CENTER FOR DRUG EVALUATION AND
`RESEARCH
`‘
`‘
`'
`
`APPLICA TIONNUMBER:
`2 l -68 8
`
`PHARMACOLOGY REVIEW
`
`

`

`PHARMACOLOGY AND TOXICOLOGY REVIEW OF NDA
`
`I NDA #:
`
`21-688
`
`Product Name :
`
`SensiparTM (Cinacalcet HCl)
`
`Sponsor:
`
`Amgen Inc, CA
`
`Indication:
`
`Treatment‘ of primary and secondary hyperparathyroidism.
`
`Division:
`
`HFD7510 (DMEDP)
`
`Reviewer:
`
`Gemma Kuijpers
`
`Date:
`
`February 12, 2004
`
`

`

`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY .............................................................................................. 3
`
`PHARMACOLOGY/TOXICOLOGY REVIEW ....................................'. ............. 10
`
`3.1,
`
`INTRODUCTION AND DRUG HISTORY................................................................. 10
`
`3.2
`3.2.1
`3.2.2
`3.2.3
`3.2.4
`
`PHARMACOLOGY .............................................................................................’.......... 12
`Summary.............................................................‘.................................................................. l 2
`Primary pharmacodynamics ................................................................................................. 13
`Secondary pharmacodynamics ............................................................................ . ................ 22 )
`Safety pharmacology .................................................................................................. 24
`
`3.3
`3.3.1
`3. 3.2
`3.3.3
`3.3.4
`3.3.5
`3.3.6
`
`PHARMACOKINETICS/TOXICOKINETICS
`Summary ............................................................................................................... I ............... 30
`Absorption ............................................................................................................................ 31
`Distribution .............................................................................................
`
`Metabolism .............................................................................................
`Excretion ............................................................................................................................... 42
`Other studies ......................................................................................................................... 44
`
`30
`
`‘
`
`3.4
`3.4.1
`3.4.2
`3.4.3.
`3.4.4.
`3.4.5.
`3.4.6
`3.4.7
`
`......................... 45
`TOXICOLOGY
`Toxicity study summary ..................................................... 45
`'
`Single— and repeat—dose toxicity ........................................................................................... 45
`Genetic toxicology.............................................................................................................. 103
`Carcinogenicity ................................................................................................................... 104
`Reproductive and developmental toxicology...................................................................... 140
`Local tolerance
`......; .....................’...................... '. .............. l 74
`Special toxicology studies .................‘.......................................................................... 175
`
`'
`
`,
`
`3.5 ' REFERENCES
`
`-
`
`179
`
`3.6
`
`3.7
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS ......................L;......... 181 .
`
`APPENDIX/ATTACHMENTS .....................
`
`................ 132
`
`

`

`EXECUTIVE SUMZWARY
`
`1. Recommendations
`
`1.1
`
`1.2
`
`1.3
`
`Recommendation on approvability
`Pending the proposed labeling changes, Pharmacology/Toxicology recommends
`approval of this NDA (AP)
`
`Recommendation for nonclinical studies
`None
`
`Recommendations on labeling
`See Team Leader Memo (K.Davis-Bruno, February 10, 2004) (Appendix)
`
`2. Summary of nonclinical findings
`
`2.1
`
`Overview of nonclinical findings
`
`The current NDA is for the use of Cinacalcet in the r———-——-— ,‘ treatment of secondary
`hyperparathyroidism (HPT) in patients with chronic kidney disease, and, the treatment of
`hypercalcemia in patients with parathyroid carcinoma or patients with primary HPT. In
`chronic kidney disease hypocalcemia results from a disturbance in renal phosphorus handling
`and decreased formation of l,25(OH)2-VitD. Hypocalcemia causes increased parathyroid
`gland secretion of PTH as primary defense of the system against lowered serum calcium.
`PrimaryHPT is a hypercalcemic disorder that results from excessive secretion of PTH and is
`usually caused by parathyroid adenoma or primary parathyroid hyperplasia.
`
`A dose titration regimen is proposed with oral doses of 30 mg up to 180 mg, once daily,m
`secondary HPT, 1M The dose15 titrated1n
`each individual patient based on a target level of PTH and/or serum calcium.
`
`The calcium sensing receptor (CaR) is a G-protein coupled receptor and plays an important
`role in calcium homeostasis. It regulates the release of parathyroid hormone (PTH) from the
`’ parathyroid gland in response to changes in extracellular calcium. Cinacalcet is a calcimimetic
`and acts at the CaR to increase its sensitivity to eittracellular calcium, thereby suppressing the
`secretion of PTH from the parathyroid gland. Cinacalcet can also stimulate calcitonin
`secretion through interaction with the CaR on thyroid C-cells.
`
`‘
`Pharmacology .
`In monkey, rat and mouse tissues CaR mRNA was detected primarily in the parathyroid gland
`but also in kidney, GI tract, thyroid, CNS, pancreatic islets, adrenal gland, thymus, testis, bone
`and/or bone marrow. In vitro pharmacology studies demonstrated a potent and concentration-
`dependent stimulation of the CaR by Cinacalcet. Modulation of the CaR by Cinacalcet led to
`
`inhibition of PTH secretion from .
`‘ cells, and stimulationxof calcitonin release
`from rat thyroid C-cells.
`
`

`

`In intact rats, cinacalcet induced inhibition of PTH secretion resulting in a rapid and reversible
`reduction in serum calcium levels with half maximal effect (EDso) at an oral dose of 3 mg/kg
`
`(Cmax:
`). Usingin vivo models of secondary hyperparathyroidism, such as the
`partially (5/6) ———-——-———~
`‘ rat, it was demonstrated that cinacalcet causes a dose-
`dependent and transient reduction1n serum PTH and reduces blood ionized calcium Upon
`repeat dosing, cinacalcet prevented or attenuated parathyroid gland hyperplasia1n the Nx rat.
`In one study in-Nx rats, cinacalcet (15 mg/kg) suppresSed bone turnover, reduced bone
`fibrosis and conical porosity and increased cortical BMD and toughness. These effects were
`most likely mediated by the reduction in serum PTH. In parathyroidectomized (PTX) rats,
`cinacalcet reduced blood ionized calcium through activation of CaR—mediated thyroid
`calcitonin secretion. The studies identified the parathyroid and thyroid as target organs for the
`pharmacologic action of cinacalcet in the rat. Cinacalcet reduced hypercalcemia but had no
`effect on vascular mineralization in VitD-treatederats; Effective oral doses (ED50400) in the ,
`
`in vivo rat studies were generally in the range of 10-30 mg/kg (Cmax
`.).
`In vitro receptor studies suggested that the transmembrane and/or intracellular domains of the
`CaR are required for sensitivity of the receptor to cinacalcet.
`An animal model for primary hyperparathyroidism was not available.
`
`Safegl pharmacology
`
`Note: Calculation ofexposure multiples in nonclinical studies are based on the maximum 180
`mg/day dose proposedfor secondary hyperparathyroidism. Clinical PK data indicated
`maximal exposure (Cmax, A UC) at the 180 mg/day dose, andfurther exposure was not
`observed at doses >180 mg/day. Exposure at the maximum dose of360 mg/day (90 mg QID)
`recommendedfor primary hyperparathyroidism is not known.
`
`In safety pharmacology studies, single oral doses of cinacalcet had no effects on
`neuropharmacologic signs or body temperature, and no analgesic, anticonvulsant or
`proconvulsant effects1n mice, at doses up to 200 mg/kg (equivalent to 6 times the human dose
`of 180 mg/day, based on mg/m2). In mice, a decrease1n spontaneous motor activity and an
`increase in gastric motility was observed at an oral dose of 200 mg/kg. In the guinea pig, an
`IV dose of 20 mg/kg caused a transient increase in airway resistance and bronchoconstriction.
`These effects may have been due to hypocalcemia or interaction of cinacalcet with central or
`peripheral ion channels/receptors. There were no significant cardiovascular or EKG effect in
`the dog at single oral doses up to 504mg/kg (i-é-‘Q human Cmax @ 180 mg/day). EKG effects
`were also not observed in a 1-month dog toxicity study at doses up to 100 mg/kg/day (0.8x
`- human AUC @ 180 mg/day). However, in repeat dose toxicity studies in the monkey QT and
`QTc interval prolongation was observed (see General Toxicity).
`
`An in vitro cardiac ion channel‘study showed thatcinacalcet at high concentrations blocked
`KAT]; channels, Kv4.3, Kvl.5 and tha channels. hERG channel activity were minimally
`affected. KATp channels are believed to be involved in the protective response of the body, e.g.
`the heart and the vasculature, to stress. In the heart, they mediate preconditioning in response
`to ischemic stress, andin blood vessels they may be involved1n vasoconstriction KATp
`channels may also have cardioprotecive effects through shortening of actiOn potential and QT
`duration. KATp channels are known to mediate the insulin secretory response of pancreat1c —-4
`
`

`

`cells to glucose. Despite the in vitro effect on KATp channels, in vivo treatment of rats with
`cinacalcet did not affect blood glucose levels (i.e. insulin secretion) after an oral glucose
`challenge. However, in repeat dose studies in the rat and the monkey serum glucose was
`decreased. Also, in (sub)chro'nic rat toxicity studies myocardial damage was observed. These
`findings were possibly related to KATP channel blockage, or to hypocalcemia. Drug-induced '
`blockage of KM]: and other ion channels by cinacalcet (or its metabolites) constitutes a
`clinical concern, since it could affect CNS and cardiac function. "
`
`
`ADME
`Cinacalcet is well absorbed upon oral administration (95%), and the major part of a dose is
`recovered in urine and bile in all species. Tmax of parent and total drug—related radioactivity is
`<6h (dose range 1-10 mg/kg) in animals and humans. Tm of parent drug is 2-9h in animals,
`and 10-35h in humans. Metabolites are cleared much slower than parent in animals, but at
`similar rate as parent in humans. 'Oral bioavailability (BA) in rats is <10%, in humans 20%.
`The ‘low bioavailability is probably the result of extensive first pass metabolism in liver and
`possibly GI tract. Cinacalcet is highly protein bound (93% to 99%) in humans and animals. In -
`rats, radioactivity representing parent or metabolite is widely distributed over numerous
`tissues. Plasmaztissue ratios exceeded 1 in liver, Harderian gland, kidney, adrenal, lung.
`
`Cinacalcet is extensively metabolized by oxidative and conjugative pathways. The two main
`pathways are N-dealkylation resulting in carboxylic acid metabolites (MS-M8) and oxidation
`of the naphthalene ring producing dihydrodiols (M2-M3). CYP3A4, CYP1A2 are the major
`contributors to cinacalcet metabolism in humans. Parent drug accounts for a minor fraction of
`circulating radicactivity in animals and humans. There are no unique human metabolites.
`' Metabolite profiles were qualitatively similar but quantitatively different across species. In
`humans, the major circulating plasma metabolite is M5, while minor plasma metabolites are
`M6 and M2-Glu. Major plasma metabolites in monkeys are M5, M7 and M2-Glu, and in rats
`M7 and M5. In vitro metabolite studies indicated that the carboXylic acid metabolites M5 and
`M7 and the glucuronated'dihydrodiol metabolites (MZa-Glu, M2b-Glu) were inactive.
`
`Excretion in mice and monkeys is mainly hepato—biliary (fecal) (20—40%), and urinary (50%).
`In rats, excretion is fecal (ca. 60%) and urinary (ca. 15%). In humans, excretion is mainly
`urinary (95%). Cinacalcet and related compounds are excreted in milk in lactating rats, with
`relatively high parent drug levels in milk. Cinacalcet Crosses the placental. barrier in rabbits,
`and fetal plasma levelsare approximately 1/10 times maternal levels. Data on liver P450
`content from a 1-year monkey toxicity study suggested the potential for microsomal enzyme
`induction.
`'
`
`_
`
`'
`
`General toxicig
`Acute oral toxicity studies were carried out in mice and rats, and chronic toxicity studies were
`conducted up to one month in dogs, six months in rats and one year in monkeys. Cinacalcet
`administration in animals was dose—limited by the calcium-lowering effect of the drug, and by
`GI toxicity. The hypocalcemia was due to the reduction in serum PTH and confounded the
`interpretation of the results. As a result of the hypocalcemia, potential hypercalcemia—like
`toxicity of the calcimimetic may have gone undetected in the animal studies. Part of the
`toxicities may have been mediated by cinacalcet metabolites.
`
`

`

`On average, parent drug exposure (AUC) in the long term toxicity studies in rats and
`monkeys, respectively, was 7.5 and 1.8 times the human AUC (648 ng-h/mL) at the 180
`mg/day dose. Low AUC multiples in the monkey limited the predictive power of the toxicity
`studies. Intrinsic qualification of the major human metabolite M5 was performed in the rat and
`monkey studies. Of the minor human metabolites, the M2-glucuronide was well qualified in
`the monkey study, but M6 was poorly qualified in the animal studies.
`'
`
`In both acute and repeat dose toxicity studies in rats, dogs and monkeys, signs of
`hypocalcemia ineluded hypoactivity, neuromuscular and respiratory effects, tremors,
`convulsions, and excessive salivation. In a 2-week rat study, convulsions were observed at
`500 mg/kg/day (23x human AUC @ 180 mg/day), in conjunction with hypocalcemia. CNS
`toxicity including convulsions was also seen with the degradation product and putative
`
`metabolite,
`at 100 mg/kg/day, with
`unknown relationshipto serum calcium. This compound was, however, not detected1n mouse
`plasma or excreta andis believed to be metabolically labile.
`
`In the 3-month and 12-month monkey studies, prolongation of QT and QTc intervals was
`observed at 3— and 6-month time points. The increase was dose—dependent and occurred at all
`doses of 5, 50 and 100 mg/kg/day (0.1-2x human AUC @ 180 mg/day). The increase was
`maximally60 msec (0. 26sec in controls—10.325ec @ 100 mg/kg/day) The increase was due to
`ST segment prolongation and was significantly correlated to the dose--dependent reduction1n
`serum ionized calcium of 10-40% (1.35, l 2, 1.0, 0.9 mM @ 0,5,50, 100 mg/kg/day). QT
`prolongation was not observed1n the l—month dog study at similar doses (5, 50, 100
`mg/kg/day) even though serum calcium was reduced by 20% at the highest dose (1 “45—91 15
`mM)
`
`The relationship between calcium and QT(c) in monkeys treated with cinacalcet was similar
`as has been described for patients with hypoparathyroidism and hypocalcemia (Bronsky et al,
`1961) and for volunteers given citrate to lower serum calcium (Davis et al, 1995). In these
`cases, a decrease in serum ionized calcium of 0.5 mmol/L was associated with an increase in
`QT(c) of approximately 60 msec, and a decrease of 0.2 mM with an increase in QaT(c) of 34
`msec, respectively. This compares to an increase in QT(c) of 60 msec in the monkey with a
`decreasein serum ionized calcium of 0. 5 mmol/L. Data on monkey QT(c) with endogenous or
`induced hypocalcemia are not available.
`
`It is likely that the EKG findings (QT prolongation) and CNS toxicity (convulsions) are
`1 related to hypocalcemia. However, it can not be excluded that these adverse events are
`partially mediated by effects of cinacalcet or its metabolites on cardiac or CNS ion
`channels/receptors.
`
`In the rat, cataracts were observed in all repeat dose toxicity studies at doses 2 2x human AUC
`@ 180 mg/day and were possibly associated with hypocalcemia. Cataracts were not seen in
`monkey or dog studies even though similar reductions in serum calcium levels were attained.
`Cataracts have been observed in rabbits when exposed to hypocalcemia and in individuals
`
`

`

`with hypoparathyroidism, and may be the result of low calcium-induced derangement in lens
`ion composition.
`
`Other toxicities ofpotential clinical concern because ofunlikely or unclear relatedness to
`serum calcium included GI toxicity (abnormal feces, poorappetite, emesis, intestinal mucosa
`hyperplasia/inflammation; monkey, dog, rat), hematologic effects (decreased red blood cell
`parameters; monkey, rat),'liver toxicity (increased enzymes, decreased serum protein, ‘
`vacuolation, necrosis; monkey, rat), renal toxicity (BUN/creatinine increase, mineralization;
`rat), cardiac toxicity (myocardial degeneration/necrosis, lefi ventricular arterial hypertrophy;
`rat, juvenile dog), endocrine hormone changes (testicular atrophy and reduced testosterone,
`T3 decrease, T4morease, Vitamin D reduction; monkey), and muscle toxicity (CPKmcrease,
`degeneration, monkey).
`
`Urine volume was increased in dogs and monkeys and urinary calcium excretion was
`increased in rats and dogs. These effects were probably due to pharmacologic effects on the
`kidney CaR affecting calcium reabsorption and urine concentration. Kidney pelvis
`mineralization was observed in rats at 1.5x human AUC @ 180 mg/day, and kidney weight
`increase and slight tubular changes were observed in monkeys at 2x human AUC @ 180
`mg/day. Renal toxicity may be particularly relevant for patients with primary
`hyperparathyroidism.
`
`Serum testosterone levels were decreased at all doses of 5-100 mg/kg/day (0.1-2x human
`AUC @ 180 mg/day) in the l—year monkey study. This was accompanied by testicular weight
`‘ decrease at the high dose of 100 mg/kg/day. Testicular tubular atrophy or degeneration was
`also observedin the l—and 6-month rat studies at 3x—7. 5x human AUC @ 180 mg/day, and the
`l-month dog study at 0.8x human AUC @ 180 mg/day.
`
`Genotoxicity
`Cinacalcet had no genotoxic potential, as demonstrated by negative resultsin three in vitro
`assays (Ames bacterial test, HGPRT mutation assay in CHO cells and chromosome aberration
`assay in CHO cells, all with and without metabolic activation), and one in vivo genotoxicity
`assay (mouse micronucleus assay).
`
`Carcinogenicig
`Two-year dietary carcinogenicity studies were conducted in rats and mice. Doses used in the
`rat study were 5, 15, 35 mg/kg/day in males, and 5, 20, 50—)35 mg/kg/day in females. In mice
`doses used were 15, 50, 125 mg/kg/day in males and 15, 70, 200 mg/kg/day in females. In
`both species, there were decreases in body weight and effects related to the calcirnimetic
`‘effects of the drug (hypocalcemia, hyperphosphatemia, soft tissue/vascular mineralization,
`particularly in kidney). In» female mice, slightly but not statistically significant increases
`(above historical control) in the incidence of intermediate pituitary hyperplasia and adenoma
`and of erythroid leukemia were observed at the high dose of 200 mg/kg/day (1.6x human
`AUC @ 180 'mg/day). In female rats, there was a slight, statistically significant increase in the
`incidence of lymphoma at the high dose of 50-35 mg/kg/day (1.4x human AUC @ 180
`mg/day). However, based on historical control rates, the effect did not appear biologically
`significant. In male rats, a slight but not statistically significant increase in the incidence of
`
`

`

`lung bronchio-alveolar adenoacarcinoma was observed at the high dose of 35 mg/kg/day (2.5x
`. human AUC @ 180 mg/day). A decrease in parathyroid and thyroid C-cell hyperplasia and
`adenoma was noted in male and female rats at all doses from 5-~50mg/kg/day (0.2x-2.5x
`human AUC @ 180 mg/day). There were no tumor findings that warranted mentioning in the
`label.
`
`_
`
`mm
`A full battery of reproductive toxicity studies was performedin rats and rabbits. High doses
`were limited by maternal body weight effects and hypocalcemia. In an oral Segment I fertility
`study in rats (5, 25, 75 mg/kg/day), there were no effects on male or female fertility at doses
`up to 25 mg/kg/day (3x human AUC @ 180 mg/day). At 75 mg/kg/day (5.6x human AUC)
`there were slight decreases in the number of corpora lutea, implantation sites and live fetuses
`concurrent with maternal toxicity of decreased body weight and clinical signs.
`
`In the oral Segment 2 study in rats (0, 2, 25, 50 mg/kg/day), there were no effects on fetal
`external, visceral or skeletal malformations or variations at doses up to 50 mg/kg/day (4.4x
`human AUC @ 180 mg/day). Fetal body weight was slightly reduced at 2, 25, 50 mg/kg/day
`in parallel with decreases1n maternal food consumption and body weight gain. Maternal
`toxicity was also evident as clinical signs at 25 and 50 mg/kg/day.
`
`In the oral Segment 2 study in rabbits (0, 2, 12, 25 mg/kg/day), there was no fetal toxicity
`(mortality, fetal weight), and there were no effects on fetal external, visceral, skeletal
`malformations (i.e., no teratogenicity) or variations at doses up to 25 mg/kg/day (0.4x human
`AUC @ 180 mg/day). Maternal toxicity was evident as clinical signs, decreased body weight
`gain and food consumption'at 12 and 25 mg/kg/day. In the dose-range finding Segment 2
`study in rabbits (0, 1, 5, 25, 100, 200 mg/kg/day), there were no external fetal anomalies at
`doses up to 100 mg/kg/day (2. 8x human AUC @ 180 mg/day) Reductions in maternal food
`consmnptionand body weight were seen at doses .25 mg/kg/day, clinical signs at >100
`mg/kg/day, and maternal mortality at 200 mg/kg/day.
`'
`
`' In the oral Segment 3 study in rats (0, 5, 15, 25 mg/kg/day), one dam dosed with 15
`mg/kg/day was found dead with a prolapsed uterus and delivery complications on the day of
`delivery. Reductions in maternal food consumption/body weight and F l pup body weight
`were observed on PPD 10-17 at 25 mg/kg/day. A minimal reduction in F 1 pup body weight
`gain unaccompanied by maternal effects was observed at 15 mg/kg/day on PPD 10- 17. There
`were no effects on F 1 pre- or postweaning development. In F1 male parental animals, there
`was an increased incidence of1ncisor abnormalities at 25 mg/kg/day.
`
`Other studies
`
`-
`
`Toxicology studies were conducted to evaluate impurities, industrial toxicology," and other
`routes (IV) of administration. The studies demonstrated adequate qualification of impurities,
`and did not raise additional concern for the proposed oral use of cinacalcet in patients with
`primary or secondary HPT.
`
`2.2 Nonclinical safety issues relevant to clinical use
`
`

`

`In long term monkey studies, QT(c) interval was increased. Most likely, this effect was at
`least partially mediated by reductions in serum calcium. In rats, dogs and monkeys, CNS
`toxicity including convulsions in rats occurred in conjunction with hypocalcemia. There are
`potential effects of cinacalcet -and possibly its metabolites- on cardiac ion (K+) channels and
`conduction. In particular, blockage of Kim: channels could impair cardiac preconditioning in
`response to ischemic stress, or impair the defense against QT prolongation. The nonclinical
`data do not exclude a potential for cardiac conduction abnormalities and CNS toxicity
`independent of reductions in serum calcium. Nonclinical data also indicate a potential for GI
`. and testicular toxicity. The CNS, Gland testicular toxicities may be related to the presence of
`CaR in those tissues.
`4
`
`Based on in vitro and in vivo nonclinical data, thorough evaluation of clinical trial data for any
`events related to cardiac conduction abnormalies under resting or stress conditions (EKG),
`myocardial and coronary artery disease, and CNS excitation (seizures) is recommended/
`
`,__,—.—_—
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`'
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`PHARMACOLOGY/1‘OXICOLOGY REVIEW
`
`E
`
`p 3.1
`
`INTRODUCTle AND DRUG HISTORY
`
`NDA number:
`
`.
`
`'
`
`'21-688
`
`Submission date/type of submission:
`Information to sponsor:
`‘
`Sponsor and/or agent:
`Manufacturer for drug substance:
`
`September 5, 2003/ 505(b)l
`Yes (X) No ()
`Amgen Inc.
`
`~ Reviewer name:
`Division name:
`
`HFD #:
`Review number:
`
`4
`
`~ Review completion date:
`
`Drug:
`Drug substance:
`Trade name:
`Generic name:
`
`V
`
`.
`
`'
`
`,
`
`Gemma Kuijpers
`Division of Metabolic and Endocrine Drug
`Products
`“
`
`510
`1
`
`‘
`
`'
`
`February 12, 2004
`
`Cinacalcet hydrochloride (AMG-073 HCI)
`SensiparTM
`n/a
`
`‘
`
`Cinacalcet hydrochloride (Cinacalcet HCl)
`USAN name:
`Cinacalcet hydrochloride
`-
`INN name:
`[364782-34—3]
`-
`'CAS registry number:
`Molecular formula/molecular weight: C22H22F3N'HC1 / 393.87
`Chirality:
`The molecule contains a chiral center;
`Cinacalcet is the active R-enantiomer.
`
`Structure:
`
`F3
`
`0 -HCI
`‘
`
`N
`
`H . O
`CH3' 0
`
`l
`
`,
`
`g
`_
`
`»
`
`_
`
`4
`
`C22H22F3N‘HCI
`(393.87)
`
`Relevant INDs/NDAs/DMFs:
`
`_ IND 56,010
`
`‘
`
`.
`
`-
`
`'
`
`V
`
`.
`‘
`
`'- -
`
`r»
`
`.
`
`,
`
`.
`
`‘
`
`7-2;?”
`
`1::
`-
`
`
`
`Drug ‘class:
`
`Calcimimetic
`
`; "~
`
`Mechanism of action:
`
`'
`
`AMG-073 HCl mimics the action of calcium at
`
`the parathyroid gland calcium receptor (CaR)
`and suppresses the release of PTH
`
`10
`
`

`

`Clinical formulation:
`
`.
`
`- Tablet (30 mg, 60 mg, 90 mg)
`
`Route of administration:
`meal).
`
`Oral (to be taken with food or Shortly after a
`
`.
`Indication and Usage (proposed label):
`
`treatment of secondary hyperparathyroidism
`SENSIPARTM is indicated for the _
`in patients with Chronic Kidney Discase, receiving or not receiving dialysis. SENSIPARTM
`controls parathyroid hormone, scrum Calcium-x phosphorus, phosphorus, and calcium levels
`in patients with Chronic Kidney Disease.
`
`SENSIPARTM is indicated for the treatment of hypercalcemia in patients with parathyroid
`carcinoma, or in patients with primary hyperparathyroidism for whom parathyroidectomy is
`not a treatment option.
`
`Proposed dosage: In patients with secondary hyperparathyrodism and end-stage renal disease
`on dialysis, cinacalcet is to be administered orally starting at 30 mg, once daily. The dose
`should be titrated every 2 to 4 weeks up to 180 mg daily, to achieve a target PTH level. 0—,
`‘W
`
`M “
`
`a :3 In this review,
`exposure multiples for nonclinical studies have been based on the maximum 180 mg/day dose
`recommended for secondary hyperparathyroidism.
`
`Disclaimer: Graphs and Tables were copied from the NDA submission.
`
`ll
`
`

`

`3.2
`
`PHARMACOLOGY
`
`3.2.1 Summary
`
`Primagl pharmacology
`In monkey, rat and mouse tissues CaR mRNA was detected primarily in the parathyroid gland
`' but also in kidney, GI tract, thyroid, CNS, pancreatic islets, adrenal gland, thymus, testis, bone
`and/or bone marrow. In vitro pharmacology studies demonstrated a potent and concentration—
`dependent stimulation of the CaR by cinacalcet. CaR modulation by cinacalcet lead to
`inhibition of PTH secretion from bovine parathroid cells, and stimulation of calcitonin release
`from rat thyroid C—cells. In intact rats, cinacalcet induced inhibition of PTH secretion resulting
`in a rapid and reversible reduction in serum calcium levels with half maximal effect (EDso) at
`
`an oral dose of 3 mg/kg (Cmax;
`),
`
`Studies in in vivo models of secondary hyperparathyroidism, such as the partially (5/6)
`nephrectomized (Nx) rat, demonstrated that cinacalcet caused a dose-dependent and transient
`reduction in serum PTH and reduced blood ionized calcium. Upon repeat dosing, cinacalcet
`also prevented or attenuated parathyroid gland hyperplasia in the Nx rat. In one study in Nx
`rats, cinacalcet (15 mg/kg) suppressed bone turnover, reduced bone fibrosis and cortical
`porosity and increased cortical BMD and toughness. These effects were most likely mediated
`by the reduction in serum PTH. In parathyroidectomized (PTX) rats, cinacalcet reduced blood
`ionized calcium through activation of CaR—mediated thyroid calcitonin secretion. The studies
`identified the parathyroid and thyroid as target organs for the pharmacologic action of
`cinacalcet in the rat. Cinacalcet reduced hypercalcemia but had no effect on vascular
`mineralization in VitD-treated Nx rats. Effective oral doses (EDsmoo) in the in vivo rat studies
`
`were generally in the range of 10-30 mg/kg (Cmax \
`).
`'
`
`An animal model for primary hyperparathyroidism was not available.
`
`Safety pharmacology
`In safety pharmacology studies, single oral doses of cinacalcet had no effects on
`neuropharmacologic signs or body temperature, and no analgesic, anticonvulsant or
`proconvulsant effects in mice, at doses up to 200 mg/kg (6 times the hurnan dose of 180 mg,
`based on mg/m2). A decrease in spontaneous motor activity and an increase in gastric motility
`was observed in mice at an oral dose of 200 mg/kg. The latter effects may have been due to
`hypocalcemia. In the guinea pig, 20 mg/kg (IV) caused a transient increase in airway
`resistance and bronchoconstriction, also possibly ’due'to hypocalcemia. There were no
`significant cardiovascular or EKGeffect in the dog at single oral doses up to 50 mg/kg (Cmax
`
`-
`
`An in vitro cardiac ion channel study showed that cinacalcet at 500 ng/mL (1.27 uM)
`significantly blocked KATP channels by 96%. It also blocked Kv4.3, Kv1.5 and tha
`channels by 20-50%. hERG channel activity was blocked by 12%. KATP channels are
`believed to be involved in the protective response of the body, e.g. the heart and the
`vas'Culature, to stress. In the heart, they mediate preconditioning in response'to ischemic
`_ stress, and in blood vessels they may be involved in vasoconstriction. KATP channels are also
`
`_
`
`12
`
`

`

`» known to mediate the insulin secretory response of pancreatic B-cells to glucose. Despite the
`in vitro effect on KATP channels, in vivo treatment of rats with Cinacalcet for 5 days (Cmax
`
`total
`) did not affect blood glucose levels (i.e. insulin secretion)
`after anoral glucose challenge However, in repeat dose studiesin the rat and the monkey
`serum glucose was decreased. Also, in (sub)chronic rat toxicity studies myocardial damage
`was observed. These findings were possibly related to KATP channel blockage. Although the
`in vitro block of KATP currents occurred at much higher free drug concentrations than
`achieved1n vivo in humans (ca. 1 ng/mL), the IC50 of the effect1s not known. Thereis a
`theoretical concern for CNS hyperexcitation (seizures) mediated by KATP channel closure,
`since KATP channels may be involved in GABA-ergic neurotransmission. Also, metabolites ‘
`'were not tested and may have similar effects on ion channels.
`
`,
`
`Drug-induced blockage of KATP. and other ion channels constitutes a clinical concern, since it
`could affect CNS and cardiac function. In particular, KATP blockage could impair the ability
`of the body to respond appropriately to hypoxic stress. Thus, thorough evaluation of clinical
`trial data for events related to cardiac conduction abnormalities in rest or stress (EKG: QT,
`ST), myocardial and coronary artery disease, vasoconstriction, CNS excitation and glucose
`homeostasis is recommended.
`
`3.2.2 Primary pharmacodynamics
`
`Mechanism of action: AMG-O73 (cinacalcet) is a type II calcimimetic that acts as an
`allosteric modulator of the calcium-sensing receptor (CaR) on the parathyroid C—cell. It
`increases the sensitivity of the CaR to calcium. The receptor is activated by extracellular
`calcium via a negative coupling mechanism, with increased levels of Ca causing an inhibition
`of PTH secretion. Cinacalcet itself does not activate the receptor, but shifts the downward
`curve relating extracellular calcium concentration to PTH secretion to the left. Thus, in the
`presence of extracellular calcium, it reduces PTH secretion and lowers circulating PTH levels.
`
`Figure 3. Cinacalcet Poterifiales the lnhthnory Effects of Extracellular Ca” on
`m Secretion From Bovine Parathyroid Celts (study Pass-007)
`
`
`
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`The calcium sensing receptor: The CaR is a “family C” G-protein coupled receptor (GPCR)
`and was cloned from bovine parathyroid gland in 1993 (Brown et al, 1993). The receptor has
`a very large NH2-terminal extracellular domain (ECD), a central core of ca. 250 amino acids
`with 7 predicted transmembrane domains (TMDs) and a large intracellular COOH-terminal
`tail of ca. 200 amino acids. Extracellular Ca (Cao) is believed binds to the ECD and perhaps
`the TMD’s.
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`Members of the family C (or 3) GPCR’s include Group I, II and HI receptors. These 3 groups
`of receptors share at least 20% amino acid identity over their 7 TMD’s. Group I contains the
`metabotropic glutamate receptors, mGluRs 1-8 (excitatory glutamate receptors in CNS),
`group II contain