CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-995
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEW! S 2
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW%
`
`NDA:
`
`21—995 (000)
`
`Submission Date: 12/16/2005
`
`Brand Name
`
`Generic Name
`
`‘
`
`Reviewer
`
`Team Leader
`
`JanuviaTM
`
`Sitagliptin
`
`Xiaoxiong (Jim) Wei, M.D., Ph.D.
`
`HaeeYoung Ahn, Ph.D.
`
`Pharmacometrics Reviewer
`
`Atul Bhattaram, Ph.D.
`
`PM Team Leader
`
`Jogarao Gobburu, Ph.D.
`
`OCP Division
`
`0ND division
`Sponsor
`
`Relevant lND(s)
`
`Submission Type; Code
`
`Division of Clinical Pharmacology II
`
`Division of Metabolic and Endocrine Products (HFD-510)
`Merck
`
`65,495
`
`Original
`
`Formulation; Strength(s)
`
`Tablets; 100 mg, 50mg, 25 mg
`
`Dosing regimen
`
`Indication
`
`Table of Contents
`
`Once a day
`
`Type 2 diabetes mellitus
`
`1..
`
`2.
`
`3.
`4.
`
`1 .1
`1.2
`1.3
`
`2.1
`2.2
`2.3
`2.4
`2.5
`2.6
`
`4.1
`4.2
`4.3
`
`Executive Summary .............................................................................................. 1
`Recommendation ................................................................................................. 2
`PhaseIVCommitments....................... ................................................................. 2
`Summary of Clinical Pharmacology and Biopharmaceutics .......................................................... 3
`QBR ...................................................................................................................4
`General Attributes of the Drug ....................................................................................................... 4
`General Clinical Pharmacology ...................................................................................................... 6
`Intrinsic Factors ............................................................................................................................ 21
`Extrinsic Factors ........................................................................................................................... 25
`General Biopharmaceutics ............................................................................................................ 33
`Analytical Section ......................................................................................................................... 36
`Detailed Labeling Recommendation .......................................................................... 37
`Appendices
`OCBP Filing/Review Form .......................................................................................................... 4]
`Proposed Package Insert: (see a separate file) .............................................................................. 43
`Pharmacometrics review (attached) .............................................................................................. 44
`
`1
`
`Executive Summary
`
`Merck submitted a 505 (b) (1) NDA for marketing of JanuviaTM (Sitagliptin). A total of 33 human
`Phase 1 and Phase 2 pharmacokinetic and pharmacodynamic studies, bioavailability/bioequivalence
`studies, in vitro drug metabolism studies and a thorough QT study were submitted to support the section of
`Clinical Pharmacology and Biopharmaceutics.
`
`ENDA2]~995NDA2l995-Januvia—I2-16—2005.doc
`
`1
`
`

`

`Sitagliptin is the first drug of a new class of oral anti—hyperglycemic agents called dipeptidyl
`peptidase 4 (DPP-4) inhibitors. Incretin hormones, including glucagon-like peptide-l (GLP—1) and glucose—
`dependent insulinotropic peptide (GIP), are released by the intestine throughout the day, and levels are
`increased in response to a meal. The activity of GLP—1 and GlP is limited by the DPP-4 enzyme, which
`rapidly hydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis
`of incretin hormones by DPP—4, thereby increasing plasma concentrations of the active forms of GLP-1 and
`GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels
`in a glucose-dependent manner.
`
`Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in patients with
`type 2 diabetes mellitus. Sitagliptin is also indicated in patients with type 2 diabetes mellitus to improve
`glycemic control in combination with metformin or a PPARy agonist (e. g., thiazolidinedione) when diet
`and exercise, plus the single agent do not provide adequate glycemic control. The recommended dose of
`sitagliptin is 100 mg once daily as monotherapy or as combination therapy.
`
`1.]
`
`Recommendation
`
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology ll (OCP/DCP—2) has
`reviewed the information provided in the original NDA 21-995 for JanuviaTM in the section of human
`pharmacokinetics and biopharmaceutics. OCP has found the application acceptable. This recommendation
`. and dissolution method and acceptance criterion below should be conveyed to the sponsor as appropriate.
`
`Apparatus 1
`
`In vitro dissolution medium
`
`Volume of dissolution medium
`
`Medium temperature
`
`Stirring speed
`
`Acceptance criterion
`
`OCP Briefing Notes:
`A Required OCP Office Level CPB Briefing was held on August 29, 2006. The following staff were
`attended: from OCP: Larry Lesko, Shiew-Mei Huang, Chandra Sahajwalla, Mehul Mehta, John Lazor, Atik
`Rahman, Dennis Bashaw, Hae—Young Ahn, Kelly Reynolds, Jaya Vaidyanathan, Albert Chen, David Lee,
`Srikanth Nallani, Sandhya Apparaju, Lei Zhang, Partha Rey, Atul Bhattaram; From DMEP: Mary Parks,
`llan Irony, Hylton Joffe, Lina Aljuburi; From ONDQA: Stephen Moore.
`
`During Briefing, the OCP management reached a consensus to recommend a dissolution method as a post »
`approval test method, not disintegration. Speaking for the fOUr OCP division directors present Dr. Bashaw
`(Division Director, DCP-3), explained that disintegration does not necessarily correlate with solubilization
`of drug substance. Dissolution testing, on the other hand, incorporates both disintegration and the
`solubilization of drug substance into the media in its specification. As in the case with this drug,
`dissolution testing did not discriminate between hardness values as once the tablet disintegrated, the high
`solubility of the drug substance allowed it to enter the media readily. However, as a general release test,
`disintegration is not generally considered adequate as there could be formulation changes in the fiiture that
`would result in decreased solubility (for example, a change in drug substance particle size) that would not
`be picked up by disintegration testing but would be detected by dissolution testing. Given that the burden
`of dissolution testing is minimal and is usually automated today, compared to the manual observation
`required for disintegration testing, it is recommended that a dissolution test be used.
`
`1.2
`
`Phase IV Commitment
`None
`'
`
`ENDAZl —995NDA21995-Januvia—l2-16-2005.d0c
`
`.
`
`2
`
`

`

`1.3
`
`Summary of Clinical Pharmacology and Biopharmaceutics Findings
`
`0 Single and multiple dose pharmacokinetics: ‘
`
`After oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed, with
`peak plasma concentrations (median Tmax) occurring 1 to 4 hours post-dose. Following a single oral 100-mg
`dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 uM-hr, Cmax was 950 nM, and
`apparent terminal half-life (ll/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14%
`following 100—mg doses at steady-state compared to the first dose. The pharmacokinetics of sitagliptin was
`generally similar in healthy subjects and in patients with type 2 diabetes.
`
`0 Absolute bioavailability and food effect:
`
`The absolute bioavailability of sitagliptin is approximately 87%. The co—administration of a high—fat
`meal with sitagliptin had no effect on the pharmacokinetics; sitagliptin may be administered with or
`without food.
`
`0 Dose proportionality:
`
`The power law model of geometric mean AUCM values versus dose administered along with the
`fitted regression line indicated that the slope (90% CI )‘was 1.00 (0.98, 1.01). The sitagliptin dose adjusted
`(to 100 mg) *AUCM geometric least—squares mean ratio (GMR, 400 mg/ 100 mg) was 1.02 with
`corresponding 90% CI of (0.99, 1.06). Therefore, sitagliptin AUC0_,c increases dose proportionally with
`increasing dose across the tested dose range. Sitagliptin Cmax increases in a modestly greater than dose
`proportional manner with dose.
`
`0 Distribution:
`
`The mean volume of distribution at steady state following a single lOO-mg intravenous dose of
`sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to
`plasma proteins is about 38%.
`
`o Metabolism:
`
`Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway.
`Approximately 79% of sitagliptin is excreted unchanged in the urine. Following a ['4C]sitag1iptin oral
`dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites
`were detected at trace levels and are not expected to contribute to' the plasma DPP—4 inhibitory activity of
`sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of
`sitagliptin wasCYP3A4, with contribution from CYP2C8. Sitagliptin is a substrate of P-gp.
`
`- Excretion:
`
`Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of
`the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing.
`The renal clearance was approximately 350 mL/min. Elimination of sitagliptin occurs primarily via renal
`excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion
`transporter-3 (hOAT—3).
`
`0 Renal impairment:
`
`Mild renal insufficiency increased sitagliptin AUC by 1.6 fold. An approximately 2-fold or greater
`increase in the plasma AUC of sitagliptin was observed in patients with moderate renal insufficiency, and
`an approximately 4-fold or greater increase was observed inpatients with severe renal insufficiency and in
`patients with ESRD on hemodialysis, as compared to normal healthy control subjects. Sitagliptin was
`
`ENDA2] ~995NDA21995—Januvia—12-16-2005.doc
`
`3
`
`

`

`modestly removed by hemodialysis (13.5% over a 3- to 4-hour hemodialysis session starting 4 hours
`postdose). To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal
`function, 50-mg and 25-mg once a day are recommended for moderately renally impaired and severely
`renally impaired or ESRD patients, respectively.
`
`0 Drug interactions:
`
`In clinical pharmacokinetic studies, sitagliptin did not meaningfully alter the phannacokinetics of
`metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives. Multiple doses of
`sitagliptin slightly increased digoxin concentrations.
`
`A single 600—mg oral dose of cyclosporine increased the AUC and Cmax of sitagliptin by approximately
`29% and 68%, respectively.
`
`0 Pharmacodynamics:
`
`In patients with type 2 diabetes, administration of single oral doses of sitagliptin leads to inhibition of
`DPP-4 enzyme activity for a 24—h0ur period, resulting in a 2— to 3-fold increase in circulating levels of
`active GLP-1
`and GIP,
`increased plasma levels of
`insulin and C-peptide, decreased glucagon
`concentrations, reduced fasting glucose, and reduced glucose excursion following an oral glucose load or a
`meal.
`
`- Exposure-response:
`-The relationship between plasma sitagliptin concentrations and inhibition of plasma DPP—IV activity
`was explored. No significant hysteresis was observed. Using an Emax model the plasma EC50 was 25.7
`nM and the EC80 was approximately 100 nM.
`In a study of multiple doses of 25 mg to 600 mg sitagliptin
`in healthy subjects, there was a dose— and concentration-related increase in the percent inhibition of plasma
`DPP-IV enzyme activity for multiple doses from 25 to 600 mg. Multiple doses of 100 mg once daily or
`higher were associated with geometric mean values for inhibition of DPP-IV activity at steady-state trough
`of approximately 80% or higher. These pharmacodynamic data support a once daily dosing regimen for
`sitagliptin in the treatment of type 2 diabetes.
`
`0 Analytical assay:
`
`High turbulence liquid chromatography (HTLC) extraction and liquid chromatography/tandem mass
`spectrometry (LC-MS/MS) methods were used to analyze sitagliptin concentrations in human biological
`fluids (plasma, urine and dialysate). The lower limit of quantitation (LLOQ) for the plasma assay is 0.500
`ng/mL (1.23 nM) and the linear calibration range is 0.500 to 1000 ngmL (1.23 to 2455 nM). The assays are
`selective and specific for sitagliptin in human biological fluids. The accuracy of the intra—day analysis
`(n=5) of quality control (QC) samples did not deviate by more than 10% of the nominal concentrations.
`The precision (coefficient of variation, CV%) of the intra-day analysis (n=5) of QC samples was less than
`10% at each concentration.
`
`2. QUESTION BASED REVIEW (QBR)
`
`2.1
`
`GENERAL ATTRIBUTES OF THE DRUG
`
`2.1.] What are the highlights ofthe chemistry and physico-chemicalproperties of the drug substance,
`and the formulations ofthe drug product?
`
`Sitagliptin phosphate is described chemically as 7—[(3R)-3-amino—1-oxo-4-(2,4,5—trifluorophenyl)
`butyl]—5,6,7,8-tetrahydro-3-(trifluoromethyl)—1,2,4—triazolo[4,3—a] pyrazine phosphate (1:1) monohydrate.
`The empirical formula is C16H15F6N50-H3PO4-H20 and the molecular weight is 523.32. The structural
`formula is as follows:
`
`ENDAZl -995NDA2 l 995-Januvia—12-l 6—2005.doc
`
`4
`
`

`

`Sitagliptin phosphate is a white to off—white, crystalline, non-hygroscopic powder. It is soluble in
`water and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone,
`and acetonitrile; and insoluble in isopropanol and isopropyl acetate.
`
`2.1.2 What are the mechanism ofaction, therapeutic indication and dosage recommendationsfor
`sitagliptin?
`
`Mechanism ofA ction
`
`Sitagliptin is the first member of a new class of oral anti-hyperglycemic agents called dipeptidyl
`peptidase 4 (DPP—4) inhibitors. Incretin hormones, including glucagon-like peptide—1 (GLP-1) and glucose—
`dependent insulinotropic peptide (GIP), are released by the intestine throughout the day, and levels are
`increased in response to a meal. The activity of GLP—1 and GIP is limited by the DPP-4 enzyme, which
`rapidly hydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis
`of incretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-l and
`GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels
`in a glucose—dependent manner. In patients with type 2 diabetes with hyperglycemia, these changes in '
`insulin and glucagon levels lead to lower hemoglobin A] c (AlC) and lower fasting and postprandial
`glucose concentrations.
`
`Proposed indications:
`
`Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in patients
`with type 2 diabetes mellitus.
`
`Sitagliptin is also indicated in patients with type 2 diabetes mellitus to improve glycemic control
`in combination with metformin or a PPARY agonist (e.g., thiazolidinedione) when diet and exercise, plus
`the single agent do not provide adequate glycemic control.
`
`Proposed dosage recommendation:
`
`The recommended dose of sitagliptin is 100 mg once daily as monotherapy or as combination
`therapy with metformin or a PPARY agonist (e.g., thiazolidinedione). Sitagliptin can be taken with or
`without food.
`
`Patients with Renal Insufficiency:
`, For patients with mild renal insufficiency (creatinine clearance [CrCl] Z50 mL/min, approximately
`corresponding to serum creatinine levels of SI .7 mg/dL in men and 51.5 mg/dL in women), no dosage
`adjustment for sitagliptin is required.
`
`For patients with moderate renal insufficiency (CrCl 230 to <50 mL/min, approximately
`corresponding to serum creatinine levels of >1 .7 to 53.0 mg/dL in men and >1 .5 to 52.5 mg/dL in women),
`the dose of sitagliptin is 50 mg once daily.
`
`ENDAZl—995NDA2l995—Januvia-l2-16—2005.doc
`
`5
`
`

`

`For patients with severe renal insufficiency (CrCl <30 mL/min, approximately corresponding to
`serum creatinine levels of >3.0 mg/dL in men and >25 mg/dL in women) or with end—stage renal disease
`(ESRD) requiring hemodialysis, the dose of sitagliptin is 25 mg once daily. Sitagliptin may be administered
`without regard to the timing of hemodialysis.
`
`2.1.3 What are the highlights ofthe formulation of drug product?
`
`Sitagliptin is supplied as a film—coated tablet. Details of the composition are shown in Table 1.
`
`1th mg; itabtet
`
`
`Table 1. Composition of Phase 111/ Final Market Image (FMI) Tablets
`Phase III/FM]
`Phase III/FM]
`
`Component
`Phase III/FMI
`
`
`
`
`Tablet T13
`Tablet T10
`Tablet T5
`
`
`
`
`
`
`55} mg itablet
`25 mg ftaitlet
`
`
`
`
`
`
`MK-0431-010X (e-uivalent free base)+
`
`
`Calcium Phosphate Dibasic,
`
`
`Microcrystalline Cellulose NF § ”NF
`
`Croscarmellose Sodium NF
`H 7
`. Sodium Stearyl Fumarate NF
`Magnesium Stearate (non-bovine) NF
`Core Tablet Weight
`
`
`
`
`
`Total Weight
`
`7 Conversion factor of
`\used for free base to monohvdrate phosphate salt fomi.
`
`
`
`
`
`
`
`1 Removed during processing
`NA=Not Applicable in this fonnulation
`NF =Nationa1 Forrnulary
`USP = United States Pharmaco eia.
`
`
`
`
`
`
`2.2
`
`General Clinical Pharmacology
`
`2.2.1 What are the pharmacokinetic characteristics of a single dose ofsitagliptin in healthy subjects
`and patients with type 2 diabetes?
`
`The sponsor conducted seven single dose pharmacokinetic studies in healthy subjects for 100 mg
`dose through the drug development. The main pharmacokinetic parameters are summarized in Table 2.
`
`Table 2. Mean pharmacokinetic parameters across Phase I studies following single oral 100-mg doses of
`sitagliptin administered alone to fasting healthy subjects
`
`EN DA21-995NDA21995-.lanuvia-12—l 6-2005.doc
`
`6
`
`

`

`
`
`
`
`
`C ‘12
`
`
`[ mLs’min) i
`Study
`Formulation
`
`
`(£796 '
`it I 6
`It}. I
`4
`,—
`.T
`7.3%
`6
`Capsule
`PDQ]
`
`9.373
`4] 5
`9.55
`2
`959
`3.623
`6
`Capsule
`W} l 3
`
`NA
`NA
`12.2
`2.5
`799
`3.33
`l2»
`Phase II tabiet
`. P027
`
`
`NA
`NA
`12.5
`1.35
`356
`8.78
`ii?
`FM] tablet
`P027
`
`
`0.651
`340
`l if?
`3
`Si?
`7.93
`12
`Fh‘ll tablet
`pill?)
`
`
`
`53338
`350
`LE4
`[.3
`950
`3.52
`19
`FIVII table-t
`13033
`
`
`FIVII tabletP03? 0.658 8 7.13 V96 4 l 1.6 366
`
`
`
`
`
`
`i Geometric Least—Squares Mean or Geometric Mean.
`‘ Median.
`
`Tamer
`(131‘! i
`
`32
`[ hr] 5‘
`
`fem;
`
`
`
`N
`
`
`
`Cm”
`{id-JCT!)—I~
`t n M Iltr} ‘ WM)1
`
`
`
`
`
`
`g Harmonie Mean for Apparent Terminal 1],;
`ii Arithenuttic Leztst-St‘nnn’es Mean.
`NAmNot applicable, urine was not collected,
`
`In a single dose pharmacokinetic study in patients with type 2 diabetes, 58 drug naive patients
`enrolled. Each patient received single oral doses of 25 mg sitagliptin or 200 mg sitagliptin or placebo in
`the fasted state in a randomized sequence. The PK parameters are summarized in Table 3.
`
`Table 3. Summary statistics of sitagliptin plasma pharmacokinetic parameters following single oral
`sitagliptin 25—mg and 200-mg doses to patients with type 2 diabetes (P005)
`
`Parameters
`
`A U (1m I" t It Min”)
`anew. .1, {gr M'hr‘fi
`Chm {11M ’1
`C34 in {HM}
`T1m {hours}
`Apparent terminal 1% (hours)§
`
`or
`
`’3 SI.) u Between—mthject standard deviation; Baek—tmnsfnrmed from log scale for
`AUG-yum. AUG“), Cm“, and C134,": Jackknife standard deviation for 1.3.
`g AUCM. and apparent tm were computed for patients with plasma MK—fNiBI samples
`collected to .72 hours postdnse only.
`
`The pharmacokinetic parameters were generally similar between patients with type 2 diabetes and
`healthy subjects from the overall comparison._
`
`2.2.1 What are the pharmacokinetic characteristics ofmultiple doses ofsitagliptin in healthy subjects
`and patients with type 2 diabetes?
`
`In a double-blind, randomized, placebo—controlled, parallel-group, incremental dose studywith 7
`treatment panels (Panels A, B, C, D, E, F, and G), each consisting of 10 healthy male subjects, Panels A to
`E, each subject received 25, 50, 100, 200, or 400 mg sitagliptin (n=8) or placebo (n=2) once daily for 10
`days (Days I to 10). In Panel F, each subject received 800 mg sitagliptin (n=8), or placebo (n=2) on Day I
`and 600 mg sitagliptin (n=8), or placebo (n=2) on Days 3 to 10. In Panel G, each subject received 300 mg
`sitagliptin (n=8), or placebo (n=2) every 12 hours (twice daily, or bid.) for 10 days (Days I to 10). The
`pharmacokinetics of sitagliptin following multiple doses of sitagliptin, 25 to 600 mg q.d. and 300 mg twice
`daily are summarized in Table 4.
`
`ENDAZI -995NDA2 I 995—Januvia—l 2-1 6-2005.doc
`
`'
`
`,
`
`7
`
`

`

`Table 4. Summary statistics of sitagliptin pharmacokinetic parameters following multiple doses of 25 to
`600 mg sitagliptin in healthy young men at steady state (N=8) (P004)
`
` Pamnteter
`
`
`AUCM ,uM‘lIri
`2.13
`
`
`
`cm, 11M§
`172
`
`33. 5
`(3,. air
`2
`1...... 111':
`
`
`13.
`Apparent terminal
`
`15,3, hl‘ri
`
`fefJ-E I
`
`
`CIR? iii-"min
`
`A iis’Cgf 2" .4 LT 5'90—:
`
`
`“*5?
`(~51?
`{mm'f'mn
`
`55' : p.51?
`C:- ,r Lac
`
`
` Accumulation I. ,3 ing
`
`Geometric least-squares mean.
`
`Median.
`Harmonic mean.
`
`
`
`
`
`
`The accumulation ratios for 25 mg, 100mg, and 400 mg QD are 1.24 (90% Cl: 1.16, 1.32), 1.14
`(90% Cl: 1.06, 1.21), and 1.07 (90% Cl: 1.00, 1.14), respectively. The average accumulation ratio (steady
`state versus single dose) across the dose range studied for q.d. doses ranged from 1.05 to 1.29. Overall, the
`multiple-dose data are consistent with that observed following single dose administration of sitagliptin.
`Plasma AUCO—oo increased approximately dose-proportionally over the range of doses studied (25 to 600
`mg q.d.). Cmax increased in a slightly greater than dose proportional manner and C34 increased in a less
`than dose proportional manner. There was a trend toward shorter Tmax with increasing dose. The apparent
`terminal elimination half—life was 1 1.8 to 14.4 hours over the dose range 0f25 mg q.d. to 600 mg q.d.
`
`ALICE“ = AUCugd h, fer once dail}r closes and 1511.16.11“, for twice flail}r doses.
`t1,“— no.2”: for once daily doses and 110.12 h, for twice dailyI doses.
`C5133; for once dailyr doses and CI; for twice daily doses.
`SS=Steady-state iDay 10}; SD=Single Dose (Day 1‘3.
`L .d.=onc:e daily: hidfiwice daily.
`
`Fraction of dose excreted 1melianged in urine. extrapolated to infinity.
`Renal Clearance.
`'
`
` «a:,—vo‘~a...
`
`
`
`
`2.2.3 What is the absolute bioavailability ofsitagliptin and what isfood effect on the
`pharmacokinetics ofsitagliptin?
`
`In a 2—Part, randomized, placebo—controlled, intravenous dose escalation study, the
`pharmacokinetics of rising intravenous doses of sitagliptin and definitive absolute bioavailability/food
`effect of sitagliptin in healthy adult subjects were evaluated,
`
`Part 1 was a fixed—sequence design in which rising single intravenous doses of 25-, 50-, and 100-
`mg sitagliptin (N=8) or matching placebo (N=2) were given in Periods l, 2, and 3, respectively. The same 2
`subjects in each period received placebo. All intravenous doses of sitagliptin were given after an overnight
`fast. There was at least a 5—day washout between doses. In each period, blood and urine samples were
`collected at specified time points for determination of sitagliptin concentrations. Continuation of each
`period was dependent on the tolerability of the previous dose. The pharmacokinetic parameters of
`intravenous administration of sitagliptin are summarized in Table 5.
`
`Table 5. Mean sitagliptin (SD) pharmacokinetic parameters following administration of 25—, 50— and 100—
`mg intravenous doses of sitagliptin to healthy adult male and female subjects (N=8)
`
`ENDAZ] -995NDA21995—Januvia-12—16—2005.doc
`
`8
`
`

`

`
`
`Parameter
`
`_._._z-‘
`3:3 mg
`
`Mean" (Between—subject SD?)
`a.—
`501112
`
`100 me
`
`
`
`
`
`
`
`
`
`
`
`
`
`.
`
`9.88 {1.33
`4.85 (0.58)
`2.47 (0.53
`AUCW (nMrhr):
`941 (184)
`330(1401
`342 (91;.
`Guiana)
`60.3 (11.1)
`33.8 (5.01)
`30.5 I63)
`C24 5331321)
`239 {1263
`340 (£34)
`249 (153}
`(71;. (ng‘an
`413 (5.6)
`4 21 (30)
`414 (88::
`C1; (mLfmin)
`
`
`o 6'? (e.__
`0 81 (a :1)
`0.60 {0.3.3
`C1}:
`(71,,
`298 (30)
`‘234 {38}
`363 (44)
`Vise (L)
`
`
`3.92 {0.55)
`9.200133
`10.39 (0.8 2)
`MRI (hr)
`10.9 {1.0}
`12. 3 (0 7}
`$1.7 (1.5}
`Apparent Terminal tag; (hr)
`
`
`
`fag“):
`0.654 (0.365)
`0.8 38 (.0 172)
`0.700 (0.193)
`
`
`
`T Mean = geometric mean for AUC‘i-OQ. Cm.
`(7'24 1”. CIR. C1p and C.IR:”C‘lp. harmonic mean for
`
`
`
`
`apparent terminal
`tm and arithmetic mean for V€1.35; MRI and 115.-.,
`
`
`1 SD = Standard deviation; back-transformed from log scale for AUC(0-1.). Cm. CIR. Cl; and Gigi-"C1g.
`
`
`iackkm'fe SD for a
`arent terminal rm.
`
`
`
`
`
`
`For Part II, a different group of 12 subjects was randomized and received 3 single doses of
`sitagliptin1n a balanced, 3--period, crossover design. subjects received a 100--mg oral dose of51tagl1pt1n1n
`the fasting state (Treatment A); after completion of a standard breakfast, subjects received a single 100--mg
`oral dose of sitagliptin in the fed state (Treatment B) and subjects received a lOO-mg intravenous dose of
`sitagliptin infused over 2 hours in the fasting state (Treatment C). All doses of Study drug were
`administered with 240 mL water. There was at least a 5—day washout between doses. The results are
`summarized in Table 6.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`ENDAZ]-995NDA2]99S—Januvia-l2—16—2005.doc
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`9
`
`

`

`Table 6. Mean sitagliptin (SD) pharmacokinetic parameters following lOO—mg intravenous doses (fasted)
`and food effect on AUCO.“ (pM'hr) and Cmax (nM) following lOO—mg oral dosing (fasted and fed) of
`sitagliptin to healthy adult male and female subjects (N=12)
`Meanlfiettt’een—mmct SD'i T;
`tee—mglv
`IOU—mg Oral
`ion—mg
`GMR§ {90%Cf”)
`Parameter (fed.="fasted oral) Fasted Fasted ' Oral Fed
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`8.17 (0.9?)
`:90 {1.23;
`9.03 (1.24)
`AUCM (gm-hr)
`1.030191 1.11}
`772 (:30)
`5717 (2:10)
`NA
`Cmax (nM)
`0.94 (0.86. 1.03}
`NA
`3.0 (NA?
`3.0 (NA)
`NA
`Twang)
`NA
`11.8 (2 .0)
`11.7 {2.0)
`19.6 (3.0}
`Apparent terminal t” (131')
`NA
`NA
`340 (124)
`249 (16 8}
`CIR (lithium)
`
`£234. NA 0.?31 (0.159} 0.551 (0.149) NA
`
`
`
`Mean = gemnett‘ic mean for AUCT(,3.,;_.3. Cmax. C11. harmonic mean for apparent terminal 15;; and
`arithmetic mean for fey“.
`Median for Tum
`; SD = Standard deviation; Back—nunsfonned fi‘om log scale for AUC‘mW}. Cmax. CIR. mid jackknife
`SD for apparent terminal tm.
`‘
`GMR = geometric mean ratio (feclf'fasted oral).
`CI = confidence intewal.
`3A = not available.
`
`
`
`
`
`
`The absolute bioavailability (AUCM following a lOO—mg fasting oral dose / AUCO.ac following a
`lOO-mg fasting IV dose) of sitagliptin was 87% with a corresponding 90% CI of (81%, 93%). The study of
`food effect showed that the 90% CI for the AUCW GMR (0.97, 1.1 l) and for the Cmax GMR (0.86, 1.03)
`fell within the bounds of (0.80, 1.25). This reviewer agrees with the sponsor that there is an absence of a
`food effect on sitagliptin bioavailability.
`
`2.2. 7
`
`Is the chiral integrity ofsitagliptin in human plasma evaluated?
`
`Sitagliptin has one chiral center. The chiral integrity of sitagliptin in clinical plasma samples was
`evaluated in Study P033. Following ZOO-mg doses, the samples collected at 2 hours (near Tmax) and 15
`hours were assayed for presence of the enantiomer of sitagliptin. The results of the analysis revealed that
`the concentration of the enantiomer to sitagliptin at each time point was below the assay limit of
`quantitation (1.23 nM). Since the Cmax following the 200—mg dose is approximately 2000 nM, these
`results indicate that sitagliptin plasma concentrations are at least l600—fold higher than that of the
`enantiomer. These results demonstrate that there is negligible chiral inversion of sitagliptin in vivo.
`
`Figure 1. Chemical Structure of [14C] sitagliptin
`.
`
`0 l
`
`l
`
`F
`
`H0
`+
`NH3 0
`
`\ _
`O
`
`Chiral
`
`F
`
`IVN
`
`\.
`
`The asterisk denotes the position of the 14C label
`
`ENDA2 l —995NDA2 l 995—Januvia—l 2-l 6-2005.doc
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`10
`
`

`

`2.2. 7
`
`Is sitagliptin pharmacokinetic-s dose-proportional?
`
`In a single—center, open-label, randomized, 5-period, balanced crossover study, the dose
`proportionality of sitagliptin tablets within the 25- to 400-mg dose range was assessed in 10 healthy adult
`subjects. In each period, the subjects received either a single 25—, 50—, 100-, 200—, or 400—mg dose of
`sitagliptin in the fasted state. Mean plasma concentration versus time profiles are depicted in Figure 2 and
`the sitagliptin pharmacokinetic parameters are shown in Table 7.
`
`Figure 2. Mean sitagliptin plasma concentrations following administration of single oral doses of Final
`Market Image 25, 50, 100, 200, and 400 mg of sitagliptin to healthy male and female subjects (N=10)
`(P033)
`
`6000 -
`
`4000
`
`SC
`v 5000
`1:
`.9
`E*x
`cT;U
`8Q
`(U
`E0‘)
`fl
`CL
`
`3000
`
`2000
`
`8
`3
`:2
`E
`
`1000 ~
`
`
`
`.
`
`'
`.
`
`O
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`Time (hr)
`
`Table 7. Mean sitagliptin pharmacokinetic parameters following single oral doses of Final Market Image
`
`tablets to healthy male and female subjects (N=10) (P033)
`MK—0431
`LS Mean'
`
`
` MR (90% CI)"
`
`
`Parameter
` Slope (90% CD‘-
`400 mgflOG mg
`
`
`
`
`
`
`AUG,” yM-llr
`1.006198, 1.01)
`1.03 (0.99, 1.06)
`Cmax nE‘vf
`1.21(1.1?.1.26)
`1.30 (1.13. 1.50)
`0.700515. 2)
`
`0.6"! (0.62, m2)
`
`
`
`
`C2411: “M
`me hr;
`[3:2 in"
`(31R nifmin
`, >
`,
`_
`.
`fa. 0—7:}
`
`’ Geometric least-squares mean. back-transformed from log scale.
`' Median.
`
`
`
`
`
`
` §
`
`
`_ Ariflunetic least—squares mean.
`I Hannom'c least—squares mean.
`Ii Slope of log[PK parameter] versus logidose} from power—law model.
`
`
`= Ratio ofdose adjusted (to 100 mg) geometric least—squares means {460 rug-"100 mg).
`
`A plot of geometric mean AUCOm values versus dose administered along with the fitted regression
`line using the power law model is presented in Figure 3(Left). For AUCM, the slope (90% C1) by the
`power—law model was 1.00 (0.98, 1.01). The sitagliptin dose adjusted (to 100 mg) AUC0_.,c geometric least-
`squares mean ratio (GMR,,400 mg/ 100 mg) was 1.02 with a corresponding 90% CI of (0.99, 1.06).
`Therefore, sitagliptin AUCOM increases dose proportionally with increasing dose across the tested dose
`range.
`
`EN DA21 ~995NDA2 l 995-Januvia—l 2-1 6—2005.doc
`
`11
`
`

`

`
`
`MOOJTGISSOd1838
`
`A plot of geometric mean Cmax values versus dose administered along with the fitted regression
`line using the power law model is provided in Figure 3(Right). For Cmax, the slope and its 90% Cl
`estimated by the power-law model was 1.21 (1.17, 1.26). These results suggest that sitagliptin Cmax
`increases in a modestly greater than dose proportional manner with dose.
`
`Figure 3. Sitagliptin AUCO-oo and Cmax versus dose following single oral doses of Final Market Image 25,
`50, 100, 200, and 400 mg to healthy male and female subjects (P033)
`
`
`
`
`AUC{wt1:4
`
`my
`my
`Dose 5mg) of IAKWS}
`wxrevlwwfnue: nun
`‘LV
`59,9;le F-
`‘
`. dummy-m” ‘
`
`(tan
`
`1
`
`base area‘- c—f ”A cat:
`l
`moms; 1m. 5.?va
`:— mgmi‘a'fvixwufl
`
`Based on the nature of drug action, this reviewer agrees that AUC is anticipated to be the most
`relevant pharmacokinetic parameter for a DPP—IV inhibitor. Sitagliptin PK can be considered as dose
`proportiOnal.
`
`2.2.10 What is characteristics ofsitagliptin metabolism and elimination?
`
`In a mass balance study, 6 healthy male subjects received 83.04 mg “4C1 Sitagliptin followed by
`collection of plasma, urine, and feces for 7 days. Approximately 100% of the oral radioactivity dose was
`recovered with 87% in urine and 13% in feces over the 1—week postdose collection interval. Approximately
`79% of the Sitagliptin dose was excreted unchanged in urine, indicating that the major pathway of
`elimination of Sitagliptin is via urinary excretion. Approximately 16% of the oral radioactivity dose was
`recovered as metabolites (13% of the dose in urine and 3% of the dose in feces), indicating that metabolism
`is a minor pathway of elimination of Sitagliptin. Parent compound, Sitagliptin accounted for the majority of
`the radioactivity in plasma (74%), as determined by the ratio of sitagliptin AUC and radioactivity AUC.
`
`Six metabolites were detected at trace levels, each representing <8% of the radioactivity
`in plasma [Figures 4 and 5]. The most abundant metabolites in plasma were M5 (4 to 7% of radioactivity)
`and M2 (1 to 6%), both of which are formed by oxidative desaturation of the piperazine ring followed by
`cyclization. Other metabolites included M6 (a group of hydroxylated derivatives; 1 to 4%), M1 (N—sulfate
`conjugate; 2 to 4%), M4 (carbamoyl glucuronide conjugate; 1%) and M3 (ether glucuronide conjugate of a
`hydroxylated derivative; <l%). Three of the six metabolites of MK—0431 (M1, M2, and M5) observed in
`plasma have a known structure and were tested in vitro and shown to have no appreciable plasma DPP—IV
`inhibitory activity (the other three metabolites were not tested for inhibition of DPP—lV activity). Two of
`the metabolites not tested for activity (