TB-Epidemiology. Tuberculosis Drug Development: PK/PD Challenges

Transcription

1 7 th Symposium on ew Developments in 7 th Global Meeting, Tuberculosis Drug Development: PK/PD Challenges Bernd Meibohm, PhD, FCP Professor & Associate Dean for Graduate Programs and Research College of Pharmacy The University of Tennessee Health Science Center Memphis, T, U.S.A. TB-Epidemiology 2 billion people are infected with latent TB in people infected with TB bacilli will become sick with active TB in their lifetime early 2 million deaths are caused by TB annually (5000 people/day) ~ million new cases/year TB is a leading killer among HIV- infected people with weakened immune systems Resistant TB 500,000 cases of MDR-TB in all 9 WH countries 55 countries: XDR-TB Global Tuberculosis Control: epidemiology, strategy, financing: WH report 2009 Bernd Meibohm, PhD, FCP, University of Tennessee

2 ) ) 7 th Symposium on ew Developments in Anti-TB Drugs Sassetti & Rubin. at Med 2007; 3: Dorman & Chaisson, at Med 2007; 3: Lee 562: Pharmacokinetics MIC mg/l 00 0 IV, mg/kg g 00 0 RAL, mg/kg Route Half-life AUCinf Volume of Distribution Clearance Bioavailability hr µg-hr/l L/kg L/hr/kg % IV RAL % Excreted unchanged Lee 562 into urine and feces was less than % after both oral and IV administration Bernd Meibohm, PhD, FCP, University of Tennessee 2

3 7 th Symposium on ew Developments in Lee 562: Metabolic Stability Pooled rat liver microsomes 2 H 20% Test Control % Remaining after 60 min: 0.46% ing % Remain % 80% 60% 40% 20% 0% Time (min) Second Generation: Structure st generation 2 H Lee nd generation 2 2 CH 3 Lee 878 MIC mg/l Microsomal stability: 3.4% remaining after 90 min Lee 952 MIC mg/l Microsomal stability: 4.3% remaining after 90 min Bernd Meibohm, PhD, FCP, University of Tennessee 3

4 7 th Symposium on ew Developments in Second Generation: In Vivo PK Lee 878 Lee IV, mg/kg 00 IV, mg/kg RAL, mg/kg 0 RAL, mg/kg 0 F = 27.4% F = 5.9% Third Generation Metabolic Stability % Remaining PC Lee 6 Lee 9 Lee 880 Lee 53 Lee 879 Lee 3 Lee 98 Lee 20 Lee 992 Bernd Meibohm, PhD, FCP, University of Tennessee 4

5 7 th Symposium on ew Developments in Third Generation: Structure st generation 2 H Lee nd generation 2 2 CH 3 Lee 878 Lee 952 F 3 rd generation 2 F F Budha et al., AAPS J 2008; : Lee 6 Third Generation: In Vivo PK Lee 6 Conc. (ug/ /L) IV, mg/kg Conc. (ug/ /L) 00 0 RAL, mg/kg Good in vitro activity: MIC mg/l Good metabolic stability: 90 min Long elimination half-life:.3 hr Poor ral Bioavailability (4.6% ) secondary to limited aqueous solubility overcome by formulation Hurdle et al., J Antimicrob Chemother 2008; 62: Bernd Meibohm, PhD, FCP, University of Tennessee 5

6 7 th Symposium on ew Developments in In vitro PK/PD Model to Determine Time-Kill Curves of Antibiotics against Slow-Growing Microorganisms Mycobacterium bovis BCG as surrogate for virulent M. tuberculosis Time-Kill Curves: Experimental Dilution µl µl µl µl µl µl Sample to be counted 900 µl medium Plate µl samples / ( -2 ) /0 ( -3 ) /00 ( -4 ) /000 ( -5 ) /0000 ( -6 ) /00000 ( -7 ) Incubation at 37ºC for 4 weeks Too many colonies to count 59 colonies 7 colonies 2 colonies 0 colonies 59 X 4 =.59 X 6 Plate count Dilution factor CFU/mL of riginal Sample Bernd Meibohm, PhD, FCP, University of Tennessee 6

7 7 th Symposium on ew Developments in Time-Kill Curves: Isoniazid mg/day SA 25 mg/day FA mg/day SA mg/day FA 300 mg/day SA 300 mg/day FA M. bovis BCG (CFU/m ml) Slow Acetylators CTL 25 mg/day mg/day 300 mg/day 92 M. bovis BCG (CFU/mL L) Fast Acetylators E+08 CTL 25 mg/day mg/day 300 mg/day 92 Time-Kill Curves: Lee 6 Data Analysis d dt k = 0 max I max C IC50 A + C Growth function Kill function (drug effect) IC50 A Adaptation Constant AUC 0 24 = IC50 e 0 t umber of bacteria (CFU/mL) 0 Initial cell numbers in the flask max Maximum cell numbers in the flask K 0 Maximum growth rate constant in the absence of drug I max Maximum bacterial kill rate IC 50 Free concentration required to produce half-maximal effect IC 50A Adaptive IC 50 AUC 0-24 : Area under free concentration-time profile of Lee 6 Bernd Meibohm, PhD, FCP, University of Tennessee 7

8 7 th Symposium on ew Developments in M. bo ovis BCG (CFU/mL) 92 Parameter Units Between Estimate Experiment (% CV) Variability (%CV) k 0 hr (5.7) na IC50 mg/l 0.55 (35.3) 57. Adaptation constant L/mg.hr (9.2) 54.2 I max hr (3.) na Residual Variability (%CV) 60.9 (33.4) Control 0. mg/kg 0.3 mg/kg mg/kg 3mg/kg mg/kg Time-Kill Curves: Lee 6 bserved & Predicted Data vs.time Time-kill Curves: Lee 6 umerical Simulations For dose optimization of efficacy studies: Efficacy studies in mouse models of TB infection Extralopation of PK from rat to mouse using allometric scaling To predict the bactericidal effect of Lee 6 on M. bovis BCG at untested t dosing regimens in mice 0 datasets simulated with stochastic variability in PD parameters for once daily, twice daily, once weekly and twice weekly dosing regimens Bernd Meibohm, PhD, FCP, University of Tennessee 8

9 7 th Symposium on ew Developments in Lee 6: Simulated Efficacy nce Daily Dosing Regimens.E+.E+ 0. mg/kg 0.3 mg/kg mg/kg g 3 mg/kg mg/kg Lee 6: Simulated Efficacy Twice Daily Dosing Regimens.E+.E+ 0. mg/kg 0.3 mg/kg E+08 mg/kg E+08 3 mg/kg mg/kg Bernd Meibohm, PhD, FCP, University of Tennessee 9

10 7 th Symposium on ew Developments in Lee 6: Simulated Efficacy nce Weekly Dosing Regimens.E+ E+09.E+ E mg/kg 0.3 mg/kg mg/kg 3 mg/kg mg/kg Lee 6: Simulated Efficacy Twice Weekly Dosing Regimens.E+.E+ 0. mg/kg 0.3 mg/kg 3 mg/kg mg/kg g mg/kg Bernd Meibohm, PhD, FCP, University of Tennessee

11 7 th Symposium on ew Developments in PK/PD Guided Lead ptimization Design of Lead Compounds In silico Predictions Feedback Chemical Synthesis Screening for in vitro Activity Feedback In vitro Screen of Biopharmaceutic/ Pharmacokinetic Properties (Solubility, Metabolic Stability and Protein Binding) In vivo PK in Rats In vitro Time-Kill Studies In vivo Efficacy Models (e.g., M.tb mouse infection model) Budha et al., AAPS J 2008; : Acknowledgements 22 University of Tennessee College of Pharmacy ational Institute of Allergy and Infectious Diseases / IH Team: ageshwar R. Budha, PhD Pavan K. Vaddady, MS Robin B. Lee, MS Julian G. Hurdle, PhD Richard E. Lee, PhD Bernd Meibohm, PhD, FCP, University of Tennessee Bernd Meibohm, PhD, FCP, University of Tennessee