Treatment of Pneumonic Plague: Medical Utility of Ciprofloxacin Robert Johnson, Ph.D. Director Office of Regulatory Affairs Director, Affairs, Division of Microbiology and Infectious Diseases NIAID NIH, NIAID, NIH DHHS April p 3, 2012 Proposed Indication The proposed indication for ciprofloxacin is the treatment of pneumonic plague in adult patients at an intravenous dose of 400 mg every 12 hours for 14 days. The treatment of pneumonic plague in pediatric patients (age 1-17 yrs) at an IV dose of 6 6-10 10 mg/kg (not to exceed 400 mg/dose) every 8 hours for 10-21 days. 2 Ciprofloxacin PIND 113289 Regulatory Pathway NIAID does not hold a license for g or distribution of any y drug, g, manufacturing including ciprofloxacin. NIAID is seeking a decision on whether this data package could be used by product manufacturers to support their own labeling supplemental application(s). 3 Ciprofloxacin PIND 113289 Regulatory Pathway A favorable FDA decision that the NIAID data package will support a labeling supplement would be shared with all generic manufacturers of ciprofloxacin. This is similar to the approach taken for doxycycline and penicillin G for inhalation anthrax (post-exposure), (post exposure) where FDA’s FDA s decision was published in the Federal Register. Register 4 Ciprofloxacin PIND 113289 Speaker Topics Efficacy of ciprofloxacin in treatment of pneumonic plague in the African Green Monkey (AGM) model Pharmacokinetics in the AGM and translation to human dosing Unmet medical need Benefit/risk of use of ciprofloxacin for treatment of pneumonic plague 5 Ciprofloxacin PIND 113289 Agenda Treatment of Pneumonic Plague: Medical Utility of Ciprofloxacin Robert Johnson, Ph.D. Director, Office of Regulatory Affairs (ORA) Division of Microbiology and Infectious Diseases (DMID) National Institute of Allergy and Infectious Diseases (NIAID) Efficacy of Ciprofloxacin Therapy for Pneumonic Plague M. Louise M. M M Pitt, Pitt Ph Ph.D. D Chief, Virology United States Army Medical Research Institute of Infectious Diseases (USAMRIID) Nonclinical Pharmacokinetics and Translation to Human Dosing Blaire Osborn, Ph.D. Pharmacokineticist ORA/DMID/NIAID Safety and Benefit/Risk of the Use of Ciprofloxacin for Treatment of Pneumonic Plague Richard Gorman, M.D. Associate Director for Clinical Research DMID/NIAID Summary Robert Johnson, Ph.D. Director, Office of Regulatory Affairs DMID/NIAID 6 USAMRIID Efficacy off Ciprofloxacin Effi Ci fl i Therapy Th for f Pneumonic Plague in the African Green M k Monkey M. Louise M. Pitt, Ph.D. United States Army Medical Research Institute of Infectious Diseases 3 April 2012 “Biodefense solutions to protect our nation” 7 Presentation Outline • • • • AGM Challenge Strain Study Design Results Conclusion Human “Biodefense solutions to protect our nation” 8 Bacterial Strain • Yersinia pestis strain Colorado 92 (CO92) – Biovar Orientalis – Fatal human case of pneumonic plague – Obtained from T Quan, Quan CDC, CDC Fort Collins, Collins CO – Passaged in mouse prior to preparation of the master seed – Master seed prepared in 1993 at USAMRIID S Used for all model development and vaccine and therapeutic efficacy studies – Working stock frozen (-70oC) in potassium phosphate buffered glycerol “Biodefense solutions to protect our nation” 9 Challenge g Material Preparation p • Tryptose blood agar base (TBAB) culture slants are inoculated with Y. Y pestis pestis, CO92. CO92 • Incubated for two days at 26 – 30 ºC. • Each slant culture is suspended in 11-22 ml of Heart Infusion Broth (HIB). • Suspensions from the slants are pooled, vortexed for approx. 10 sec sec. • Optical density (O.D.) of the suspension is determined at 620 nm. (1 unit equates to a Y. pestis concentration of 109 cfu/ml). • Suspensions diluted with HIB to desired concentration. – For a 100 LD50 target, a concentration of 3 X 106 cfu/ml “Biodefense solutions to protect our nation” 10 Study Design • Species: Chlorocebus aethiops / African Green monkey (AGM) • Source: St. Kitts, West Indies • Vendor: Three Springs Scientific, Inc. • Health Status: Released from colonyy for studyy by veterinarian – Screened for TB,, SA8,, Measles,, STLV-1,, SA-11, SIV, SRV-VI “Biodefense solutions to protect our nation” 11 Study Design • Animals: 12 adults – (50% ffemale l / 50% male) l ) – Weight Range: 3.0 – 6.0 kg • Study: 2 Iterations – 10 Treated and 2 Aerosol placebo treated controls 5 Treated and 1 Control / iteration – Randomization stratified by sex and challenge day “Biodefense solutions to protect our nation” 12 Study Design • Aerosol Challenge: Head – only (Mass Median Aerosol Diameter ~1 1.5 5 µm) • • • • Challenge Strain: Y. pestis CO92 Target Inhaled Dose: 100 ± 50 LD50 Central Venous Catheters Telemetry: implants DSI temperature-pulse-pressure Telemetr temperat re p lse press re (TL11M2-D70-PCT) – Every 30 minutes – Fever criteria: ≥ 1.5 oC increase over baseline “Biodefense solutions to protect our nation” 13 Study Design • Treatment initiation: Fever for 2 hours in the majority of the animals • Ciprofloxacin dose: 15 mg/kg IV BID (60-min IV infusion) for 10 days – Recommended by the FDA • • • • • Ciprofloxacin levels in sera: reversed phase HPLC Subjective clinical signs Manual respiratory rate Euthanasia criteria established in the protocol Not blinded “Biodefense solutions to protect our nation” 14 Clinical Assessments and Euthanasia Criteria Score / category Activity Behavior Stimuli Response Breathing 5 Normal Normal Normal Normal 4 Active Anti‐social Enter room Rapid 3 Slow Active Depressed Approach cage Abdominal breathing 2 Sluggish Hunched Rattle cage Dyspnea 1 I ti Inactive I Ignoring i Pi h Pinch R l Rales Maximum Score = 20 • Euthanasia criteria – A cumulative score of ≤ 5 OR – Any of the following Comatose; loss of consciousness Convulsions Presence P off abdominal bd i l respiration i i with i h rales l “Biodefense solutions to protect our nation” 15 Study Design Summary of blood draws Time Post Exposure (days) 0 Treatment (day) Treatment (day) 3 5 7 9 11 13 0 2 4 6 8 10 15 17 Culture * * * * * * * * * CBC * * * * * * * * * Chemistry Panel Ciprofloxacin (Peak / Trough) * * * * * * * “Biodefense solutions to protect our nation” 16 Simulated Ciprofloxacin Serum Concentrations in AGMs Provided by Francis Pelsor (FDA) “Biodefense solutions to protect our nation” 17 Rationale for Treatment Study Design Natural History Study of Pneumonic Plague Conclusions – Fever is the most consistent sign g of clinical illness - When fever present, animals are bacteremic – Y. pestis bacteremia is the gold standard for systemic disease - Takes 2 days to confirm positive blood culture – Fever therefore considered an appropriate marker of the presence of illness Initiation of Treatment Criteria – D Development l t off consistent i t t fever f (≥ 1 1.5°C 5°C above b baseline b li temperature x 2 hours) in the majority of animals – Treated as a group “Biodefense solutions to protect our nation” 18 Results “Biodefense solutions to protect our nation” 19 Delivered Doses Iteration # Order Animal # Sex Wt (kg) MV (ml) Dose (cfu) LD50 1 V494 F 3.9 763 4.2 X 104 124 2 V463 M 5.0 991 3.1 X 104 92 3 V246 M 5.0 1033 4.3 X 104 127 4 V311 M 5.1 846 4.1 X 104 119 5 V527 F 3.4 581 3.3 X 104 97 6 W319 F 3.7 673 3.3 X 104 97 1 W318 F 3.8 600 3.3 X 104 96 2 V524 M 5.7 814 3.9 X 104 114 3 W161 F 3.3 711 3.8 X 104 110 4 V515 M 5.4 965 4.1 X 104 118 5 W352 F 4.3 597 3.8 X 104 110 6 V286 M 5.6 827 3.8 X 104 112 Mean 3.8 X 104 109.7 S.D. 4.1 X 103 11.7 1 2 “Biodefense solutions to protect our nation” 20 Study Outcome Animal # Group Outcome Time to Death (hr) V494 T Live V463 T Live V527 T Live W319 T Li Live W318 T Live W524 T Live W161 T Live V515 T Live V286 T Live V246 TT* Succumbed 248.5 W352 C Succumbed 98.5 V311 C Succumbed 99 T - Treated C – Control •Animal received ~ 8 doses of ciprofloxacin – catheter failure “Biodefense solutions to protect our nation” 21 Survival Curve P = 0.0455 One-tailed Fisher’s exact test “Biodefense solutions to protect our nation” 22 Euthanized Control Time of Placebo Initiation 40 Day Time Clinical Score Respiratory Rate (rpm) AM 20 36 PM 20 28 AM 20 24 PM 20 20 AM 19 24 PM 20 44 AM 17 102 PM 11 82 PM* 5 100 38 37 1 36 35 34 0 24 48 72 Hours Post Exposure 96 120 2 3 CBCs % Te emperature (oC) 39 80 60 40 20 0 LY MO 0 1 2 3 GR Chemistry Panel: Normal 4 *Met criteria for euthanasia Days Post Exposure “Biodefense solutions to protect our nation” 23 Representative Survivor Time of Treatment Initiation Time of Last Treatment CBCs 80 60 % Chemistry Panel: Within normal range throughout study 40 LY 20 MO 0 GR 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Days Post Exposure “Biodefense solutions to protect our nation” 24 Representative Control and Survivor Co pa so Comparison Time of Treatment Initiation Time of Last Treatment 40 Tempera ature (oC) 39 38 37 36 35 34 0 24 48 72 96 120 144 168 192 216 240 264 288 312 336 360 384 408 432 456 480 504 528 552 576 600 624 648 672 696 720 Hours Post Exposure “Biodefense solutions to protect our nation” 25 Temperature (C) AGM with Catheter Failure Day Time Clinical Score Respiratory Rate (rpm) 1 AM 20 32 PM 20 24 AM 20 20 PM 20 24 AM 19 24 PM 20 60 AM 18 53 PM 18 44 AM 17 56 PM 17 64 AM 16 56 PM 17 44 AM 17 40 PM 15 52 AM 20 48 PM 16 52 AM 16 48 PM 10 100 AM 11 108 PM 10 112 AM* 11 120 Time of Treatment Initiation 41 40 39 38 37 36 35 34 Time of Last Treatment * Animal met criteria 0 24 48 72 96 120 144 168 192 Hours Post Exposure 216 240 264 for euthanasia due to abdominal breathing with rales; was anesthetized but succumbed prior to delivery of euthanasia solution 2 3 4 5 6 % CBCs 7 100 80 60 40 20 0 LY MO 0 2 4 6 Days Post Exposure 8 10 GR 8 Ch i t Panel: Chemistry P l High LDH on day 7, otherwise normal 9 10 11 “Biodefense solutions to protect our nation” 26 Bacteremia Summary Time Post Exposure (days) Animal # 3 5 7 9 11 13 Treatment (days) 15 17 Terminal Post Treatment 0 2 4 6 8 10 V494 2830 140 ‐ ‐ ‐ ‐ ‐ ‐ NA V463 7170 ‐ ‐ ‐ ‐ ‐ ‐ ‐ NA V515 5730 ‐ ‐ ‐ ‐ ‐ ‐ ‐ NA V286 2430 ‐ ‐ ‐ ‐ ‐ ‐ ‐ NA V527 190 ‐ ‐ ‐ ‐ ‐ ‐ ‐ NA W319 5400 73 ‐ ‐ ‐ ‐ ‐ ‐ NA W318 2900 ‐ ‐ ‐ ‐ ‐ ‐ ‐ NA V524 22000 30 ‐ ‐ ‐ ‐ ‐ ‐ NA W161 1930 ‐ ‐ ‐ ‐ ‐ ‐ ‐ NA V246 1430 ‐ ‐ 10 W352 993000 > 10E +08 (98.5 hr) V311 30 2.3E +05 (99 hr) 0 (248.5 hr) “Biodefense solutions to protect our nation” 27 Ciprofloxacin Peak and Trough Levels (µg/ml) Day of Treatment 2 Animal # 6 10 Human Target Mean Cmax Pk Tr Pk Tr Pk Tr V494 2.93 <0.5 4.32 <0.5 6.29 <0.5 V463 3.69 <0.5 3.16 <0.5 3.16 <0.5 V515 3.92 <0.5 3.88 <0.5 3.21 <0.5 V286 3.75 <0.5 3.77 <0.5 3.13 <0.5 V527 2.93 <0.5 3.31 <0.5 3.33 <0.5 W319 2.77 <0.5 3.98 <0.5 5.90 <0.5 W318 3.38 <0.5 5.04 <0.5 3.87 <0.5 V524 3.82 <0.5 3.86 <0.5 3.33 <0.5 W161 4.34 <0.5 >ULOQ <0.5 3.99 <0.5 V246 <0.5 <0.5 Mean 3.5* 3.92^ 4.02 4.56 SD 0 53 0.53 0 58 0.58 1 22 1.22 NA * Mean does not include V246 ^ Mean does not include W161 “Biodefense solutions to protect our nation” 28 Pathology • Necropsies and histopathological evaluations were performed on the three monkeys that succumbed to pneumonic plague, plague – 2 controls – Animal with the failed catheter • Both control monkeys had – G Gross evidence id off pneumonia i with ith fluid fl id in i the th nares, tracheal lumen and pleural cavity and mediastinal lymphadenopathy. – Gross and histological lesions and myriad bacilli consistent with acute pneumonic plague. – One had histologic evidence of disseminated intravascular g , which has been reported p as a sequela q to Y. coagulation, pestis infection in the AGM and man. “Biodefense solutions to protect our nation” 29 Summary of Data for AGM with Failed Catheter (V246) • Animal was given 8 doses of ciprofloxacin • Drug level on day 2 (<0.5 µg/ml) of treatment suggests animal received minimal amount of drug prior to complete catheter failure – Documented continuous catheter issues • ~ 48 hr after catheter removal animal bacteremic and fever present • Succumbed within 48 hrs of reappearance of fever • At d death th had h d lesions l i consistent i t t with ith pneumonic i plague l – Some resolution of initial pneumonia (fibrin organization, fibroblast proliferation) – Recr Recrudescence descence of ac acute te pne pneumonic monic plag plague e (al (alveolar eolar flooding flooding, ne neutrophil trophil infiltration and necrosis) “Biodefense solutions to protect our nation” 30 Conclusion • Ciprofloxacin is efficacious in the treatment of p pneumonic plague p g in AGM – 10 day regimen – Dosage of 15 mg/kg delivered over 60 min twice a day in AGM mimics the human regimen of 400 mg IV twice a day in humans “Biodefense solutions to protect our nation” 31 Acknowledgements NIAID Judith Hewitt Kristin DeBord USAMRIID Personnel past and present FDA Lewis Schrager Tracy Macgill Tracy Macgill Dianne Murphy Mary Purucker Brad Leissa Francis Pelsor Francis Pelsor Janice Soreth Susan Thompson Mark Goldberger William Rodriguez William Rodriguez Center for Aerobiological Sciences Veterinary Medicine Division Pathology Division Biostatistics The research described herein was sponsored by FDA / NIAID / USAMRIID Interagency Agreements “Biodefense solutions to protect our nation” 32 Disclaimer Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the US Army. All animal research was conducted in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals and adheres to principles stated in the “Guide for the Care and Use of laboratory Animals”,, Institute of Laboratory Animal Resources, Commission on Animals Life Sciences, National Research Council, National Academy Press, Washington, DC, 1996. The USAMRIID facility, where the animal research was conducted, is fully accredited by the Association for the A Assessment t and d Accreditation A dit ti off Laboratory L b t Animal A i l Care C International. I t ti l “Biodefense solutions to protect our nation” 33 Agenda Treatment of Pneumonic Plague: Medical Utility of Ciprofloxacin Robert Johnson, Ph.D. Director, Office of Regulatory Affairs (ORA) Division of Microbiology and Infectious Diseases (DMID) National Institute of Allergy and Infectious Diseases (NIAID) Efficacy of Ciprofloxacin Therapy for Pneumonic Plague M. Louise M. M M Pitt, Pitt Ph Ph.D. D Chief, Virology United States Army Medical Research Institute of Infectious Diseases (USAMRIID) Nonclinical Pharmacokinetics and Translation to Human Dosing Blaire Osborn, Ph.D. Pharmacokineticist ORA/DMID/NIAID Safety and Benefit/Risk of the Use of Ciprofloxacin for Treatment of Pneumonic Plague Richard Gorman, M.D. Associate Director for Clinical Research DMID/NIAID Summary Robert Johnson, Ph.D. Director, Office of Regulatory Affairs DMID/NIAID Nonclinical Pharmacokinetics and Translation to Human Dosing g Blaire Osborn, Ph.D. Office of Regulatory Affairs Division of Microbiology and Infectious Diseases NIAID, NIH, DHHS April 3, 2012 Approach to This Project Plasma concentration data provide the link between the use of the drug in humans and in the animal model for disease. Ciprofloxacin concentrations attained in humans are documented in the product label. The label concentrations served as the target for the animal exposures. The Th route t and d schedule h d l off administration d i i t ti used matched those approved in the product label. label 36 Ciprofloxacin PIND 113289 Ciprofloxacin Fluoroquinolone antibiotic Concentration-dependent bactericidal activity Bactericidal activity is dependent on both Cmax and d AUC AUC0-24/MIC ~ 100-125 is associated with activity against gram negative bacteria (e.g. Yersinia pestis) 37 Ciprofloxacin PIND 113289 The Target: g Ciprofloxacin Concentrations Reported in Humans A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours. S Source: C Cipro® ® Label - 2/11 / 38 Ciprofloxacin PIND 113289 Data Available Two studies of ciprofloxacin in AGMs 1) Pharmacokinetic study 126-03 • Provided pharmacokinetic data in healthy animals animals. • Pharmacokinetic modeling and simulation was employed to select a dose and schedule for the subsequent efficacy study. 2) Efficacy study A05-04G • Evaluated the efficacy of the selected dose and schedule in pneumonic plague-infected animals. 39 Ciprofloxacin PIND 113289 Pharmacokinetic Study 6 healthy AGMs (3 of each sex) – Single oral doses of 15, 20 and 25 mg/kg – Single IV dose of 15 mg/kg – IV doses of 20 mg/kg once daily for 14 days The same animals were used for all doses following appropriate washout periods. Only the IV route was pursued in the subsequent study, so only those data are presented. 40 Ciprofloxacin PIND 113289 Mean ± SD Plasma Ciprofloxacin Concentrations 0.33 hour IV infusion 41 Study SRI B126-03 Ciprofloxacin PIND 113289 First Hour of Study 0 33 hour IV infusion 0.33 42 Study SRI B126-03 Ciprofloxacin PIND 113289 IV Pharmacokinetic Parameters Ci Ciprofloxacin fl i Dose D 15 mg/kg 20 mg/kg (1st dose) 20 mg/kg (14th dose) Cmax (µg/mL) 9.34 ± 0.89 11.7 ± 1.56 27.33 ± 23.95 tmax (h) 0.31 ± 0.06 0.3 ± 0.07 0.23 ± 0.08 6118 ± 991 5456 ± 802 4815 ± 779 AUC(0-t) (µg•h/mL) ( h/ L) 12 12 ± 2.43 12.12 2 43 18 83 ± 3.22 18.83 3 22 17 82 ± 3.22 17.82 3 22 t1/2 (h) 3.37 ± 0.57 2.8 ± 0.33 2.36 ± 0.5 CL (mL/kg/h) 1277 ± 235 1361 ± 236 1447 ± 291 Parameter Vz (mL/kg) Ciprofloxacin PIND 113289 43 Exposure in Humans and AGMs Human 1 hr infusion AGM 15 mg/kg 0.33 hr infusion AGM AGM 20 mg/kg 0.33 hr infusion Cmax (µg/mL) 4.56 9.34 11.7 AUC AUC (µg/mL•h) 12.7 12.1 18.8 Parameter Conclusion Human target Cmax exceeds target exposure based concentration on label AUC comparable to target exposure target exposure Ciprofloxacin PIND 113289 Cmax and AUC both exceed target exposure 44 Increasing the Infusion Time 0 33 h 1 h Reduces the Cmax 0.33 Concen ntration (g/mL L) 10 0.33 h infusion time Exceeds Target C max 1 0.1 0 1 2 3 4 5 6 7 8 9 10 11 12 Hours ou s Con ncentration (g g/mL) 10 1 h infusion time AchievesTarget C max 1 0.1 0 1 Ciprofloxacin PIND 113289 2 3 4 5 6 Hours 7 8 9 10 11 12 45 Simulated Serum Concentrations i AGMs in AGM Source: USAMRIID Final Report A05-04G: Ciprofloxacin Therapy for pneumonic plague in the African Green Monkey 46 Ciprofloxacin PIND 113289 Efficacy Study S d Design Study D i 12 AGMs Exposure dose ~100 LD50s of Yersinia pestis (CO92) 10/12 given i ciprofloxacin i fl i (15 mg/kg /k every 12 hr for 10 days). 2/12 control group given 5% dextrose in saline Serum samples for ciprofloxacin concentration y were obtained p prior to dosing g ((trough) g ) analysis and at the conclusion of the 1 hour infusion (peak) on the 2nd, 6th and 10th day of drug administration. administration 47 Ciprofloxacin PIND 113289 PK Results – Efficacy Study No animal had q quantifiable drug g in trough g samples. Drug clears completely between doses. 9/10 drug-treated drug treated animals had ciprofloxacin in peak samples. 9/10 drug-treated animals survived pneumonic plague. l 1/10 drug-treated animals had no detectable peak ciprofloxacin p concentration. This animal had a malfunctioning drug catheter and did not survive plague exposure. 2/2 control animals succumbed to pneumonic plague. 48 Ciprofloxacin PIND 113289 No Quantifiable Serum Ciprofloxacin Trough Concentrations in Plague-Infected AGMs 2 Malfunctioning catheter Animal ID V494 V463 V515 V286 V527 W319 W318 V524 W161 V246 Day of Treatment 6 10 Serum Ciprofloxacin Concentrations (µg/mL) <0.5 <0 5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0 5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 NS <0.5 <0 5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 <0.5 NS Dose and schedule: 15 mg/kg every 12 h as a 1 hour IV infusion for 10 days Source: USAMRIID Final Report A05-04G: Ciprofloxacin Therapy for pneumonic plague in the African Green Monkey Ciprofloxacin PIND 113289 49 Mean Peak Serum Ciprofloxacin Concentrations are Below the Average g Human Cmax in Plague-Infected AGMs 50 Ciprofloxacin PIND 113289 Efficacy Study C Conclusions l i Ciprofloxacin-treated Ciprofloxacin treated monkeys survived and control monkeys did not. The mean Cmax in plague plague-infected infected AGMs is 77-88% of the 4.56 µg/mL Cmax reported for humans given 400 mg by IV infusion infusion. AUC was not determined in this study, h however, an estimate ti t off AUC iin th the FDA dosing simulation is 12.6 µg•h/mL. 51 Ciprofloxacin PIND 113289 Pharmacodynamics in Adults Parameter Human AGM Cmax µg/mL 4.56 3.8† AUC0-12 µg•h/mL 12.7 12.6‡ AUC/MIC 423 420 Cmax/MIC 152 127 • MIC = 0.03 µg/mL • AUC/MIC ratio of 100 - 125 is associated with activity against gram negative bacteria • Cmax/MIC ratio of >10 is associated with activity against gram negative bacteria • †Mean peak data (all days) • ‡Approximated A i t d ffrom th the FDA dosing d i prediction di ti 52 Ciprofloxacin PIND 113289 Pediatric Patients Ciprofloxacin is approved for use in pediatric patients for certain severe infections (complicated urinary tract tract, pyelonephritis and anthrax) The dose is 6 6-10 10 mg/kg every 8 hours for 10-21 days 53 Ciprofloxacin PIND 113289 Pediatric Exposure Dose IV 1 h infusion Cmax (µg/mL) AUC (µg•h/mL) <1 year 10 mg/kg 6.1 17.4 1-5 years 10 mg/kg 7.2 16.5 Age Pediatric patients given 10 mg/kg have higher Cmax and larger AUC than adults given 400 mg IV 54 Ciprofloxacin PIND 113289 Pharmacodynamics in Children Parameter <1 year 1-5 years Adults AGM Cmax µg/mL 6.1 7.2 4.56 3.8 AUC µg•h/mL 17.4 16.5 12.7 12.6 AUC/MIC 580 550 423 420 Cmax/MIC 203 240 152 127 • MIC = 0.03 µg/mL • The predicted elimination half-life in children is similar to adults (4-5 hours) • The Th drug d iis llargely l excreted t d unchanged h d iin th the urine i iin adults. d lt 55 Ciprofloxacin PIND 113289 Conclusions A dose of 15 mg g ciprofloxacin/kg p g every y 12 h is sufficient to treat an otherwise lethal exposure to pneumonic plague in AGMs The achieved Cmax in AGMs is ≤88% of that reported for humans given 400 mg by IV infusion The Cmax/MIC ratio in AGMs is below that calculated for humans (127 in AGMs vs. 152 in humans) Given the 400 mg dose in humans results in a higher Cmax and a similar AUC compared to the AGMs, a 400 mg IV dose should be sufficient to treat pneumonic plague in adults 56 Ciprofloxacin PIND 113289 Conclusions continued Conclusions, Pediatric p patients g given 10 mg/kg g g IV every y 8 hours have a greater Cmax and AUC than adults given 400 mg IV every 12 hours Cmax in AGMs is 56 56-66% 66% of that reported for pediatric patients given 10 mg/kg by IV infusion. The Cmax/MIC ratio in AGMs resulted in efficacy, y but is below that calculated for children (127 in AGMs vs. 203-240 in pediatric patients) Given the greater Cmax and AUC in children children, an IV dose of 10 mg/kg every 8 h should be sufficient to treat pneumonic plague in this population. 57 Ciprofloxacin PIND 113289 Agenda Treatment of Pneumonic Plague: Medical Utility of Ciprofloxacin Robert Johnson, Ph.D. Director, Office of Regulatory Affairs (ORA) Division of Microbiology and Infectious Diseases (DMID) National Institute of Allergy and Infectious Diseases (NIAID) Efficacy of Ciprofloxacin Therapy for Pneumonic Plague M. Louise M. M M Pitt, Pitt Ph Ph.D. D Chief, Virology United States Army Medical Research Institute of Infectious Diseases (USAMRIID) Nonclinical Pharmacokinetics and Translation to Human Dosing Blaire Osborn, Ph.D. Pharmacokineticist ORA/DMID/NIAID Safety and Benefit/Risk of the Use of Ciprofloxacin for Treatment of Pneumonic Plague Richard Gorman, M.D. Associate Director for Clinical Research DMID/NIAID Summary Robert Johnson, Ph.D. Director, Office of Regulatory Affairs DMID/NIAID 58 Ciprofloxacin for Pneumonic Plague Risks vs. Benefit Richard L. Gorman, M.D. Associate Director for Clinical Research Division of Microbiology and Infectious Diseases NIAID, NIH, DHHS April 3, 2012 Risk vs. Benefit Disclaimer: – Almost everything you have heard about ciprofloxacin for use in this treatment model for pneumonic plague is based on intravenous dosing. g – Almost everything y g yyou will hear about safety, y, efficacy and indications for ciprofloxacin in this presentation is based on oral dosing. 60 Ciprofloxacin PIND 113289 The Target: g Ciprofloxacin Concentrations Reported in Humans ≈ A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours. S Source: C Cipro® ® Label - 2/11 / Ciprofloxacin PIND 113289 61 Drug Description A synthetic broad spectrum antimicrobial agent Mechanisms of Action – Bactericidal – Inhibits topoisomerase II and topoisomerase IV – Both are DNA – gyrases enzymes that are involved in replicating and repairing genetic material Mechanisms of Resistance – Decrease membrane permeability – Increase drug efflux – DNA gyrase mutations 62 Ciprofloxacin PIND 113289 Clinical Pharmacology Absorption • Well absorbed orally • 500 mg orally equivalent to 400 mg IV • Little first pass metabolism Distribution Di t ib ti • 20% to 40% protein bound • Tissue levels often higher than serum levels Metabolism M t b li • Inhibits human cytochrome P450 1A2 (CYP1A2) • 4 metabolites in urine: all have weak antimicrobial activity Excretion E ti • Renal excretion: 50% unchanged • Serum half-life 4 hours 63 Ciprofloxacin PIND 113289 Regulatory History 1987: Ciprofloxacin approved by the FDA for Gram positive and Gram negative infections 1991: 1991 IV fformulation l ti approved d 1994: Expanded indications to include uncomplicated gonorrhea and typhoid fever 1996: FDA publishes warning about acute tendon rupture in FDA Medical Bulletin 1997: Precautions added for CNS events: convulsion, increases in intracranial pressure 64 Ciprofloxacin PIND 113289 Regulatory History 1998: Safety information from a pediatric trial added 2000: Anti- Infective Advisory Committee recommends and FDA approves indications for inhalation anthrax: Not by “Animal Rule” 2004: Pediatric indication for complicated UTI and pyelonephritis 2008: Black box warning for acute tendon rupture 2011: Black box warning for exacerbation of Myasthenia Gravis 65 Ciprofloxacin PIND 113289 Black Box Warning presently on the Package Insert 66 Ciprofloxacin PIND 113289 Acute Tendon Rupture Signal Detected in FDA Adverse Event Reporting System (AERS) Different age • “Athletically” induced 35 years • “Ciprofloxacin” induced 64 years Estimated E i dF Frequency off ciprofloxacin i fl i iinduced d d6 6-37/100,000 3 /100 000 • ~ 90% are Achilles Tendons Odds Ratio: ciprofloxacin induced:naturally occurring • 4 X age matched controls • 46 X age matched controls on corticosteroids 67 Ciprofloxacin PIND 113289 Contraindications Hypersensitivity to any quinolone Concomitant administration of tizanidine – Tizanidine: decreases muscle tone and spasms in multiple sclerosis 68 Ciprofloxacin PIND 113289 Warnings • • • • • • • • • Tendon rupture Exacerbation of Myasthenia Gravis Hypersensitivity reactions Pregnant/Lactating women Theophylline Central nervous system effects C difficile-associated C. diffi il i t d di diarrhea h Peripheral neuropathy Musculoskeletal disorders in pediatric patients and arthropathic effects in animals • Prolongation of the QT interval Cytochrome o e P450 50 (C (CYP450) 50) d drug ug interactions te act o s • Cytoc 69 Ciprofloxacin PIND 113289 Drug Interactions • Tizanidine • Theophylline • Other Xanthine Derivatives: Caffeine • Methotrexate • Duloxetine • Oral Anti-coagulants Anti coagulants • Ropinirole • Sildenafil • Class 1A and III Antiarrhythmics • Chelation Complex Formation • Omeprazole • Phenytoin y • Glyburide • Metronidazole • Cyclosporine • Probenecid • Metoclopramide • Lidocaine • Clozapine 70 Ciprofloxacin PIND 113289 Special Populations Pediatrics – Multiple pediatric and adult studies demonstrate increased adverse events related to joints and surrounding tissues – Preclinical studies: lameness in immature dog g • Histopathology: Persistent lesions in the cartilage Pregnancy – Animal reproductive studies have shown adverse effect on fetus – Multiple limited studies in pregnant women did not demonstrate risk Lactation – No toxicityy signal g Geriatrics – Acute tendon rupture Renal Failure – Dose adjustment if creatinine clearance ≤ 50 mL/min Ciprofloxacin PIND 113289 71 Usage 1987: Declared “safe and effective” by the FDA 1999 1999: Ci Ciprofloxacin fl i # 11 in i scripts i t and d # 20 iin dollars spent in the USA. Estimated market ~$1 Billion 2010: The fourth most commonlyy prescribed p antibiotic after amoxicillin, azithromycin and cephalexin 72 Ciprofloxacin PIND 113289 The Target: g Ciprofloxacin Concentrations Reported in Humans ≈ A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours. S Source: C Cipro® ® Label - 2/11 / 73 Ciprofloxacin PIND 113289 Selected Indications Indication Severity Oral Dose (mg) Duration (days) Acute UTI Uncomplicated 250 3 Lower Respiratory Tract Lower Respiratory Tract Mild /Moderate Mild /Moderate 500 7 14 7 – Chronic Prostatitis Mild/Moderate 500 28 Bones and Joints Severe/Complicated 750 28 – 42 500 60 Inhalation Anthrax 74 Ciprofloxacin PIND 113289 Selected Indications Indication Severity Dose (mg) Duration( days) Acute UTI Uncomplicated 250 3 Lower Respiratory Tract Mild /Moderate 500 7 – 14 400 IV ≈ 500 PO 14 500 28 Pneumonic Plague Chronic Prostatitis Mild/Moderate Bones and Joints Bones and Joints Severe/Complicated 750 Inhalation Anthrax 500 28 – 42 28 60 75 Ciprofloxacin PIND 113289 Restatement of Issue The mortalityy rate of untreated p pneumonic p plague g is close to 100%. There is presently no antibiotic with a labeled indication for pneumonic plague. 76 Ciprofloxacin PIND 113289 Conclusion Ciprofloxacin has been widely used and is well understood. Ciprofloxacin is labeled safe and effective for similar infections with similar doses and duration of treatment. Ciprofloxacin is labeled safe and effective for other infections with both higher doses and longer duration. 77 Ciprofloxacin PIND 113289 Agenda Treatment of Pneumonic Plague: Medical Utility of Ciprofloxacin Robert Johnson, Ph.D. Director, Office of Regulatory Affairs (ORA) Division of Microbiology and Infectious Diseases (DMID) National Institute of Allergy and Infectious Diseases (NIAID) Efficacy of Ciprofloxacin Therapy for Pneumonic Plague M. Louise M. M M Pitt, Pitt Ph Ph.D. D Chief, Virology United States Army Medical Research Institute of Infectious Diseases (USAMRIID) Nonclinical Pharmacokinetics and Translation to Human Dosing Blaire Osborn, Ph.D. Pharmacokineticist ORA/DMID/NIAID Safety and Benefit/Risk of the Use of Ciprofloxacin for Treatment of Pneumonic Plague Richard Gorman, M.D. Associate Director for Clinical Research DMID/NIAID Summary Robert Johnson, Ph.D. Director, Office of Regulatory Affairs DMID/NIAID Treatment of Pneumonic Plague: Medical Utility of Ciprofloxacin p Robert Johnson, Ph.D. Director Office of Regulatory Affairs Director, Affairs, Division of Microbiology and Infectious Diseases NIAID NIH, NIAID, NIH DHHS April 3, 2012 79 Summary The efficacy study demonstrated that p cured p pneumonic p plague g in ciprofloxacin the African Green Monkey model. The achieved serum concentrations in the AGM aligned with those achieved in humans following doses of 400 mg IV every 12 hours hours. 80 Ciprofloxacin PIND 113289 Summary Based on the safety profile of ciprofloxacin and mortality associated with untreated pneumonic plague plague, the risk:benefit of the proposed dosing regimen is comparable to that of other approved indications of ciprofloxacin. Currently, Currently there are no licensed antibiotics with an indication for treatment of pneumonic plague plague. 81 Ciprofloxacin PIND 113289 Thank you y 82
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