Maximizing Rifamycins

Transcription

1 Maximizing Rifamycins Charles A. Peloquin, Pharm.D. Director Infectious Disease Pharmacokinetics Laboratory Professor, College of Pharmacy & The Emerging Pathogens Institute University of Florida Page 1

2 We re # 1! The WHO has stated that, as of 2015, tuberculosis ( TB ) is the single most lethal infection on the planet, surpassing HIV. And, TB deaths in HIV infected individuals still are counted as HIV deaths. We re # 1! Roughly 9 million people had active TB disease last year, and roughly 1.5 million people died from TB One person died of TB every 20 seconds! Page 2

3 We re # 1! By the end of this seminar, roughly 180 people will have died from TB Maybe someone you knew This qualifies as a serious problem in need of serious solutions What are we looking for? Highly effective regimens shorter than 6 months in duration Page 3

4 Have we found it? Not yet Three quinolone - based 4 month regimens failed to provide sufficient efficacy to replace the current 6 month regimen. Lanoix JP, Chaisson RE, Nuermberger EL. Shortening Tuberculosis Treatment Clin Infect Dis Nov 1 Have we found it? No Jawahar MS et al. Randomized clinical trial of thrice weekly 4 - month moxifloxacin or gatifloxacin PLoS One 2013; 8 (7): e [ South Indian trial ] Gillespie SH et al. Four-month moxifloxacin-based regimens N Engl J Med 2014; 371 (17): [ ReMox ] Merle CS et al. A four month gatifloxacin - containing regimen. N Engl J Med 2014; 371 (17): [ OFLOTUB ] Page 4

5 Why Not? Despite the inconsistent and altogether modest benefit of the fluoroquinolones in phase 2 trials, large phase 3 trials were organized and launched, even before all phase 2 results were available. Lanoix JP, Chaisson RE, Nuermberger EL. Shortening Tuberculosis Treatment Clin Infect Dis Nov 1 Why Not? Future phase 2 trials may be more efficient and informative regarding such one size fits - all shortening regimens if they exclude subjects with non-cavitary disease or otherwise enroll adequate numbers of participants with cavities to allow robust subgroup analysis.. Lanoix JP, Chaisson RE, Nuermberger EL. Shortening Tuberculosis Treatment Clin Infect Dis Nov 1 Page 5

6 Therefore. Should TB treatment be one size fits - all? [ hint NO ] TB is a spectrum of clinical conditions, ranging from mild (i.e., less destructive to the lungs ) to severe (i.e. large cavities in the lung ). We stage cancer, we classify diabetes, hypertension, and strokes, so why do we just have TB ( excluding brain and bone TB )? Back to Why Not? Quinolones do not appear to have sufficient sterilizing capacity ( i.e. prevent relapses ). Currently, 2 drugs types clearly have this capacity : Pyrazinamide and the Rifamycins ( Rifamycins = rifampin, rifapentine, rifabutin ) Page 6

7 Why Not? The factors contributing to the relapse diathesis associated with cavitary disease are multifactorial and include higher bacterial burdens, reduced drug penetration to the site of infection, and lack of adequate immune effector function at the cavity surface. Lanoix JP, Chaisson RE, Nuermberger EL. Shortening Tuberculosis Treatment Clin Infect Dis Nov 1 Why Not? For example, low systemic exposures to key sterilizing drugs ( i.e., rifamycins and pyrazinamide ) due to pharmacokinetic variability among patient populations reduces the rate of sputum sterilization. Lanoix JP, Chaisson RE, Nuermberger EL. Shortening Tuberculosis Treatment Clin Infect Dis Nov 1 Page 7

8 Why Not? Of these factors, you cannot control higher bacterial burdens or the lack of adequate immune effector function at the cavity surface. However, you can address the reduced drug penetration by the drugs and doses you choose. You can control the concentrations that you achieve, at least in the plasma, and that drives what penetrates into the lesions. Why are these soldiers using tracers? To see if they are hitting their targets [ from the movie Fury ] Page 8

9 How do we treat TB? The vast majority of TB patients in the US are treated exclusively with TB drugs. TB drugs are 100 % of the active treatment. Therefore, you have to get this part right How do we treat TB? The vast majority of TB patients in the US are treated with the same doses of the same drugs ( ex. isoniazid 300 mg and rifampin 600 mg ). Page 9

10 How do we treat TB? We assume the doses are right for every situation. We assume every patient is the same as the average patient in the BMRC trials. We rule out the possibility of inter individual variability affecting treatment outcome. How do we treat other disease? Would you treat every hypertensive patient with 50 mg of atenolol once daily? Would you treat every diabetic patient with 10 units of regular insulin thrice daily? Would you treat every stroke patient with 5 mg of warfarin once daily? No - that would be bad practice Page 10

11 How do we treat other disease? You would check the blood pressure on every hypertensive patient and adjust. You would check the blood glucose on every diabetic patient and adjust. You would check the INR on every stroke patient and adjust. That would be good practice How do we treat other disease? Virtually every other disease treatment is moving towards personalized or precision medicine. In sharp contrast, TB continues to use standardized doses in standardized regimens designed in the 1970 s, and often we do not confirm the adequacy of our doses. That is not precision medicine. Page 11

12 The TB Treatment Mantra TB Treatment is 6 months long and is over 95 % effective. [ Clearly, in clinical trials with per protocol analyses, this is true. ] The TB Treatment Mantra Per protocol ( PP ) analyses: Only the patients who took the study drugs within the confines of the protocol are tested Typical BMRC studies: About 10 % not assigned to study About 10 % drop out of the study Thus, 95% effective per protocol is closer to 75 % of patients who were evaluated. Page 12

13 Completion of TB Therapy, United States, * Percentage * Updated as of June 5, Data available through 2012 only. Note: Includes persons alive at diagnosis, with initial drug regimen of one or more drugs prescribed, who did not die during therapy. Excludes persons with initial isolate rifampin resistant, or patient with meningeal disease, or pediatric patient (aged <15) with miliary disease or positive blood culture. Completion of TB Therapy, United States, * * Updated as of June 5, Data available through 2012 only. Note: Includes persons alive at diagnosis, with initial drug regimen of one or more drugs prescribed, who did not die during therapy. Excludes persons with initial isolate rifampin resistant, or patient with meningeal disease, or pediatric patient (aged <15) with miliary disease or positive blood culture. Page 13

14 Completion of TB Therapy, United States, * 100 Percentage Completed in 1 year or less Completed * Updated as of June 10, Data available through 2010 only. Note: Includes persons alive at diagnosis, with initial drug regimen of one or more drugs prescribed, who did not die during therapy. Excludes persons with initial isolate rifampin resistant, or patient with meningeal disease, or pediatric patient (aged <15) with miliary disease or positive blood culture. Length of Treatment in the US Page 14

15 So what? Remember, this is supposed to be a 6 month short course therapy. If it takes 12 to 18 months, it is no longer short course therapy and you pay for every month. 12 / 6 = 2 And another thing The average weight of the patients, predominantly male, in the BMRC Hong Kong and East Africa trials was 48 kg. 600 mg / 48 kg = 12.5 mg / kg 600 mg / 90 kg = 6.7 mg / kg For many patients, we give a lot less drug than was studied originally Page 15

16 And this is what it looks like Full 48 kg 96 kg Not Full 600 mg in 600 mg in Original Current patients patients Kind of like putting 10 gallons of gas in each of these vehicles Full Not Full Page 16

17 Antibiotic Terms Pharmacokinetics ( PK ) Movement of the drug through the body. Pharmacodynamics ( PD ) Ability of the drug to produce an inhibitory or lethal effect. Antibiotic Terms Minimal inhibitory concentration ( MIC ) The concentration of the drug required to inhibit the growth of an organism in the laboratory. From this: susceptible or resistant [ This test cannot be done within the patient. ] Page 17

18 How Do Antibiotics Work? A drug must enter the organism, bind to a specific target, and produce an inhibitory or lethal effect. Unless the drug is delivered to the site of infection ( PK ), nothing happens ( PD ). PK and PD Page 18

19 Pharmacodynamics ( PD ) Pharmacodynamics ( PD ) Killing of TB by most TB drugs can be described very well using AUC / MIC, and more AUC is better. This has been known for many years, and has been widely published. Page 19

20 Pharmacodynamics ( PD ) How Do Antibiotics Work? Reading : The association between sterilizing activity and drug distribution into tuberculosis lesions. Prideaux B, Via LE, Zimmerman MD, et al. Nature Medicine Oct; 21 (10): Page 20

21 How Do Antibiotics Work? Reading : Optimizing the clinical pharmacology of tuberculosis medications. Egelund EF, Alsultan A, Peloquin CA. Clin Pharmacol Ther Oct; 98 (4): TB Treatment : This is You Page 21

22 TB Treatment : Outcome 1 TB Treatment : Outcome 2 Page 22

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24 Rifampin ( RIF ) role: action: dosage: dose: cleared: toxicity: primary drug, along with INH DNA - dependent RNA polymerase oral, I.V. 600 mg QD // mg / Kg for kids liver >> kidneys hepatotoxicity, flu - like syndrome Rifapentine ( RPNT ) role: action: dosage: dose: cleared: toxicity: primary drug, along with INH DNA - dependent RNA polymerase oral 600 mg QD // moving to 1200 mg QD liver >> kidneys hepatotoxicity, flu - like syndrome Page 24

25 Rifabutin ( RBN ) role: action: dosage: dose: cleared: toxicity: instead of RIF for HIV + patients DNA - dependent RNA polymerase oral 300 mg ( mg ) QD liver >> kidneys neutropenia, thrombocytopenia, uveitis Rifamycin Comparison CYP 3A4 induction Unique features Rifampin 1.00 flu - like syndrome Rifapentine 0.85 to % protein bound Rifabutin 0.40 uveitis, neutropenia Page 25

26 Rifamycin Comparison MIC * Cmax ^ Ratio t ½ ( µg / ml ) ( µg / ml ) ( hr ) Rifampin Rifapentine Rifabutin * 7H12 broth ^ total Rx ( free and bound ) Rifamycin Comparison MIC * Cmax # Ratio t ½ ( µg / ml ) ( µg / ml ) ( hr ) Rifampin Rifapentine Rifabutin * 7H12 broth # free Rx ( only free is active ) Page 26

27 Rifampin has profound concentration dependent killing Week 5 mg/kg 10 mg/kg 20 mg/kg 40 mg/kg Lung week 1 Lung week 10 CFU CFU 100,000, ,000, ,000, ,000,000 10, % reduction % % % % Verbist L. Acta Tuberculosa et Phneumolgia Belgica 1969 ; number 3-4: ; Pharmacodynamics ( PD ) Page 27

28 Rifampin has profound concentration dependent killing Week 5 mg/kg 10 mg/kg 20 mg/kg 40 mg/kg Lung week 1 Lung week 10 CFU CFU 100,000, ,000, ,000, ,000,000 10, % reduction % % % % Verbist L. Acta Tuberculosa et Phneumolgia Belgica 1969 ; number 3-4: ; Rifampicin - What dose for pulmonary tuberculosis? Holland MD. S Afr Med J. 1972; 46: PMID: Page 28

29 Rifampin 600 mg in Humans Cumulative percentage culture negative: month HRZS QD HRZE QD H 300 mg, S 750 mg, Z 35 mg / Kg, E 25 mg / Kg isoniazid streptomcyin pyrazinamide ethambutol Br J Dis Chest 1981 ; 75 : Rifampin 1200 mg in Humans Cumulative percentage culture negative month HRS QD HRS QOD H 900 mg, S 1000 mg QD both regimens isoniazid streptomycin Kreis B et al. Bull Int Union Tuber 1976 ; 51 : Page 29

30 Rifampin 600 mg vs mg Cumulative percentage culture negative month HRZS QD R 600 mg, with Z HRS QD R 1200 mg, NO Z INH 900 mg Rifampin 1200 mg Flu - like syndrome was NOT reported by Kreis et al ( 3 months of treatment ) Even with highly - intermittent RIF, syndrome usually appears after 3 to 6 months. Kreis B et al. Bull Int Union Tuber 1976 ; 51 : Peloquin C. Int J Tuberc Lung Dis 2003 ; 7: 3-5. Page 30

31 What is the 'right' dose of rifampin? Peloquin C. Int J Tuberc Lung Dis ; 7: 3-5. PMID: Page 31

32 PD: Sterilizing Activity of Rifampin Mean value after 600 mg oral dose Jayaram et al, AAC 2003 ; 47: 2118 Pharmacodynamics ( PD ) Page 32

33 PD: Sterilizing Activity of Rifampin Mean value after 600 mg oral dose Jayaram et al, AAC 2003 ; 47: 2118 Let s move from the lab to the clinic Page 33

34 What happens if you reduce the exposure of a concentration dependent TB drug? Rifabutin in HIV+ TB Patients Association between Acquired Rifamycin Resistance and the Pharmacokinetics of Rifabutin and Isoniazid among Patients with HIV and TB. [ USPHS TB Study 23 A ] Weiner M, Benator D, Burman W, Peloquin CA, Khan A, Vernon A, Jones B S, Silva-Trigo C, Zhao Z, Hodge T and the Tuberculosis Trials Consortium Clinical Infectious Diseases 2005 ; 40: Page 34

35 What happens if you reduce the exposure of a concentration dependent TB drug? You don t kill the pathogen, and you select for drug resistance exactly as predicted in vitro. ARR was avoidable had these protocols included TDM and dose adjustments, something that has been available for over a quarter century. Page 35

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37 Pharmacodynamics ( PD ) Rifabutin and LPV / r in HIV+ TB Patients So, there are over 12 reported cases of ARR with low concentrations of RBN in HIV+ positive patients. These are clinical examples of pharmacodynamics ( PD ) in action. There remains a reluctance in some centers to use rifabutin therapeutic drug monitoring ( TDM ) to avoid such ARR events, even though ARR is avoidable. Why? Page 37

38 TB Costs It s too expensive to do TDM. But, is it really too expensive? TB Costs TDM, 1 drug, 2 time points $ 140 TDM, 4 drugs, 2 time points $ 560 Published typical costs of TB treatment in US : TB $ 17,000 MDR-TB $ 133,000 ( treatment ~ same as ARR ) XDR-TB $ 430,000 S. Marks et al. Emerging Infectious Disease, May 2014 Page 38

39 TB Costs Just one case of MDR-TB created vs. TB = $ 133,000 extra cost for re-treatment, on top of $17,000 for the failed 1 st treatment. TDM, 1 drug, 2 time points $ 140 For $ 133,000, you could check 950 pairs of drug concentrations, or you could check 4 drugs at 2 time points for over 237 patients Rifabutin and LPV / r in HIV+ TB Patients Again, there are over 12 reported cases of ARR with low concentrations of RBN in HIV+ positive patients. Approximately $133,000 x 12 = $1,596,000 was spent to correct these man made problems. That equals 11,400 pairs of serum concentrations, more than the annual TB case load in the US. Page 39

40 TB Costs TDM is not too expensive when you consider the alternative costs. So, What s in your wallet? A Tale of Two Treatments Heart Lung Transplant : Spare no expense cost approaches $1,200,000 per person TB Treatment : Have no expense Clinicians routinely look to cut the average $17,000 cost per person, typically paid by Public Health Departments Page 40

41 A Tale of Two Treatments Heart Lung Transplant : What is it about these patients that we are willing to pay so much for 1 life? TB Treatment : What is it about these patients that we are NOT willing to pay so much for 1 life? TB Treatment : No time to skimp Page 41

42 Rifamycin PK Why is ARR happening? Pharmacodynamics ( PD ) Page 42

43 10 Rifampin RIF free RIF Lq. MIC Rifabutin in HIV positive patients Lq. MIC RBN 300 free RBN Page 43

44 0.80 Rifabutin in HIV positive patients Lq. MIC RBN 600 free RBN Rifapentine RPNT free RPNT Lq. MIC Page 44

45 RPNT free RPNT Lq. MIC free RIF free RPNT free RBN RBN MIC Page 45

46 free INH free RIF free EMB free INH free EMB free RBN Page 46

47 free INH free EMB free RPNT Rifamycin Pharmacokinetics RIF, INH, PZA, and EMB are reasonably well matched for PK, especially when given daily. Intermittent RBN regimens using INH, PZA, and EMB leave sub MIC RBN serum concentrations as monotherapy for about 3 days every week. Intermittent RPNT regimens using INH, PZA, and EMB leave supra MIC RPNT serum concentrations as monotherapy for about 3 days every week. Page 47

48 What is the 'right' dose of rifampin? Boeree M. CROI, March 11, th Conference on Retroviruses and Opportunistic Infections; Session 42, Paper # 148 LB. Dose Ranging Trial to Optimize the Dose of Rifampin Boeree MJ et al. Int J Tuberc Lung Dis 2011; 15: Am J Respir Crit Care Med 2015; 191: Page 48

49 Dose Ranging Trial to Optimize the Dose of Rifampin Series of 3 clinical trials: 1. Dose escalation trial in groups of 15 patients to study PK and safety. 2. Phase II study of 10, 15, and 20 mg / kg for 2 months ( ~ same as HiRIF study by C. Mitnick et al. ) Int J Tuberc Lung Dis 2011; 15: Dose Ranging Trial to Optimize the Dose of Rifampin Series of 3 clinical trials: 3. Phase IIB study of highest tolerated dose with 3 groups of 200 patients across 3 countries. Int J Tuberc Lung Dis 2011; 15: Page 49

50 Dose Ranging Trial to Optimize the Dose of Rifampin 1. Maximum tolerated dose study : RIF 10, 15, 20, 25, 30, 35 mg / kg for 14 days in patients with drug susceptible TB [ 70 kg * 35 mg / kg = 2,450 mg, round to 2,400 mg ] All patients received standard doses of isoniazid, pyrazinamide, and ethambutol days 7-14 Am J Respir Crit Care Med 2015; 191: Dose Ranging Trial to Optimize the Dose of Rifampin 1. Maximum tolerated dose study : Adverse events were evenly distributed across all dosing groups More than proportional increases in Cmax and AUC occurred as doses increased ( more bang for your buck at higher doses ) Am J Respir Crit Care Med 2015; 191: Page 50

51 Dose Ranging Trial to Optimize the Dose of Rifampin 1. Maximum tolerated dose study : High inter individual variability in Cmax and AUC within any given dose Greatest reduction in sputum colony counts of Mtb were seen with the highest AUC. Am J Respir Crit Care Med 2015; 191: Daily Rifapentine for Treatment of Pulmonary Tuberculosis Dorman SE, Savic RM, Goldberg S et al. Am J Respir Crit Care Med 2015; 191: Page 51

52 Daily Rifapentine for Treatment of Pulmonary Tuberculosis Prospective, randomized study of 3 doses of daily rifapentine with food to enhance absorption ( 10, 15, or 20 mg / kg ) compared to the standard 10 mg / kg for the first 2 months of treatment ( initial phase, 8 weeks ) All patients received standard doses of isoniazid, pyrazinamide, and ethambutol Am J Respir Crit Care Med 2015; 191: Daily Rifapentine for Treatment of Pulmonary Tuberculosis 1135 Patients were assessed 334 Patients were assigned to study ( 29 % ) ITT = intent to treat analysis MITT = modified intent to treat analysis PP = per protocol analysis Am J Respir Crit Care Med 2015; 191: Page 52

53 Daily Rifapentine for Treatment of Pulmonary Tuberculosis 334 Patients assigned to study RIF10 RPNT10 RPNT15 RPNT20 ITT MITT PP PP / ITT 67% 72% 79% 63% ( recall BRMC estimates earlier in presentation ) Am J Respir Crit Care Med 2015; 191: Daily Rifapentine for Treatment of Pulmonary Tuberculosis Doses were well tolerated compared to control 254 patients evaluable in the modified intent to to treat analysis ( MITT ) Culture results tested both on traditional solid agar and in the newer liquid media Am J Respir Crit Care Med 2015; 191: Page 53

54 Daily Rifapentine for Treatment of Pulmonary Tuberculosis Across the rifapentine groups: There were no statistically significant differences based on assigned treatment group, or based on administered rifapentine dose ( mg ) In other words, knowing the dose told you little about who would do best. Am J Respir Crit Care Med 2015; 191: Daily Rifapentine for Treatment of Pulmonary Tuberculosis High RPNT exposures (AUC) WERE associated with high levels of sputum sterilization at the completion of 8 weeks of treatment ( end of intensive phase ) This is exactly what was predicted by the in vitro and animal models of rifamycins - this proves ( once again ) rifamycins have concentration dependent killing since 1969 Page 54

55 Daily Rifapentine for Treatment of Pulmonary Tuberculosis The percent of culture negative patients was highest in the RPNT20 arm, but there was no clear trend across RPTN arms Most strikingly, antimicrobial activity was strongly associated with RPNT exposures PK PD evaluations provided important insights Pharmacodynamics ( PD ) Page 55

56 Daily Rifapentine for Treatment of Pulmonary Tuberculosis A dose will be selected that ensures most patients reach target AUC, especially given that TDM is not feasible in most high burden settings This implies that all patients could achieve target exposures if TDM were feasible, which it is throughout the US, Canada, and Western Europe. Dosing Drugs It is not possible to give drugs for the explicit purpose of avoiding toxicity. To guarantee no toxicity, do not give the drug. Page 56

57 Dosing Drugs If you must give the drug, you must accept some probability of toxicity. The best way to avoid toxicity is to give the most effective doses for the shortest possible time. Dosing Drugs Rifamycin efficacy is dependent on drug exposure ( Cmax and AUC ) The best way to achieve the needed exposure is to measure the exposure. Page 57

58 Pharmacodynamics ( PD ) TDM The decision to use TDM is the same as the decision to check a CBC with diff., or the decision to get a CT or MRI. None of these guarantees the outcome of Tx. However, all of these inform the clinician prior to making clinical decisions. Page 58

59 TDM Do I have to use TDM? No. But if you keep doing what you have been doing, You will keep getting what you have been getting. Completion of TB Therapy, United States, * Percentage * Updated as of June 5, Data available through 2012 only. Note: Includes persons alive at diagnosis, with initial drug regimen of one or more drugs prescribed, who did not die during therapy. Excludes persons with initial isolate rifampin resistant, or patient with meningeal disease, or pediatric patient (aged <15) with miliary disease or positive blood culture. Page 59

60 TB completion rates Currently, it is 89 % at 12 months. That is not 95 %. That is not 6 months. It certainly is not 4 months. If you do the same thing, you will get the same thing. Role for TDM TDM allows you to individualize therapy. TDM allows you to optimize the PD - linked variable [ typically Cmax or AUC ]. Page 60

61 TDM Доверяй, но проверяй doveryai, no proveryai Trust but Verify Acknowledgements Page 61

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