Exposure-Response Analysis of Lee 1810, a Lead Spectinamide Antibiotic in Mycobacterium tuberculosis Infected Mice

Transcription

1 15 th October 2017 Exposure-Response Analysis of Lee 1810, a Lead Spectinamide Antibiotic in Mycobacterium tuberculosis Infected Mice Santosh Wagh 1, Chetan Rathi 1, Gregory T. Robertson 3, Jiuyu Liu 2, Michael S. Scherman 3, Richard E. Lee 2, Anne J. Lenaerts 3, Bernd Meibohm 1 1 University of Tennessee Health Science Center, Memphis, TN 2 St. Jude Children's Research Hospital, Memphis, TN 3 Colorado State University, Fort Collins, CO 1

2 Global New TB Drug Pipeline

3 Study Objective To assess the exposure-response relationship of Lee 1810 in Mycobacterium tuberculosis infected mice using a semi-mechanistic PK/PD modelling approach Provide a mechanistic basis for dose and dosing regimen selection in subsequent preclinical and clinical studies, including combination trials 3

4 Concentration HOLIDAY HOLIDAY HOLIDAY Study design for Exposure-Response analysis of Lee1810 SC Dose Response Bacterial Growth Phase (5 weeks) Treatment (4 weeks) Wash out (2 days) CFU Inoculum Rx Start Rx End Euthanized DAY Study conducted at CSU by Dr. Lenaerts Group Exposure Time (Day) PK h 8h 4

5 Dose Fractionation Scheme (27 groups) Total Weekly Dose (mg/kg) x per week twice daily BID 10 BID 20 BID 50 BID 100 BID 200 BID 300 BID 400 BID 5x per week QD 20 QD 40 QD 100 QD 200 QD 400 QD 600 QD 3x per week TIW 20 TIW 40 TIW 100 TIW 167 TIW 200 TIW TIW 400 TIW 2x per week BIW 20 BIW 40 BIW 100 BIW 200 BIW 1x per week QW 20 QW 40 QW 100 QW N=5 mice in each group PK Sampling Day: Monday: QW, BIW Tuesday: BID Wednesday: TIW Thursday : QD 5

6 Concentration HOLIDAY HOLIDAY HOLIDAY Pharmacokinetic Analysis PK h 8h Time (Day) 6

7 Simultaneous PopulationPK analysis of infected and healthy mice PK data Single dose of 200 mg/kg by subcutaneous route in healthy BALB/c mice n=3 at each time Dose K a P Q/F Q/F C CL/F 7

8 Pharmacodynamic Results Log CFU 8

9 Lee 1810 shows dose-dependent response Individual dose mg/kg Std. Error Mean Observed 9

10 Lee1810 exhibits concentration-dependent killing Weekly dose mg/kg Std. Error Mean Observed 10

11 Bacterial count Bacterial count Concentration Scheme for development of PK/PD model of Lee 1810 PK Model Time Bacterial Growth Model Time PK/PD Model Time 11

12 Drug-responsive (sensitive) population Two-subpopulation Mtb growth model adequately describes untreated group data Drug-unresponsive (persister) population K rep (K rep K ir ) (N 1 + N 2 ) N max Parameters Typical value %BSV Krep (h -1 ) N 1 N 2 PRED (N 1 + N 2 ) Observed data N 1,0 (Log CFU) 1.93 K ir K ir Nmax (Log CFU) K ir (h -1 ) RUV (% CV) 32.4 N 1,0 is the bacterial cell count in Log CFU at the start of experiment, K rep is the bacterial net growth rate constant, N max is the maximum number of bacteria, K ir is the death rate constant (in the absence of drug induced by the immune system) Based on Nielsen et al., Antimicrob Agents Chemother 2007, 51,

13 Integration of Mtb growth model with PK model to form the PK/PD model PK PD Dose K a K rep (K rep K ir ) (N 1 + N 2 ) N max P Q/F C N 1 N 2 Q/F CL/F K ir K ir E max C γ EC γ 50 + C γ E max is the maximum kill rate induced by Lee 1810, C is concentration of Lee 1810 at time t, EC 50 is the concentration of Lee1810 at half maximal rate and γ is the hill function, C is the central drug compartment, P is the peripheral drug compartment. 13

14 Weekly dose-response relationship indicates concentration-dependent killing with plateau effect Pink, purple and green bands represents 80% prediction interval, 70% prediction interval, and 60% prediction interval of simulated data respectively. Solid black line is the median of simulated data and open circles are the observations. 14

15 Simulation with two-subpopulation Mtb growth model Hypothesis: Combination of spectinamides with agents active against slow growing bacteria can improve efficacy N 1 (Sensitive) N 2 (Persister) N 1 + N 2 (Total) 15

16 Log CFU in lung Combination of spectinamides with sterilizing anti-tb agents significantly improves efficacy BALB/c high dose aerosol model * Sensitive Persister * P < by pairwise multiple comparison procedures 1 0 Untreated Lee 1599 (200) Lee 1810 (200) Lee PZA (150) Lee 1599 (200) + PZA (150) J Antimicrob Chemother Mar 1;72(3):

17 Clinical Concentration Preclinical Concentration Efficacious Human Dose Prediction Dose Exposure AUC C max Physiologically-based PK modeling and interspecies scaling (Simcyp v.16, Certara) suggest that efficacious systemic exposures can be achieved with daily doses feasible in humans:? Time Human dose of 15 mg/kg provided similar exposure as 50 mg/kg dose in mouse C max AUC Human dose of 55 mg/kg provided similar exposure as 200 mg/kg dose in mouse Time

18 Summary for Exposure-Response Analysis for Lee 1810 Efficacy is largely driven by concentration-dependent killing This supports the use of intermittent dosing Combination with other anti-tb agents having activity against slow growing mycobacteria can increase bacterial kill and potentially efficacy Preclinical PK/PD relationships can be used to determine optimal doses and dosing regimens in subsequent preclinical and clinical studies, including combination trials 18

19 Acknowledgments Dr. Bernd Meibohm Dr. Chetan Rathi Dr. Pradeep Lukka Dr. Richard Lee Dr. Jiuyu Liu Dr. Anne Lenaerts Dr. Gregory Robertson Michael Scherman