CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-372
`
`Clinical Pharmacology and Biopharmaceutics
`Review
`
`

`

`CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
`
`NDA: 21-372
`Brand Name:
`
`'
`
`' Submission Date: 09/27/02
`Aloxi
`
`Generic Name:
`
`Palonosetron Hydrochloride
`
`Reviewers:
`
`Sue-Chih Lee, Ph.D.
`
`Team Leader:
`
`OCPB Division:
`
`0ND Division:
`
`Suliman Al-Fayoumi, PhD.
`
`Suresh Doddapaneni, Ph.D.
`
`Division of Pharmaceutical Evaluation 11
`
`Division of Gastrointestinal and Coagulation Drug
`Products (HFD-l 80)
`
`Sponsor:
`Helsinn Healthcare SA (Switzerland)
`Relevant IND(s): E
`
`Submission Type; Code:
`
`NME, ls
`
`Formulation; Strength(s):
`
`IV Injection, 0.25 mg/5 mL
`
`Dosing regimen:
`
`.
`
`Proposed Indication:
`
`Single 0.25 mg dose, administered 30 minutes prior
`to chemotherapy
`
`_
`Prevention of acute and delayed nausea and
`vomiting associated with initial and repeated courses
`of emetogenic cancer therapy
`
`1. EXECUTIVE SUMMARY
`
`Palonosetron is a novel 5-HT3 receptor antagonist. The sponsor is seeking approval of
`single IV dose of palonosetron hydrochloride 0.25 mg forthe prevention of acute and
`delayed nausea and vomiting associated with emetogenic cancer therapy, including
`highly emetogenic chemotherapy. To evaluate the'potential QT effect of palonosetron
`following IV administration, the sponsor analyzed lZ-lead ECG data collected from
`Phase 3 trials in which palonosetron was studied at two dose levels (0.25 mg and 0.75
`mg). A subset of the patients also received Holter monitoring. Based on the overall QT
`data and cardiac safety profiles, the QT effect of palonosetron appears to be similar to the
`approved comparator drugs (dolasetron and ondansetron) used in the trials. Palonosetron
`is eliminated through both renal excretion and metabolic pathways with the latter
`mediated via multiple CYP isozymes. In vitro studies indicated that it does not inhibit or
`induce the activity of many CYP isozymes at the therapeutic concentrations. Therefore,
`the potential for drug interactions with palonosetron is lowf N0 dosage adjustment is
`necessary based on age (18 yrs and up) or gender, nor is it necessary for any degree of
`
`

`

`renal or hepatic inipairment. Safety and efficacy in pediatric patients have not been
`established.
`
`1.] RECOMMENDATION
`
`From the standpoint ofthe Office of Clinical Pharmacology and Biophannaceutics, the
`Human Pharmacokinetics and Biopharmaceutics section ofthe application is acceptable
`provided that a satisfactory agreement is reached between the Agency and the sponsor
`regarding the language in the package insert.
`
`[S/
`
`/‘S/
`
`'
`Sue-Chih Lee, Ph.D.
`Division of Pharmaceutical Evaluation H
`
`Suliman Al-Fayoumi, PhD.
`Division of Pharmaceutical Evaluation 11
`
`RD/FT lnitialed by Suresh Doddapaneni, PhD.
`
`

`

`2. TABLE OF CONTENTS
`
`1 Executive Summary .............................................................. '. ..
`1.] Recommendation ............................................................
`2 Table of Contents .......................................................................
`
`3 Summary of CPB Findings ............................................................
`4 Question Based Review ...............................................................
`4.1 General Attributes ...............................................................
`
`4.2 General Clinical Pharmacology ................................................
`4.3 Intrinsic Factors ...................................................................
`4.4 Extrinsic Factors ...................................................................
`
`l
`2
`3
`
`3
`6
`6
`
`7
`13
`16
`
`17
`4.5 General Biophannaceutics ........................................................
`17
`4.6 Analytical............... .......- .....................................................
`5 Labeling Recommendations ............................................................ 20
`6 Appendices ................................................................................ 35
`6.]
`Individual Study Reviews ........................................................ 36
`In vitro Metabolism ......................................................... 37
`
`Protein Binding .............................................................. 49
`Mass Balance Study ......................................................... 50
`Dose Escalation Study ...................................................... 53
`PK in CYP2D6 Poor Metabolizers ........................................ 57
`
`Renal Impairment Study .................................................... 61
`Hepatic Impairment Study ................................................... 66
`Drug-Drug Interaction Study ................................................ 71
`Dose Ranging Study .......................................................... 76
`Population PKJPD Analysis ................................................ 81
`Analytical Methods ........................................................... 85
`6.2 Cover Sheet and OCPB Filing/Review Form .................................... 89
`
`3. SUMMARY OF CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS FINDINGS
`
`3.1 Pharmacokinetics
`
`3.1.1 Dose Proportionality
`In a Phase 1 study, healthy subjects received a single IV dose of palonosetron. Both Cmax
`.and AUC were found to be approximately dose proportional over the dose range of
`03-90 - g/kg.
`
`.
`'
`3.1.2 Distribution
`Following single IV administration to healthy volunteers, plasma palonosetron
`concentration exhibited a biphasic decline. 'The mean volume of distribution (V2) was
`
`

`

`8.34:2.45 L/kg. Protein binding in human plasma was constant over the concentration
`range of 5-412 ng/mL and averaged approximately 62%.
`
`.
`3.1.3 Metabolism
`In vitro studies suggested that metabolism of palonosetron is mediated primarily via
`CYP2D6 followed by CYP3A4 and CYP1A2. The major metabolites are an N-oxide
`metabolite (M9; 12.5% of the administered dose) and a hydroxy metabolite (M4; 10.9%
`of the administered dose). The metabolites had negligible pharmacological activities.
`
`3.1.4 Elimination
`
`Both renal excretion and hepatic metabolism play important roles in the elimination of
`palonosetron. Following single IV administration of MC-palonosetron hydrochloride 10
`° g/kg (0.7 mg/70 kg), renal clearance amounted to 42% of the total clearance while
`approximately 50% of the administered dose was metabolized. The mean terminal
`half-life based on a Phase 1 study was 37.4il4.2 hrs.
`
`3.1.5 Special Populations
`
`Age/Gender/Race
`The disposition of palonosetron seemed to be similar between males and females after
`I.V. administration of a single dose of palonosetron to 6 healthy subjects (3 males and 3
`females) in a mass balance study. A population PK analysis was performed using data
`obtained from the Phase III trials in which palonosetron was studied at two dose levels
`(0.25 mg and 0.75 mg). Age, gender and race were not found to be significant covariates
`for clearance. However, the final model yielded a high intersubject variability (88.8%) in
`clearance. Since analysis of the Phase III trial data did not reveal any subgroup with
`significant differences in the safety profiles, no dosage adjustment based on age or gender
`is considered necessary. It should be noted that Blacks were poorly represented in the
`Phase 111 trials. Hence, no conclusion can be made about PK in Blacks compared to
`Caucasians.
`
`Renal insufficiency
`Mean values of the primary PK parameters for palonosetron in patients with mild to
`moderate renal impairment were similar to those of healthy subjects. In patients with
`severe renal impairment, the mean AUCo...° increased by around 30% compared to healthy
`subjects. No dosage adjustment is recommended for patients with any degree of renal
`impairment.
`
`Hepatic insufficiency
`The mean values of cum and AUC for palonosetron and the M9 metabolite were
`significantly reduced in patients with moderate and severe hepatic impairment relative to
`those of healthy subjects. Albeit the apparent half-life of palonoéetron is prolonged by
`50% in patients with moderate and severe hepatic impairment, dosage adjustment is not
`necessary as palonosetron will be administered as a single dose in the clinical setting.
`
`

`

`3.2 Drug-Drug Interactions
`Palonosetron was eliminated from the body by both renal excretion and metabolic
`pathways. In vitro studies showed that metabolism of palonosetron is mediated via
`multiple CYP enzymes: Further in vitro studies indicated that palonosetron is not an
`inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A
`
`(CYP2C19 was not investigated) and does not induce the activity of CYP1A2, CYP2D6
`or CYP3A. Therefore, the potential of drug interactions with palonosetron is low.
`An in viva phannacokinetic study showed that single dose palonosetron (0.75 mg I.V.)
`did not interact with metoclopramide (10 mg Q 6 hrs dosed to steady state). It should be
`noted that the metoclopramide dose used in this study is lower than that recommended for
`prevention of chemotherapy-associated nausea and vomiting.
`
`3.3 QT-Related Studies
`
`._ in the synthesis of palonosetron and is suspected of
`
`being cardiotoxic. In vitro (human hepatic microsomes, cryopreserved hepatocytes and
`fresh liver slices) and in vivo studies were carried out to determine whether.
`is a
`
`metabolite of palonosetron. At a detection limit of IO ng/L for _“ and 500 ng/L
`for
`(metabolite of . — , in plasma and approximately lO-times greater in
`urine, neither compound could be detected following a 0.75 mg IV dose. In vitro studies
`did not detect any formation of . —‘
`. However, the sensitivity of the studies was
`unclear. No further information was requested because the QT data and cardiac safety
`profiles reflected the overall effect following IV administration of palonosetron,
`including the effect of
`‘— , if any was formed in vivo .
`
`The sponsor conducted a QT analysis using data collected from 12-lead ECG in Phase III
`trials and indicated that no relationship between palonosetron exposure and QTc or heart
`rate was found. However, the information that can be derived from this analysis is
`limited because of the study design. Separate analysis based on 12-lead ECG data, Holter
`data and cardiac safety profiles were reviewed and found to be comparable to the
`approved comparator drugs (ondansetron and dolasetron) by Dr. Narayan Nair, Medical
`Officer of HFD-l 80.
`
`APPEARS THIS WAY
`on ORIGINAL
`
`

`

`4. QUESTION BASED REVIEW
`
`4.] General Attributes
`
`4.1.1 What are the highlights of the chemistry and physico-chemical
`
`properties of the drug substance, and the formulation of the drug product?
`
`The structure and physico-chemical properties of palonosetron hydrochloride are given
`below:
`
`Empirical formula: C19H24N20-HC1
`
`Molecular weight: 332.87
`
`
`
`Chemical name:
`
`Structure:
`Solubility:
`
`(3a§)-2-[(§)-l-Azabicyclo [2.2.2]0ct—3-yl]-2,3,3a,4,5,6-
`hexahydro- 1 -oxo- l Hbenz[de]isoquinoline hydrochloride
`exist as a single stereoisomer, the (S,S)—isomer
`freely soluble in water; slightly soluble in ethanol
`
`The components and composition of the to-be-marketed formulation are shown below:
`
`Table: Formulation of nialonse ron HCI IV in ection
`
`ri Sodium Citrate Dihydrate, USP/E?
`itric Acid Monoh drate USP/EP
`
`__
`
`.. _
`
`__
`
`__
`
`
`
`1
`
`,
`
`ater for ln'ection, USP/EP
`' 5 ml. vials containing 0.25 mg (0.05 mg/mL).
`c
`" Calculated as palonosetron free base.
`
`. _ .
`‘ For pH adjustment
`5 ad 1.0ml.—
`
`4.1.2 What is the' proposed mechanism of action?
`
`Palonosetron is a potent and highly selective 5-HT3 receptor antagonist. Certain cancer
`chemotherapy agents such as cisplatin are associated with a high incidence of nausea and
`vomiting. 5-HT; receptors are located on the nerve terminals of the vagus in the
`periphery and centrally in the chemoreceptor trigger zone of the area postrema. It is
`thought that chemotherapeutic agents produce nausea and vomiting by releasing
`
`

`

`serotonin from the enterochromaffm cells of the small intestine and that the released
`
`serotonin then activates 5—HT; receptors located on vagal afferents to initiate the
`vomiting reflex.
`
`4.2 General Clinical Pharmacology
`
` 4.2.] What-is the basis for selecting the response endpoints, i.e., clinical or
`
`
`
`surrogate endpoints, or biomarkers (also called pharmacodynamics, PD)
`and how are they measured in clinical pharmacology and clinical studies?
`
`
`
`
`For efficacy assessment in clinical trials, the primary endpoint was the proportion of
`patients with a complete antiemetic response (no vomiting, retching or rescue
`medication) for 24 hours after emetogenic chemotherapy in chemotherapy-naive cancer
`patients. The secondary efficacy variables include among other measures time to the first
`emetic episode, and time to administration of rescue therapy.
`
`4.2.2 Are the active moieties in the plasma (or other biological fluid)
`appropriately identified and measured to assess pharmacokinetic parameters
`
`and exposure response relationships?
`
`The concentrations of palonosetron and its major metabolite, M9, in plasma and urine
`samples were determined by validated analytical methods. M9 has low activity as a
`5—HT; receptor antagonist and present in plasma at low concentrations, determination of
`its concentrations in the biological fluids was at the end considered to be not crucial.
`
`.,_.\.
`
`compound, n _ exists as a related impurity of the drug
`A suspected
`substance. Efforts were made to determine the potential of its formation in vivo. A
`-
`method was used to detect the presence of ;
`"’
`and its metabolite
`~ in human plasma and urine samples (detection limit: ~10 ng/L (plasma) and
`100 ng/L (urine) for' s
`and ~500 ng/L (plasma) and 2000 ng/L (urine) for
`v j). There was no indication of. ‘ formation following single IV dose
`administration ofpalonosetron 0.75 mg.
`
`/ <3???)
`
`Paonosetron
`
`

`

` 4.2.3 What are the characteristics of the exposure-response relationships
`
`
`
`(dose—response, concentration-response) for efficacy and safety?
`
`4.2.3.1 Efficacy
`
`A Phase II dose ranging study was conducted in chemotherapy-naive cancer patients
`receiving highly emetogenic chemotherapy. Single IV dose of palonosetron was
`administered to patients 30 minutes before chemotherapy. The figure below shows the
`dose-response relationship in terms of three key response variables. The dose levels of 3,
`10, 30 and 90 ' g/kg, were approximately equally effective as compared with the
`combined results from a cohort of 0.3 and l - g/kg in suppressing chemotherapy-induced
`emesis for 24 hours. No apparent dose-response relationship was found for adverse
`events in this trial. Based on the results, the dose levels of 0.25 mg (~3.6 ° g/kg) and 0.75
`mg (~lO.7 ° g/kg) were studied in the Phase III trials.
`
`
`60
`
`i I % Complete Response (for at least 24 hrs)
`
`‘LD Median Time to FaHure (H)
`
`it;%CompleteControl(toratleast24hrs)
`
`
`
`I
`
`I l|l
`
`i
`
`Resp—onse
`
`1 ug/kg
`
`3 ug/kg
`
`10 ug/kg
`
`30 ug/kg
`
`90 uglkg
`
`free from emetic episodes and requiring no rescue medication
`IComplete control:
`2Complete response: free from emetic episodes and rescue medication who
`experienced only mild or no nausea.
`JMedian time to failure (first emetic episode or rescue medication)
`
`4.2.3.2 Safety:
`
`4.2.3.2.] Adverse events:
`
`According to Dr. Narayan Nair, Medical Officer of HFD-180, no clear dose response
`relationship for adverse event rate can be derived from the available clinical data.
`Dr. Nair shared, among other information from his review, the following summary tables
`of adverse event rate observed in the integrated Phase I-III or Phase II/lll trials:
`0 All adverse events by System Organ Class (Phase 1-111)
`0
`Serious adverse events (Phase I-III)
`
`

`

`0
`
`Selected cardiovascular adverse events (Phase lI/Ill)
`
`Table: All adverse events (AB) in all integrated Phase l-lll trials by number and percent of subjects
`Active Comparators
`Placebo
`Doll [00mg
`
`(n = l94)/
`
`
`
`-nfccnon
`Injury/Poisoning
`Investigational
`Onda- Undenwrmn Dola - Dolascuon
`
`,~'\
`
`Table: Serious adverse events (SAE) in all integrated Phase l-lil trials by number and percent of
`subjects for various dose levels of palonosetron, active comparators and placebo
`
`
` Placebo
`
`
` Active Comparators
`Palonosetron (mg)
`< 0.25
`025
`0.75
`> o.75
`Onda
`Dola
`Com-
`
`Total
`
`
`
`
`n (%)
`n(%)
`NW NW bined
`n (%)
`n (%)
`n (%)
`
`
`
`saw» me» am
`
`
`4. (>)
`
`
`Ondu = 0ndansctrun: Dola = Dolasctmn.
`
`The following table shows the rate of selected cardiac adverse events of interest, which
`was 13%, 9%, 10%, and 16% for palonosetron at the dose levels of <0.25 mg, 0.25mg,
`0.75 mg and >O.75 mg, respectively.
`
`Table: Selected cardiac adverse events of interest in pivotal Phase lI/lll trials
`
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`
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`
`4. 2.3.2.2.
`
`T interval:
`
`Concentration- Trelationshi :
`
`

`

`The sponsor conducted an analysis using data collected from l2-lead ECG in Phase II]
`trials and indicated that no relationship between palonosetron exposure and QTc or heart
`rate was found. This analysis did not examine the changes in heart rate or QTc (instead
`of heart rate or QTc itself) in relation to palonosetron exposure. However, a further
`inspection ofthe data by Dr. He Sun, Pharmacometn'cs Specialist of DPEII, did not
`reveal any apparent QTc change from baseline following administration of palonosetron
`at the ECG measurement time points.
`
`Time of Qch measurments
`43000-12000 -6000
`
`0
`
`6000 12000
`
`Y-axis: QTcF (msec)
`
`X-axis: Time (min)
`
`48000 -12000 -6000
`
`0
`
`6000 12000
`DIFF
`
`Figure: QTCF versus Time by Dose
`
`It should be noted that the information that can be derived from this study is limited
`because 12-lead ECG measurements were not performed frequently following the IV
`administration of palonosetron. Most patients had ECG measurements at pre-dose, 24 hr
`postdose and on Day 6-8. Although some patients had a measurement at 15 minutes
`postdose, it is not sufficient to capture the maximum QTc change since Cmax and Emax do
`not necessarily coincide.
`
`In addition to EKG measurements, 159 patients (0.25 mg dose: 57 patients; 0.75 mg
`dose: 102 patients) randomized to palonosetron 0.25 mg or 0.75 mg in the Phase III trials
`received Holler monitoring. These data were not subject to the above analysis.
`
`All cardiac safety data from Phase I-Ill trials were reviewed by Dr. Narayan Nair. Based
`on his review, the cardiac adverse event profile for palonosetron appears similar to that of
`other drugs in this class although there seems to be more subjects with tachycardia in the
`palonosetron group versus comparator (ondansetron and dolasetron) arms (1% vs. 0.5%).
`The following is information excerpted from Dr. Nair’s review:
`
`”ECG Datd.‘
`
`10
`
`

`

`In the Phase Ill trials, the mean change from baseline QTc ranged from -] to +3 msec
`without any dose trends and without any case of major change from baseline. When all
`the Phase 3 ECG data was pooled, the effect on the OTC parameter by Bazett or
`Fridericia correction was 2 msec at both palonosetron doses.
`In the comparator arms the
`OTC mean changes from baseline were larger (4-5 msec). There were several cases of
`new absolute QTcB or QTCF >500 msec but these were equally distributed in all
`treatment arms.
`
`Table: Number and percentage of patients with postdose changes in QTc based on the ECG
`measurements in the Phase II] trials
`
`
`
`Ondansetron
`32 mg
`(N = 410)
`Nt=404 _
`
`Dolasctron
`I00 mg
`(N = 194)
`Nt=192
`
`l]
`
`7
`
`32
`
`Palonosetron
`0.25 mg
`(N = 605)
`Nt=594
`
`Palonosetron
`0.75 mg
`(N = 610)
`Nt=60l
`
`o/o
`
`QTcB
`> 60 msec
`
`QTcB
`> 500 msec
`
`QTcF
`30 to 60 msec
`
`'
`
`QTcF
`> 60 msec
`
`QTcF
`> 500 msec
`
`S
`
`27
`
`5
`
`3
`
`31
`
`2
`
`0
`
`5
`
`N= Number ofpatients in specific group.
`Nt= Total Number of patients with ECG parameter.
`n = Number of patients with changes
`% = Percentage of patients with changes.
`QTcF = QT interval corrected by Fridcrieia formula
`Q l'cU = QT interval corrected by Balett formula.
`msec = Milliscconds
`Source' Expert Report PALO-02é04. Appendix A.
`
`Holler Data:
`
`A subset of patients in the Phase 3 trials underwent Holter monitoring. Evaluable Holters
`in 193 subjects were obtained from 2-hours before dosing to 22-hours after dosing.
`Individual infrequent cases of Mobitz Type H block, sinus pauses, and occasional runs of
`nonsustained ventricular tachycardia were identified, however no difference in treatment
`groups was seen. No clinically relevant difference seen between palonosetron at two
`different doses compared to ondansetron and dolasetron.”
`
`ll
`
`

`

`4.2.3.] Based on PK parameters, what is the degree of linearity 0r nonlinearity in the
`dose-concentration relationship?
`
`Palonosetron PK was found to be approximately dose proportional following single IV
`dose administration (over 5 min.) for the dose range of 1-90 - g/kg. Dose proportionality
`upon multiple dosing was not studied since the drug product is intended for single dose
`administration.
`(Note: In later studies, palonosetron was administered over 30 seconds.
`This is the way palonosetron will be administered in clinical use conditions.)
`
`4.2.4 How does the PK of palonosetron in healthy volunteers compare to that in
`
`patients?
`
`4.2. 4.1 What are the basic PK parameters?
`
`The PK parameter values for palonosetron following single lV dose of 3 ' g/kg and 10
`- g/kg in healthy subjects in a Phase I study and in chemotherapy-naive patients
`undergoing chemotherapy in a Phase II trial are listed in the table below. Both Cmax and
`. Tmax were highly variable in patients compared to healthy volunteers. It should be noted
`that the two studies differed in time period ofIV dosing and sampling schemes. In the
`study in healthy subjects, palonosetron was administered over 5 minutes and the first
`sample was collected at 5 minutes post close.
`In the Phase II trial in patients,
`palonosetron was administered over 30 seconds and the first sample was collected at l
`min postdose. Mean AUC value was comparable between healthy subjects and patients
`receiving chemotherapy, however, the intersubject variability was greater in patients.
`
`Dose
`
`(' g/kg)
`
`Cmax
`(ng/mL)
`
`
`
`
`
`
`
`Tl/2
`AUCo.
`Tmax
`(hr)
`n_.h/mL
`(hr)
`Healthv Volunteers (Phase 1 Stud
`0083100
`29.81902
`35018.8
`0.09010024
`Patients (Phase 1] Trial
`014410.196
`35.81209
`50415.81
`5.631548
`082711.51
`81.81239
`49.81144
`”- 1301200
`Equivalent to 0.21 mg/70 kg (close to the proposed clinical dose of 0.25 mg)
`
`0.921025-
`-_ 35311.44
`
`
`
`
`
`CL
`(mL/min/kg)
`
`Vz
`(L/kg)
`
`1.811055
`2.661061
`
`6.881087
`78311.81
`
`1.661059
`2.231033
`
`
`
`79112.53
`95614.21
`
`
`
`
`
`
`
`
`
`
`4.2.4.2
`
`Does mass balance study suggest the major route of elimination is renal or
`hepatic?
`
`Following single dose administration of I.V. radiolabeled palonosetron, 79.9% of the
`administered dose was recovered in urine over a l44-hr period with 39.3% of the
`recovered dose being intact drug. Overall, renal clearance amounted to 42% of the total
`systemic clearance. Around 50% of the palonosetron dose was metabolized in humans
`with the major metabolites being an N-oxide metabolite (M9; accounts for 12.5% of the
`dose) and a hydroxy metabolite (M4; accounts for 10.9% of the dose).
`
`12
`
`

`

`Both renal and hepatic systems play important roles in the clearance of palonosetron.
`The proposed metabolic pathway is shown below:
`
`Figure: Metabolic pathways of palonosetron
`
`f N
`
`‘rl
`
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`
`5-”-
`
`T.r
`
`0 .fiI
`
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`
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`
`lama. a
`
`Bold arrows indicate major pathways
`
`4.3 Intrinsic Factors
`
`recommended for each of these subgroups
`
`What intrinsic factors (age, gender, race, weight, height, disease, genetic
`polymorphism, pregnancy, and organ dysfunction) influence exposure
`and/or response and what is the impact of any differences in exposure on
`the pharinacodynamic? What dosage adjustments, if any, are
`
`4.3.1.1 Age/Gena’er/Race
`
`A population PK analysis was performed using data obtained from the Phase III trials.
`Age, gender and race were not-found to be significant covariates for clearance. However,
`the final analysis yielded a low population mean of clearance estimate (less than half of
`the mean value found in the Phase II trial) with a high intersubject variability (88.8%) in
`
`13
`
`

`

`clearance. The sponsor did not explain why. Since analysis ofthe Phase III trial data did
`not reveal any subgroup with significant differences in the safety profiles, no dosage
`adjustment based on age or gender is necessary.
`It should be noted that Blacks were
`poorly represented in the Phase III trials. Hence, no conclusion can be made about PK in
`Blacks compared to‘Caucasians.
`
`4.3.1.2 Renal impairment
`Mean values of the primary PK parameters for palonosetron in patients with mild to-
`moderate renal impairment were similar to those of healthy subjects. In patients with
`severe renal impairment, the mean AUC0_... increased by around 30% compared to healthy
`subjects. In addition, Cum and AUCO..., of M9, the major metabolite of palonosetron,
`increased by 1.5 to 2-fold and 3 to 4—fold, respectively, in severe renal impairment.
`Dosage adjustment for palonosetron is not necessary in patients with severe renal
`impairment.
`
`1
`
` I
`
`Mean palonosetron plasma concentrations, 0-240 h post dose
`
`.0._Group A - healthy sub—feas—
`300° -—-————-———-
`l + Group B - mild/moderate renal impairment
`
`i
`+Group C - severe renal impairment
`-——————.—l
`
`2500
`
`l
`l
`{
`
`88
`
`§
`
`palonosetroh—(iiglL) §
`
`0
`
`24
`
`48
`
`72
`
`96
`
`120
`
`144
`
`168
`
`192
`
`216
`
`240
`
`264
`
`l
`
`
`
`Time (hours) after dose
`
`Figure: Mean palonosetron plasma concentration-time profile in subjects with varying
`grades of renal impairment.
`
`4.3.1.3 Hepatic impairment
`
`The mean values of Cmax and AUC for palonosetron in patients with rrrild to severe
`hepatic impairment were significantly reduced relative to those of healthy subjects. The
`mean values of Cm” and AUC for the M9 metabolite were significantly reduced in
`patients with moderate to severe hepatic impairment relative to those of healthy subjects.
`This has been attributed to the combination of a reduction in the metabolic pathway in
`hepatic impairment with an increase in the volume of distribution, altogether resulting in
`a net reduction in palonosetron and M9 plasma concentrations. In addition, the apparent
`
`l4
`
`

`

`half-life of palonosetron was significantly prolonged in patients with moderate to severe
`hepatic impairment compared to that of healthy subjects.
`'
`
`Despite a prolongation in the apparent half-life ofpalonosetron by 50% in patients with
`moderate and severe hepatic impairment, dosage adjustment is not necessary as
`palonosetron Will be administered as a single dose in the clinical setting.
`
`Mean palonosetron plasma concentrations, 0-240 h post dose
`
`3 Time (hours) after close
`
`3B5I
`
`:oho 8
`
`.5
`
`Fig.2. Mean palonosetron plasma conc.-time profile in subjects with varying grades of hepatic
`impairment.
`
`4.3.1.4 CYP2D6 Poor metabolizers
`
`Palonosetron PK parameter values following single IV dose of 0.75 mg were compared
`between CYP2D6 extensive (n=3) and poor metabolizers (n=3). There is no indication
`that CYP2D6 poor metabolizers had higher exposure to or longer half-life of
`palonosetron.
`
`15
`
`

`

`100
`
`
`
`
`
`MoonPlum-concentrauonu(nyL)
`
`+ Poor Metabolisers
`- - D - -Exl9nsiv9 Morabolisers
`
`‘
`1
`
`5
`
`0
`
`24
`
`48
`
`72
`
`98
`
`120
`
`144
`
`168
`
`192
`
`216
`
`240
`
`Time (ham) after dose
`
`Figure: Mean plasma palonosetron concentrations following single IV injection of 0.75 mg
`palonosetron HCI in extensive and poor metabolizers of CYPZDé substrates
`
`4.4
`
`Extrinsic Factors
`
`4.4.1 What extrinsic factors (drugs, herbal products, diet, smoking, and alcohol
`use) influence exposure and/or response and what is the impact of any
`
`differences in exposure on pharmacodynamics?
`
`At this time, there are no known factors that influences exposure or response of
`palonosetron.
`
`4.4.2 Drug-Drug Interactions
`
`4. 4.2.]
`
`Is there an in vitro basis to suspect in vivo drug-drug interactions?
`
`In in virro studies using cDNA-expressed CYP enzymes, CYP2D6 was identified as the
`major enzyme for the metabolism of palonosetron with other enzymes (CYP1A1,
`CYP1A2 and CYP3A4) playing a lesser role. In a correlation analysis using human
`microsomes, CYP2D6 was identified as the major enzyme for the metabolism of
`palonosetron, followed by CYP3A4. The correlation coefficient for CYP2D6 was 0.58
`for the M9 formation, and 0.74 for the formation of the other two polar metabolites. The
`potential for drug-drug interactions causing significant increase in palonosetron
`concentrations is low. This is because metabolism accounts for only 50% of the total
`clearance of palonosetron, and multiple CYP enzymes appear to be involved in the
`metabolism of palonosetron.
`
`The inhibitory potential of palonosetron and its metabolite M9 on the activity of human
`liver microsomal CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1, CYP3A
`
`l6
`
`

`

`was investigated. At the therapeutic concentrations, either palonosetron or M9 is not an
`inhibitor ofthese enzymes. CYP2C19 was not studied.
`
`The induction potential of palonosetron and M9 on the enzymatic activities catalyzed by
`CYP1A2, CY-PZD6,‘ and CYP3A were studied using fresh isolated human hepatocytes.
`At the therapeutic concentrations, either palonosetron or M9 does not induce the acitivity
`of these enzymes.
`
`4.4.2.2 Is the drug a substrate and/or inhibitor ofP-glycoprotein transport process?
`
`The sponsor did not conduct any studies related to P-gp transporters.
`
`4.4.2.3 What interaction data are available? What is the impact?
`
`Metoclopramide was given concomitantly with palonosetron in a Phase I study.
`Administration of multiple oral doses of metoclopramide 10 mg Q.l.D. does not have a
`significant effect on the pharmacokinetics ofa single I.V. dose of 0.75 mg palonosetron.
`Also, a single I.V. dose of 0.75 mg palonosetron does not have a relevant effect on the
`steady-state pharmacokinetics of metoclopramide (10 mg Q 6 hrs). It should be noted that
`the metoclopramide dose used in this study is lower than the dose recommended for the
`prevention of chemotherapy-associated nausea and vomiting. On the other hand, the
`palonosetron dose used was higher than that proposed by the sponsor.
`
`There is no need for dosage adjustment of metoclopramide when administered
`concomitantly with palonosetron.
`
`4.5 General Biopharmaceutics
`
`4.5.1 What is the in vivo relationship of the proposed to-be-marketed formulation
`
`to the pivotal clinical trial formulation in terms of comparable exposure?
`
`The to-be-marketed formulation was used in the Phase 3 trials. The formulation used in
`the Phase 2 dose ranging study was different. However, both formulations were solutions
`with palonosetron hydrochloride completely dissolved in the formulation. Thus, there is
`no bicequivalence issue.
`
`4.6 Analytical Section
`
`4.6.1 Which moieties have been selected for analysis and why?
`
`The concentrations of palonosetron and its major metabolite, M9, in plasma and urine
`samples were determined by validated analytical methods. M9 is a major metabolite of
`palonosetron.
`It has low activity (at least 100 times lower than palonosetron) as a 5-HT3
`receptor antagonist and is present in plasma at low concentrations.
`
`17
`
`

`

`exists as a related impurity ofthe drug
`: compound, _ ‘h
`A suspected
`substance. Efforts were made to determine the potential ofits formation in vivo. A
`~
`‘ method was used to detect the presence of
`“ and its metabolite
`— '
`in human plasma and urine samples (detection limit: ~10 ng/L (plasma) and
`100 ng/L (urine) for._" -
`and ~500 ng/L (plasma) and 2000 ng/L (urine) for
`" I. There was no indication of.
`in. '" formation following single lV dose
`administration ofpalonosetron 0.75 mg.
`
`4.6.2 For all moieties measured, is free, bound or total measured? What is the basis for that decision, if any, and is it appropriate?
`
`Total palonosetron or M9 was measured. Plasma protein binding for palonosetron was
`constant over the concentration range of 5. l 5412 ng/mL.
`
`4.6.3 What analytical methods are used to assess concentrations?
`
`Three analytical methods have been utilized to measure palonosetron and M9 in plasma
`samples during the development of palonosetron.
`
`(L) I v Method for Determination of Palonosetron and M9 (JAR B-1009)
`This method was used to measure palonosetron in plasma in Studies 2092. The
`validation results are given below.
`
`Parameter
`Lineari
`
`
`Palonosetron
`
`
`Precision (%CV)
`
`4 runs at the lowest conc.:
`25.7%
`
`
`
`
`
`Stabilit —2o°c for > 6 wks
`
`Selectivi
`
`:<40%
`
`S 20% (except for the lowest
`conc onO n_
`
`Method for Determination of Palonosetron and M9 '(PALO-99-09; July 2001)
`13 3. 9'
`The method was developed and validated by
`——-.
`The assay was used to quantitate plasma palonosetron and M9 concentrations in studies
`
`._‘.
`
`18
`
`

`

`PALO-99-O3, PA