# Presentation: 806699

## Telithromycin (KetekTM): 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**

## Ketek Phase 3 safety database

## Extent of exposure - phase 3

## 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)**

## Serious AEs - Phase 3

**4 drug-related SAEs in uncontrolled trials: gastroenteritis, vasculitis, hepatitis, leukopenia**

## AEs - Phase 3

## AEs by 3A4 inhibitor intake

## Telithromycin (KetekTM): Cardiac Effects

## Telithromycin: Cardiac Effects

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

## QTc vs. QTn

## QTc effects: in vitro and preclinical data

**Inhibits IK****r**** channel (major repolarization current)**
**K****i**** 42.5 μM (moxifloxacin 129 μM)**
**Mean serum C****max**** 2.4 μM; max C****max**** 12 μM**
**Rat myocardial:serum conc. ratio = 6**
**Prolongs action potentials in isolated fibers**
**>75% increase in APD****90**** at K****i**
**Potentiates sotalol-induced APD prolongation**
**Prolongs QT****c**** 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) **

## QTc with telithromycin: Phase 1

*** p<0.05 vs. placebo**

## QTc in Phase 1 subjects with CV disease

**Source: Study 1049**

## QTc vs. telithromycin concentration (Phase 1 studies)

**ΔQTc = -1.30 + 3.90 * concentration (p < 0.0001)**

## Telithromycin vs. Cisapride

## 3A4 inhibitor interactions

** ****Telithromycin C****max**** increased by 52% with ketoconazole**
** ****Telithromycin AUC increased by 95% with ketoconazole**

***comparison with placebo**

## Telithromycin: PK variability

**Phase 1**
**Nonlinear pharmacokinetics******** ******** ******** predictability**
**Single dose (800 mg)**
**mean C****max****: 1.99 mg/L**
**maximum C****max****: 5.13 mg/L (renally impaired subject)**
**Multiple dose (800 mg)**
**mean C****max****: 2.07 mg/L**
**maximum C****max****: 6.66 mg/L (elderly subject)**
**Phase 3**
**Maximum observed concentration: 7.6 - 9.9 mg/L**

## Telithromycin pharmacokinetics in special populations

**Elderly subjects: C****max**** and AUC ******** by 100%**
**Hepatic impairment**
**Single-dose study: t****1/2**** ******** by 40%**
**Mult. dose: AUC and C****max**** ~ 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):**
**C****max**** ******** by 33%; AUC ******** by 42%**
**Severe impairment (CrCl <40 mL/min):**
**C****max**** ******** by 44%; AUC ******** by 59%**

## Phase 1 conclusions

**Concentration- and dose-dependent ******** in QT****c**
**QT****c**** increase comparable to cisapride**
**QT****c**** 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**

## Issues in QTc assessment

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

## 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 Mg****2+**

## Exclusion criteria for telithromycin phase 3 trials

**Long QTc syndrome**
**Severe hypokalemia**
**QTc >450 msec***
**Sick sinus syndrome***
**Bradycardia <50 bpm* **
**ALT ******** 3x ULN**
**AST ******** 3x ULN**
**Bilirubin > 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**

## QTc: controlled phase 3 trials

## QTc: telithromycin vs. clarithromycin

## QTc with CYP substrates

## QTc vs. clarithromycin with CYP substrates

## Slide 27

## Slide 28

## QTc: In vitro/preclinical conclusions

**Telithromycin inhibits repolarization *****in vitro***
**Effect seen in cell culture and isolated fibers**
**myocardial concentration may approximate K****i**** **
**Telithromycin significantly increased QT****c**** in dogs**
**Effect seen with both oral and IV dosing**
**IV telithromycin ********QT****c**** > IV clarithromycin ********QT****c**** **

## QTc: phase 1 conclusions

**Telithromycin ****increased QT****c**** 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**

## 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)**

## Telithromycin (KetekTM): Risk/benefit issues

## S. pneumoniae resistance 1995-1998

**Whitney CG *****et al. *****N Engl J Med 2000;343:1917-24.**

## Risk factors for mortality in pneumococcal pneumonia

**Pallares R *****et al. *****N Engl J Med 1995; 333:474-80**

## Resistance and mortality in pneumococcal pneumonia

**Pallares R *****et al. *****N Engl J Med 1995; 333:474-80**

## 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**

## Telithromycin-ketoconazole interaction

- *

- *p=0.004, compared to placebo

## 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**

## Telithromycin effects on co-administered drugs

## Mibefradil (Posicor)

**Ca****2+****-channel blocker**
**CYP 3A4 inhibitor**
***In vitro*****, inhibited metabolism of  simvastatin, lovastatin, atorvastatin, cerivastatin (K****i**** < 1 μM)**
**No statin-associated events seen in phase III **

## 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**
**>25 interacting drugs identified**
**Continued reports of AEs from interacting drugs**
**Further labeling changes impractical**
**No special benefits relative to other agents**

## 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 ΔQTc**
**Very limited data on at-risk subjects**
**Few patients in any given risk group**
**Limited range of concentration data in phase III**

## 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**

## Outpatient Antimicrobial Therapy, U.S. 

**(millions of courses in 1992)**

**McCaig LF and Hughes JM. JAMA 1995; 273:214-9**

**Otitis media**

**URI (non-specific)**

**Bronchitis**

**Pharyngitis**

**Sinusitis**

**All other diagnoses**

**23.6**

**17.9**

**16.3**

**13.1**

**12.9**

**26.5**