Population PK-PD modeling of Phase 1 data of PNU to guide doses for Phase 2a study

Transcription

1 Population PK-PD modeling of Phase 1 data of PNU to guide doses for Phase 2a study V Kumar 1, J Liu 1, RS Wallis 1, W Jakubiec 2, AM Silvia 1, T Zhu 1, Paige D 1, G Nucci 1 1 Pfizer Global R&D, Groton Laboratories, CT, 2 VA Hosptial, New Haven, CT 1

2 PNU (Oxazolidinone) X N F Thiomorpholinyl derivative of linezolid Superior activity compare to LZD in mouse TB model* PNU is oxidized to active 2 metabolites PNU (sulfoxide, mean plasma levels 5-7x parent) PNU (sulfone, mean plasma levels 1/7 th parent) M. tuberculosis MIC90 parent = 0.25 g/ml O N O X = O = Linezolid X = S = PNU X = S(O) = PNU X = S(O) 2 = PNU H N O *Williams KN et al. Antimicrob Agents Chemother. 2009; 53(4):

3 Phase 1 Study Design Randomized, investigator & subject blinded, placebo substitution Objectives of Studies Safety and tolerability after single and multiple doses PK of PNU and its metabolites Bactericidal activity using Whole Blood Assay (WBA) First in Human Wallis RS et al. J Infect Dis. 2010; 202(9):

4 Phase 1 Study Design Multiple Ascending Study (MAD) With Food 9/20/2010 Pfizer confidential

5 Whole Blood Assay (WBA) Intracellular TB infection model Appropriate biomarker to study ex vivo: Drug combinations Drugs with active metabolites Drugs with intracellular accumulation Blood diluted with equal volume tissue culture medium, and infected with M. tuberculosis H37Rv Cultured 72 hrs, RBCs lysed, pellet washed, bacilli recovered and inoculated into Mycobacterial Growth Indicator Tubes (MGIT) Change in viability ( log CFU) determined by measuring time to positive (TTP) Wallis RS et al. J Infect Dis 2001; 183:

6 Objectives To describe the exposure-response relationship of PNU active moiety using Phase 1 data Use PK/PD analysis to select the doses/regimen for Phase 2a study 6

7 Observed SS Mean PNU T max 1-2 hrs (Fasting) Slight shift in Tmax with food (1.5 to 3 hours) Fast Turnover in Humans Terminal T 1/ hrs Concentration above MIC for ~ 6hrs at doses > 600mg 7

8 Observed SS Mean PNU (Major Metabolite) Exposure of major metabolite is 5-7 times of parent Combined exposures of the active analytes increased approximately proportionally 8

9 Observed Mean Bacterial Killing (WBA) WBA (Delta log CFU) Placebo 100 mg BID 300 mg BID 600 mg BID 1200 mg QD Time (Hours) Increasing dose resulted in increased net killing Maximal mean WBA activity observed is -1.1 Log in SAD (-0.37 log/day) and Log (-0.42 log/day) in MAD study 9

10 PK Data Analysis PK and PK-PD analyses were performed using NONMEM v6 A mixed-effects, one- compartment PK model (ADVAN2, TRANS2) with lagged first order absorption and first order elimination was fitted to the concentration-time data PK data is composite concentration of parent and major metabolite (PNU PNU ) Minor metabolite concentration was ignored as it stayed well below the MIC value Model selection was based on the change in objective function value based on the maximum likelihood test and goodness of fit plots. 10

11 PK-PD Data Analysis Log CFU declined were modeled using a direct, 4 parameters Imax response model using the $PRED subroutine I max * C Eff I0 IC C where, Eff = Model predicted decline in Log(CFU) I 0 = Baseline Log(CFU) I max = Maximum decline IC 50 = Concentration at which 50% of maximal killing occurs C = Observed concentration (Parent + Major Metabolite) Similar Protein binding and highly free Assumed equipotent Formation rate limited elimination Final model parameters from PopPK and PD model were used to simulate the responses at various doses/regimen

12 Final PopPK Model: Goodness of Fit Plots Parameter estimates from PNU PK model Parame ter Typical Value (% RSE) K a (/hr) 3.52 (26.5) CL /F (L/hr) 25.1 (3.5) V (L) 119 (4.8) T lag (hr) (5.6) Food 0.15 (29) IIV % CV (% RSE) 64 (16) 17 (13.5) 18 (27) 16 (26) - 12

13 Final PK-PD Model Parameter Estimates from Final I max Model Parame ter Typical Value (% RSE) I (12.3) I max 1.77 (5.6) IIV % CV (% RSE) 31 (17) NE Observations Basic goodness-of-fit plots (Run 8) Basic GOF Plots Population predictions Observations Individual predictions IC (10.6) 1.47 (15) 34 (22) NE iwres Weighted residuals Individual predictions Concentration Time 13

14 Log(CFU) vs Concentration (Observed & Model Predicted) Individual observations and model predictions with 5th and 95th conf. interv Delta log(cfu) CONC (ng/ml) 14

15 Projected Time Course of Bacterial Killing Total Daily Dose: mg PNU Simulations were performed from 600 to 1200 mg total daily doses using different regimens 15

16 Summary PNU was well tolerated in single doses up to 1500 mg and total daily doses up to 1200 mg for 28 days in MAD study Bactericidal activity in WBA increased approx. proportionally with dose, and was mainly due to the sulfoxide metabolite One compartment model provided a good description of the active moiety data I max model described the FIH WBA data appropriately I max = 1.77 drop in log CFU and IC 50 = 647 ng/ml Simulations using PNU as monotherapy suggested that a total daily dose of mg would likely provide the optimum efficacy 16