
`healthy subject that received 15 ng/kg/min in the P01 :07 study. Cmax and AUC Mn; in healthy
`subjects were dose normalized for a 10 ng/kg/min dose. The PK parameters were compared
`using descriptive statistics.
`
`PHARMACOKINETIC RESULTS: The concentration versus time profile are shown in the figure
`below for the patients with mild and moderate hepatic insufficiency.
`
`MWWW. mmwwm.
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`APPEARS THIS WAY
`ON ORIGINAL
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`Page 83 ofl 12
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`N’DA 21-272, Remodulinm, UT-IS, trepmstinol sodium for injection
`Office of Clinical Pharmacology & Biopharamceutics Review
`Nhi Nguyen and Joga Gobburu
`
`Mean-+ SD PK parameters for the healthy subjects and hepatically impaired patients are shown
`in the table below.
`
`Parameter
`
`Healthy
`subjects '
`n=15
`
`Mild hepatic
`dysfunction
`n=5
`
`Moderate hepatic
`dysfunction
`n=4
`
`.
`
`0.98
`\ ...—......
`NR
`2.65 "
`589.4 i 129.6
`1113.614530
`1.38 10.66
`
`2.22...+ 0.43
`4.32...+ 1.48
`
`250
`2.58
`6.47 i 1.59
`12.73 :1: 4.57
`6.91 i 1.80
`13.57 i 4.16
`228.2 i 54.39
`118.75 i 36.22
`451.61 141.80
`225.00i 164.21
`1.42 i 0.48
`1.32 i 0.83
`
`Cmax (ug/L)
`Tmax(hr)c
`AUC o.1(ng*hr/mL)
`AUC Mur(ng“hr/mL)
`CL/F (mL/hr/kg) a
`Vz/F (mL/kg)‘l
`T '/2 (111') d
`NR = not reported
`' The results for healthy subjects from study P01:07 which gave a SC dose of 15 ng/kg/min for l50 minutes.
`" Cmax and AUC 0..., mean values listed1n this table are dose-normalized for a 10 ng/kg/min dose and assume that UT- 15 PK
`parameters are linear with respect to dose and not dose dependent. No SD values are reported for Cmax and AUC M, since
`mean values are reported afler dose normalization.
`‘ Median (min, max) are shown for Tmax of patients with hepatic dysfunction however, only (min, max) is shown for Tmax of
`healthy subjects.
`‘ Comparison of CUF, Vz/F and T V: assumes that these parameter are dose independent.
`
`Observation shows that patients with hepatic insufficiency have higher concentrations of UT-lS
`than normal subjects. Concentrations were highest at the end of the 150 minute infusion in
`moderately impaired patients and 10 minutes post infusion in mildly impaired patients. Cmax
`and AUC 0.3”; for patients with mild hepatic dysfimction were higher by ~ 127% and 161%,
`respectively compared to the healthy subjects. The corresponding values for patients with
`moderate hepatic dysfunction were higher by ~ 340% and 412%, respectively.
`
`Apparent total clearance and volume of distribution was lower in patients with mild and
`moderate hepatic dysfunction compared to healthy subjects. Apparent clearance was lower by ~
`62 % and 80% in mild and moderate hepatic dysfunction, respectively.
`
`S