CENTER FOR DRUG EVALUATION AND '
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -976
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEW! S 2
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW
`
`NDA: 21-976
`
`Brand Name
`
`Generic Name
`
`Reviewer
`
`Submission Date: December 22, 2005
`
`PREZISTA
`
`DARUNAVIR
`
`Vikram Arya, Ph.D.
`
`In Vitro Metabolism Reviewer. Yuanchao (Derek) Zhang, Ph.D.
`
`Pharmacometrics Reviewer
`Team Leader 1
`
`Christine Gamett, PharmD.
`Kellie S. Reynolds, PharmD.
`
`‘ Pharmacometrics Team Leader
`
`Jogarao Gobburu, ‘Ph.D.
`
`OCP Division
`
`OND Division
`
`Sponsor
`
`'
`
`Division of Clinical Pharmacology 4
`
`DAVP
`
`Tibotec
`
`Relevant IND(s)
`
`Submission Type; Code
`
`IND 62, 477
`
`505 (b) (1), IP
`
`Formulation; Strength(s)
`
`Tablet ; 300 mg
`
`Dosing regimen
`
`Indication
`
`Table of Contents
`
`600 mg TMC114, co—administered with 100 mg
`ritonavir, b.i.d.
`
`Treatment of HIV-1 infection in protease inhibitor—
`experienced adults
`
`Table of Contents .......................................................................................................................................... 1
`
`1.
`
`Executive Summary............................................................................................................................. 2
`Recommendation .......................................................................................................................... 2
`Phase IV Commitments ................................................................................................................ 2
`
`1.]
`1.2
`
`2
`
`3.
`4.
`
`Summary of Important Clinical Pharmacology and Biopharmaceutics Findings .................. 3
`1.3
`Question based review (QBR).......................................................................................I..................... 12
`2.1
`General Attributes of The drug ................................................................................................. 12
`2.2
`General Clinical Pharmacology 13
`2.3
`Intrinsic Factors ...............................................i ........................................................................... 22
`2.4
`Extrinsic Factors: ....................................................................................................................... 24
`Labeling Recommendations.....................'...................................................................................... 41
`Appendices ...................................................................................................................................... 56
`Individual Study Review ................................................................................' ............................ 5 6
`Consult Reviews (including pharmacometric reviews) ......................................................... 326
`DCP 4 Division Directors Concurrence on PMCs ................................................................. 374
`
`4.]
`4.2
`4.3
`
`4.4
`
`OCPB Filing/Review Form ...................................................................................................... 375
`
`

`

`1.
`
`Executive Summary
`
`Darunavir (TMCl 14) is an inhibitor of the human immunodeficiency virus (HIV)
`protease. Darunavir, in combination with low dOse ritonavir, is proposed for the
`treatment of HIV—1 infectionin adults. The clinically recommended dose1s 600 mg
`darunavrr/ 100 mg ritonavir b1. d.
`
`The accelerated approval decision for darunavir is based on the 24—week data generated
`in pivotal Phase 11B randomized open label, controlled, efficacy and safety trials
`(TMC114—C202 and TMC114-C213). In addition, to expand the safety database at the
`clinically recommended dose, safety data were collected from two additional non—
`randomized clinical trials (TMCl 14-C208 and TMCl l4—C215). The data from the
`ongoing Phase III trials were not used to support the current submission.
`
`The sponsor conducted 35 clinical trials to characterize the biopharrnaceutics (12 trials),
`pharmacokinetics (4 trials), potential of darunavir to prolong the QT interval (1 trial), and
`drug—drug interaction potential of darunavir (l 8 trials). In addition, the sponsor
`developed a population pharmacokinetic model using data from healthy and HIV—1
`infected subjects. This model was used to obtain the pharmacokinetic parameters based
`on sparse sampling from subjects enrolled in the two phase Ilb trials.
`
`1.1
`
`Recommendation
`
`The Clinical Pharmacology and Biophannaceutics Information provided by the Sponsor
`is acceptable.
`
`1.2
`
`Phase IV Commitments
`
`The following postmarketing commitments (PMCs) will provide further information
`regarding the safe and effective use of darunavir/11v in the target population. PMC # l
`and PMC # 3 were originally included by the sponsor in the list of ongoing/planned
`. studies.
`
`These PMCs address the pharmacokinetics and safety of darunavir/riitonavir in special
`population (PMC # 1), assess the inhibitory/induction potential of darunavir/rtv on
`various CYP enzymes (PMC # 2), and provide quantitative drug interaction information
`(PMC # 3, 4, and 5).
`
`1. Evaluate the pharmacokinetics of Darunavir/rtv in HIV-negative subjects with
`Child-Pugh A and Child-Pugh B liver disease in order to determine dosing
`recommendations.
`
`2. Please conduct a cocktail study to determine the effects of steady state
`Darunavir/rtv 600/100 mg b.i.d. on the metabolism of CYP450 probe substrates
`for the following enzymes: CYP2C9, CYP2C19, and CYP2D6.
`
`

`

`Conduct an in vivo drug—drug interaction study between Darunavir/11V b.i.d. and
`rifabutin.
`
`Conduct an in vivo drug-drug interaction study between Darunavir/rtv b.i.d. and
`buprenorphine/naloxone.
`
`Conduct an in vivo drug—drug interaction study between Darunavir/11v b.1.d. and
`carbamazepine.
`
`In addition to the PMC's listed above, the sponsor has planned to conduct a drug-drug
`interaction study between darunavir/rtv bid. and methadone (TMC114—C127).
`
`1.3
`
`Summary of Important Clinical Pharmacology and Biopharmaceutics Findings
`
`Darunavir is an inhibitor of the human immunodeficiency virus (HIV) protease. It
`selectively inhibits the cleavage of HIV encoded Gag—Pal polyproteins in virus infected
`cells, thereby preventing the formation of mature infectious virus particles. Darunavir
`coadministered with low dose ritonavir, is proposed for the treatment of HIV— 1 infection
`in adults. The clinically recommended dose13 600/100 mg b1d.
`
`Exposure Response
`
`Exposure—response analyses were conducted on pooled data from two dose-
`ranging controlled trials (studies C202 and C213) in antiretroviral treatment—
`experienced HIV—infected adult patients (total number of subjects, 637). In these
`studies, patients were randomized to a control group (investigatoréselected
`protease inhibitor based regimen) or to 400/100 mg QD, 800/100 mg QD,
`400/ 100 mg BID or 600/ 100 mg BID dosing regimens of darunavir/ritonavir in
`addition to an optimized background regimen. At 24 weeks, the virologic
`response rate was evaluated (primary efficacy evaluation).
`
`The exposure—response analysis of combined phase 2b trials (C202 and C213)
`demonstrated that the probability of having a response to darunavir treatment
`(measured either by 1 log reduction in viral load or HIV-1 RNA <50 copies/ml)
`by week 24 is related to the patient’s darunavir inhibitory quotient (IQ; ratio
`between the trough concentration and ICso). The primary driver for response rate
`is the fold change (FC; measure of the fold-increase in the 1C50 value relative to a
`standard IC50 value for a wild—type HIV-l virus with no mutations) at baseline
`and response was less dependent on darunavir exposure.
`
`Individualized doses above 600/ 100 mg b.i.d. to compensate for an increased IC50
`value is not expected to improve the response rate in HIV-1 patients because of
`less than dose proportional increase in plasma concentrations with increasing
`dose. However, it may increase the likelihood of response in some individuals.
`
`

`

`0 Analysis of safety data from all four dosing regimens showed no apparent
`relationship between darunavir exposure (measured by AUC24h) and maximum
`change in cholesterol, lipids and LFT markers as well as in the incidence of
`adverse events.
`
`0 Based on the population pharmacokinetic analysis of darunavir, dose adjustments
`are not required for race, gender, renal impairment, hepatitis B or C co—infection,
`and age greater than 65 years.
`
`Table 1 shows the summary of exposure parameters (based on intensive sampling
`in the PK sub—study) in studies TMC114-C202 and TMC14—C213
`(pivotal Phase llb studies in HIV—1 infected subjects).
`
`Table 1: Summary of Exposure Parameters (based on intensive sampling in
`the PK sub-study) in studies TMCl 14-C202 and TMCl4—C213
`(pivotal Phase llb studies in HIV-1 infected subjects).
`
`'
`
` H
`
`N
`4.!)(3b430)
`335?
`~. 3043
`
`:
`
`,
`
`3.0(10—41’12
`125:9
`-:
`89!)
`
`132‘)
`[083 :::
`41%:
`r:
`‘> :7:
`;;
`
`5:};ch ,1
`263
`
`~ ml.
`ng- ml.
`213.1111.
`
`.ngir mi.
`.ngh mi.
`
`In addition, Bayesian estimates of darunavir pharmacokinetic parameters from sparse
`sampling in trials TMC114—C202 and TMC114-C213 suggested a less than dose
`proportional increase within the q.d. (400/100 mg [n = 118] and 800/100 mg [n =
`118]) and the b.i.d. regimens (400/100 mg [n = 113] and 600/100 [n = 119]). Based
`on the analysis, a 50 % increase in dose (from 400 mg b.i.d to 600 mg b.i.d.) resulted
`in a 29 % increase in exposure (as compared to an increase in AUC by 18 %
`estimated based on the results from the intensive sampling). However, there was an
`increase in Cmin by approximately 50 %.
`
`Absorption
`
`- Darunavir has an intermediate to high absorptive permeability in Caco-2
`monolayers indicating sufficient membrane permeability to show adequate
`intestinal absorption. The absolute bioavailability of darunavir, in the absence
`and presence of ritonavir (100 mg b.i.d) is 37 % and 82 % respectively.
`In vitro results suggest that darunavir is a P—gp substrate.
`In vitro studies have shown that darunavir is a CYP3A substrate. This was further
`confirmed in viva from the results of a clinical trial that showed a 14-fold increase
`
`0
`0
`
`in exposure of darunavir in the presence of 100 mg b.i.d. ritonavir, a potent
`
`

`

`CYP3A4 inhibitor. This increase in exposure is, in part, due to an approximate
`5.5 fold reduction in systemic clearance (observed after IV administration).
`The exposure to darunavir (co—administered with low-dose RTV) under fasted
`conditions was approximately 30 % lower than under fed conditions. Therefore,
`the proposed label recommends that darunavir should be taken with, food. Within
`the range of meals studied, darunavir exposure is similar. The total caloric
`content of the various meals evaluated ranged from 240Kca1 (12 gms fat) to
`928Kcal (56 gms fat).
`
`Distribution
`
`The in vitro plasma protein binding of darunavir is approximately 95 % in
`humans.
`
`Darunavir is mainly present in the plasma, with limited distribution to the
`erythrocytes, and is mostly bound to (1-1 acid glycoprotein (AAG) and to a lesser
`extent to albumin.
`
`The volume of distribution of darunavir is 130 L (after intravenous
`administration).
`
`Metabolism
`
`The results from the mass balance study showed that at 48 hours after dosing with
`I4C—TMCl 14 (in the presence of ritonavir), 41.2 % and 7.7 % of the drug was
`recovered unchanged in the feces and urine respectively.
`Darunavir primarily undergoes oxidative metabolism.
`In an in vitro study
`conducted to characterize the various CYP isozymes involved in the oxidative
`metabolism of darunavir, only ketoconazole (predominantly CYP3A4 inhibitor)
`showed significant inhibition of the darunavir metabolism, and only CYP3A4
`showed metabolic activity towards darunavir.
`
`Excretion
`
`The results of the mass balance study showed that after a single dose
`administration of l4C-TMC114 with ritonavir, the majority of the radioactivity
`was excreted in the feces. At 168 hours after dosing, 79.5 % of the radioactivity
`was recovered in the feces and 13.9 % of the radioactivity was recovered in the
`urine. The results from other Phase I studies suggested that less than 7 % of the
`drug is excreted unchanged in the urine.
`In addition, the % of absorbed drug
`eliminated through the renal route is < 10 %. These results suggest that renal
`elimination is a minor route for darunavir elimination.
`
`Intrinsic Factors
`
`The intrinsic factors that have been considered for their potential effect on the
`pharmacokinetics of darunavir include gender, race, body weight, hepatitis B
`and/0r C virus co—infection status, and AAG concentrations in plasma at baseline.
`
`

`

`The subgroup analysis showed that race, gender, body weight, and hepatitis B
`and/or C virus co-infection status had no clinically significant effect on the
`exposure to darunavir.
`,
`
`The exposure to darunavir was positively correlated with baseline AAG
`concentrations in plasma. There was a trend towards higher darunavir AUC24h
`and cab in subjects with higher concentrations of AAG in plasma at baseline.
`
`In View of the limited renal excretion of darunavir (< 7 % across all studies), a
`study to investigate the exposure to darunavir in subjects with renal impairment
`was not conducted. Further, the results from population pharmacokinetic analysis
`and safety evaluations suggested that the slightly higher darunavir exposure in
`HIV-1 infected subjects with moderate renal impairment (CLcrbetween 30—60
`mL/min, n = 20) is not clinically relevant.
`
`A clinical study to assess the impact of hepatic impairment on the
`pharmacokinetics of darunavir is currently being planned.
`
`Extrinsic Factors
`
`Drug—Drug Interactions
`
`Drug-Drug interaction studies were conducted using the solution or tablet under
`fed conditions. When given in the presence of low-dose ritonavir (100 mg b.i.d.),
`darunavir doses of 300 or 400 mg b.i.d. were generally used in the drug-drug
`interaction studies. It is acceptable to extrapolate the drug interaction results to
`the commercial tablet (F016) and dose (600/100 mg b.i.d.).
`
`The following drugs should not be co—administered with darunavir/rtv due to
`serious adverse events (because of the co—administered drug) or due to potential
`loss of efficacy because of reduction in darunavir exposure. These conclusions
`are based on either clinical studies or expected drug—drug interactions based on
`mechanism.
`
`0 Drugs that should not be co—administered with darunavir/ritonavir due to
`serious adverse events: Antihistamines (astemizole, terfenadine), Ergot
`Derivatives (dihydroergotamine, ergonovine, ergotamine,
`methylergonavine), GI motility agent (cisapride), neuroleptic (pimozide),
`and sedative/hypnbtics (midazolam, tn'azolam) and HMG-CoA reductase
`inhibitors (lovastatin, simvastatin)
`’
`0 Drugs that should not be co—administered with darunavir/ritonavir due to
`potential loss of efficacy of darunavir: Anticonvulsants (carbamazepine,
`phenobarbital, phenytoin), antimycobacterial (rifampin), herbal products
`(St. Johns. Wort), HIV protease inhibitors (Kaletra, saquinavir), "
`
`Table 2 shows the established and other potentially significant drug interactions based on
`which alterations in dose or regimen may be recommended. The interaction between
`darunavir and the drug preceding the asterisk (*) sign was evaluated in a clinical study;
`the interactions between darunavir and other drugs (not preceding the asterisk sign) are
`predicted. Further, some of the listed drug interactions are typical for ritonavir boosted
`PIs.
`
`

`

`
`
`Table 2: Established and other potentially significant drug interactions:
`alterations in dose or regimen may be recommended based on drug
`interaction studies or predicted interaction.
`
`
`- Clinical-Cornment
`
`efavirenz decreased darunavir AUC by
`:
`13% and cm by 31%. The clinical
`significance has not been established. The;
`combination of PREZISTA/rtv and
`efavirenz should be used with caution.
`
` _ <
`
`—> darunavir
`
`T nevirapine
`
`PREZISTA/rtv and nevirapine can be co-
`administered without any dose
`adjustments.
`
`ngvjAntiyirai Agents; Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
`It is recommended that didanosine be
`§Didanosine
`
`administered on an empty stomach.
`Therefore, didanosine should be
`administered one hour before or two hours
`
`Effect on
`§Concomitant Drug
`Concentration of
`§Class:
`Darunavir
`§Drug Name
`or
`'
`
`Concomitant Drug
`
`'iHlV-A‘ntiviral Agents: VNon-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
`Co-administration of darunavir/rtv and
`§Efavirenz*
`i darunavir
`i
`T efavirenz
`
`
`
` the combination have not been
`
`
`
`
`
`
`§Nevirapine*
`i
`i.1
`
`SE
`
`after PREZISTA/rtv (which are.
`administered with food).
`
`
`§Tenofovir Disoproxil
`iFumarate*
`
`<—> darunavir
`T tenofovir
`
`FPREZISTA/rtv and tenofovir disoproxil
`fumarate can be co-administered without
`
`any dose adjustments.
`
`
`
`§HIV5Antivirai Agents: HIV-Protease inhibitors (Pls)
`<—> darunavir
`§Atazanavir*
`<—> atazanavir
`'
`
`PREZI§TAlrtv and atazanavir (300 mg
`q.d.) can be co-administered.
`
`;(The reference regimen for
`gatazanavir was
`gatazanavir/ritonavir 300/100
`3mg q.d.) ‘7
`glndinavir"
`:(The reference re imen for
`gindinavir was
`9 -
`i.
`.
`.
`.
`.
`ngdinaVIr/ntonawr 800/100 mg .
`gb.i.d.)
`
`
`_
`I T darunavir
`T mdmavrr
`
`The appropriate dose of indinavir in
`combination with PREZISTA/rtv has not
`been established. The reference regimen
`used in the study was not approved
`
`'
`
`’
`
`‘
`
`
`
`idpinavir/ritonavir"
`
`J, darunavir
`T Lopinavir
`
`.
`
`_.
`
`rDue to decrease in thegexposure (AUC) of'
`darunavir by 53%, appropriate doses of
`
`

`

`
`
`
`
`
`
`' aquinavir*
`
`i darunavir
`
`<—> saquinavir
`
`established. Hence, it is not
`recommended to coadminister
`lopinavir/ritonavir and PREZISTA, with or
`without an additional low—dose of ritonavir,
`
`Due to a decrease in the exposure (AUC) I
`of darunavir by 26%, appropriate doses of'
`the combination have not been
`
`established. Hence, it is not
`recommended to coadminister saquinavir
`and PREZISTA, with or without low—dose
` ritonavir.
`
`
` ther Agents
`
`T antiarrhythmics
`
`
`
`Concentrations of bepridil, lidocaine,
`quinidine and amiodarone may be
`increased when coadministered with
`PREZISTA/rtv. Caution is warranted and
`therapeutic concentration monitoring, if
`available, is recommended for
`antiarrhythmics when coadministered with
`PREZISTA/rtv.
`
`Warfarin concentrations may be affected
`, when coadministered with PREZISTA/rtv.
`It is recommended that the international
`
`normalized ratio (INR) be monitored when
`warfarin is combined with PREZISTA/rtv.
`
`
`
`
`: ntiarrhythmics:
`ibepridil,
`glidocaine (systemic),
`Equinidine,
`,
`jamiodarone
`
`i
`
`Anticoagulantz
`§Warfarin
`2s
`
`l ia
`
`.}ie
`Antidepressant:
`jTrazodone
`
`iAnti-infective:
`=Ecl_arithromycin*
`
`1 l warfarin
`<—> darunavir
`
`
`
`
`. _...
`“"""‘”‘""‘f................................................ m.
`Concomitant use of trazodone and
`. T Trazodone .
`
`' T clarithromycin
`
`PREZISTA/rtv may increase
`concentrations of trazodone. Adverse
`
`events of nausea, dizziness, hypotension,
`and syncope have been observed
`following co-administration of trazodone
`and ritonavir.
`lf trazodone is used with a
`
`'
`
`CYP3A inhibitor such as PREZISTA/rtv,
`the combination should be used with
`caution and a lower dose of trazodone
`
`. should be considered.
`No dose adjustment of darunavir or
`clarithromycin is required for patients with
`normal renal function. For patientswith
`renal impairment, the following dose
`adjustments should be considered:
`
`For subjects with CLcr of 30-60
`mL/min, the dose of clarithromycin
`should be reduced by 50%.
`For subjects with CLcr of <30
`mL/min,
`the dose of clarithromycin should
`
`-
`
`o
`
`be
`
`reduced by 75%.
`
`_ §
`
`

`

`
`
`EAntifungals:
`Eketoconazolei
`Eitraconazole,
`Evoriconazole
`
`T ketoconazole
`T darunavir
`T itraconazole
`
`- (not studied)
`i voriconazole
`. (not studied)
`
`
`
`Ketoconazole and itraconazole are potent
`inhibitors as well as substrates of CYP3A.
`
`W
`
`Concomitant systemic use of
`ketoconazole, itraconazole, and
`: darunavir/ritonavir may increase plasma
`concentration of darunavir.
`
`Plasma concentrations of ketoconazole or
`itraconazole may be increased in the
`presence of darunavir/ritonavir. When
`' coadministration is required, the daily dose
`of ketoconazole or itraconazole should not
`
`exceed 200 mg.
`
`Co-administration of voriconazole with
`darunavir/ritonavir has not been studied.
`3 Administration of voriconazole with
`
`ritonavir (100 mg twice daily) decreased
`the AUC of voriconazole by an average of
`39%. Voriconazole should not be
`
`administered to patients receiving
`‘ darunavir/ritonavir unless an assessment
`
`. Rifabutin is an inducer and substrate of
`
`
`
`of the benefit/risk ratio justifies the use of
`voriconazole.
`
`
`rT—rifabutin
`i darunavir
`
`iAntimycobacterial:
`ERifabutin"
`
`gNote: Due to dropouts, the
`Estudy results were not
`ginterpretable.
`
`
`
`CYP450 enzymes. Concomitant use of
`. rifabutin and darunavir in the presence of
`f ritonavir is expected to increase rifabutin
`. plasma concentrations and decrease
`darunavir plasma concentrations. When
`indicated, it is recommended to administer
`rifabutin at a dosage of 150 mg once every
`other day when coadministered with
`PREZISTA/rtv. .
`
`
`
`
`ECalcium Channel
`EBlockers:
`Efelodipine,
`inifedipine,
`Enicardipine
`
`T calcium channel
`blockers
`
`ErCorticosteroid:
`Edexamethasone
`fluticasone propionate
`
`l
`
`J, darunavir
`T fluticasone
`propionate
`
`Plasma concentrations of calcium channel
`
`
`. blockers (e.g. felodipine, nifedipine,
`- nicardipine) may increase when
`PREZISTA/rtv are coadministered.
`- Caution is warranted and clinical
`
`monitoring of patients is recommended.
`
`' Use with caution". Systemic
`dexamethasone induces CYP3A and can
`
`thereby decrease darunavir plasma
`concentrations. This may result in loss of
`' therapeutic effect to PREZISTA.
`Concomitant use of inhaled fluticasone
`
`
`
`propionate and PREZISTA/rtvmay
`increase plasma concentrations of
`fluticasone propionate. Alternatives should
`be considered, particularly for long term
`use.
`
`
`

`

`
`1.
`
`iHMG-CoA
`gReductase Inhibitors:
`EAtorvastatin*
`EPravastatin*
`
`‘1‘ Atorvastatin
`T Pravastatin
`
`
`
`_ When atorvastatin and PREZlSTA/rtv is
`. co-administered, it is recommended to
`start with the lowest possible dose of
`atorvastatin with careful monitoring. A
`gradual dose increase of atorvastatin may
`be considered based on the clinical
`. response.
`
`When PREZlSTA/rtv was administered
`
`with pravastatin, the mean increase in
`' pravastatin AUC was 81 %. However,
`pravastatin AUC increased by up to 5—fold
`, in some patients. The mechanism of
`interaction is not known.
`
`[SEEZISTA/rtv can be coadifiifiigié—Eé'EWit—ii
`g’i'izliieceptoF’KH’E'QEEEiEi;"""""“ <——>darunaVIr
`, H2—recept0r antagonists and proton pump
`gand Proton Pump Inhibitors:
`inhibitors without any dose adjustments.
`gomeprazolei
`
`iranitidine*
`
`T
`immunosuppressants
`
`Plasma concentrations of cyclosporine,
`tacrolimus or sirolimus may be increased
`when coadministered with PREZlSTA/rtv.
`
`Therapeutic concentration monitoring of
`the immunosuppressive agent is
`recommended for immunosuppressant
`agents when coadministered with
`PREZlSTA/rtv.
`
`
`
`
`
`
`Elmmunosuppressants:
`gcyclosporine,
`gtacrolimus,
`isirolimus
`
`§Narcotic Analgesic:
`Emethadone
`
`i
`
`EOral
`EContraceptives/estrogen:
`éethinyl estradiol
`Enorethindrone
`
`{L methadone
`
`i ethinyl estradiol——
`i norethindrone
`
`§(study completed; results not
`gpart of NBA submission)
`
`
`When methadone is coadministered with
`. PREZlSTA/rtv, patients should be
`monitored for opiate abstinence syndrome,
`as ritonavir is known to induce the
`
`metabolism of methadone, leading to a
`decrease in its plasma concentrations. An
`increase in methadone dosage may be
`considered based on the clinical response.
`
`
`Plasma concentrations of ethinyl estradiol
`' may be decreased due to induction of its
`metabolism by ritonavir. Alternative or
`' additional contraceptive measures should '
`be used when estrogen-based
`contraceptives are coadministered with
`PREZlSTA/rtv.
`
`§PDE-5 inhibitors:
`§si|denafi|*,
`ivardenafil,
`Etadalafil
`
`
`
`
`
`T PDE-5 inhibitors
`
`Concomitant use of PDE-5 inhibitors, with
`PREZlSTA/rtv should be done with
`caution. If concomitant use of
`PREZlSTA/rtv with sildenafil, vardenafil, or
`tadalafil is required, sildenafil at a single
`dose not exceeding 25 mg in 48 hours,
`vardenafil at a single dose not exceeding
`
`10
`
`
`
`
`
`

`

`
`
`i
`g
`
`2.5 mg dose in 72 hours, or tadalafil at a 0
`.
`single dose not exceeding 10 mg dose in
`72 hours, IS recommended.
`
`i
`
`
`
`
`
`2:) darunavir
`gSelective Serotonin
`Reuptake Inhibitors (SSRIs): l sertraline
`isertralinei
`'
`l paroxetine
`iparoxetine*
`
`If sertraline or paroxetine is
`coadministered with PREZISTA/rtv, the
`recommended approach is a careful dose
`titration of the SSRl based on a clinical
`assessment of antidepressant response.
`In addition, patients on a stable dose of
`sertraline or paroxetine who start
`treatment with PREZISTA/rtv should be
`
`monitored for antidepressant response.
`
`PIVOTAL BIOEQUIVALENC STUDY
`
`The results of study TMC114—C116 (pivotal bioequivalence study) showed an
`approximately 35 % higher exposure (AUC) with the commercial tablet formulation
`(F016) compared to each of the clinical tablet formulations (F001 and F002). This higher
`exposure was not clinically relevant because:
`
`0
`
`Population pharmacokinetic analysis showed that the relative bioavailability of
`the commercial formulationwas 18 % higher as compared to the clinical trial
`formulation in HIV—1 patients.
`
`0 There was similarity in the safety profiles (incidence of adverse events) in study
`TMC114-C202 and TMC114—C213 before and after the switch to the commercial
`formulation.
`'
`o No apparent relationship was observed between exposure and safety endpoints for
`study TMCl 14—C215 (Phase llb safety study) in which all 292 subjects were
`. started at the clinically recommended 600/100 mg dose using the commercial
`formulation (F016)).
`
`Concurrence:
`
`Vikram Arya, Ph.D.
`Clinical Pharmacology Reviewer
`Division of Clinical Pharmacology 4
`
`Kellie S. Reynolds, Pharrn. D
`Team Leader
`
`Division of Clinical Pharmacology 4
`
`11
`
`

`

`2 Question based review (QBR)
`
`2.1 General Attributes of The drug
`
`2.1.1. What are the highlights of the chemistry. and physical—chemical properties of the
`drug substance and the formulation of the drug product as they relate to the clinical
`pharmacology and biopharmaceutics review?
`
`Darunavir is an inhibitor of the human immunodeficiency Virus (HIV) protease. The
`chemical name for darunavir is [(l S,2R-3-[[(4-aminophenyl)sulfonyl](2—
`methylpropyl)amino]—2-hydroxy-l-(phenylmethy])propyl]~carbamic acid (3R,3aS,6aR)—
`hexahydrofiiro[2,3-b]furan-3-yl ester. The molecular formula is C27H37N307S and its
`molecular weight is 547.66. Darunavir has the following structural formula:
`
`<f—\>
`
`\\S//
`
`(Kl/Q
`> 1*)
`/
`11
`” 11‘0/Lt
`{ ”(\H
`
`'-
`
`on
`
`("-3H
`
`The composition of the proposed to—be-marketed formulation — is shown below.
`
`Table 1: Composition of the proposed to-be—marketed formulation —
`
`
`
`'
` TlVlCl 14 Ethanolate
`
`Microcrystalline cellulose and colloidal
`
`
`_ silica
`
`
`Cros oovidone
`Ma nesium Stearate
`
`
`Total Core Weight
`
`
`
`OPADRY Orange Film Coat
`
`
`
`I Total Tablet Weight
`
`
`2.1.2. What are the proposed mechanism(s) of action and therapeutic indication(s)?
`
`Darunavir is an inhibitor of the HIV—1 protease. It selectively inhibits the cleavage of
`HIV encoded Gag—Pal polyproteins in virus infected cells, thereby preventing the
`formation of mature infectious virus particles.
`
`2.1.3. What are the proposed dosage(s) and route(s) of administration?
`
`The proposed oral dose of darunavir is 600 mg (two 300 mg tablets), co-administered
`with 100 mg ritonavir, twice daily.
`
`12
`
`

`

`2.2 General Clinical Pharmacology
`
`2.2.1. What are the design features of the clinical pharmacology and clinical studies
`used to support closing or claims?
`
`The sponsor collected pivotal efficacy and safety data from the following two Phase 11b
`trials:
`
`TMC1 14-C202 (POWER 2)
`
`A Phase II, randomized, controlled, partially blinded trial to investigate the dose response
`of TMC1 14/RTV in 3—class-experienced HIV—infected subjects, followed. by an open
`label period on the recommended dose of TMC1 l4/RTV.
`
`TMC114—C213 (POWER 1)
`
`A Phase II, randomized, controlled,'partially blinded trial to investigate the dose response-
`of TMC1 14/RTV in 3—class-experienced HIV-infected subjects, followed by an open
`label period on the recommended dose of TMC1 l4/RTV.
`'
`
`The trials were designed as two part hybrid i.e., the randomized controlled (standard of
`care), partially blinded dose finding part study (24 weeks) in 3-class experienced patients
`followed by the open label, controlled, long term efficacy and safety part (96 weeks).
`Four dosing regimens [total number of subjects in the two trials] (400/ 100 mg q.d. [n =
`129], 800/100 mg q.d.[n = 127], 400/100 mg b.i.d. [n = 126], and 600/100 mg b.i.d. [n =
`131]) in combination with an optimized background regimen were tested. The
`comparator [n = 124] was an active control group in which the subjects received an
`individually optimized protease inhibitor (Pl) based regimen.
`
`Due to the limited safety database at the 600/ 100 mg b.i.d. dose, additional subjects were
`'enrolled- in trials TMC114—C208 and TMC114—C215. These trials were originally
`designed to provide darunavir/RTV to subjects who previously participated in trials with
`darunavir (TMC1 14-C202, TMC114—C213, TMC1 14-C201, TMC114—C207) and
`sponsor—selected trials in HIV-infected subjects.
`
`At the time of the current submission, 375 HIV—1 infected subjects have been treated at
`the recommended dose of darunavir/RTV 600/ 100 mg b.i.d. for 6 months (and 92'
`subjects for 48 weeks) which meets the specified ICH criteria of safety data in 300-600
`subjects receiving the proposed dose for 6 months. Table 2 shows the efficacy results at
`the clinically recommended dose (600/ 100 mg b.i.d.).
`
`13
`
`

`

`
`
`69.5%
`
`baseline through Week 24
`(< 50 copies/mL at
`
`Virolo-ic failures
`
`resonsea
`
`
`
`
`
`6
`
`
`
`
`
`
`69%
`
`
`
`Table 2: Outcomes of Randomized Treatment Through Week 24 of Studies
`TMC114-C213 and TMC114—C202 (Pooled Analysis)
`
`
`
`
`Randomized Studies TMC114—C213 and TMC114—C202
`
`
`PREZISTA/rtv 600 mg
`Comparator Pl + OBR
`N=124
`b.i.d. + OBR
`
`
`N=131
`
`
`
`
`21.0%
`Virologic Responders
`
`confirmed at least 1 logm
`(45.0%)
`(12.1%)
`
`
`
`HIV—1 RNA below
`
`
`
`
`
`
`
`due to adverse events
`
`Discontinuation due to
`
`
`
`other reasons.
`
`3Subjects who did not achieve at least a confirmed 0.5 logm HIV—1 RNA drop from
`
`
`baseline at Week 12
`
`
`bSubjects with an initial response (confirmed 1 logo drop in viral load), but without
`confirmed 1 logo drop in viral load at Week 24
`'
`CSubjects who never reached a confirmed 1 logo drop in viral load before Week 24
`
`
`2.2.2. What is the basis for selecting the response endpoints (i.e., clinical or surrogate
`endpoints) or biomarkers (collectively called pharmacodynamics [PD]) and how
`are they measured in clinical pharmacology and clinical studies?
`
`Viral load and CD4+ cell count are accepted as surrogate markers for efficacy in trials
`with antiretroviral agents. The amended primary endpoint selected for trials TMC] 14-
`C202 and TMC114—C213 was confirmed virologic response at Week 24, defined as a
`decrease in viral load of at least 1.0 loglo copies/mL versus baseline (primary endpoint),
`without (1) introduction of any ARV not originally foreseen in the trial regimen, or (2)
`discontinuation from the trial. In addition, various secondary efficacy endpoints, such as
`fiill suppression (defined as viral load < 50 copies/mL), and effects on CD4+ cell count,
`were also assessed.
`'
`
`2.2.3. Are the active moieties in the plasma (or other biological fluid) appropriately
`identified and measured to assess pharmacokinetic parameters and exposure
`response relationships?
`
`14
`
`

`

`Yes, the sponsor quantified the appropriate moieties in all the clinical pharmacology
`studies. Darunavir and ritonavir were quantified using sensitive and validated
`HPLC/MS/MS methods. In addition, concentrations of other moities were also
`determined in the drug-drug interaction studies. It was not necessary to measure
`concentrations of darunavir metabolites, except for in the mass balance study since in
`vitro studies indicate that the metabolites were at least 90 % less active than darunavir.
`
`See Analytical section (section 2.6.4.) for more details.
`
`2.2.4. Exposure—Response
`
`2.2.4.].
`
`What are the characteristics of exposure—response relationships
`(dose—response, concentration—response) for efficacy? If relevant,
`indicate the time to the onset and offset of the desirable
`
`pharmacological response or clinical endpoint.
`
`The exposure—response analysis of combined phase 2b trials (C202 and C213)
`demonstrated that the probability of having a‘ response to darunavir treatment
`(measured either by 1 log reduction in viral load or HIV-1 RNA <50 copies/ml)
`by week 24 is related to the patient’s darunavir inhibitory quotient. The
`inhibitory quotient (IQ) is the ratio between steady-state trough
`concent