CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -976
`
`PHARMACOLOGY REVIEW
`
`

`

`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER:
`
`21-976
`
`DATE RECEIVED BY CENTER:
`
`7
`
`12/23/2005
`
`PRODUCT:
`
`TMC 114, Darunavir, PREZISTA
`
`INTENDED CLINICAL POPULATION:
`SPONSOR:
`
`HIV patients
`Tibotec-Virco
`
`‘
`
`REVIEW DIVISION:
`
`Division of Antiviral Products (HFD-530)
`
`PHARM/TOX REVIEWER:
`
`James G. Farrelly, Ph.D.
`
`DIVISION DIRECTOR:
`
`PROJECT MANAGER:
`
`Pritam S. Verma, Ph.D.
`
`Debra Birnkrant, M.D.
`
`Elizabeth Thompson, M.S.
`
`Date of review submission to Division File System (DFS):
`
`

`

`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY ..................................................'............................................ 1
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW ................................................... 8
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY ................................................................... 8
`
`2.6.2 PHARMACOLOGY ......................................................................................................... 9
`2.6.2.1
`Brief summary ........................................................................................................................ 9
`2.6.2.2
`Primary pharmacodynamics ................................................................................................... 9
`2.6.2.3
`Secondary pharma'codynamics .....................................'.......................................................... 9
`2.6.2.4
`Safety pharmacology .............................................................................................................. 9
`2.6.2.5
`Pharmacodynamic drug interactions ..................................................................................... 10
`
`2.6.3 PHARMACOLOGY TABULATED SUMMARY .................................'...................... 10
`
`2.6.4 PHARMACOKINETICS/TOXICOKINETICS .......................................................... 10
`2 6.4. 1
`Brief summary ...................................................................................................................... 10
`2.6.4.2
`Methods of Analysis ............................................................................................................. 10
`2.6.4.3
`Absorption ............................................................................................................................ 10
`2.6.4.4 Distribution ...................... 11
`2.6.4.5
`Metabolism ........................................................................................................................... 11
`
`2.6.4.6
`2.6.4.7
`2.6.4.8
`2.6.4.9
`
`Excretion ......................._...............................’. ........................................................................ 1 2
`Pharmacokinetic drug interactions ........................................................................................ 13
`Other Pharmacokinetic Studies ...........I.................................................................................. 13
`Discussion and Conclusions ................................................................................................. 13
`
`2.6.4.10
`
`Tables and figures to include comparative TK summary ................................................. 13
`
`2.6.5 PHARMACOKINETICS TABULATED SUMMARY ............................................... 13
`
`2.6.6 TOXICOLOGY............................................................................................................... 13
`2.6.6.1
`Overall toxicology summary ................................................................................................ 13
`2.6.6.2
`Single—dose tox1c1ty 13
`2.6.6.3
`Repeat-dose toxicity ...........V.................................................................................................. 13
`2.6.6.4
`Genetic toxicology ................................................................................................................ 38
`2.6.6.5
`Carcinogenicity ..................................................................................................................... 35
`2.6.6.6
`Reproductive and developmental toxicology ........................................................................ 41
`2.6.6.7 Localtolerance ............................... 57
`2.6.6.8
`Special toxicology studies .................................................................................................... 58
`2.6.6.9
`Discussion and Conclusions ........................................................................... 64
`2.6.6.10
`Tables and Figures ..................................................................................... 64
`
`2.6.7 TOXICOLOGY TABULATED SUMMARY
`lZERROR! BOOKMARK NOT DEFINED.
`
`OVERALL CONCLUSIONS AND RECOMMENDATION 8.... .......... ................................ 63
`
`APPENDIX/ATTACHMEN TS .‘................................................................................................ 64
`
`

`

`

`

`NDA 21-976
`
`Pharmacologist’s Review
`
`EXECUTIVE SUMMARY
`
`1.
`
`Recommendations
`
`A. Recommendation on approvability
`
`The pharmacology/toxicology studies submitted to NDA 21—976 support the labeling for
`this submission and are sufficient for approval.
`
`B. Recommendation for nonclinical studies I
`
`The sponsor has a Phase 4 commitment to complete the ongoing carcinogenicity studies
`in mice and rats.
`'
`
`C. Recommendations on labeling
`
`The label should read:
`
`Carcinogenesis, .Mutagenesis, Impairment Q/‘FertiliU;
`Carcinogenesis and Mutagenesis.’
`Long-term carcinogenicity studies of darunavir in rodents have not been completed. Darunavir,
`however, was tested negative in the in vitro Ames reverse mutation assay and in vitro
`chromosomal aberration assay in human lymphocytes, both tested in the absence and presence of
`metabolic activation system. Darunavir does not induce chromosomal damage in the in vivo
`micronucleus test in mice.
`
`Impairment Q/Fertililys
`There were no effects on fertility and early embryonic development with darunavir in rats and
`darunavir has shown no teratogenic potential in mice (in the presence or absence of ritonavir),
`rats and rabbits.
`
`,
`Pregnancy
`Pregnancy Category B: Reproduction studies conducted with darunavir have shown no
`embryotoxicity or teratogenicity in mice, rats and rabbits. Because of limited bioaVailability of
`darunavir in animals and/or dosing limitations. the plasma exposures (AUC values) were
`approximately 50% in mice and rats and 5% in the rabbit of those obtained in humans at the
`recommended clinical dose boosted with ritonavir.[l 39]
`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 or mating
`performance of offspring was 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.
`There are, however, no adequate and well—controlled studies in pregnant women.
`PREZISTA should be used during pregnancy only if the potential benefitjustifies the potential
`risk.
`
`11.
`
`Summary of nonclinical findings
`
`

`

`NDA 21—976
`
`Pharmacologist’s Review
`
`A. Brief overview of nonclinical findings
`
`Three month study in mice:
`The most relevant findings were in the hematological examinations. In both males and females .
`there were essentially dose dependent decreases in red blood cell parameters and increases in
`bilirubin and reticulocyte measurements. The results are consistent with the studies in rats and
`indicate a tendency of rodents to exhibit the signs of anemia, a toxicity related to sulfonamide ‘
`therapy. There were some toxic effects in the liver of females at the high dose (1000
`mg/kg/day). This was shown as slight necrosis over controls and an increase in ALT.
`
`Six month study in rats:
`Effects on the hematopoietic system were seen with decreases (up to 11%) in RBC count,
`hemoglobin, and hematocrit and an increase in reticulocyte count occurring in animals given the
`high dose (500 mg/kg/day). Similar, but generally less marked changes in reticulocyte count
`occurred in animals given 100 mg/kg/day. There was an increase in bilirubin values which,
`together with the reticulocytes increases, indicated red blood cell tumover. Platelet count
`increased (up to 37%) in animals given 500 mg/kg. Less marked changes in platelet count
`occurred in animals given 100 mg/kg/day.
`
`An increase in APTT occurred in animals given 100 and 500 mg/kg/day (up to 20% and 44%,
`respectively). Bilirubin was up as high as seven—fold and cholesterol was up to 74% higher
`while triglycerides were decreased in animals given 500 mg/kg/day. There was some effect at
`100 mg/kg/day. Bilirubin increased slightly in males given 20 mg/kg/day at week 26 only. No
`other serum chemistry parameters were considered of consequence. At necropsy there was a
`slight increase in male kidney and spleen weight and male and female liver weight in animals
`given 100 and 500 m g/kg/day. The increase was confirmed to be a consequence ofhepatocellular
`hypertrophy, an adaptive rather than a toxic response. Lipofuscin was present in the liver and
`kidney. Minimal hypertrophy and hyperplasia of the bile ducts was noted in most animals
`treated at 500 mg/kg/day.
`
`'Six month stud I in rats with darunavir./ritonavir RTV :
`
`
`
`Groups of male and female rats were administered darunavir/RTV via oral gavage at dose levels
`of 0 (vehicle control; PEG 400 in water), 20/50 (low), 100/50 (mid), 500/75 (high) or 1000/75
`mg/kg/day (highest), or RTV alone (75 mg/kg/day) for 26 consecutive weeks. Thirty-three
`animals were found dead or were sacrificed prematurely during the study. In the main study,
`these animals were 2 (vehicle control), 10 (RTV alone), 3 (low), 4 (mid), 6 (high) and 3
`(highest). Clinical signs: salivation, brown staining of the fur and hunched posture were noted in
`all groups other than the vehicle control. The incidence of salivation and hunched posture
`increased ’with increasing dose level of darunavir. Body weight and body weight gain: lower
`body weight gains were observed for male and females (high or highest). The deficits in total
`body weight gain were 16% and 12% for males and 8% and 9% for females for the high and
`highest dose levels, respectively. Treatment related disturbances of the hematological parameters
`consisted of several affected red blood cell parameters: lower hemoglobin, hematocrit, mean
`corpuscular volume, mean corpuscular hemoglobin and increased red cell distribution width,
`bilirubin levels and reticulocyte counts, all indicative of an increased blood cell turnover.
`. Creatinine (males), bilirubin and cholesterol were increased (up to 18%, 3—fold and 3—fold,
`respectively) and triglycerides increased in females (2.4-fold) and decreased in males (73%) in
`
`2
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`

`NDA 21—976
`
`Pharmacologist’s Review
`
`animals at the high and highest dose levels. Phospholipids were increased in both sexes (high and
`
`
`highest). An increase in ALT (29—fold) and AST (73%) was noted in males (RTV alone) and to
`a lesser extent, in groups treated with darunavir/RTV combination (up to 78%).
`
`
`Six month studv in doos:
`
`Groups of male and female dogs (4/sex/group) were administered darunavir via oral gavage at
`dose levels of 0 (vehicle control; PEG 400 in water), 30 (loW), 60 (mid) or 120 (high) for a
`period of 26 consecutive weeks. Loose or liquid feces and vomiting were reported at an
`increased incidence in all treated animals (low, mid or high) in comparison to the vehicle
`controls. The incidence was greatest in the high dose group of animals. Salivation was present
`during and especially after dosing in the animals. Evidence of a drug related effect was restricted
`to the thymus only (high). Thymus involution was noted in animals from all groups including the
`vehicle control animals but the severity was only marginally higher in dogs at the high dose in
`comparison with the vehicle controls.
`
`.
`Twelve month study in dogs:
`Groups of male and female dogs (4/sex/group) were administered darunavir via oral gavage at
`dose levels of 0 (vehicle control; PEG 400 in water), 30 (low), 60 (mid) or 120 (high) for a
`period of 12 months. Vomiting was increased in treated groups, particularly in animals at the ,
`two high doses. There was no effect on body weight, food consumption, ophthalmoscopy or
`EKG measurements. There was an increase in flat the high dose (2 male and 2 females) and
`the intermediate dose (2 females). Hematological and urinalysis parameters Were unchanged.
`Liver weight was slightly higher in animals given the high and intermediate doses.
`Histopathological examination discovered increased hepatocellular pigment at all doses and
`vacuolation in both sexes at the two higher doses. Spleen weight of females at the high dose was
`decreased (36%) relative to controls in the absence of any histopathological change.
`
`Genetic toxicology studies:
`
`Darunavir was not inutagenic in an Ames Test, an in vitro mammalian chromosome aberration
`assay and an in vivo mammalianmicronucleus test. Thus, it was not mntagenic in the full
`battery of lCH genetic toxicity tests.
`
`Carcinogenicitv studies:
`
`Darunavir is presently being assayed in carcinogenicity tests in mice and rats. The studies will
`be completed as a Phase 4 commitment. The protocols for the studies were presented to the
`Executive Carcinogenicity Assessment Committee and received concurrence. The minutes of
`the Committee meeting are contained in the Appendix.
`
`Reproductive toxicology studies:
`
`Segment I
`
`I
`
`Darunavir, at doses up to 1000 mg/kg/day dosed to pregnant rats from gestation day (GD) 7 to 9
`and from GD 13 to 19, did not induce any adverse events on any maternal and fetal parameters
`measured.
`'
`
`

`

`NDA 21-976
`
`‘
`
`Pharmacologist’s Review
`
`Segment ll Rats
`
`Pregnant Sprague Dawley rats were dosed with darunavir at 0 (PEG 400), 40, 200 and 1000
`mg/kg/day between gestation days seven and 19. There was no evidence that TMC l 14 was
`teratogenic in the dosed rats. Based on the fact that body weights and food consumption were
`reduced in the high dose dams, the maternal NOAEL was considered to be 200 mg/kg/day. There
`were no effects of darunavir treatment on embryo—fetal development at any of the doses
`administered. The embryo—fetal NOAEL was considered to be 1000 mg/kg/day.
`
`Segment ll Rabbits
`
`. Pregnant New Zealand white rabbits were dosed with darunavir at 0 (vehicle), 40, 200 and 1000
`mg/kg/day between gestation days eight and 20. There were two deaths, 1 at 40 and l at 1000
`mg/kg/day at which the cause was not determined. Two animals at the 1000 mg/kg/day dose
`aborted on gestation day 20 and were sacrificed but no relevant clinical signs were discerned.
`There were no differences in mean body weight among groups. Some high dose animals showed
`body weight gain decreases when compared to controls. There was a similar effect on food
`consumption during the treatment period with individual high dose animals showing a decrease
`compared to controls.
`
`There was no evidence that darunavir was teratogenic in rabbits.
`There was no effect on gross pathology, gravid uterine weight, pregnancy rate, number of
`corpora lutea, number of pre-implantation loss, post-implantation loss or live implantations, fetal
`body weight, sex ratio or fetal abnormalities. The maternal and fetal NOAEL was considered to
`be 1000 mgfkg/day.
`
`Segment Ill Rats
`
`Maternal Performance:
`
`Maternal treatment with darunavir at 1000 mg/kg/day throughout the gestation and lactation
`periods was associated with clinical signs and reduced bodyweight gain and food consumption.
`At 200 mg/kg/day there was a single interval of lower bodyweight gain and reduced mean food
`intake. The No Observed Adverse Effect Level (NOAEL) for maternal treatment was therefore
`considered to be 40 mg/kg/day.
`
`When darunavir was administered together with Ritonavir at 1000+75/50 mg/kg/day similar
`observations were recorded but the effect was greater than with darunavir alOne.
`
`Maternal treatment with Ritonavir at a dose level of 75/50 mg/kg/day was assOciated with
`maternal clinical signs and lower mean food consumption and bodyweight gain in comparison
`with the Controls, but values were greater than those in the combination groups.
`
`' Pup growth and Pup/Fl development:
`Maternal administration of darunavir alone had no effect upon pup survival during lactation at
`dose levels up to and including 1000 mg/kg/day. An overall lower mean pup bodyweight
`throughout lactation and F1 maturation was associated with treatment at 1000 mg/kg/day. There
`was a slight delay in the acquisition of the developmental milestones pinna detachment and eyes
`open at 200 and 1000 mg/kg/day related to the lower bodyweight in these groups. There was no
`
`4
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`

`NDA 21—976
`
`Pharmacologist’s Review
`
`effect of maternal treatment on Fl developmental tests or mating and fertility at any dose level.
`The No Observed Effect
`
`Level (NOEL) for pup development after maternal treatment with the test article was therefore
`considered to be 40 mg/kg/day.
`
`When darunavir was administered together with Ritonavir at 1000+75/50 mg/kg/day similar
`observations were recorded for bodyweight and developmental milestones but the effect was
`more pronounced than with darunavir alone. In addition, pup survival during lactation was
`reduced in comparison with the Controls. The reduced bodyweight gain during lactation was
`observed only in the group where dosing was continued until PND 14.
`In the group where
`dosing stopped at the .end of gestation, bodyweight performance was comparable with the
`Controls. This confirms that this finding was directly related to administration to the mother
`during lactation and not resulting from in utero exposure.
`Lower mean bodyweight was also evident for Fl post-weaning but there was considered to be no
`effect on F1 develOpmental tests or the fertility and mating performance of the F1 animals.
`
`Maternal administration of Ritonavir at 75/50 mg/kg/day was associated with decreased pup
`survival during the second half of lactation and poor bodyweight performance of surviving pups
`and a delay in the acquisition of developmental milestones. Lower mean bodyweight was evident
`for F1 selected animals post—weaning but there was no effect on F1 development or the fertility
`and mating performance of the F 1 animals.
`
`Local tolerance:
`
`Local lymph node assay: In a T-lymphocyte proliferation assay, darunavir was studied to
`determine its potential to cause skin sensitization. Under the conditions of the study, darunavir
`was found to be negative to have the potential to cause skin sensitization.
`
`Four week immunotoxicology study in rats:
`
`Darunavir was not found to cause any immunological toxic response at doses ranging from 20 to
`500 mg/kg/day. Similarly, for RTV alone or in combination (darunavir/RTV 100/50 mg/kg/day),
`no immunotoxicological response was observed.
`'
`
`B. Nonclinical safety issues relevant to clinical use
`
`Darunavir has a classical sulfonamide structure and, as such, should be expected to elicit certain
`class-specific toxicities. In the clinic, the most common toxicities are disturbances to the urinary
`tract (crystalluria), hemolytic anemia and hypersensitivity reactions (usually manifested as rash).
`In a low percentage of patients, liver necrosis has been known to occur.
`Very few kidney toxicities were seen in nonclinical studies. In rats, there were some increases in
`kidney weight with some accumulation of brown pigment (lipofuscin). However, no related
`histology was seen. In rodents, darunavir had profound effects on the hematopoietic system with
`decreases in RBC counts as well as decreases in hemoglobin and hematocrit measurements with
`an increase in reticulocytes. These results with an increase in bilirubin measurements indicated
`increased red cell turnover, indicative of hemolytic anemia.
`In the mouse, darunavir showed
`hepatocellular hypertrophy and AST increases in the three month study. In the 12 month dog
`
`5
`
`

`

`NDA 21—976
`
`Pharmacologist’s Review
`
`study, darunavir elicited hepatocellular hypertrophy with an increase of pigments. On long—term
`dosing darunavir showed some hepatocellular vacuolation. It also induced an increase in
`alkaline phosphatase and a decrease in spleen weight.
`
`Comparison of the toxicity profile of agenerase and darunavir in rodents and dogs
`
`The structure of agenerase and darunavir are extremely similar (see structures below).
`
`Agen erase:
`
`NH2
`
`> CH3SO3H
`
`Darunavir:
`
`0
`0'" On
`|\__.-
`
`..
`
`0
`“o/ILNH
`
`-
`
`NH2
`
`<1 _
`3*
`N/ \‘0
`0H Y
`
`o
`
`.Both drugs are sulfonamides and differ in basic structure by only two carbons and one oxygen
`and one would expect their toxicity profiles to be similar.
`
`Comparing the toxicity of agenerase and darunavir in the 12 month dog studies one will find that
`agenerase in the dog showed a lower hematocrit but also a decrease in reticulocytes. There was a
`decrease in the APPT and albumin levels and an increase in alkaline phosphatase. Agenerase
`administration showed hepatocellular hypertrophy with pigments in the liver. Darunavir elicited
`hepatocellular hypertrophy with an increase of pigments. On long—term dosing darunavir
`showed some hepatocellular vacuolation. It also induced an increase in alkaline phosphatase and
`a decrease in spleen weight. Thus, the toxicities were similar in the dog one year studies.
`
`In rodents, both compounds induced cholesterol increases and triglyceride decreases. However,
`in rats, in six month studies, both compounds induced hepatocellular hypertrophy with increased
`
`6 .
`
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`

`NDA 21-976
`
`Phannacologist’s Review
`
`liver pigments but agenerase showed increased ALT and AST values with hepatocellular
`' necrosis after long—term dosing.
`In the mouse, darunavir showed hepatocellular hypertrophy
`and AST increases in the three month study.
`In both the rat and mouse study, darunavir induced
`a decreasein red blood cells and red blood cell parameters (decreased hemoglobin and
`hematocrit) with an increase in reticulocytes and a profound increase in bilirubin. These effects,
`which signal'red blood cell turnover, were not seen with agenerase.
`
`

`

`NDA 21—976
`
`Pharmacologist’s Review
`
`2. 6 PHARMA COLOGY/TOXICOLOGY RE VIE W
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY
`
`NDA number: 21-976
`Review number:
`1
`
`*
`
`Sequence number/date/type of submission: 000/ 12/23/05/New Chemical Entity
`Information to sponsor: Yes ( ) No (X)
`Sponsor and/or agent: Tibotec-Virco
`Manufacturer for drug substance: Tibotec—Virco
`
`Reviewer name: James G. Farrelly and Pritam S. Verma
`Division name: Division of Antiviral Products
`HFD #: HFD-530
`
`Review completion date:
`
`Drug:
`
`Trade name: PREZISTA
`Generic name: Darunavir
`Code name: TMC 114
`
`Chemical name: {3—[-amino-benzensulfonyl)-isobutyl—amino]-] —benzyl-2—hydroxy—propyl} -
`carbamic acidhexahydro-furo[2,3—b]furan—3 -y1 ester ethanolate
`CAS registry number: 313682-08-5
`Molecular formula/molecular weight:
`+ ethanol) 547.656 (active moiety)
`
`.
`C 27 H 37 N 3 O 7 SC 2H 5 OH; 593.724 (active moiety
`
`Structure:
`
`NH2
`
`K. W0
`
`Ii
`H
`
`N/ \\
`
`CJHSOH
`
`Relevant INDs/NDAs/DMFs: IND 62,477
`
`Drug class: Anti-HIV protease inhibitor
`
`Intended clinical population: Treatment of HIV infection
`
`Clinical formulation: Tablets containing200 mg or 400 mg darunavir base formulated as
`darunavir ethanolate, — microcrystalline cellulose, —— and
`magnesium stearate
`' Ritonavir: Ritonavir (Norvir) soft gelatin capsule (100 mg RTV/capsule, Abbott)
`
`

`

`NDA 21—976
`
`Pharmacologist’s Review
`
`Route of administration: Oral
`
`Disclaimer: Some graphical information was constructed by the sponsor unless cited otherwise.
`
`2.6.2 PHARMACOLOGY
`
`2.6.2.1 Brief summary
`
`Darunavir was investigated in a series of in vitro and in vivo safety pharmacology studies. There
`were no adverse effects of drug on in vitro cardiovascular electrophysiological parameters, and
`none observed on cardio—hemodynamic and ECG measurements in dogs given single oral doses
`up to 120 mg/kg. There were no relevant effects in rats on neurobehavior and motor activity, or
`on gastrointestinal and pulmonary safety at single oral doses up to 2000 mg/kg.
`
`2.6.2.2 Primary pharmacodynamics
`
`For primary phamiacodynamic effects, mechanism of action and drug activity, see the
`Microbiology review.
`
`2.6.2.3 Secondary pharmacodynamics
`
`Not applicable
`
`2.6.2.4 Safety pharmacology
`
`Neurological effects:
`There were no adverse effects on neurobehavior and motor activity of rats assessed before
`treatment and over 24 hours after single oral administration up to 2000 mg/kg darunavir when
`compared with vehicle (PEG400) and a positive control substance (chlorpromazine
`hydrochloride).
`'
`
`Cardiovascular effects:
`
`In vitro, darunavir at a concentration of 10 uM, showed no significant effect on membrane
`potassium (K+) current in an hERG assay. At concentrations up to 10 uM, there were no effects,
`in vitro, on the electrophysiological cardiac action potential parameters in sheep isolated cardiac
`Purkinje fibers.
`
`ln vivo, single oral doses of 0 (PEG 400), 30, 60 or 120 mg/kg darunavir administered to
`conscious, telemetered dogs had no effect on cardio—liemodynamic and electrocardiogram (ECG)
`parameters.
`In addition, in 12—month repeat dose dog studies at doses up to 120 mg/kgfday, no
`treatment—related effects on heart rate or ECG morphology were seen. On day one of the repeat-
`dose study, at 120 mg/kg, mean TK values detemiined were Cmax values for male and female
`dogs ofl6.6 and 15.0 ug/ml and AUCs of 69.4 and 53.4 ugh/ml.
`
`

`

`NDA 21—976
`
`Pharmacologist’s Review
`
`Pulmonafl effects:
`Ora] administration of darunavir had no acute effects on respiration in rats at doses up to 2000
`mgfkg when compared with vehicle (40% aqueous PEG 400) and a methacholine, a positive
`control substance.
`
`Gastrointestinal effects:
`
`There was no effect on gastrointestinal transit time of a charcoal solution after oral
`administration of up to 2000 mg/kg darunavir when compared with vehicle (40% aqueous
`PEG400) and atropine, a positive control substance in rats.
`
`Abuse liability:
`None noted.
`
`2.6.2.5 Pharmacodynamic drug interactions
`Not applicable
`
`2.6.3 PHARMACOLOGY TABULATED SUMMARY
`
`See above
`
`2.6.4 PHARMACOKINETICS/TOXICOKINETICS
`
`Results are shown in relevant studies
`
`2.6.4.1 Brief summary
`See above
`
`2.6.4.2 Methods of Analysis
`[See under individual study reviews]
`
`2.6.4.3 Absorption
`
`Since (Taco—2 human‘colon tumor cells revealed a reasonably high transepithelial intestinal
`permeability, the proposed mechanism for absorption of darunavir was passive transcellular
`diffusion.
`
`Based on observed tmax values. (0.5 to 6 hours), darunavir absorption was rapid following oral
`administration in all tested species. The absolute oral bioavailability was 37 to 58% in rats.
`Bioavailability was higher in dogs ranging between 60 to 122%. The plasma clearance and the
`volume of distribution were moderate to high in rats and dogs and elimination wasrapid. in all
`species. The kinetics of darunavir was less than dose—proportional in mice, rats and dogs after
`single oral administration, especially at the high dose levels. Repeated oral dosing often resulted
`in a decrease in systemic exposure. The induction of metabolic enzymes could have contributed
`to the phenomenon. Darunavir was an inducer of CYP3A isoenzyme in rodents while UDP-GT
`activity was also induced in rats. However, in dogs, no decrease in exposure and enzymatic
`induction was observed upon repeated administration.
`Intravenous administration was examined in an attempt to increase the exposure ofdarunavir in
`animal studies. This route was not successful due to the difficulty in findin g a fomiulation into
`which a sufficiently high concentration of drug could be dissolved. Administration by dietary
`admixture resulted in systemic exposure levels comparable to those attained after gavage.
`
`10
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`

`NDA 21-976
`
`Pharmacologist’s Review
`
`However, greater exposures could not be attained, even at very high levels of drug in the feed.
`The two above methods were abandoned by thelsponsor.
`
`The recommended clinical dose of da‘runavir/RTV for treatment of experienced HIV- infected
`patients is 600/]00 mg b.i.d. At this dose level, Cmax was approximately 10 pg/ml while the
`estimated AUCo-34h was 123 ugh/ml.
`
`2.6.4.4 Distribution
`
`The tissue distribution of 14C-darunavir in rats was extensive and rapid with the highest
`concentrations of radioactivity in the liver and adrenal gland. Except in melanin-rich tissues, no
`unusual retention or accumulation of radioactivity occurred. Even then, a gradual decrease of
`radioactivity levels occurred, showing the reversibility of binding.
`In pregnant rats, I4C—darunavir was distributed to the placenta and fetus. Total radioactivity
`exposure in the fetus was about l3 to 27 % of that of maternal blood, while in placenta it was the
`' same as in blood.
`
`2.6.4.5 Metabolism:
`
`Plasma protein binding was moderate to high both in humans (free, fraction, 5%) and animals,
`ranging from 5% in the rat to 38% in the rabbit.
`In most species, binding was concentration
`dependent.
`The metabolism ofdarunavir was extensive and qualitatively similar in all species, including
`humans. Metabolism studies were carried out mainly in rats. dogs andhumans and, in general,
`discovered three types of expected Phase 1 metabolites. aromatic hydroxylation at the aniline
`moiety. earbamate hydrolysis and aliphatic hydroxylation at the isobutyl moiety. The major
`Phase I metabolic pathway in dogs and humans was earbamate hydrolysis.
`In rats, hydroxylation
`was the most prevalent. Glueuronidation was a minor pathway in all species tested. N0 unique
`human metabolites were found. Metabolic pathways proposed on the basis of in vitro studies
`were carried out using tissues from rats, dogs, mice and rabbits as well as humans. Since the
`metabolic profiles in the rat, dog and human, in vitro was very similar to those found in vivo, it
`was assumedthat the in vitro profile in mice and rabbits would also mimic that which would be
`found in vivo (which may not necessarily be true).
`
`The known in vivo pathways of metabolism for the dog, rat and human are shown in the
`following diagram:
`'
`
`I].
`
`

`

`NDA 21-976
`
`Phannacologist’s Review
`
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`

`NDA 21—976
`
`Pharmacologist’s Review
`
`2.6.4.6 Excretion:
`
`l4C— darunavir excretion was evaluated in three separate single dose gavage studies in male and
`female Sprague—Dawley rats at 40 mg/kg, in a biliary excretion study in male Sprague Dawley
`rats at the same dose level and in male dogs at 30 mg/kg. In the first study, darunavir was
`investigated alone and also in combination with RTV (25 mg/kg/day).
`The major route of excretion of 14C— darunavir was via feces in both rats and dogs. In rats
`monitored over a 96—hour period, excretion in both sexes averaged 94%. In the first 24—hours,
`excretion of radioactivity in the feces was rapid and accounted for mere 80 of the label. Co—
`administration with RTV in rats had no substantial effect on the excretion and the elimination
`rate of 14C- darunavir.
`In the dog, excretion was monitored over a l68-hour period, and 86% of
`the administered radioactivity was recovered in the. In the first 24 hour period, fecal excretion
`was rapid and accounted for 70%. Urinary excretion was limited representing 4.2% and 3.9% of
`the administered dose in rats and dogs.
`
`2.6.4.6 Pharmacokinetic drug interactions
`See the review by the member of the Biopharrnaceutics team.
`
`2.6.4.8 Other Pharmacokinetic Studies
`
`2.6.4.9 Not applicable (see the individual toxicology studies)
`
`2.6.4.10 Tables and figures