CENTER FOR DRUG EVALUATION AND
`
`' RESEARCH
`
`-
`
`APPLICA TIONNUMBER; ,
`2 1 -688
`
`CLINICAL PHARMACOLOGYAND-
`
`BIOPHARMACEUTICS REVIEW! S)
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
`
`_ NDA
`Submission Date
`' Brand Name
`Generic Name
`
`'
`Reviewers
`Team Leader
`
`OCPB Division
`ORM Division
`
`Sponsor-
`Relevant IND
`
`21—688
`September 5.2003
`SENSIPARTM
`Cinacalcet HCl
`
`S.W. Johnnv Lau and Sang M. Chung
`Hae-Young Ahn
`'
`
`DPE II (HFD-870)
`Metabolic and EndoCrine (HFD-5101
`
`Amgen
`56.010
`
`Submission Tvne: Code
`
`Original: P
`
`Formulation; Strengths
`Indications
`
`30. 60, and 90 mg film coated tablets
`
`To treat ..
`secondary hyperparathyroidism in chronic
`kidney disease patients; to treat hypercalcemia in primary.
`hyperparathyroidism and parathyroid cancer patients
`
`1 Executive Summary
`The sponsor submitted NBA 21-688 to seek approval for the 30, 60, and 90 mg cinacalcet oral tablets
`
`to treat.
`secondary hyperparathyroidism from chronic kidney disease and treat
`hypercalcemia from primary hyperparathyroidism and parathyroid carcinoma. Cinacalcet decreases
`parathyroid hormone release via modulating calcium receptors on the parathyroid gland. CinacalcetIS
`the 1St calcimimetic to seek U. S. marketing approval
`
`Briefly, the cinacalcet clinical pharmacology and biopharmaceutics information follows:
`; Cinacalcet1s well absorbed upon oral administration1n humans. Cinacalcet has a mean steady state .
`volume of distribution of 913- 1235 L andIS é—Kbound to plasma protein(s). The ratio of red
`blood cells cinacalcet concentration to plasma cinacalcet concentration is — at a blood cinacalcet
`concentration of 10 ng/mL. Cinacalcet terminal half-life is 30 —- 40 hours upon oral administration.
`. Mean plasma cinacalcet clearance is‘ 60.9 — 77.1 L/hr.
`-
`
`Cinacalcet pharmacokinetics is proportional upon oral 25 — 200 mg cinacalcet once daily oral
`administration to chronic renal impaired patients. However, cinacalcet exposure does not increase
`- beyond the 200 mg oral dose. Cinacalcet pharrnacokinetics does not appear to change with time upon
`multiple once daily oral administration. In general, steady state plasma cinacalcet concentrations are
`reached afier 4 days )of once daily oral administration and the mean accumulation ratio is 1.5 — 2.1 and
`1.7 — 2.1 for cinacalcet Cmax and AUCmm, respectively. The median accumulation ratio is 1.2 — 3.7
`and 2.3 — 4.6 for cinacalcet Cm and AUC(o_z4h), respectively, upon twice daily oral administration.
`
`Cinacalcet is metabolized by multiple enzymes, primarily cytochrome P450 3A4, 2D6, and 1A2.
`Cinacalcetis a strong cytochrome P450 2D6 inhibitor1n vitro The major plasma cinacalcet
`metabolites were hydrocinnamic acid and hydroxy-hydrocinnamic acid. Glucuronides of the
`dihydrodiol metabolites are also present in plasma. The major urinary metabolites are glycine
`conjugates of hydroxy-hydrocinnamic acid and glucuronides of the dihydrodiol metabolites. The
`calcimimetic activity of hydrocinnamic acid and hydroxy-hydrocinnamic acid are unknown.
`1
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`

`

`Glucuronides 'of the dihydrodiol metabolites shows 333-fold less potent calcimimetic activity than
`cinacalcet. Cinacalcet is extensively metabolized and the metabolites are renally excreted.
`
`Cinacalcet Cmax and AUC(o-inf) are increased 82% and 68%, respectively, under a high-fat meal as
`compared to that under fasting conditions. The low-fat meal vs. fasting conditions indicates that the
`cum and AUCamo are increased 65% and 50%, respectively. Cinacalcet Cmax and AUC(o-in0 upon
`high-fat meal are 11% and 12% higher, respectively, than that for a low-fat meal.
`
`
`
`The efficacy endpoints for the secondary hyperparathyroidism are proportion of patients achieved a
`mean reductiOn of parathyroid hormone to < 250 pg/mL, proportion of patients achieved a__> 30%
`reduction1n mean parathyroid hormone, and % change1n serum Ca x P (calcium phosphorus product).
`[L“XV?
`Since the maximum proportion ofparathyroid hormone suppression (law) by cinacalcet has not been
`reached, the ICso can not be reliably estimated111 secondary hyperparathyroidism patients 1'x
`
`
`,
`
`L T
`
`he starting 30 mg cinacalcet doseIS chosen because thisIS the lowest effective dose to lower
`parathyroid hormone and the 180 mg highest dose1s chosen because this dose15 safe and effective and
`higher doses will not increase exposure for secondary hyperparathyroidism patients. The 30 mg twice
`daily dose to 90 mg 4 times daily dose are determined per experience with earlier calcimimetic in
`primary hyperparathyroidism and parathyroid carcinoma patients.
`
`Cinacalcet blocks 11.7% (mean) of the hERG channel at 500 ng/mL. A 3-month monkey study shows
`QT prolongation by cinacalcet,- whereas a 12-month monkey study shows no significant QT
`prolongation by cinacalcet. A multivariate linear regression analysis adjusting for age, gender, race,
`.
`history of diabetes, history of congestive heart failure, and baseline QTc demonstrates a weak
`association (correlation= - 0.227) that the magnitude of the1ncrease in QTc averages 6 mSec for each
`1 mg/dL reduction in serum calcium.
`
`Per meta-analysis and population pharmacokinetic analysis, age, body weight, and body mass index do
`not show impact on cinacalcet pharmacokinetics. However, female shows a 40% lower apparent
`clearance than that for male and smokers show'a.38% higher apparent clearance than thatfor
`nonsmokers. Race is a significant covariate of the central volume of distribution. These differences
`may not be clinical relevant since cinacalcet dose is titrated for individuals.
`
`.
`
`No trend exists that cinacalcet exposure increases with increasing degree of renal impairment from‘
`normal subjects to hemodialysis patients. Hemodialysis does not alter cinacalcet pharmacokinetics.
`Cinacalcet pharmacokinetics for patients receiving continuous ambulatory peritoneal dialysis is similar
`to that for hemodialysis patients and healthy volunteers. Cinacalcet AUC(0.inf)S between healthy
`volunteers and mild hepatic impairment patients are comparable. However, cinacalcet exposures for
`moderate and severe hepatic impairment patients are 2.4 and 4.2 times higher, respectively, than that
`for healthy volunteers upon single 50 mg cinacalcet administration.
`
`

`

`Coadrninistration with 200 mg ketoconazole twice daily increases 90 mg cinacalcet’s exposure by
`about 2.3 times. No evidence exists for a pharmacokinetic interaction between cinacalcet and either
`pantoprazole, calcium carbonate, or sevelamer HCl.
`'
`
`coadministration with 25 or 100 mg cinacalcetmcreases amitriptyline and nortriptyline’s exposure by
`about 20%m cytochrome P450 2D6 extensive metabolizers. Coadministration with 25 or 100 mg
`cinacalcet does not appear to increase amitriptyline and nortriptyline’s exposure in cytochrome P450
`2D6 poor metabolizers. No evidence exists for pharmacokinetic and pharmacodynamic interactions
`between cinacalcet and warfarin.
`'
`
`Cinacalcet HCl is a Biophannaceutics Classification System class 4 drug. The clinically tested 30, 60,
`and 90 mg cinacalcet tablets for the secondary hyperparathyroidism studies are identical to the to—be-
`marketed cinacalcet tablets, except the clinical formulation contains —’ tablet film coating and the
`to-be-marketed formulation contains —- tablet film coating. The tablet film coating difference13
`
`acceptable via SUPAC-IR. r"
`.
`
`
`
`A. Recommendations
`
`The Office of Clinical Pharmacology and Biopharmaceutics/Division of Pharmaceutical Evaluation 11
`(OCPB/DPEII) has reviewed the Clinical Pharmacology and Biopharmaceutics data of NDA 21-688
`and it is acceptable. However, the recommended1n vitro dissolution specification for the 30, 60, and
`90 mg cinacalcet tabletsIs “Not less than ""—(Q=
`,“‘1 of the labeled amount of cinacalcet1s
`dissolved111— minutes.”
`‘
`'
`
`'
`
`’ B. Phase IV Commitments
`The followings issues should be addressed as Phase IV commitments, if NDA 21-688 will be
`approved:
`
`' F
`
`
`
`o The sponsor should conduct a clinical cinacalcet drug interaction study with preferred1n vivo
`CYP2D6 substrate such as desipramine (J Clin Pharmacol 2003-,43:443) to address cinacalcet’5
`inhibition potential on CYP2D6. Reasons: Study 980234 examined the effect of cinacalcet on
`amitriptyline and nortriptyline pharmacokinetics to assess cinacalcet’3 inhibition potential on
`CYP2D6. However, the metabolism of amitriptyline to nortriptyline15 via CYP2C19 and does
`not reflect CYP2D6 activity (Levy et al. Metabolic Drug Interactions. page 234, 2000 edition, Lippincott Williams &
`Wilkins). The Icsos for inhibiting the in vitro l’-hydroxylation of bufuralol are 70 nM and 200
`nM for cinacalcet (Study 100157) and quinidine (BrJCIinPharmacoI1986;22:739), respectively.
`
`3
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`

`

`Quinidine is a preferred in vitro CYP2D6 inhibitor and bufuralol is a preferred in vitro
`CYP2D6 substrate (J Clin Pharmacol 2003 ;43;443).
`o The sponsor should conduct an in vitro drug metabolic enzymes induction study for cinacalcet
`in hurhan liver cells. Reasons. From the 3 key clinical studies in secondary
`hyperparathyroidism patients, the seizure incidenceis higherin the cinacalcet treatment group
`than thatin the placebo group (1.7% vs. 0“4%) Cinacalcetmay induce drug metabolic
`enzymes that caused lowering of concomitant anticonvulsants’ exposure, which can increase
`seizure risk. Moreover, the sponsor has not conducted drug metabolic enzymes induction study
`for the NDA.
`
`\9}
`
`' s.w. Johnny Lau, R.Ph., Ph.D.,
`OCPB/DPEH
`
`An Office Level Clinical Pharmacology and Biopharmaceutics Briefing for NDA 21-688 was
`conducted on February 10, 2004; participants includedP. Beaston, T. Kehoe, G. Kuijpers, J. Mele, D.
`Hedin, L. Lesko, S. Huang, R. Powell, A. Selen, C. Sahajwalla, H. Malinowski, Y. Uyama, T. Chen, S.
`Nallani, H. Ahn, J. Vaidya'nathan,‘ and]. Lau.
`
`. FT signed by Hae-Young Ahn, Ph.D., Team Leader
`
`2/
`
`./04
`
`7
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`

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`2 Table of Contents
`
`’
`
`i
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`3'
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`i
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`Page
`
`1 Executive Summary
`A. Recommendations
`B. Phase IV Commitments
`
`2 Table of Contents
`List of Figures and Tables
`
`,
`
`I
`
`3 Summary of Clinical Pharmacology and Biopharmaceutics Findings
`
`'
`
`1
`3
`3
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`5
`
`8
`
`4 Question Based Review
`4.1 General Attributes
`1. What are the highlights ofthe chemistry and physical-chemical properties ofcinacalcet HCl?
`2 What1s the formulation of the to—be-marketed 30, 60, and 90 mg cinacalcet oral tablet?
`3. What15 cinacalcet’s mechanism of action?
`4 What are cinacalcet’s proposed therapeutic indications, dosage, and route of administration?
`4.2 General Clinical Pharmacology
`1. What are cinacalcet’3 clinical pharmacokinetic (PK) characteristics?
`2. Is the cinacalcet PK proportional upon oral administration?
`3. How does chronic dosing alter cinacalcet PK?
`4. Does cinacalcet PK differ between 2° and 1° HPT patients?
`5 What are the characteristics of the exposure-response relationships (dose-response, concentration-response) for
`cinacalcet efficacy?
`.
`6.15 there a PK/PD relationship for efficacy parameters?
`7. How were cinacalcet doses selected for 2° and 1° HPT?
`
`12
`
`13
`
`'
`
`8. What are the characteristics of the exposure-response relationships (dose-response, concentration—response) for
`safety? Is there a PK/PD relationship for safety parameters?
`9. Does cinacalcet prolong QT interval?
`‘
`.4.3 Intrinsic Factors
`1. Do age, gender, body weight, smoking, and race affect cinacalcet PK?
`2. How does renal impairment afi‘ect cinacalcet PK?
`1
`3. How does hepatic 1mpa1rment ‘afl‘ect cinacalcet PK?
`4.4 Extrinsic Factors
`‘
`1. How does food affect cinacalcet bioavailability?
`2. What are the drug-drug interaction studies for cinacalcet?
`4.5 General Biopharmaceutics
`1. What class does cinacalcet HCl belong to the Biopharmaceutics Classification System (BCS)?
`2 Does difference exist between the tube-marketed formulation and the pivotal clinical study formulation?
`3. What is the proposed in vitro dissolution method and specifications for the 30, 60, and 90 mg cinacalcet tablets?
`4.6 Bioanalytical
`1. Aretha bioanalytical methods properly validated?
`
`24
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`27 .
`
`32
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`36
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`i
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`‘
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`5 Labeling Comments .
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`'
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`6 Attachment
`l. Meta-analysis and population pharmacokinetic analysis
`2. Proposed Labeling
`
`37
`
`42
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`

`

`List of Figures:
`Figure 1. Molecular structure of cinacalcet HCl.
`Figure 2. pH-solubility profile of cinacalcet HCl.
`Figure 3. Proposed Cinacalcet’s Human Metabolic Pathways: '
`Figure 4. Log Cinacalcet AUCwu) vs. Log Cinacalcet Dose Plot.
`Figure 5. Log Cinacalcet Cum. vs. Log Cinacalcet Dose Plot.
`Figure 6. Multiple-dose Cinacalcet PK (mean :tSE) After Daily Administration to Subjects with 2° HPT.
`Figure 7. Proportion (:1: SE) of Subjects with a ReductionIn Mean iPTH to_< 250 pg/mL (Controlled Phase 3 ESRD Studies —
`ITT Analysis Set).
`Figure 8. Mean (SE) Percent Change from BaselineIn Ca x P (Controlled Phase 3 ESRD Studies~ ITT Analysis Set)
`Figure 9. Proportion of Subjects with a Reduction from Baseline in Serum Calcium of_> 1 mg/dL at the End of the Titration
`Phase- LVCF (Study 20000204)
`Figures 10. QTc (Bazett’s) Interval by Serum Calcium Levels at Week 14/18 (Phase 3 ESRD Safety Subjects— 6 Month
`Exposure).
`Figure 11. Change from Baseline'In QTc (Bazett’s) Interval by Serum Calcium Levels at Week 14/18 (Phase 3 ESRD Safety
`Subjects— 6 Month Exposure)
`Figure 12. AUCWnD'In Subjects with Normal Renal Function vs. Subjects With Various Degrees of Renal Impairment.
`Figure 13. Mean (SE) Plasma Concentration-Time Profile of Cinacalcet'In ESRD Subjects
`Figure 14. Plasma Concentration-Time Profiles (Mean, SD) of Cinacalcet'In Subjects with Various Degrees of Hepatic
`Impairment.
`Figure 15. AUCMW (ng*hlmL; left sub-figure) and’Cm, (ng/mL; right sub-figure) in Patients with Various Degrees of Hepatic
`Impairment.
`Figure 16. Mean (SE) Plasma Concentration-time Profiles After Administration of a 90-mg Cinacalcet Phase HI Formulation
`Tablet With a Low— and High-fat Meal and Under Fasted Conditions
`. Figure 17. Mean (SE) Plasma CinacalcetConcentration-Time Profiles after Administration of cinacalcet Alone or cinacalcet
`with Ketoconazole.
`-
`Figure 18. Mean (SE) Plasma Concentration-time Profiles of Cinacalcet'In Healthy Volunteers Receiving 100 mg Cinacalcet
`Alone and 100 mg Cinacalcet Plus 1500 mg CaC03.
`Figure 19. Mean (SE) Plasma Cinacalcet Concentration-time Profiles after Administration of Cinacalcet Plus Pantoprazole or
`Cinacalcet Alone to Healthy Volunteers.
`Figure 20. Mean (SE) Plasma Cinacalcet Concentration-time Profiles After Administration of Cinacalcet Plus Sevelamer HCl or
`Cinacalcet Alone to Healthy Volunteers.
`Figure 21. Mean (SE) Plasma Amitriptyline and Nortriptyline Concentration-time Profiles for Extensive Metabolizers Receiving
`Cinacalcet.
`
`Figure 22. Mean (SE) Plasma Amitriptyline and Nortriptyline PK Profiles for Poor Metabolizers Receiving Cinacalcet
`(Separated by Dose).
`Figure 23. Mean (SD) Plasma Concentration of R-Warfarin (light side) and S-Warfarin (lefi side) After Cinacalcet Plus
`Warfarin and Placebo Plus Warfarin.
`Figure 24. Mean (SD) PT After Cinacalcet Plus Warfarin and Placebo Plus Warfarin.
`.
`.
`Figure 25. Mean (SD) Factor VII Concentrations (%) After Cinacalcet Plus Warfarin and Placebo Plus Warfarin.
`Figure 26. Mean (SE) Plasma Cinacalcet Concentration-time Profile after Administration of 90-mngormulation X Tablets or
`Phase III Formulation Tablets.
`
`APPEARS THIS WAY
`0N ORIGINAL
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`

`

`List of Tables:
`Table 1. Cinacalcet HCI Tablet Composition (mg/tablet).
`Table 2. Apparent permeability coefficients (Paw) across Caco-2 cell layers for various agents (mean :t SD; x 10" cm/sec).
`Table 3. Permeability of cinacalcet, aspirin, and mannitol across in vitro human Caco-2 cells from A- B direction.
`Table 4. Cinacalcet’s'In vitro CYPIsozymes inhibition potential.
`-
`Table 5. pg Equivalents of Cinacalcet'In Plasma (Left Sub-table) and Urine (Right Sub~table) After Oral Administration of ["C-
`CF3]-Cinacalcet.
`Table 6. Mean :1: SD of Plasma Cinacalcet PK Parameters (Left Sub-table) and % Recovery of Radioactive Dose (Right Sub-
`table).
`Table 7. PK Parameters for Subjects with Chronic Renal Failure Receiving Hemodialysis.
`Table 8. Mean PK parameters (SD) for 2 x 25 mg cinacalcet capsules once daily oral administration for Studies 990126 and
`990125.
`Table 9. Effects of Cinacalcet on iP’I'H, Serum Ca 1 P, Calcium, and Phosphorus (Controlled Phase 3 ESRD Studies - 111‘
`Analysis Set)
`Table 10. Serum Calcium and % Change from Baseline in Serum Calcium in Subjects with Primary HPT (Studies 980125,
`990120, 990160, and 20000159).
`Table 11. Mean (SD) cinacalcet exposure (AUC and Cm“) in age < 65 and age 2 65.
`-
`Table 12. Mean (SD) Single Dose PK Parameters in Subjects with Various Degrees of Renal Impairment.
`Table 13. Mean (SD) Cinacalcet PK Parameters in Healthy Volunteers and in Patients with Various Degrees of Hepatic
`Impairment After Receiving 50—mg Cinacalcet.
`Table 14. Mean (SD) Phannacokinetic Data with Point Estimates (90% Confidence Intervals) After Administration of a 90-mg
`Cinacalcet Phase III Formulation Tablet With a Low- and High—fat Meal and Under Fasted Conditions.
`Table 15. Mean (SD) Cinacalcet PK Data, Point Estimates, and 90% Confidence Intervals.
`Table 16. Mean (SD) Cinacalcet PK Parameters and Comparative Statistics for Healthy Volunteers Receiving 100 mg Cinacalcet
`and 100 mg Cinacalcet Plus 1500 mg CaCO3.
`Table 17. Mean (SD) Cinacalcet PK Parameters and Comparative Statistics for Healthy Volunteers Receiving Cinacalcet Plus
`Pantoprazole or Cinacalcet Alone.
`Table 18. Mean (SD) Cinacalcet PK Parameters and Comparative Statistics for Healthy Volunteers Receiving Cinacalcet Plus
`Sevelamer HCI or Cinacalcet Alone.
`Table 19. Mean (SD) PK Parameters with Point Estimates and 95% Confidence Intervals for Amitriptyline and Nortriptyline'In
`Extensive Metabolizers Receiving Cinacalcet.
`Table 20. Mean (SD) PK Parameters with Point Estimates and 95% Confidence Intervals for Amitriptyline and Nortriptyline'In
`Poor Metabolizers Receiving Cinacalcet.
`Table 21. Mean (SD) Comparative Statistics of R-Warfarin (right side) and S-Warfarin (left side) PK Parameters for Healthy
`Subjects Receiving Multiple Doses of Cinacalcet or Placebo.
`Table 22. Summary of Pharmacodynamic Parameters for Prothrombin Time and Factor VII After Multiple-Dose
`Administration of Cinacalcet or Placebo to Healthy Volunteers.
`‘
`Table 23. Comparative Statistics of Cinacalcet PK Parameters after Administration of 90-mg Formulation X Tablets or Phase'
`HI Formulation Tablets.
`~
`Table 24. Composition of Formulation X Tablet Strengths.
`Table 25. The sponsor’s proposed in vitro dissolution method and specification for the 30, 60, and 90 IIig cinacalcet oral tablets.
`Table 26. Bioanalytical validation studies’ results for cinacalcet.
`
`APPEARS nus w
`on ORIGINAL. AV .
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`3 Summaryjof Clinical Pharmacology and Biopharmaceutics Findings
`
`
`_, secondary hyperparathyroidism
`The sponsor develops Cinacalcet, a calcimimetic to treat ..
`'
`(2° HPT) for chronic kidney disease patients and treat hypercalcemia in primary hyperparathyroidism
`
`(1° HPT) and parathyroid cancer patients. The dose for treating.
`‘
`2° HPTIS 30 — 180 mg
`once daily titrated to target parathyroid hormone concentrations (PTH). The dose for treating 1° HPT
`and parathyroid carcinoma is 30 mg twice daily to 90 mg 4 times daily titrated to lower serum calcium
`concentrations.
`
`Basic Human Pharmacology of Cinacalcet
`Cinacalcet is well absorbed orally since 80% of the orally administered radioactivity is recovered in
`urine and 15% of the orally administered radioactivity is recovered in feces.
`
`Cinacalcet has a mean steady state volume of distribution, V55, of 913-1235 L after single intravenous
`
`administration of 2, 5, and 10 mg to healthy volunteers. Cinacalcet1s
`'
`bound to human
`plasma protein(s). The ratio of red blood cells Cinacalcet concentration to plasma Cinacalcet
`concentration is —- at a blood Cinacalcet concentration of 10 ng/mL.
`
`Cinacalcet is metabolized by multiple enzymes, primarily, CYP3A4, CYP2D6, and CYP1A2.
`Cinacalcet is a strong CYP2D6 inhibitor in vitro.
`
`The major plasma Cinacalcet metabolites are hydrocinnamic acid (P18) and hydroxy-hydrocinnamic
`acid (P13). Glucuronides of the dihydrodiol metabolites (P6 and P12) are also present in plasma. The
`major urinary metabolites are glycine conjugates of P13 and glucuronides of the dihydrodiol
`metabolites (U6, U10, and U12). The calcimimetic activity of P18 and P13 are unknown; U6 and U12
`showed 333-fold less potent calcimimetic activity than Cinacalcet. Cinacalcet terminal half-life is 30 —
`40 hours. Cinacalcet is extensively metabolized and the metabolites are renally excreted. Mean
`plasma Cinacalcet clearance, CL, is 60.9— 77. 1 L/hr afier smgle intravenous administration of 2, 5, and
`10 mg to healthyvolunteers.
`‘
`
`Cinacalcet pharmacokinetics (PK) is proportional upon oral 25— 200 mg Cinacalcet once daily oral
`administration to chronic renal impaired patients. However, Cinacalcet exposure did not increase
`beyond the 200 mg oral dose.
`
`J
`
`Cinacalcet PK did not appear to change with time upon multiple‘once daily oral administration. In
`general, steady state plasma cinacalcetconcentrations are reached after 4 days of once daily '
`administration and the mean accumulation ratio is l .——5 2.1 and 1.7- 2.1 for Cinacalcet Cmax and
`AUC(M41.), respectively. The median accumulation ratio is 1.2— 3.7 and 2.3— 4.6 for Cinacalcet Cmax
`and AUC(M4h), respectively, upon twice daily dosing.
`
`At the 50 mg Cinacalcet once daily oral administration, PK between 2° and 1° HPT patients is similar.
`
`The starting dose was 30 mg Cinacalcet because it is the lowest dose to appreciably lower PTH. The
`highest dose was 180 mg because it was safe and effective. Higher doses did not increase exposure for
`
`

`

`2° HPT patients. The starting dose of 30 mg twice daily to 90 mg 4 times daily are determined per
`experience with earlier calcimimetic1n 1° HPT and parathyroid carcinoma patients.
`
`A multivariate linear regression analysis adjusting for age, gender, race, history of diabetes, history Of
`congestive heart failure, and baseline QTc demOnstrated a weak association (correlation i -.0.227) that
`the magnitude of the increase in QTc averages 6 msec for each 1 mg/dL reduction in serum calcium.
`
`Cinacalcet blocks 117% (mean) of the hERG channel at 500 ng/mL. A 3-month monkey study
`showed QT prolongation by cinacalcet, whereas a 12-month monkey study showed no significant QT
`prolongation by cinacalcet.
`
`
`
`Age, body weight, and body mass index did not show impact on Cinacalcet pharmacokinetics. ~
`However, female showed a 40% lower apparent clearance than that for male and smoker showed a
`38% higher apparent clearance than that for nonsmokers. Race is a significant covariate for the central
`volume of distribution.
`
`No trend existed that cinacalcet exposure increased with increasing degree of renal impairment fi'om
`normal subjects to hemodialysis patients. Hemodialysis did not alter cinacalcet PK. Cinacalcet PK for
`patients on continuous ambulatory peritoneal dialysis is similar to that for hemodialysis patients and
`healthy volunteers.
`.
`7
`,
`
`Cinacalcet AUCMD between healthy volunteers and mild hepatic impairment patients were
`'comparable. However, cinacalcet exposure for moderate and severe hepatic impairment patients were
`2.4 and 4.2 times higher, respectively, than that for healthy volunteers.
`
`

`

`Extrinsic Factors
`
`
`
`Food-Drug interaction
`Cinacalcet Cmax and AUC(o-m0 were increased 82% and 68%, respectively, under a high-fat meal as
`comparedto that under fasting conditions. The low-fat meal vs. fasting conditions indicated that the z ,.
`Cmax and AUC(0.mf) were increased 65% and 50, respectively.
`
`Drug-Drug Interaction
`Cinacalcet AUC and Cmax increased 2.3 and 2.2 times, respectively, when 90 mg Cinacalcet was
`coadministered with 200 mg ketoconazole twice daily as Compared to that for 90 mg Cinacalcet alone.
`
`I Per the 90% confidence interval for Cinacalcet Cmax and AUC(0.mf) ratios, no significant PK drug
`interaction was observed.
`,
`~
`,
`.
`-
`,
`0 When 80 mg pantoprazole daily was coadministered with 90 mg Cinacalcet ,
`0 ' when 1500 mg CaCO; was coadministered with 100 mg Cinacalcet
`o
`coadministration of 2400 mg sevelamer HCl 3 times daily did not change the Cinacalcet PK
`upon oral administration of a 90 mg Cinacalcet tablet.
`
`In CYP2D6 extensive metabolizers who received 50 mg amitriptyline, amitriptyline AUC(o-in0 and
`Cm increased about 20% with coadministration of 25 mg or 100 mg Cinacalcet. Nortriptyline AUG“;
`inf) increased 17 — 23% and Cmax increased 11 - 15% with coadministration of 25 mg or 100 mg
`Cinacalcet. In CYP2D6 poor metabolizers who received 50 mg amitriptyline, AUC(o.i,,0 and Cmax for
`
`10
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`

`

`both amitriptyline and nortriptyline’did, not appear to change with coadministration of 25mg or 100
`mg cinacalcet.
`
`' Both R-and S-warfarin PK were not affected when 30 mg cinacalcet twice daily was coadministered
`with 25 mg warfarin. Warfarin pharmacodynamic endpoints (maximal rise in prothrombin‘ time and
`factor VII concentrations) were not affected when 30 mg cinacalcet was coadministered twice daily
`with 25 mg warfarin.
`
`Cinacalcet HCl is a Biophannaceutics Classification System class 4 drug.
`
`Bioequivalence between the Clinically Tested and To-Be-Marketed Formulations
`
`The clinically tested 30, 60,7 and 90 mg cinacalcet tablets for the 2° HPT studies are identical to the to-
`, be-marketed cinacalcet tablets, except the tablet film coating was changed from
`‘ (clinicalto
`to-be—marketed formulation) This change was justified per SUPAC-IR Guidance (+ 1%'for film coat
`changes) and similarity ofthem vitro dissolution data between the clinical and to-be-marketed
`I
`
`formulation r
`
`Proposed In Vitro Dissolution Method and Specification
`
`Apparatus
`~
`USP Type 2;
`
`Dissolution medium
`‘
`Medium volume
`
`-
`
`
`
`.
`
`Medium temperature
`Stirring Speed
`7
`Sampling time
`Not less than * 3 (Q) of the labeled amount of
`A
`Specifications
`cinacalcet is dissolved in - minutesm
`
`
`
`The proposed dissolution method is acceptable. However, the recommended specification for the 30,
`60, and 90 mg cinacalcet tabletsIS “Not less than -" (Q—— ’7’ ) of the labeled amount of cinacalcet
`is dissolvedm V ’mnutes.”
`
`ll
`
`

`

`4 Question-Based Review
`
`4.1 General Attributes
`
`1. What are the highlights of the chemistry and physical-chemical properties of cinacalcet HCl?
`
`zi-
`
`CH3
`
`
`
`szszF3N-HCI
`(393.87)
`Figure 1. Molecular structure of cinacalcet HCI. Figure 2. pH-solubility profile of cinacalcet HCl.
`Cinacalcet (AMG 073)is the R enantiomer. Cinacalcet HCl’5 pH solubility profile follows: The
`
`maximum solubility18 about
`'
`' from pH 3 to 5. Below pH 2, solubility decreases due to the
`_ common ion effect. Hence, cinacalcet HCl exhibits relatively low solubilityin a
`Above pH :olubility decreases rapidly due to the unionized form’s low solubility. . Cinacalcet HCl
`
`
`2. What is the formulation of the to-be—marketed 30, 60, and 90 mg cinacalcet oral tablet?
`Table l. Cinacalcet HCl Tablet Com - osition m_ tablet).
`90 mag Component ' to Standards Fur-odor: “é. (w/w)‘ 30 rhg 60 r'ng
`Referertcze
`'
`
`
`
`
`
`
`
`
`
`
`Clnaca lcet HCI
`Hse"
`
`
`
`
`Pl-aoelatlnlzed 5(aroh Ph Eur,A USP/NF
`
`
`
`Mlcrocrx'zsmlllne,oellulose
`Ph ELlr. A :1
`USP/NF
`.
`,
`.1
`
`’
`e
`)
`v.
`)
`Povldone
`_
`Ph Eur.
`'
`
`__’-——.—-—-—" USP/NFmCrospovldone F’h Eur, '
`
`
`' ' _.
`"
`'
`'
`' " '
`USP/NF
`”——
`
`_'—_._—_—
`
`USP/NF
`Mlcrooryetalllne cellulose
`F'h Eur. ~———.—-——\
`
`
`._—._——‘
`’
`
`Colloidal alllqofi dlokloe
`, Ph Eur.
`
`
`_
`USP/NF
`1
`
`
`Crospovloone
`Ph Eur.
`’
`__________'§ ,
`-
`U$P(NF
`,
`
`
`
` Magneelum e'tearate
`55h Eur.
`,
`)
`‘
`USP/NF
`
`
`’fl—R
`
`
`540.00
`360.00
`‘1 80.00
`
`
`Core Tablet Total
`
`(Cont nuecl)
`
`% (w/w) ls ldentlcal regardless of close strength
`" HSE =3 ln—house Specificatlon M
`° Molecular welghts of the HO! salt and the free base are
`1
`<-
`respectively: therefore. the free base accounts for 90 74‘Yo of the salt.
`The Burn total of clnecalce! Hcl and mlcmcrystalllne cellulose per Qablet Is I'Ixed; ‘herel’ore.
`as the amoumt of clnaoalcet HCI varies In regard to potency. the amour“ of
`mlcrooryetalllne ceIlLtlose Isa aolested to meet the fixed total emoLlnt.
`W
`
` W
`
`e
`
`
`
`Ph Eur.
`USP/NF
`
`12
`
`

`

`
`Reference to
` ,
`
`Functlon
`% (w/w)‘
`30 mg
`60 mg
`90 mg'
`Component
`-‘
`Standards
`
`
`
`
`Oyaadry‘“x ll Green"°‘
`f
`
`
`‘Opedry" CleaH‘a'"
`
`v USP/NF
`. f,“
`Ph Eur.
`
`Camaube \Naxg‘h
`Ph Eur.
`USP/NF
`
`
`W . W
`
`Opaoode" Black”
`
`
` 04. leun I4: INAr-flnnl ronnrrflaaa n1 Arman afranr‘th,
`C
`M———‘
`'fl "v: film floats (clear and color) and black ink
`. .... “u-..“fl..- _. n. H..- "flu“... -_..
`are Incorporated by reference from .4.
`f————— ‘l
`.
`lnl'orrnatlon related to the
`Opaler Clear and Opadry’“ ll Green we: .. .eu ._-. r... 394 (page 3426) and 28 Aug 2002
`(page 4495) respectlvely Onacode‘m Black was filed on 1 0 March 2003 (page 4576). The
`letter of amhorlzatlon from 1 —\
`ls provlded in Module 1. Also provlded In Table 2 is
`#—
`the qualitatlve endquantltatz.
`\ositlon of these materials from
`"’ Flnel amount I: typically less than stated.
`1h Amount applled ls based on the core tablet weight.
`
`
`'
`
`Active and inactive Ingredients tor ditterent strengths otthe to-be-marketed tablets are proportionally
`similar.
`
`3. What is cinacalcet’s mechanism of action?
`Cinacalcet binds to the calcium-sensing receptors of the parathyroid gland and amplifies the receptor
`sensitivity to extracellular calcium (calcimimetic), thereby decreasing parathyroid hormone (PTH)
`release Cinacalcet1s the biologically active R enantiomer.
`,__————\'___’P
`
`r
`
`4. What are cin'ac'alcet’s proposed therapeutic indications, d’osage,’and route of administration?
`ForM treatment of secondary (2°) hyperparathyroidism (HPT)1n chronic kidney diseaSe
`patients the proposed starting oral doseis 30 mg Cinacalcet once daily and should be titrated every 2 —4
`weeks to a maximum dose of 180 mg Cinacalcet once daily to achieve a target PTH: 1.-—5 5 times the
`upper limit of normal for dialysis patient and > 30% reduction of PTH concentrations for patients not
`receiving dialysis. For treatment of hypercalcemia1n parathyroid carcinoma and a
`
`4.2 General Clinical Pharmacology-
`1. What are cinacalcet’s clinicalpharmacokinetic (PK) characteristics?
`Absorption
`Cinacalcet18 well absorbed upon oral administration as evidenced via 80% of the orally administered
`radioactivity is recovered in urine (Study 980233, see the Metabolism section of this question below
`for details).
`
`13
`
`

`

`Study 100154 examined the permeability of cinacalcet across in vitro human colon carcinoma cells
`(Caco-2) for the apical-to-basolateral (A— B) and basolateral—to——apical (B— A) directions.
`Table 2. Apparent permeability coefficients 1!Eli across Cacti-2 cell layers for various agents (mean 1 SD; 11 10" cm/sect.
`
`
`'n=3. A B
`mannitol
`1.65 i 0.08
`1.25 i 0.18
`0.76
`
`4.1
`~ 21.7 i 2.73
`5.28 :t 0.58
`verapamil
`
`
`
`3.2 :t 0.34 3.33 i- 0.10cinacalcet 1.04
`
`Verapamil Papp (B — A)/ Papp (A - B) is 4.1, which is consistent with verapamil being a P-gp substrate.
`No significant difference exists in thePapp for cinacalcet across Caco-2 monolayers between the A — B
`and B — A directions. Hence, cinacalcet appears not to be a P-gp substrate.
`
`‘
`
`Study 103270 examined the permeability of cinacalcet, aspirin, and mannitol across in vitro human
`Caco—2 cells from A- B direction. The Pam follows (Table 3!:
`_
`n = 6 wells
`Mean i SD (x 1045 cm/sec!
`cinacalcet
`5.8 i 0.56
`aspirin
`8.14 i 0.48
`mannitol
`0.99 i 0.05
`
`Mannitol Papp from both studles was h1gher than 0.5 x 10 cm/sec as reported 1n literature. Study
`103270 also showed that transepithelial electrical resistance across the Caco—2 cell layers used for
`determining mannitol, aspirin, and cinacalcet fluxes were not significantly different between each
`group. The sponsor claimed that aspirin was a high permeability drug and concluded that cinacalcet
`was a high permeability drug per —— Per the Biopharmaceutics Classification System (BCS)
`Guidance, 20 model drugs are recommended to be used to demonstrate suitability for an in vitro cell
`culture permeability method. Hence, the sponsor’s conclusion of high cinacalcet absorptive
`permeability cannot be established based on 1 reference drug.
`
`,Cinacalcet’s P-gp inhibition and induction potentials are unknown.
`
`.
`Distribution ‘
`.————\_’
`CinacalCet is -'\‘ \ bound to human plasma protein(s) in vitro via 1
`method (Study 100158). However,the plasma proteins that bind cinacalcet and their respective extent
`of binding are unknown. The ratio of red blood cells cinacalcet concentration to plasma cinacalcet
`concentration is “' at a blood cinacalcet concentration of 10 ng/mL (Study 102739). Cinacalcet has '
`a mean steady state volume of distribution, V53, of 913- 1235 L after single intravenous administration
`of 2, 5, and 10 mg to healthy volunteers (Study 990751). The large V55 suggests extensive cinacalcet
`tissue distribution