Efflux Pump Inhibitors: Increase Activity with the Same or Lower Drug Dosing

Transcription

1 Efflux Pump Inhibitors: Increase Activity with the Same or Lower Drug Dosing William R. Bishai, MD, PhD Professor Co-Director, Center for TB Research Division of Infectious Diseases Dept. of Medicine Johns Hopkins School of Medicine June 16, 2015

2 Outline 1. Observations on drug repurposing 2. Drug potentiation examples 3. Verapamil for TB 4. Verapamil Safety with QT-prolonging drugs

3 Observations on Drug Repurposing Lung CFU Counts x Lung CFU Counts INH INH + Repurposed Drug 5 10 Time post-treatment initiation (d) Log Lung CFU Counts Lung CFU Counts RHZ RHZ + Repurposed Drug Time post-treatment initiation (m) It is difficult to improve on standard therapy

4 Drug Potentiation Examples Ritonavir booster for other HIV protease inhibitors Probenecid competitively inhibits renal excretion of some drugs. combined with penicillin for gonorrhea Cilastatin inhibitor of the human kidney dehydropeptidase combined with imipenem to prevent rapid clearance Potentiation is used to prevent renal or hepatic clearance To date no licensed potentiators at the microbial or cellular level (eg, efflux pump inhibitors)

5 Outline 1. Observations on drug repurposing. 2. Drug potentiation examples 3. Verapamil for TB 4. Verapamil Safety with QT-prolonging drugs

6 Verapamil with RHZ Standard Therapy Gupta et al. AJRCCM C3HeB/FeJ mice Untreated Untreated C3H/HeJ mice Log 10 CFU (Lungs) Log 10 CFU RHZ RHZ + VER Time post-treatment initiation (m) Day -13 Day 0 Week 2 Week 4 Week 8 Week 12 Week 16 Week 20 Week RHZ + VER RHZ Day - Day 0 Week Week Week Week Week Week Week Time post-treatment initiation (m) Relapsed at 3 mo. RHZ + VER RHZ 4 mo 5/10 10/10 5 mo 0/10 2/10 6 mo 0/10 0/10 Conclude: 1 log faster kill month 1-3 Sterilized 1 month earlier (mo 5) Relapsed at 3 mo. RHZ + VER RHZ 4 mo 5/10 6/10 5 mo 0/10 1/10 6 mo 0/10 0/10 Equivalent killing Sterilized 1 month earlier (mo 5)

7 Verapamil with RHZ Standard Therapy Gupta et al. AJRCCM 2013 VER was give 9.4 /mg once daily, 5 d per week This VER dose gave an AUC 0-8 of ~255 ng hr/ml (adjusting for RIF) The VER T 1/2 in mice is ~1 hr In this study VER was underdosed

8 Verapamil with Bedaquiline BDQ 12.5 mg/kg BDQ 12.5 mg/kg BDQ 12.5 mg/kg + VER 12.5 mg/kg BDQ 25 mg/kg BDQ 12.5 mg/kg + VER 12.5 mg/kg Conclude: 1 log faster kill with VER added BDQ VER is comparable to BDQ 25 VER may enable BDQ use at lower doses 6 month, multidrug studies AND relapse studies are needed Gupta et al. AAC 2015

9 Outline 1. Observations on drug repurposing 2. Drug potentiation examples 3. Verapamil for TB 4. Verapamil Safety with QT-prolonging drugs

10 ... there s no way you ll ever be able to use verapamil for MDR with all the QT prolongation of moxi, PA-824, and bedaquiline... -anonymous funder PR Prolonged by VER QT Prolonged by MXF, PA-824, BDQ

11 Torsade de Pointes (twisting of the spikes) Polymorphic ventricular tachycardia Responsible for: Hemodynamically unstable withdrawal of Cisapride (Propulsid ) Associated with pulselessness and FDA warning for citalopram (Celexa ) hypotension May degenerate into ventricular fibrillation and sudden death Associated with long QT syndrome

12 Verapamil and Torsade de Pointes

13 EKG recordings in perfused rabbit heart Veratridine: a neurotoxin which binds to Na+ channels producing prolonged excitability Milberg et al. Basic Res Cardiol 2005; 100: 365

14 Abstract An 18-year-old schizophrenic female was recently treated after overdosing on trihexyphenidyl, thioridazine and an unknown antidepressant. On presentation to a local hospital, she was cyanotic with dilatated pupils and in acute respiratory failure. She was intubated prior to transfer. While in our Emergency Department, she exhibited occasional premature ventricular contractions which later became intermittent torsade de pointes. As this was an anticholinergic overdose we infused sodium bicarbonate in an attempt to increase protein binding, hoping to decrease the concentration of toxic metabolites. We also tried to suppress the dysrhythmia by infusing magnesium. The potassium level was borderline low so a supplemental infusion was initiated. Defibrillation was attempted. To try to shorten the action potential duration by activating the K+ channel, an isuprel infusion was also attempted. All methods failed. The patient fluctuated between an irregular sinus rhythm with prolonged QT interval and pulseless torsade de pointes for almost 24 hours. At all times, she responded appropriately to pain. Finally we attempted blockade of the calcium channel using verapamil with dramatic results. Each single bolus (0.1 mg/kg) successfully converted the patient back to sinus rhythm for some minutes before the torsade recurred. After the initiation of a continuous verapamil infusion (0.005 mg/kg/hr), the patient remained in stable sinus rhythm. Verapamil proved highly effective in this patient with an anticholinergic overdose induced dysrhythmia. Liao et al. Jpn Heart J. 1996; 37:

15 Outline 1. Observations on drug repurposing TB standard therapy is hard to beat 2. Drug Potentiation Examples Many human excretion inhibitors No microbial efflux inhibitors 3. Verapamil for TB Modest but credible effect 4. Verapamil Safety with QT-prolonging drugs Paradoxically, VER likely to be beneficial for long QT

16 Norverapamil (major metabolite of VER) and R-Verapamil have poor Ca 2+ channel blocking activity NorVER & R-VER remain potent M.tb. efflux pump inhibitors Potential novel efflux pump blockers with human offtarget activity Adams et al. JID 2015

17 Piperine is natural product abundant in black pepper Has efflux-blocking activity vs. M. tb.. Already being marketed in India Fixed dose tablet of INH-RIF + Piperine Cadila Pharmaceuticals. Ahmedabad, India

18 Verapamil and TB Clinical Trials? Inhibition of Host-induced Mycobacterial Efflux Pumps as a Novel Strategy to Counter Drug Tolerance and Virulence Of PTB PI: Dr. Soumya Swaminathan Funding: DBT of India Study Period: Phase 2, Single Center, Open Label Trial 1. Dose finding PK of VER when given with RIF 2. Determine the safety and tolerability of VER in TB patients without cardiac disease

19 Should Verapamil Advance to More TB Clinical Trials? 1. Animal models show a modest, but clear-cut signal for VER as a potentiator for: Standard RHZ therapy Bedaquiline Clofazimine 2. Two potential roles for VER Treatment shortening Dose reduction (bedaquiline) 3. VER is cardioprotective for QT prolongation and Torsade de Pointes No contraindication for co-administration with QT prolonging drugs: MXF, BDQ, CLO 4. Other worthy efflux pump inhibitors: Norverapamil (not licensed) Piperine (already clinically used outside of US)

20 Shashank Gupta, PhD Thank you

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