CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICA TION NUMBER:
`
`21-821
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEW! S 2
`
`
`
`Apotex Exhibit 1026
`Page 1 of 130
`
`Apotex Exhibit 1026
`Page 1 of 130
`
`

`

`CLINICAL PHARMACOLOGY & BIOPHARMACEUTICS REVIEW
`
`
`
`NDA# 21-821
`PRODUCT Tigecycline (Tygacil™)
`FORMULATION Sterile Powder for injection
`DOSAGE STRENGTH 50mg vial
`SUBMISSION DATES December 15, 2004; March 14, 2005; April 12, 2005;
` May 5, 2005; May 16, 2005; May 19, 2005; May 27,
` 2005
`SUBMISSION TYPE New Molecular Entity
`SPONSOR Wyeth Pharmaceuticals
`OCPB DIVISION Division of Pharmaceutical Evaluation III
`MEDICAL DIVISION Division of Anti-Infective Drug Products
`REVIEWER Jeffrey J. Tworzyanski, Pharm.D.
`PM REVIEWER Yaning Wang, Ph.D.
`TEAM LEADER Venkat R. Jarugula, Ph.D.
`PM TEAM LEADER Joga Gobburu, Ph.D.
`
`
` 1
`
` EXECUTIVE SUMMARY
`Wyeth Pharmaceuticals submitted a New Drug Application for Tygacil™ (Tigecycline
`for injection) on December 15, 2004. The FDA granted this submission a priority review
`based upon the sponsor’s studies in the treatment of resistant organisms. Tigecycline
`represents a new class of antimicrobials known as glycylcyclines. The glycylcycline class
`of antimicrobial agents is a synthetic derivative of minocycline. The mechanism of action
`of the tetracyclines is by binding to the 30S ribosomal subunit at the A-site which blocks
`entry of amino-acyl transfer RNA molecules into the ribosome which prevents
`incorporation of amino acid residues into elongating peptide chains. The glycylcyclines
`(tigecycline) also inhibit the 30S ribosomal subunit but bind with substantially higher
`affinity than the tetracyclines. The glycylcyclines interact directly with another region of
`the A-site.
`
`
`Wyeth is requesting approval for two indications for tigecycline. The first indication is
`complicated skin and skin structure infections caused by Escherichia coli, Enterococcus
`faecalis (vancomycin-susceptible strains only), Staphylococcus aureus (methicillin-
`susceptible and –resistant strains), Streptococcus agalactiae, Streptococcus anginosus
`grp. (includes S. anginosis, S. intermedius, and S. constellatus), Streptococcus pyogenes
`and Bacteroides fragilis. The second indication for tigecycline that Wyeth is seeking is
`complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter
`cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumonia, Enterococcus
`faecalis (vancomycin-susceptible strains only), Staphylococcus aureus (methicillin-
`susceptible strains only), Streptococcus anginosus grp. (includes S. anginosus, S.
`intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron,
`Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and
`Peptostreptococcus micros.
`
`
`
`1
`
`Apotex Exhibit 1026
`Page 2 of 130
`
`

`

`
`The proposed intravenous dosage regimen for tigecycline is an initial dose of 100mg,
`followed by 50mg every 12 hours. Intravenous infusions of tigecycline should be
`administered over approximately 30 to 60 minutes every 12 hours. The recommended
`duration of treatment with tigecycline for complicated skin and skin structure infections
`or for complicated intra-abdominal infections is 5-14 days depending upon severity and
`site of infection.
`
` A
`
` total of 17 Phase 1 clinical pharmacology studies were conducted to investigate single
`dose and multiple dose pharmacokinetics, metabolic disposition, the effect of special
`populations ( renal and hepatic impairment), drug-drug interactions (digoxin, warfarin),
`and the effect of race, age, and gender on the pharmacokinetics. Eleven phase 2/3 studies
`were submitted of which four Phase 3 and two Phase 2 studies were pertinent to the
`proposed indications. In addition the sponsor performed population PK analysis on the
`sparse sample data collected in Phase 2/3 studies. Thirteen out of 17 submitted Phase 1
`studies were evaluated in this review. Four Phase 1 studies were not reviewed because
`they did not provide relevant or additional information. Sponsor has adequately
`characterized the pharmacokinetics and pharmacodynamics of tigecycline following
`intravenous infusion.
`
`1.1 RECOMMENDATIONS
`The Office of Clinical Pharmacology and Biopharmaceutics/Division of Pharmaceutical
`Evaluation III (OCPB/DPE III) has reviewed NDA 21-821. The submission is acceptable
`from a Clinical Pharmacology point of view. The labeling comments need to be
`communicated to the sponsor.
`
`1.2 PHASE 4 COMMITMENTS
`There are no phase 4 commitments.
`
`1.3 SUMMARY OF CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS FINDINGS
`
`
`Pharmacokinetic characteristics:
`Following intravenous infusion of tigecycline, the drug concentrations in serum declined
`in a polyphasic manner. The initial steep decline in serum concentrations at the end of
`infusion represents the distribution phase during which the drug is distributed out of the
`systemic circulation into various tissues. The terminal elimination phase represents the
`movement of the drug out of tissues into systemic circulation and the subsequent
`elimination from the body. The pharmacokinetics of tigecycline (Cmax and AUC) after
`single dose infusion over 60 minutes are linear over the dose range of 12.5 mg to 300 mg.
`The mean systemic clearance (CL) values were consistent among dose groups and ranged
`from 0.2 L/h/kg to 0.3 L/h/kg. Tigecycline was well distributed into various tissues as
`shown by the mean steady state volume of distribution (Vss), which ranged from 7 to 14
`L/kg. The estimated terminal phase half life varied among dosages (ranges from 18 hrs at
`50 mg dose to 42 hrs at 200 mg dose) because the terminal phase was not adequately
`characterized at lower doses due to assay sensitivity. The steady state plasma
`
`
`
`2
`
`Apotex Exhibit 1026
`Page 3 of 130
`
`

`

`concentrations are achieved by Day 3 with the proposed dosage regimen of 100 mg
`loading dose followed by 50 mg q 12hrs. The mean terminal elimination half-life at
`steady state following the administration of the therapeutic regimen was approximately
`40 hrs.
`
`Distribution:
`In vitro plasma protein binding of tigecycline is concentration dependent and ranges from
`71% at 0.1 µg/ml to 89% at 1 µg/ml to 96% at 15 µ/ml. Following intravenous infusion
`of 100 mg dose, the concentration of tigecycline was 38 times higher in the gallbladder
`than in the serum, two-fold higher in the colon than in the serum and 8.6 times higher in
`the lung compared to serum. The degree of penetration of tigecycline into skin blister
`fluid as measured by the ratio of AUC in blister to AUC in serum was 74%.
`
`Metabolism and Excretion:
`Based on the results of in vitro metabolism studies, tigecycline is not metabolized by the
`cytochrome P450 (CYP 450) enzyme system and it does not inhibit the metabolism of the
`drugs that are metabolized by CYP 450 system. Therefore, tigecycline is not expected to
`cause CYP 450 based metabolic drug interactions.
`
`Following administration of [14C]tigecycline, approximately 33% of the administered
`dose is recovered in urine and 59% of the administered dose is recovered in feces, for a
`total recovery of 92% of the administered dose. Approximately 22% of the total dose is
`excreted as unchanged tigecycline in urine. The biliary excretion of tigecycline and its
`metabolites is the primary route of elimination. The secondary elimination pathways of
`tigecycline and its metabolites are renal excretion, glucuronidation, and amide hydrolysis
`followed by N-acetylation to form N-acetyl-9-aminominocycline; and these secondary
`pathways each account for 15% or less of the total elimination of tigecycline.
`
`Special populations:
`Renal Impairment:
`In study 103-US (Protocol 3074A1) the sponsor evaluated the PK of tigecycline 100mg
`dose in 20 subjects. Approximately one third of the subjects were with normal renal
`function, one third subjects with CrCl < 30 ml/min, and one third subjects with end-stage
`renal disease (ESRD) who were receiving hemodialysis. The renal clearance of
`tigecycline in healthy subjects was similar to creatinine clearance (ClCr), and it
`represented approximately 20% of the total systemic clearance of tigecycline.
`Consequently, the systemic clearance of tigecycline was reduced by approximately 20%
`in subjects with severe renal impairment (ClCr<30 ml/min) or ESRD, and tigecycline area
`under the curve (AUC) increased by approximately 30% in these subjects. Based on the
`results of this study, tigecycline dose does not need to be adjusted in patients with renal
`impairment. Hemodialysis did not remove tigecycline from the systemic circulation of
`the subjects.
`
`Hepatic Impairment:
`In study 105-EU (Protocol 3074A1) the sponsor evaluated the effect of hepatic
`impairment on the pharmacokinetics of tigecycline following the administration of a
`
`
`
`3
`
`Apotex Exhibit 1026
`Page 4 of 130
`
`

`

`single dose of 100mg in patients with mild (Child-Pugh-A: score of 5 or 6, n=10),
`moderate (Child-Pugh-B: score of 7 to 9, n=10), and severe hepatic impairment (Child-
`Pugh-C: score of 10 to 13, n=5) in comparison to 23 healthy subjects matching the
`cirrhotic subjects for age, sex, weight, and smoking habit. The results of the study
`indicate that dosage adjustment is not warranted in patients with mild hepatic impairment
`(Child-Pugh A) because of no change in the clearance of drug compared to healthy
`subjects. In moderate and severe hepatic impairment (Child-Pugh B and Child-Pugh C)
`the clearance was approximately 25% and 50% lower, respectively, than the healthy
`subjects. Since the clearance of the drug in the severe hepatic impairment population was
`decreased by 50% and the AUC was increased by 105% these patients should receive an
`initial dose of 100mg followed by a reduced maintenance dose of 25 mg every 12 hours.
`
`Drug Interactions:
`Digoxin: Concomitant administration of the proposed tigecycline regimen (100 mg
`loading dose followed by 50 mg q 12hrs) did not significantly alter the pharmacokinetics
`of digoxin.
`
`Warfarin: Coadministration of the therapeutic regimen of tigecycline significantly
`decreased the oral clearance of both R-warfarin and S-warfarin, thereby increasing the
`Cmax (38% and 43%, respectively) and AUC (68% and 29%, respectively) of both
`compounds. The pharmacodynamic endpoint, the mean INRmax was reduced by 10%.
`Sponsor recommended in the label that prothrombin time or other suitable coagulation
`parameters should be monitored if tigecycline is administered with warfarin.
`
`Oral contraceptives: Sponsor did not conduct a drug interaction study with oral
`contraceptives. However, tetracyclines are reported to reduce the effectiveness of oral
`contraceptives. Tigecycline is eliminated predominantly through biliary excretion and is
`shown to reduce the intestinal microflora. Therefore, the sponsor stated in the label that
`concurrent use of antibiotics with oral contraceptives may render oral contraceptives less
`effective.
`
`Exposure response:
`Animal data:
`Based on the dose fractionation studies in murine neuropenic thigh model, both AUC and
`the time of plasma concentration above MIC (T>MIC) appeared to be best correlated
`with antimicrobial efficacy of tigecycline.
`
`Human data:
`Efficacy:
`Even though good exposure-response relationships were established in animal model (see
`2.2.4.1), the limited exposure levels studied in patients and high success rate in clinical
`trials made the exposure-response analysis quite challenging in human studies. For both
`cSSSI and cIAI indications the exposure-response analysis showed that AUCss(0-
`24)/MIC was a borderline statistically significant predictor of microbiologic and clinical
`response. However, the relationship between exposure and efficacy is so shallow that
`
`
`
`4
`
`Apotex Exhibit 1026
`Page 5 of 130
`
`

`

`under the proposed dosage regimen (100mg loading dose and 50mg maintenance dose),
`the exposure change did not cause clinically relevant difference in efficacy.
`
`Safety:
`First occurrence of nausea and vomiting was selected as the endpoint for tigecycline
`safety evaluation. No exposure-response relationship was established within the observed
`exposure levels in Phase 2/3 studies for safety. The analysis based on phase 1 studies (84
`subjects from Study 3074A1-100, 46 subjects from Study 3074A1-102, and 6 subjects
`from Study 3074A1-103) showed AUC0-inf and Cmax were significant predictors for
`both first nausea and first vomiting occurrence due to the wide range of doses studied.
`The lack of exposure-response relationship for the first nausea and first vomiting
`occurrence in phase 2/3 studies was due to the narrow range of exposure under the two
`doses, 25mg and 50mg.
`
`
`
`
`
`
` __________________________________________________
` Jeffrey J. Tworzyanski, Pharm.D.
` Office of Clinical Pharmacology and Biopharmaceutics
` Division of Pharmaceutical Evaluation III
`
`
`
`
`RD/FT Initialed by Venkat R. Jarugula, Ph.D.,__________________________________
`Team Leader
`
`cc:
`Division File: NDA 21-821
`HFD-520 (CSO/Milstein)
`HFD-520 (MO/Cooper)
`HFD-520 (Microbiology/Marsik)
`HFD-880 (Division File, Lazor, Selen, Jarugula, Tworzyanski)
`CDR (Clin. Pharm./Biopharm.)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`5
`
`Apotex Exhibit 1026
`Page 6 of 130
`
`

`

`
`
`
`Table of Contents
`
` 1
`
` Executive Summary………………………………………………………………….1
` 1.1 Recommendations……………………………………………………………….2
` 1.3 Summary of Clinical Pharmacology and Biopharmaceutics Findings………….2
`
` 2
`
` Question Based Review
` 2.1 General Attributes of the Drug…………………………………………………..7
` 2.2 General Clinical Pharmacology………………………………………………….9
` 2.3 Intrinsic Factors………………………………………………………………….30
` 2.4 Extrinsic Factors…………………………………………………………………35
` 2.5 General Biopharmaceutics……………………………………………………....39
` 2.6 Analytical Section……………………………………………………………….39
`
` 3
`
` 4
`
` Detailed Labeling Recommendations………………………………………………42
`
` Appendices
` 4.2 Individual Study Reports
` 4.2.1 Study 3074A1-104-US………………………………………………63
` 4.2.2 Study 3074A1-100-EU………………………………………………69
` 4.2.3 Study 3074A1-101-US………………………………………………77
` 4.2.4 Study 3074A1-109-US………………………………………………85
` 4.2.5 Study 3074A1-113-US………………………………………………91
` 4.2.6 Study 3074A1-117-US………………………………………………95
` 4.2.7 Study 3074A1-116-EU……………………………………………..102
` 4.2.8 Study 3074A1-103-US……………………………………………..107
` 4.2.9 Study 3074A1-105-EU……………………………………………..112
` 4.2.10 Study 3074A1-115-US……………………………………………..121
` 4.2.11 Study 3074A1-111-US……………………………………………..128
` 4.2.12 Study 3074A1-102-US……………………………………………..135
` 4.2.13 Study 3074A1-112-US……………………………………………..141
`
` 4.3 Pharmacometric Consult Request Form……………………………………......146
` 4.4 Cover Sheet and OCPB Filing/Review Form…………………………………..148
`
`
`
`
`
`
`
`
`
`
`
`
`6
`
`Apotex Exhibit 1026
`Page 7 of 130
`
`

`

`
`
`
` 2
`
` QUESTION BASED REVIEW
`
`
`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 clinical
`pharmacology and biopharmaceutics review?
`
`
`Tigecycline is a glycylcycline antibacterial for intravenous infusion. The chemical name
`of tigecycline is (4S, 4aS, 5aR, 12aS)-9-[2-(tert-butylamino)acetamido]-4,7-
`bis(dimethylamino)-1, 4, 4a, 5, 5a, 6, 11, 12a-octahydro-3, 10, 12, 12a-tetrahydoxyl-1,
`11-dioxo-2-naphthacenecarboxamide. The empirical formula is C29H39N5O8 and the
`molecular weight is 585.65. The chemical structure of tigecycline is shown below:
`
`
`
`
`
`
`Tigecycline for injection is supplied as an orange lypholized powder or cake. Each
`Tygacil vial contains 50mg lypholized powder for intravenous infusion. The product does
`not contain excipients or preservatives.
`
`
` when titrated with
`Tigecycline is freely soluble
` Tigecyline has five ionizable groups, three basic
` in a wide pH range of
`nitrogens and two acidic hydroxyl groups. The pKa’s are expected to overlap and
`assignment of each pKa to its respective functional group is difficult. The NMR method
`was employed by the sponsor because it can determine the overlapping pKa values as
`well as allow the assignment of each pKa to its respective functional group. Figure 1
`shows the chemical structure with pKa values determined by NMR.
`
`
`
`
`
`
`
`
`7
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`Apotex Exhibit 1026
`Page 8 of 130
`
`

`

`
`
`
`Figure 1. Tigecycline pKa Values
`
`
`
`
`
`Tigecycline’s solubility is independent of pH because no changes in solubility were seen
`in a wide pH range.
`
`2.1.2 What are the proposed mechanism(s) of action and therapeutic indication(s)?
`The bacterial ribosome is the target for the tetracyclines. Binding to the 30S ribosomal
`subunit at the A-site blocks entry of amino-acyl transfer RNA molecules into the
`ribosome, preventing incorporation of amino acid residues into elongating peptide chains.
`Tigecycline has in its chemical structure a 9-glycyl amido residue substitution that allows
`for novel drug-amino acid interactions at binding sites. The sponsor’s in vitro data
`suggest that tigecycline has a ribosomal binding site affinity that is at least 10-fold greater
`than tetracycline-class antibiotics. Ribosomal protection and efflux are the two major
`resistance mechanisms for tetracyclines. Tigecycline is active against strains with either
`mechanism of tetracycline resistance. In general, tigecycline is considered bacteriostatic.
`
`The sponsor is seeking an indication for the treatment of complicated skin and skin
`structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-
`susceptible strains only), Staphylococcus aureus (methicillin-susceptible and –resistant
`strains), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus,
`S. intermedius, and S. constellatus), Streptococcus pyogenes and Bacteroides fragilis.
`The sponsor is also seeking an indication for complicated intra-abdominal infections
`caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella
`oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible strains
`only), Staphylococcus aureus (methicillin-susceptible strains only), Streptococcus
`anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides
`fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus,
`Clostridium perfringens, and Peptostreptococcus micros.
`
`
`
`
`8
`
`Apotex Exhibit 1026
`Page 9 of 130
`
`

`

`2.1.3 What are the proposed dosage(s) and route(s) of administration?
`The proposed dosage regimen for intravenous tigecycline is an initial dose of 100mg,
`followed by a dose of 50mg administered every 12 hours following the initial dose. These
`doses are administered over approximately 30 to 60 minutes. The proposed duration of
`treatment with tigecycline for complicated skin and skin structure infections or for
`complicated intra-abdominal infections is 5-14 days, depending upon severity and site of
`infection.
`
`2.2 General Clinical Pharmacology
`
`2.2.1 What are the design features of the clinical pharmacology and clinical studies
`used to support dosing or claims?
`The sponsor performed 17 Phase I studies to assess the single dose and multiple dose
`effects of safety, tolerability, pharmacokinetics, metabolic disposition, renally impaired
`patients, hepatically impaired patients, and drug interactions (digoxin, warfarin) with
`tigecycline.
`
`
`The sponsor performed two Phase 2 studies (3074A1-200-Us and 3074A1-202-US)
`evaluating the safety and efficacy of tigecycline in subjects with cSSSI and cIAI.
`In study 3074A1-200-US subjects were randomized to receive either an initial 100 mg IV
`tigecycline load dose, followed by 50 mg tigecycline IV q12h (n=54), or 50mg IV
`tigecycline load dose, followed by 25 mg tigecycline IV q12h (n=55) for the treatment of
`cSSSI for seven to 14 days. In study 3074A1-202-US subjects received an initial 100mg
`IV tigecycline load followed by 50 mg IV tigecycline q12h for the treatment of cIAI
`(n=66) for at least five days but not more than 14 days of therapy.
`
`The sponsor performed four Phase 3 studies evaluating the safety and efficacy of
`tigecycline for the treatment of cSSSI and cIAI. Table 1 shows the features of these
`studies.
`
`Table 1. Phase 3 Study Features
`Study
`Indications
`
`Treatment of known
`or suspected
`diagnosis of cSSSI
`Treatment of
`hospitalized subjects
`with cSSSI
`Treatment of cIAI
`
`Study Drug
`(number of subjects)
`Tigecycline 100mg load
`followed by 50mg IV q12h
`x 14days (n=292)
`Tigecycline 100mg load
`followed by 50mg IV q12h
`x 14days (n=281)
`Tigecycline 100mg load
`followed by 50mg IV q12h
`x 14 days (n=413)
`
`3074A1-
`300-US/CA
`
`3074A1-
`305-WW
`
`3074A1-
`301-WW
`
`3074A1-
`306-WW
`
`Comparator Drug
`(number of subjects)
`Vancomycin 1 g IV
`followed by Aztreonam
`2g IV q12h (n=281)
`Vancomycin 1g IV
`followed byAztreonam 2
`g IV q12h (n=269)
`Imipenem/cilistatin IV
`q6h dose adjusted based
`upon weight, CrCl
`(n=412)
`Imipenem/cilistatin
`IV q6h dose adjusted
`upon weight, CrCl
`
`Treatment of cIAI
`
`Tigecycline 100mg load
`followed by 50mg IV q12h
`x 14days (n=404)
`
`
`
`9
`
`Apotex Exhibit 1026
`Page 10 of 130
`
`

`

`(n=413)
`
`
`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?
`
`
`cSSSI:
`The primary efficacy endpoint was the assessment of clinical response at the test of cure
`(TOC) visit. The TOC visit was at least 12 but not more than 92 days after the last dose
`of study drug. Clinical response was measured according to predefined criteria. The
`secondary efficacy endpoints were microbiological response from specimens obtained
`from 2 sets of blood cultures, aerobic and anaerobic cultures from the primary site of
`infection.
`
`cIAI:
`The primary efficacy endpoint was the TOC assessment. The TOC visit was at least 12
`but not more than 44 days after the last dose of study drug. Clinical response was
`measured according to predefined criteria. Microbiologic efficacy was evaluated by two
`sets of blood cultures, aerobic and anaerobic cultures from the primary intra-abdominal
`site of infection at baseline. The outcome of the microbiologic response at the subject
`level and pathogen level was described according to predefined criteria.
`
`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?
` Yes, refer to 2.6, Analytical Section
`
`2.2.4.1 What are the characteristics of the exposure-response relationships (dose-
`response, concentration-response) for efficacy?
`
`
`Animal studies:
`The exposure-response relationship of tigecycline has been evaluated using in vivo
`animal models of infection. A murine thigh model study was performed by
`Six week old, specific-pathogen-free female ICR/Swiss mice (weight 23 to 25 g) from
`Sprague-Dawley were used. The mice were rendered neutropenic (<100 neutrophils/µl)
`by injecting a dose of cyclophosphamide intraperitoneally at four days (150mg/kg) and
`one day (100 mg/kg) before the infection experiment. After a 1:10 dilution of
`pneumococci in fresh broth, 0.1ml (~106 CFU) was injected into the thighs of ether-
`anesthetized mice. Mice were treated for 24 hours with total doses in the range of 0.19 to
`24 mg/kg body weight/day for the experiments with the strains of S. pneumoniae.
`Antibiotics were administered subcutaneously in 0.2ml volumes beginning 2 hours after
`thigh inoculation. Mouse thighs were removed and homogenized and cultured
`quantitatively. The level of detection of this assay was
`/thigh. Single-dose
`pharmacokinetic studies were performed with sera from thigh-infected mice with the
`following doses of tigecycline: 3, 12, and 48 mg/kg. The pharmacokinetics appeared to
`
`.
`
`
`
`10
`
`(b) (4)
`
`(b) (4)
`
`Apotex Exhibit 1026
`Page 11 of 130
`
`

`

`be nonlinear, resulting in a higher elimination t½ at a dose of 48mg/kg. The results of the
`pharmacokinetic-pharmacodynamic parameters for tigecycline are shown in figure 2.
`
`Figure 2. Relationship between pharmacokinetic-pharmacodynamic parameters
`and therapeutic efficacy of tigecycline (free drug) against S. pneumnoniae 1199 in
`the neutropenic mouse thigh muscle infection model
`
`
`
`
`
`(R2 = 0.82, 0.83, and 0.54 for panels a, b, and c, respectively)
`(a) time above the 0.5 x MIC versus effect
`(b) Log AUC versus effect
`(c) Log Cmax versus effect
`
`The pharmacokinetic parameter that correlated best with efficacy was the time above a
`certain factor times the MIC for five of the six organism-drug combinations studies. The
`magnitude of this factor varied from 0.5 to 4. The only exception to this observation was
`the combination of tigecycline and S. pneumoniae 1199, for which both AUC and time
`above MIC were important in predicting outcome (R2 = 0.83 and 0.82, respectively).
`The results of the study indicated that tigecycline exhibited time-dependent antimicrobial
`activity in vivo. However, due to the relatively long t½ and the long post-antibiotic effect
`(PAE), the AUC was also reasonably predictive, with slightly lower R2 values.
`
` murine intraperitoneal model was used for tigecycline to determine PK in CD-1 mice
`after 0.15, 1, 4, 10 and 20mg/kg doses. Tigecycline concentrations in blood were assayed
`by HPLC methods at various times after dosing. The pharmacokinetic analysis indicates
`that AUC is linear over the dose range tested. Table 2 presents the range of AUCs and
`AUC/MIC from the murine intraperitoneal test performed at Wyeth (MIRACL-26501;
`MIRACL-26884; GTR-28013; MIRACL-25770).
`
`
`
`
`
`
`
`
`
`
` A
`
`
`
`11
`
`Apotex Exhibit 1026
`Page 12 of 130
`
`

`

`Table 2. Range of AUCs and AUC/MICs in the mouse Intraperitoneal Infection
`Model
`
`
`
`
`Human studies
`Dose selection:
`Animal studies have shown that both AUC and the T>MIC ratio as important parameters
`for efficacy and tigecycline was efficacious in animals at AUC exposures comparable to
`those observed in humans with a 50 to 100mg total daily dose. Based on this data, doses
`of 25mg and 50mg every 12 hours were studied in Phase 2. A Phase 2 study for cSSSI
`showed that the cure rate was higher in the 50mg q12h group (75%) than the 25mg q12h
`dose group (67%). Phase 1 studies showed tigecycline was tolerable up to 50mg q12 and
`75mg q12 was not well tolerated because of high incidence of nausea and vomiting.
`Therefore, the sponsor selected the current dose regimen of 100mg load followed by
`50mg q12h for Phase 3 studies.
`
`Efficacy:
`Even though good exposure-response relationships were established in animal model (see
`2.2.4.1), the limited exposure levels studied in patients and high success rate in clinical
`trials made the exposure-response analysis quite challenging in human studies. For cIAI
`microbiological efficacy, 1 phase 2 study (3074A1-202: 19 patients, 32 observations) and
`2 phase 3 studies (3074A1-301: 12 patients, 17 observations; 3074A1-306: 40 patients,
`57 observations) were combined for exposure-response analysis at the pathogen level
`(Table 3). Formal statistical analysis, however, could not be applied unless cohorts 1, 2
`and 3 are combined due to the low failure rate in each single cohort. The sponsor found
`that AUCss(0-24)/MIC, as a continuous covariate, was a borderline statistically
`significant predictor of microbiologic response for cohorts 1, 2 and 3 combined. Under
`the proposed dosage regimen (100mg loading dose and 50mg maintenance dose), the
`exposure change did not cause clinically relevant difference on microbiological efficacy
`as indicated by Figure 3.
`
`Table 3: Baseline Pathogen Classification Used in Exposure-Response Analysis for cIAI Efficacy
`Cohort
`Baseline Pathogen(s) Included
`Monomicrobial E. coliinfections
`1
`2
`Other monomicrobial or polymicrobial Gram-negative infections
`(Klebsiellaspp., Enterobacterspp. and/or Citrobacterspp. plus or
`minus E. coli)
`Infections with at least one Gram-negative pathogen plus at least
`one anaerobic pathogen
`
`3
`
`
`
`12
`
`Apotex Exhibit 1026
`Page 13 of 130
`
`

`

`4
`
`5
`
`Infections with at least one Gram-negative pathogen plus at least
`one Gram-positive pathogen
`All other monomicrobial or polymicrobial infections
`
`
`For cIAI clinical efficacy, similar results were obtained. Both baseline APACHE II score
`and AUCss(0-24)/MIC were identified as statistically significant predictors of clinical
`response based on univariate logistic analysis. Under the proposed dosage regimen
`(100mg loading dose and 50mg maintenance dose), the exposure change did not cause
`clinically relevant difference on clinical efficacy as indicated by Figure 4.
`
`Figure 3. Exposure-Response Analysis of cIAI Efficacy - Final Logistic Regression
`Model of Microbiological Response versus AUCSS(0-24)/MIC Ratio with Histogram of
`Observed Data (71 patients with 106 observations.)
`
`=26 n=26
`
`n=27
`
`n=27
`
`0
`
`20
`
`40
`
`60
`80
`AUCss(0-24)/MIC Ratio
`
`100
`
`120
`
`140
`
`
`
`13
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0.0
`
`Probability of Bacteriologic Cure
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Apotex Exhibit 1026
`Page 14 of 130
`
`

`

`Figure 4. Exposure-Response Analysis of cIAI Efficacy - Final Logistic Regression
`Model of Clinical Response versus AUCSS(0-24)/MIC with Histogram of Observed Data
`(71 patients)
`
`n=17
`
`n=18
`
`n=18
`
`n=18
`
`0
`
`20
`
`40
`
`60
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0.0
`
`Probability of Clinical Cure
`
`AUCss(0-24)/MIC Ratio
`
`
`
`For cSSSI microbiological efficacy, 1 phase 2 study (3074A1-200: 25 patients) and 2
`phase 3 studies (3074A1-300: 2 patients; 3074A1-305: 9 patients) were combined for
`exposure-response analysis at the patient level (Table 4). Formal statistical analysis,
`however, could not be applied unless cohorts 2 and 3 are combined due to the low failure
`rate in each single cohort. The sponsor found that AUCss(0-24)/MIC, as a continuous
`covariate, was a borderline statistically significant (p=0.113) predictor of microbiologic
`response for cohorts 2 and 3 combined. Under the proposed dosage regimen (100mg
`loading dose and 50mg maintenance dose), the exposure change did not cause clinically
`relevant difference on microbiological efficacy as indicated by Figure5.
`
`Table 4: Baseline Pathogen Classification Used in Exposure-Response Analysis for cSSSI
`Efficacy
`Cohort
`1
`2
`3
`4
`5
`
`Baseline Pathogen(s) Included
`Monomicrobial S. aureus
`Monomicrobial S. aureus or Streptococcus spp.
`Polymicrobial S. aureus plus Streptococcus spp. or two Strep. spp.
`Other polymicrobial Gram-positive and/or Gram-negative pathogens
`Gram-negative or anaerobic monomicrobial pathogens
`
`
`For cSSSI clinical efficacy, similar results were obtained. Both AUCss(0-24) (p=0.065)
`and AUCss(0-24)/MIC (p=0.1723) were identified as marginally significant predictors of
`clinical response based on univariate logistic analysis. Under the proposed dosage
`regimen (100mg loading dose and 50mg maintenance dose), the exposure change did not
`cause clinically relevant difference on clinical efficacy as indicated by Figure 6.
`
`
`
`14
`
`Apotex Exhibit 1026
`Page 15 of 130
`
`

`

`
`Figure 5. Exposure-Response Analysis of cSSSI Efficacy - Final Logistic Regression Model of
`Microbiological Response versus AUCSS(0-24)/MIC Ratio with Histogram of Observed Data in
`Cohorts 2 and 3 and AUCSS(0-24)/MIC Ratio Range under Each Dose (36 subjects)
`dose50mg
`
`1.0
`
`n=9
`
`n=9
`
`n=9
`
`dose25mg
`
`n=9
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`0.0
`
`Probability of Bacteriologic Cure
`
`20
`
`40
`
`60
`
`80
`
`100
`
`AUCss(0-24)/MIC Ratio
`
`
`Figure 6. Exposure-Response Analysis of cSSSI Efficacy - Final Logistic Regression Model of
`Clinical Response versus AUCSS(0-24)/MIC Ratio with Hi