Telithromycin Ketek: General Safety Profile

1
Telithromycin (Ketek) General Safety Profile

• Anti-Infective Drugs Advisory Committee
• April 26, 2001
• David Ross, M.D., Ph.D.
• Division of Anti-Infective Drug Products
• Center for Drug Evaluation and Research
• U.S. Food and Drug Administration

2
Ketek Phase 3 safety database
3
Extent of exposure - phase 3
4
Deaths

• No deaths in phase I trials
• 11 deaths in phase III (10 CAP, 1 pharyngitis)
• 7 deaths in telithromycin pts, 4 in comparator
  pts
• None directly attributed to drug
• 6 deaths (4 Ketek, 2 comp) scored as tx failures
• 6/7 Ketek-treated patients who died had CV cause
• 0/4 comparator patients who died had CV cause
• Most CAP deaths occurred in high-risk patients
  (Fine category III or higher)

5
Serious AEs - Phase 3
4 drug-related SAEs in uncontrolled trials
gastroenteritis, vasculitis, hepatitis, leukopenia
6
AEs - Phase 3
7
AEs by 3A4 inhibitor intake
8
Telithromycin (Ketek) Cardiac Effects
9
Telithromycin Cardiac Effects

• In vitro and preclinical data
• Phase 1 data
• Phase 3 data
• Conclusions

10
QTc vs. QTn
11
QTc effects in vitro and preclinical data

• Inhibits IKr channel (major repolarization
  current)
• Ki 42.5 µM (moxifloxacin 129 µM)
• Mean serum Cmax 2.4 µM max Cmax 12 µM
• Rat myocardialserum conc. ratio 6
• Prolongs action potentials in isolated fibers
• gt75 increase in APD90 at Ki
• Potentiates sotalol-induced APD prolongation
• Prolongs QTc and increases HR in dogs
• 30 ms ? 1 min after single IV dose (17 ms for
  clari)
• 27-30 ms after multiple oral doses (100 mg/kg/d)

12
?QTc with telithromycin Phase 1
plt0.05 vs. placebo
13
?QTc in Phase 1 subjects with CV disease
Source Study 1049
14
?QTc vs. telithromycin concentration (Phase 1
studies)
?QTc -1.30 3.90 concentration (p lt 0.0001)
15
Telithromycin vs. Cisapride
16
3A4 inhibitor interactions
comparison with placebo

• Telithromycin Cmax increased by 52 with
  ketoconazole
• Telithromycin AUC increased by 95 with
  ketoconazole

17
Telithromycin PK variability

• Phase 1
• Nonlinear pharmacokinetics? ? ? predictability
• Single dose (800 mg)
• mean Cmax 1.99 mg/L
• maximum Cmax 5.13 mg/L (renally impaired
  subject)
• Multiple dose (800 mg)
• mean Cmax 2.07 mg/L
• maximum Cmax 6.66 mg/L (elderly subject)
• Phase 3
• Maximum observed concentration 7.6 - 9.9 mg/L

18
Telithromycin pharmacokinetics in special
populations

• Elderly subjects Cmax and AUC ? by 100
• Hepatic impairment
• Single-dose study t1/2 ? by 40
• Mult. dose AUC and Cmax healthy subjects, but
  renal clearance increases to compensate
• Potential accumulation if ?CrCl with hepatic
  impairment
• Renal impairment (single dose study)
• Moderate impairment (CrCl 40-80 mL/min)
• Cmax ? by 33 AUC ? by 42
• Severe impairment (CrCl lt40 mL/min)
• Cmax ? by 44 AUC ? by 59

19
Phase 1 conclusions

• Concentration- and dose-dependent ? in QTc
• QTc increase comparable to cisapride
• QTc increase enhanced by 3A4 inhibitor
• Concentration increased by 3A4 inhibitor
• PK variability seen
• ? exposure with age, renal impairment
• Potential ? exposure in hepatic impairment with
  decreased CrCl

20
Issues in ?QTc assessment

• Rare related clinical events (e.g., cisapride)
• Variability
• Inter-individual
• Inter-observer
• Inter-measurement
• Significance of ?QTc
• Small ? may lead to torsade (e.g., terfenadine)
• Increase in risk for given ? not clear

21
Limitations of phase 3 EKG data

• EKG data not collected on all patients
• Controlled trials 1515 Ketek, 1276 comparator
• Few data from high risk patients
• 2 telithromycin-treated pts with low baseline K
• 5 telithromycin-treated pts on anti-arrhythmics
• EKG timing ? peak QTc effect
• EKGs obtained at different times after dosing
• EKGs obtained at 25 mm/sec
• No data on Mg2

22
Exclusion criteria for telithromycin phase 3
trials

• Long QTc syndrome
• Severe hypokalemia
• QTc gt450 msec
• Sick sinus syndrome
• Bradycardia lt50 bpm
• ALT ? 3x ULN
• AST ? 3x ULN
• Bilirubin gt 2x ULN
• PT ? 1.3x control
• Encephalopathy
• CrCl ? 50 mL/min
• AIDS

• Concomitant
• ergot alkaloid derivatives
• terfenadine
• astemizole
• cisapride
• pimozide
• cholinesterase inhibitors
• ketamine
• digoxin
• itraconazole
• fluconazole
• quinidine
• diisopyramide
• procainamide
• bretylium
• sotalol

criterion dropped 2/99
23
?QTc controlled phase 3 trials
24
?QTc telithromycin vs. clarithromycin
25
?QTc with CYP substrates
26
?QTc vs. clarithromycin with CYP substrates
27
(No Transcript)
28
(No Transcript)
29
QTc In vitro/preclinical conclusions

• Telithromycin inhibits repolarization in vitro
• Effect seen in cell culture and isolated fibers
• myocardial concentration may approximate Ki
• Telithromycin significantly increased QTc in dogs
• Effect seen with both oral and IV dosing
• IV telithromycin ?QTc gt IV clarithromycin ?QTc

30
QTc phase 1 conclusions

• Telithromycin increased QTc in phase 1
• Controlled cross-over studies show consistent
  effect
• Concentration- and dose-dependent increase
• Comparable to cisapride additive with cisapride
• Increased by 3A4 inhibitor (ketoconazole)
• Telithromycin PK variability
• Nonlinear pharmacokinetics
• Increased exposure in special populations

31
QTc phase 3 conclusions

• Telithromycin increased QTc in phase 3
• Small but consistent increase in controlled
  trials
• ? larger than comparators
• ? larger than clarithromycin
• Possible interactions with 3A4 and 2D6 substrates
• Mean with 3A4 2D6 11.5 msec (clarithromycin
  5.4 msec)

32
Telithromycin (Ketek) Risk/benefit issues
33
S. pneumoniae resistance 1995-1998
Whitney CG et al. N Engl J Med 20003431917-24.
34
Risk factors for mortality in pneumococcal
pneumonia
Pallares R et al. N Engl J Med 1995 333474-80
35
Resistance and mortality in pneumococcal pneumonia
Pallares R et al. N Engl J Med 1995 333474-80
36
Assessing benefits of resistance claims

• Public health impact
• benefit in cases due to resistant pathogens
• benefit in outpatients with mild to moderate
  disease
• Seriousness of infection (e.g., CAP vs. AECB)
• Mechanism of action
• out-of-class vs. in-class resistance
• in-class potential for concurrent resistance
• Evidence for clinical efficacy vs. resistant
  isolates
• Evidence for susceptible and resistant isolates
• Evidence for resistant isolates
• Evidence in invasive disease due to resistant
  isolates

37
Telithromycin-ketoconazole interaction

p0.004, compared to placebo
38
Drugs associated with ?QTc/TdP

• Amiodarone
• Amitriptyline
• Astemizole
• Aresenic trioxide
• Azelastine
• Bepridil
• Chlorpromazine
• Cisapride
• Clarithromycin
• Desimpramine
• Disopyramide
• Dofetilide
• Doxepin
• Droperidol
• Erythromycin
• Felbamate

• Flecainide
• Fluoxetine
• Foscarnet
• Fosphenytoin
• Gatifloxacin
• Grepafloxacin
• Halofantrine
• Haloperidol
• Ibutilide
• Imipramine
• Indapamide
• Isradipine
• Levomethadyl
• Mesoridazine
• Moexipril/HCTZ
• Moxifloxacin

• Naratriptan
• Nicardipine
• Octreotide
• Pentamidine
• Pimozide
• Probucol
• Procainamide
• Quetiapine
• Quinidine
• Risperidone
• Salmeterol
• Sotalol
• Sparfloxacin
• Sumatriptan
• Tacrolimus
• Tamoxifen

• Terfenadine
• Thioridazine
• Tizanidine
• Trimethoprim/ Sulfamethoxazole
• Venlafaxine
• Zolmitriptan

39
Telithromycin effects on co-administered drugs
40
Mibefradil (Posicor)

• Ca2-channel blocker
• CYP 3A4 inhibitor
• In vitro, inhibited metabolism of simvastatin,
  lovastatin, atorvastatin, cerivastatin (Ki lt 1
  µM)
• No statin-associated events seen in phase III

41
Mibefradil regulatory history

• 8/97 Approved for angina, HTN
• Warnings re astemizole, cisapride, terfenadine
• 12/97 Additional warnings re
• Use of lovastatin or simvastatin
• Use of any statin AND tacrolimus or cyclosporine
• 6/98 Withdrawal from market
• gt25 interacting drugs identified
• Continued reports of AEs from interacting drugs
• Further labeling changes impractical
• No special benefits relative to other agents

42
Ketek safety concerns

• Potential confluence of multiple risk factors
• (1) QTc prolongation
• (2) Concentration dependence of QTc effect
• (3) Pharmacokinetic variability
• (4) Potential for hepatotoxicity
• (5) ? exposure in elderly pts, hepatic/renal
  disease
• (6) ? exposure with concomitant medications
• (1) - (6) may lead to clinically significant ?QTc
• Very limited data on at-risk subjects
• Few patients in any given risk group
• Limited range of concentration data in phase III

43
Ketek safety concerns (cont.)

• Potential hepatotoxicity
• Uncertainty re dosing in special populations
• Altered pharmacokinetics in special populations
• Nonlinearity of pharmacokinetics
• Potential effects on concomitant medications
• Potentially wide exposure

44
Outpatient Antimicrobial Therapy, U.S. (millions
of courses in 1992)
URI (non-specific)
17.9
Otitis media
23.6
Bronchitis
16.3
Pharyngitis
13.1
All other diagnoses
26.5
Sinusitis
12.9
McCaig LF and Hughes JM. JAMA 1995 273214-9