CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
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`202895Orig1s000
`
`PHARMACOLOGY REVIEW(S)
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`

`

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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA/BLA REVIEW AND EVALUATION
`
`Application number(s):
`Supporting document/s:
`
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`Applicant:
`Review Division:
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`
`202-895 and 21-976
`000 for 202-895
`020 for 21-976
`March 30, 2011
`March 30, 2011
`Darunavir
`HIV
`Tibotec
`DAVP
`L. Peyton Myers, PhD
`Hanan Ghantous, PhD, DABT
`Debra Birnkrant, MD
`Linda Onaga
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA(s) 202-895 and 21-976 are owned by Tibotec, Inc. or are
`data for which Tibotec, Inc. has obtained a written right of reference.
`
`Any information or data necessary for approval of NDA(s) 202-895 and 21-976 that
`Tibotec, Inc. does not own or have a written right to reference constitutes one of the
`following: (1) published literature, or (2) a prior FDA finding of safety or effectiveness for
`a listed drug, as reflected in the drug’s approved labeling. Any data or information
`described or referenced below from reviews or publicly available summaries of a
`previously approved application is for descriptive purposes only and is not relied upon
`for approval of NDA(s) 202-895 and 21-976.
`
`Reference ID: 3009095
`
`1
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`

`

`NDA # 202-895 and 21-976/S-020
`
`
`
`
`Reviewer L. Peyton Myers, PhD
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 3
`1.1
`INTRODUCTION.................................................................................................... 3
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 3
`1.3 RECOMMENDATIONS............................................................................................ 4
`2 DRUG INFORMATION ............................................................................................ 5
`2.1 DRUG................................................................................................................. 5
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS........................................................... 6
`2.3 DRUG FORMULATION ........................................................................................... 6
`2.4 COMMENTS ON NOVEL EXCIPIENTS....................................................................... 6
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ......................................... 6
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ...................................... 6
`2.7 REGULATORY BACKGROUND ................................................................................ 6
`3 STUDIES SUBMITTED............................................................................................ 6
`3.1
`STUDIES REVIEWED............................................................................................. 6
`3.2
`STUDIES NOT REVIEWED ..................................................................................... 6
`3.3
`PREVIOUS REVIEWS REFERENCED........................................................................ 6
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .................................. 7
`EMBRYONIC AND FETAL DEVELOPMENT................................................................. 7
`9.2
`11
`INTEGRATED SUMMARY AND SAFETY EVALUATION................................. 18
`
`
`Reference ID: 3009095
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`NDA # 202-895 and 21-976/S-020
`
`
`1
`
`Executive Summary
`
`
`
`Reviewer L. Peyton Myers, PhD
`
`Introduction
`
`1.1
`
`1.2 Brief Discussion of Nonclinical Findings
`Darunavir is an HIV protease inhibitor approved for the treatment of HIV infection in
`various populations. Darunavir selectively inhibits the cleavage of HIV encoded Gap-
`Pol polyproteins in infected cells, thereby preventing the formation of mature virus
`particles. Darunavir is orally administered as a tablet at a concentration of 300 mg BID,
`400 mg BID, or 600 mg QD with ritonavir (100 mg) and with food. The rationale for
`combination with a low dose of ritonavir is to improve the oral bioavailability of
`darunavir. Darunavir may be coadministered with other anti-retroviral agents.
`
`Previous studies have shown the safety and effectiveness of darunavir as well as the
`toxicology profile. Please see the prior reviews for this drug for a complete summary of
`the toxicological profile.
`
`The toxicology studies submitted with this Supplement were designed to respond to a
`Post-Marketing Requirement under NDA 21-976/S-6 (SDN 44) for “an embryofetal study
`of adequate AUC exposure in order to establish a safety profile for darunavir prior to a
`pregnancy protocol initiation.” The PMR was requested due to juvenile toxicology
`effects (CNS effects such as tremors that were related to death) as well as AUC levels
`for the reproductive toxicology studies that was <1. These data increased a safety
`concern for human trials in pregnant women that were being proposed at the time.
`
`In the current application, three studies were submitted. Two of the studies were range
`finding studies in 2 species: rat and minipig with and without Ritonavir. In both species,
`a NOAEL was achieved in the Dams. However, in the minipig, AUC exposures did not
`increase significantly when boosted with Ritonavir. Therefore, the pivotal GLP
`toxicology study to address the PMR for reproductive toxicology was performed in the
`rat.
`
`In the pivotal GLP-compliant reproductive toxicology study with Ritonavir, all dams
`survived to the end of dosing (except for several gavage-related mortalities). No drug-
`related deaths were noted. However, body weight and food consumption were
`decreased in dams at all doses (which did reach statistical significance). Soft and pale
`feces were noted at all doses (both 600 mg/kg/day and 1000 mg/kg/day of darunavir
`boosted with ritonavir). Due to the body weight loss and decreased food consumption
`at all doses, the maternal NOAEL was not determined. However, a NOAEL was
`achieved in the pups.
`
`There were no changes in litter parameters (implantations, corpora lutea, resorptions,
`etc) at any dose. However, fetal weights were decreased in both the pups dosed during
`GD (gestation day) 6-11 (~5-8%) as well as the pups dosed GD 12-17 (~15-21%). The
`
`Reference ID: 3009095
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`
`Reviewer L. Peyton Myers, PhD
`
`NDA # 202-895 and 21-976/S-020
`
`weight changes noted at 1000 mg/kg/day was slightly more than in the 600 mg/kg day
`group, but the differences were not significant.
`
`The Sponsor proposed a NOAEL in the pups to be the low dose (600 mg/kg/day
`darunavir + 100 mg/kg RTV). The sponsor did not give a rationale for determining that
`the lower dose was the NOAEL. The fetal weight losses were slightly lower in the low
`dose (600 mg/kg/day of darunavir), which may support this conclusion. Otherwise,
`findings between the low dose and the high dose groups were similar.
`
`In the pivotal embryofetal study, an AUC for darunavir increased significantly, compared
`to previous embryofetal studies with darunavir. Human safety margins were calculated
`based on the increased AUC in rats, which ranged from 1.6 to 3.2. The range of safety
`margins was calculated from two dose groups (600 and 1000 mg/kg/day), two gestation
`day points, as well as two clinical trials. The new safety margins allowed for a significant
`increase over previous exposures in rats that equated to roughly 0.5x the human
`exposure.
`
`Given that the submitted GLP study in rats increased the safety margins from less than
`1 to ~ 3-fold and no safety signals of concern have been noted, the Sponsor has fulfilled
`the PMR and established an adequate safety margin for pregnant women.
`
`1.3 Recommendations
`
`1.3.1 Approvability
`The pharmacology/toxicology studies submitted to NDA 202-895 and NDA 21-976
`support the labeling for this submission and are sufficient for approval.
`1.3.2 Additional Non Clinical Recommendations
`The Post-Marketing Requirement for NDA 21-976/S-6 (SDN 44) “an embryofetal study
`of adequate AUC exposure in order to establish a safety profile for darunavir prior to a
`pregnancy protocol initiation” has been satisfied.
`
`1.3.3 Labeling
`Suggested P/T Labeling
`
`Section 8.1 Pregnancy
`
`Pregnancy Category C: PREZISTA should be used during pregnancy only if the potential benefit
`justifies the potential risk.
`
`No adequate and well-controlled studies have been conducted in pregnant women. Reproduction
`studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice and rats in
`the presence or absence of ritonavir as well as in rabbits with darunavir alone. In these studies,
`darunavir exposures with ritonavir (based on AUC) were higher in rats (3-fold), whereas in mouse
`and rabbit, exposures to darunavir alone were lower (<1-fold) compared to those obtained in
`humans at the recommended clinical dose of darunavir boosted with ritonavir.
`
`Reference ID: 3009095
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`NDA # 202-895 and 21-976/S-020
`
`
`
`
`Reviewer L. Peyton Myers, PhD
`
`
`In the rat pre- and postnatal development study, a reduction in pup body weight gain was
`observed with darunavir alone or in combination with ritonavir during lactation. This was due to
`exposure of pups to drug substances via the milk. Sexual development, fertility and mating
`performance of offspring were not affected by maternal treatment with darunavir alone or in
`combination with ritonavir. The maximal plasma exposures achieved in rats were approximately
`50% of those obtained in humans at the recommended clinical dose boosted with ritonavir.
`
`Section 8.4 Pediatric Use
`
`Do not administer PREZISTA/ritonavir in pediatric patients below 3 years of age because of
`toxicity and mortality observed in juvenile rats dosed with darunavir. In.the juvenile toxicity study
`where rats were directly dosed with darunavir (from 20 mg/kg to 1000 mg/kg up to days 23 to
`26 of age), deaths occurred from post-natal day 5 through 11 at plasma exposure levels ranging
`from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing was
`initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were
`observed with a plasma exposure (in combination with ritonavir) of 0.1 of the human plasma
`exposure levels. [see Warnings and Precautions (5.11), Use in Specific Populations (8.1), Clinical
`Pharmacology (12.3) and Nonclinical Toxicology (13.2)]
`
`
` Drug Information
`
` 2
`
`2.1 Drug
`CAS Registry Number (Optional) 313682-08-5
`
`Generic Name Darunavir
`
`Code Name TMC114
`
`Chemical Name {3-[-amino-benzensulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-
`carbamic acidhexahydro-furo[2,3-b]furan-3-yl ester ethanolate
`
`Molecular Formula/Molecular Weight C 27 H 37 N 3 O 7 S.C 2 H 5 OH; 593.724 (active moiety +
`ethanol) 547.656 (active moiety)
`
`
`Structure or Biochemical Description
`NH2
`
`O O
`
`S
`
`N
`
`O
`
`O
`
`O
`
`O
`
`NH
`
`OH
`
`
`Pharmacologic Class Anti-HIV protease inhibitor
`
`
`Reference ID: 3009095
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`
`
`Reviewer L. Peyton Myers, PhD
`
`NDA # 202-895 and 21-976/S-020
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`IND 62,477
`NDA 21-976
`NDA 202-895
`2.3 Drug Formulation
`Tablets containing 200 mg or 400 mg darunavir base formulated as darunavir
`ethanolate,
` microcrystalline cellulose,
` and magnesium
`stearate
`2.4 Comments on Novel Excipients
`None
`2.5 Comments on Impurities/Degradants of Concern
`None
`2.6 Proposed Clinical Population and Dosing Regimen
`HIV infected patients
`2.7 Regulatory Background
`The FDA review team requested a Post Marketing Requirement for an embryofetal
`study of adequate AUC exposure in order to establish a safety profile for darunavir prior
`to a pregnancy protocol initiation. Prior embryofetal studies had exposure values below
`1, which significantly affected the risk assessment for a pregnancy protocol.
`3
`Studies Submitted
`
`3.1 Studies Reviewed
`Pilot Rat DART study
`Rat DART study
`Pilot Minipig DART study
`3.2 Studies Not Reviewed
`All studies were reviewed.
`3.3 Previous Reviews Referenced
`None.
`
`
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`Reference ID: 3009095
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`6
`
`(b) (4)
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`(b) (4)
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`NDA # 202-895 and 21-976/S-020
`
`9 Reproductive and Developmental Toxicology
`
`
`
`Reviewer L. Peyton Myers, PhD
`
`9.2 Embryonic and Fetal Development
`Study title: Pilot oral developmental toxicity study of TMC114 in the rat.
`Study no.:
`TMC114-TiDP3-NC397
`Study report location:
`EDR
`Conducting laboratory and location:
`Janssen R & D
`Beerse Site
`Belgium
`Date of study initiation: March 24, 2009
`GLP compliance:
`Yes
`QA statement:
`Yes
`Drug, lot #, and % purity:
`TMC114, batch ZR319064EIA201, 99.1%
`pure
`
`
`Key Study Findings
`The overall goal of the study was to compare 2 doses of darunavir (1000 and 2000
`mg/kg/day) without boosting with RTV to a dose of darunavir 1000 mg/kg with RTV
`boosting.
`
`There were marked effects on body weight performance with darunavir at the dose
`level of 2000 mg/kg/day. Fetal effects (resorptions and a higher post-implantation
`loss and a decrease in live fetuses) were noted at the 2000 mg/kg/day level. No
`major effects were noted at 1000 mg/kg/day of darunavir (with or without RTV).
`
`Furthermore, there was a substantial increase in pharmacokinetics of darunavir with
`RTV boosting. Therefore, with the favorable PK at 1000 mg/kg (with RTV), the fetal
`affects at 2000 mg/kg (without RTV), and the lack of effects at 1000 mg/kg (with RTV)
`the dose of 1000 mg/kg darunavir + RTV boosting was considered acceptable for the
`definitive study based on acceptable PK and toxicity profiles.
`
`
`Methods
`
`Doses: See table below
`Frequency of dosing: See dosing days in table below
`Route of administration: Oral administration (to dams)
`Dose volume: See below
`Formulation/Vehicle: 60% or 100% PEG 400 for TMC 114 and 40%
`PEG 400 for RTV
`Species/Strain: Female Sprague Dawley rats (CRL)
`Number/Sex/Group: See table below
`Age: 9-10 weeks
`Weight: 164 to 275 grams
`Satellite groups: None.
`Unique study design: None.
`Deviation from study protocol: No significant deviations.
`
`
`
`Reference ID: 3009095
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`NDA # 202-895 and 21-976/S-020
`
`
`
`
`Reviewer L. Peyton Myers, PhD
`
`
`
`Observations and Results
`For simplicity, the Sponsor referred to the groups as Low (A) and Low (B), High (A) and
`High (B), and Super High (A) and Super High (B). See table above. The A and B
`designations were made to separate GD 6-11 (A group) from GD 12-17 (B group).
`
`
`• Low (A): 1000 mg/kg/day Darunavir (TMC114) for GD 6-11.
`• Low (B): 1000 mg/kg/day Darunavir for GD 12-17
`• High (A): 2000 mg/kg/day Darunavir for GD 6-11.
`• High (B): 2000 mg/kg/day Darunavir for GD 12-17.
`• Super High (A): 1000 mg/kg/day Darunavir + 100 mg/kg RTV for GD 6-11.
`• Super High (B): 1000 mg/kg/day Darunavir + 100 mg/kg RTV for GD 12-17
`
`
`Toxicokinetics
`
`The addition of Ritonavir substantially increased the darunavir AUC and Cmax on day
`11 (from 284 ug·h/ml to 419 ug·h/ml) and day 17 (275 ug·h/ml to 397 ug·h/ml) in both
`GD groups compared to Darunaivr alone. (See table below.)
`
`
`
`
`
`
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`Reference ID: 3009095
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`NDA # 202-895 and 21-976/S-020
`
`
`
`
`Reviewer L. Peyton Myers, PhD
`
`Pharmacokinetics of Darunavir with or without RTV boosting in Rats
`
`
`
`
`
`
`Reference ID: 3009095
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`NDA # 202-895 and 21-976/S-020
`
`
`
`
`Reviewer L. Peyton Myers, PhD
`
`Study title: Oral Developmental Toxicity Study of TMC114 in the Rat.
`Study no.:
`TMC114-TiDP3-NC398
`Study report location:
`EDR
`Conducting laboratory and
`Janssen R & D
`location:
`Beerse Site
`Belgium
`Date of study initiation: May 18, 2010
`GLP compliance:
`Yes
`QA statement:
`Yes
`Drug, lot #, and % purity:
`TMC114, batch 09P0202, 99.6% pure
`
`
`Key Study Findings
`All dams survived to end of dosing (except for several gavage-related mortalities). No
`drug-related deaths noted. However, body weight and food consumption were
`decreased in dams at all doses (which did reach statistical significance). Soft and
`pale feces was noted at all doses.
`
`Maternal NOAEL: Not determined due to body weight loss and decreased food
`consumption at all doses.
`
`There were no changes in litter parameters (implantations, corpora lutea, resportions,
`etc) at any dose. However, fetal weights were decreased both the pups dosed during
`GD (gestation day) 6-11 (~5-8%) as well as the pups dosed GD 12-17 (~15-21%).
`The weight changes noted at 1000 mg/kg/day was slightly more than in the 600 mg/kg
`day group, but the differences were not significant.
`
`Fetal NOAEL: Determined to be the low dose (600 mg/kg/day TMC114 + 100 mg/kg
`RTV). The sponsor did not give a rationale for determining that the lower dose was
`the NOAEL. The fetal weight losses were slightly lower in the low dose (600
`mg/kg/day), which may support this conclusion. Otherwise, findings between the low
`dose and the high dose groups were similar.
`
`The Sponsor, however, did achieve an increased pharmacokinetic AUC compared to
`previous studies in rats. The PK of the rats was roughly 2.1x the human exposure
`(2.61 ug·h/ml for rat vs 124 ug·/ml for human). This was a significant increase over
`previous AUCs in rats that equated to roughly 0.5x the human exposure.
`
`
`Methods
`
`Doses: See table below
`Frequency of dosing: See dosing days in table below
`Route of administration: Oral administration (to dams)
`Dose volume: See below
`Formulation/Vehicle: 60% or 100% PEG 400 for TMC 114 and 40%
`PEG 400 for RTV
`Species/Strain: Female Sprague Dawley rats (CRL)
`
`Reference ID: 3009095
`
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`NDA # 202-895 and 21-976/S-020
`
`
`
`
`Reviewer L. Peyton Myers, PhD
`
`Number/Sex/Group: See table below.
`Age: 63-70 days
`Weight: 205-285 g
`Satellite groups: See table below.
`Unique study design: None.
`Deviation from study
`No significant deviations.
`protocol:
`
`
`
`
`
`Observations and Results
`For simplicity, the groups are referred to as Low (A) and Low (B) as well as High (A)
`and High (B). See table above. The A and B designations were made to separate GD
`6-11 (A group) from GD 12-17 (B group).
`
`
`• Low (A): 600 mg/kg/day TMC114 + 100 mg/kg RTV for GD 6-11.
`• Low (B): 600 mg/kg/day TMC114 + 100 mg/kg RTV for GD 12-17
`• High (A): 1000 mg/kg/day TMC114 + 100 mg/kg RTV for GD 6-11.
`• High (B): 1000 mg/kg/day TMC114 + 100 mg/kg RTV for GD 12-17.
`
`
`
`Maternal Results:
`Mortality
`Maternal mortality was monitored 1x daily. 4 females died on study (1 Low B, 1 High B,
`and 2 High A). The deaths were attributed to gavage error.
`Clinical Signs
`Maternal signs were monitored 1x daily. Pale feces in all groups. Reduced feces in
`High (B). Some of the High (A) females had increased pilorerection and audible
`respiration which appeared to be dose related. The findings in the High (A) females
`was not statistically significant.
`
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`
`
`Reviewer L. Peyton Myers, PhD
`
`NDA # 202-895 and 21-976/S-020
`
`Body Weights
`Measured days 0, 4, 6-12, 14, 18, 21. Body weight loss was noted in all groups on GD
`6-11 (but recovered) and GD 12-17 (did not recover).
`
`Feed Consumption
`Maternal feed was measured days 0, 6, 10, 12, 14, 18, 21. Food consumption
`decreased with body weight decreases.
`
`Gross Pathology
`Maternal pathology was evaluated at sacrifice. No changes were noted. Pathology on
`the females that were sacrificed prematurely revealed trauma consistent with accidental
`dosing.
`
`Litter Data:
`Cesarean Section Data (Implantation Sites, Pre- and Post-Implantation Loss, etc.)
`(cid:122) Pregnancy parameters (corpora lutea, implantations, resorptions, live/dead
`fetuses, implantation loss) were not affected at any dose. There was a slight
`increase in litter loss in some High (A) dose females (1000 mg/kg/day, days 6-
`11) due to poor maternal condition (maternal toxicity) rather than direct effects on
`the embryo.
`
`
`Offspring (Malformations, Variations, etc.)
`Fetal weight loss significantly increased at GD 12-17 in both males and females at both
`doses (see below). The loss was dose dependent with a decrease of ~21% at the 1000
`mg/kg/day dose and ~16% at the 600 mg/kg/day dose.
`
`
`Dose of DRV
`
`Fetal weight loss (males)
`
`Body weight change – gms (% body wt loss)
`
`GD 6-11
`
`Control (vehicle) 5.81
`600 mg/kg/day 5.49 (5%)
`1000 mg/kg/day 5.41 (7%)
`
`GD 12-17
`
`4.91 (15%)
`4.57 (21%)
`
`
`
`12
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`NDA # 202-895 and 21-976/S-020
`
`
`
`
`Reviewer L. Peyton Myers, PhD
`
`Dose of DRV
`
`Fetal weight loss (females)
`
`Body weight change – gms (% body wt loss)
`
`GD 6-11
`
`Control (vehicle) 5.55
`600 mg/kg/day 5.13 (8%)
`1000 mg/kg/day 5.08 (8%)
`
`GD 12-17
`
`4.65 (16%)
`4.38 (21%)
`
`
`Sex ratio was normal. No major external or visceral changes. Increased incidence of
`incompletely descended thymus in GD 6-11 animals. This indicated a slight
`developmental delay (commonly observed in low weight animals).
`
`Toxicokinetics
`TK parameters of TMC114 was comparable for both group A and group B (referring to
`GD days 6-11 and 12-17). After the first day and 6 days of dosing, AUC values
`increased somewhat less than dose-proportionally to rather dose proportionally over the
`studied dose levels in Subset A/B. Cmax and AUC values were comparable in Subset
`A/B for each group.
`Generally, Cmax1 values (the first Cmax) were comparable to higher, Cmax2 values (the
`second Cmax) were comparable to lower, AUC0-6 h values were comparable to higher and
`AUC0-24 h values were comparable to lower after 6 days of dosing compared to the first
`day of dosing in Subset A and B.
`
`
`Reference ID: 3009095
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`NDA # 202-895 and 21-976/S-020
`
`
`
`
`Reviewer L. Peyton Myers, PhD
`
`Pharmacokinetics of Darunavir (TMC114)
`
`
`
`
`
`Reference ID: 3009095
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`NDA # 202-895 and 21-976/S-020
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`
`
`
`Reviewer L. Peyton Myers, PhD
`
`Pharmacokinetics of Ritonavir
`
`
`Dosing Solution Analysis
`Dosing solutions were made from stock solutions. QC on these solutions was
`acceptable.
`
`
`
`Reference ID: 3009095
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`NDA # 202-895 and 21-976/S-020
`
`Reviewer L. Peyton Myers, PhD
`
`Study title: Combined PK/DRF Study in Female Minipigs
`Study no.:
`TMC114-TiDP2-NC399 TOX9288
`Study report location:
`EDR
`Conducting laboratory and location:
`
`W"
`
`Date of study initiation:
`GLP compliance:
`QA statement:
`
`Feb 25, 2009
`No
`No
`
`Drug, lot #, and % purity:
`
`TMC114, batch ZR319064E|A201, 99.4%
`pure
`
`Key Study Findings
`
`TMC114 was not well tolerated by the minipig. Adverse clinical signs were noted in
`all groups. The single dose (Phase 1 -- a BID dosing scheme, 6 hrs apart) resulted
`in most animals in all groups vomiting on one or both dosing occasions. Several
`animals were noted to be less active/passive or even subdued. During the Phase 2
`repeat-dose BID scheme (9 hrs apart), vomiting, passivity, and soft/watery feces
`was noted. Although improved tolerance was noted with time, the dose was
`considered to be unacceptable for future embryofetal toxicity testing in minipigs.
`
`In Phase 2 B (repeat dose QD), the clinical conditions were better throughout the
`day, although passiveness and soft feces were noted in all groups 1 hour after
`dosing. The signs were considered acceptable for repeated testing. Therefore, a
`QD testing scheme appeared to result in acceptable toxicity in minipigs with
`tolerable adverse events.
`
`Methods
`
`Doses: 500 or 1000 BID (Phase 1)
`250 or 500 BID or 250 BID with RTV (Phase 2)
`See tables below
`
`Frequency of dosing: See tables below
`Route of administration: Oral administration (to dams)
`Dose volume: See below
`
`FormulationNehicle: PEG 400
`Species/Strain: Gottingen SPF minipigs from
`
`"M"
`
`Number/Seleroup: 9 pigs total (3 groups of 3 pigs -- see tables
`below)
`Age: 7-8 months old
`Weight:
`15-18 kg
`Satellite groups: See table below.
`Unique study design: None.
`Deviation from study protocol: No significant deviations.
`
`Reference ID: 3009095
`
`1 6
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`

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`NDA # 202-895 and 21-976/S-020
`
`
`
`
`Reviewer L. Peyton Myers, PhD
`
`
`
`
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`
`
`
`
`Observations and Results
`This study was performed in order to evaluate the Minipig as a possible model for DART
`studies with TMC114. Tolerance and TK were the major endpoints.
`
`TMC114 was evaluated with or without RTV boosting by oral gavage to minipigs for a
`single day or at lower repeated doses.
`
`
`Reference ID: 3009095
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`17
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`

`

`
`
`NDA # 202-895 and 21-976/S-020
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`Toxicokinetics
`Surprisingly, RTV boosting did not result in significant increases in TMC114 levels in
`minipigs. Although there was a slight increase in TMC114 AUC levels, it was not
`significant, compared to TMC114 alone.
`
`Reviewer L. Peyton Myers, PhD
`
`
`
`Integrated Summary and Safety Evaluation
`11
`Darunavir (Prezista®) is an HIV protease inhibitor approved for the treatment of HIV
`infection in various populations.
`
`
`
`Reference ID: 3009095
`
`18
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`

`
`
`Reviewer L. Peyton Myers, PhD
`
`NDA # 202-895 and 21-976/S-020
`
`
`The toxicology studies submitted with this Supplement to fulfill a post marketing
`requirement “an embryofetal study of adequate AUC exposure”. These studies were
`performed in order to establish a safety profile for darunavir to support a pregnancy
`protocol that was proposed at the time of the PMR. The nonclinical studies were
`requested after safety concerns were mounted due to juvenile toxicology effects in rats
`(CNS effects such as tremors that were related to death). Due to these toxicities,
`combined with a low margin of safety (from AUC exposure margin in mice, rats, and
`rabbits from previous developmental toxicity studies that were <1), the review team
`issued the PMR for an embryofetal study that would increase the safety margins for
`pregnant women.
`
`Three studies were submitted in the current application Two studies were pilot studies
`in the rat and the minipig (with and without Ritonavir). In both the rat and minipig, a
`NOAEL was achieved. The rat, unlike the minipig, exhibited a significant increase in
`AUC after ritonavir boosting. Therefore, the rat was used for the pivotal GLP toxicology
`study to address the PMR.
`
`In the pivotal reproductive toxicology study, all of the rat dams survived to the end of
`dosing (except for several gavage-related mortalities). The toxicities in the rat dams
`were limited to body weight decreases, food consumption decreases, soft feces, and
`pale feces at all doses (both 600 mg/kg/day and 1000 mg/kg/day of darunavir boosted
`with ritonavir). Due to the body weight and food consumption decreases, there was no
`NOAEL for the rat dams.
`
`In the pups, there were no changes in litter parameters (implantations, corpora lutea,
`resorptions, etc) at any dose. Similar to the dams, fetal weights decreased at all time
`points and doses. The weight decreases at 1000 mg/kg/day was slightly (but not
`significantly) more than in the 600 mg/kg day pups.
`
`Although there were body weight decreases at both the low dose (600 mg/kg/day) and
`the high dose (1000 mg/kg/day), the lack of significant body weight decreases or any
`other toxicities at 600 mg/kg allowed a NOAEL estimation at 600 mg/kg/day.
`
`The PK for darunavir in the rats did increase with ritonavir boosting. The overall
`increase in safety margins based on the new PK data from rats ranged from 1.6 to 3.2
`(see table below). The safety margin ranges varied based on calculations using:
`exposure in the animals (600 mg/kg or 1000 mg/kg) or exposure values from different
`gestation days (GD) in rats, as well as the AUC values from clinical trials in naïve or
`treatment experienced adults. This increase of ~3-fold increased the overall safety
`margin in humans from the prior safety factor of ~0.5-fold.
`
`Reference ID: 3009095
`
`19
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`

`

`NDA # 202-895 and 21-976/S-020
`
`Reviewer L. Peyton Myers, PhD
`
`Table 1: NOAEL and Safety Margins for Darunavir in Pregnant Rats
`
`Toxicity
`
`Species
`
`NOAEL
`(mg/kg) M/F
`
`Safety Margin
`Based on AUC
`for na‘ive adults*
`
`Safety margin
`based on AUC
`for treatment
`
`experienced
`adults“
`
`
`
`Rat (dam) Not determined
`
`
`600 mg/kg (M/F)
`GD 11 or GD 17
`
`1000 mg/kg (M/F)
`GD 11 or GD 17
`
`3.2 or 2.5
`
`2.3 or 1.8
`
`*A UC in naive adults: 88 pg.hr/ml at 600 mg/day boosted with RTV.
`** AUC in treatment experienced adults: 123 pg.hr/ml at 600 mg/day boosted with RTV.
`
`With the increase in the safety margins from the rat AUC (from less than 1 to ~ 3-fold),
`combined with the lack of any concerning safety signals, the Sponsor has established
`an adequate safety margin for pregnant women.
`
`Reference ID: 3009095
`
`20
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`LAINE P MYERS
`08/31/2011
`
`HANAN N GHANTOUS
`08/31/2011
`
`Reference ID: 3009095
`
`

`

`PHARMACOLOGY/TOXICOLOGY FILING CHECKLIST FOR
`NDA/BLA or Supplement
`Applicant: Tibotec
`
`Stamp Date: 3/29/2011
`
`NDA Number: 202-895
`Cross reference NDA 21-976
`Drug Name: Darunavir
`
`NDA Type: Supplement with
`Post-Marketing P/T Studies
`
`
`
`
`On initial overview of the NDA/BLA application for filing:
`
`
`
`
`
`Content Parameter
`Yes
`No
`1 Is the pharmacology/toxicology section
`organized in accord with current regulations
`and guidelines for format and content in a
`manner to allow substantive review to
`begin?
`
`Is the pharmacology/toxicology section
`indexed and paginated in a manner allowing
`substantive review to begin?
`
`Is the pharmacology/toxicology section
`legible so that substantive review can
`begin?
`
`Are all required (*) and requested IND
`studies (in accord with 505 b1 and b2
`including referenced literature) completed
`and submitted (carcinogenicity,
`mutagenicity, teratogenicity, effects on
`fertility, juvenile studies, acute and repeat
`dose adult animal studies, animal ADME
`studies, safety pharmacology, etc)?
`
`If the formulation to be marketed is
`different from the formulation used in the
`toxicology studies, have studies by the
`appropriate route been conducted with
`appropriate formulations? (For other than
`the oral route, some studies may be by
`routes different from the clinical route
`intentionally and by desire of the FDA).
`Does the route of administration used in the
`animal studies appear to be the same as the
`intended human exposure route? If not, has
`the applicant submitted a rationale to justify
`the alternative route?
`7 Has the applicant submitted a statement(s)
`that all of the pivotal pharm/tox studies
`have been performed in accordance with the
`GLP regulations (21 CFR 58) or an
`explanation for any significant deviations?
`
`
`
` 2
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` 3
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` 4
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` 5
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` 6
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`
`
`Comment
`Three studies are included which were in
`response to a PMR from NDA 21-976.
`
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`x
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`x
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` x
`
`x
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` x
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`x
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`x
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`File name: 5_Pharmacology_Toxicology Filing Checklist for NDA_BLA or Supplement
`010908
`
`Reference ID: 2951708
`
`

`

`PHARMACOLOGY/TOXICOLOGY FILING CHECKLIST FOR
`NDA/BLA or Supplement
`
`
`
`
`
`Content Parameter
`Yes
`No
`
`Comment
`
`8 Has the applicant submitted all special
`
`studies/data requested by the Division
`during pre-submission discussions?
`9 Are the proposed labeling sections relative
`to pharmacology/toxicology appropriate
`(including human dose multiples expressed
`in either mg/m2 or comparative
`serum/plasma levels) and in accordance
`with 201.57?
`10 Have any impurity – etc. issues been
`addressed? (New toxicity studies may not
`be needed.)
`11 Has the applicant addressed any abuse
`potential issues in the submission?
`
`
`
`No modifications to Section 8.1 were
`proposed to reflect the new Embryofetal
`development study in rats. Paragraph 2 of
`section 8.1 should be updated.
`
`
`N/A
`
`
`N/A
`
`
`
`N/A
`
` x
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`
`x
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`12 If this NDA/BLA is to support a Rx to OTC
`switch, have all relevant studies been
`submitted?
`
`
`
`
`
`
`IS THE PHARMACOLOGY/TOXICOLOGY SECTION OF THE APPLICATION
`FILEABLE? __Yes______
`
`If the NDA/BLA is not fileable from the pharmacology/toxicology perspective, state the reasons
`and provide comments to be sent to the Applicant.
`
`
`
`
`
`Please identify and list any potential review issues to be f