Long Half-life Drugs in Infectious Diseases: Implications and Complications

Transcription

1 Long Half-life Drugs in Infectious Diseases: Implications and Complications In Session: Drugs That Just Won t Leave: From Stars of the Party to Unwelcome Guests Annual Meeting of the AAPS, San Diego, California Tuesday November 4, 2014 Alan Forrest 1,3* Jürgen B. Bulitta 2,1 Olanrewaju Okusanya 1,3 Elizabeth Lakota 3,1 1: State University of NY at Buffalo Schools of Pharmacy & of Medicine 2: Monash University Institute of Pharmaceutical Sciences Melbourne Australia 3: Institute for Clinical Pharmacodynamics Buffalo & Latham NY * forrest@buffalo.edu Authors Copyright All rights reserved. 1

2 Paul Ehrlich ( ): 1908 Nobel Prize for Physiology/Medicine German physician and scientist Pioneer in hematology, immunology, oncology and infectious diseases Invented the predecessor of Gram staining Autoimmunity, side-chain theory, antigenantibody interactions Named and defined the concept of chemotherapy Early work illuminated the existence of the bloodbrain barrier Therapia magna sterilisans, chemotherapia specifica; arsphenamine (Salvarsan), the first magic bullet (1910) 2

3 Outline Heterogeneity of bacterial isolates Mixture models for antibacterial PD Definition and rationale for PD front loading Azithromycin (AZT) sustained release formulation Oritavancin (ORI) and Staph aureus pneumonia ORI: complicated skin and skin structure infections Dalbavancin and optimal sparse sampling strategies Take-home messages 3

4 Heterogeneous 12 Resistance: Subpopulation Analysis 11 in a Clinical Staph. aureus Isolate 10 9 Log 10 (CFU/mL) Before Therapy After Suboptimal Therapy (MIC, for the green curve, is 1.0, but MIC of sub-populations are > 1 to 8) Vancomycin concentration (mg/l) Concentrations Tsuji BT et al. Unpublished data. 4

5 Mixture Models for Antibacterial PD dcfu/dt = VGmax CFU/(CFUm + CFU) Kd CFU capacity-limited replication natural death VGmax = Kd (CFUm + CFUmax) Let Kg = VGmax/(CFUm + CFU) dcfu/dt = CFU (Kg Kd) PD model with effect (E) on either Kd or Kg: Kd (1 + Emax C H /(EC50 H + C H )) = Kd E or Kg (1 Emax C H /(EC50 H + C H )) = Kg E dcfu/dt = CFU (Kg Kd E) or dcfu/dt = CFU (Kg E Kd) One ODE per sub-population, which differ, at least, in EC50 and initial inoculum (differences in VGmax have also been used for differing fitness ) Numbers of populations are a problem in model discrimination, tested using the corrected Akaike s Information Criterion (caic) Meagher AK, Forrest A, et al. 2004, AAC 48:

6 The concept of PD front-loading (FL) At T=0 for a serious infection, total bacterial burden is high (too much for the host defenses, alone) and the percent of bacteria in resistant sub-populations, is low At the start of therapy (6-48 hours?), maximize rate and extent of killing of drug-susceptible bacteria, leaving the smallest possible residual (of more resistant bacteria) to be killed by the capacity-limited immune system For AUC-dependent drugs, with high maximum rate of kill and with a good safety margin, FL with monotherapy should be feasible For drugs with slower rates of kill, consider FL with sustained-release, or multiple doses, or combinations 6

7 Pre-clinical Evaluation of Sustained Release Azithromycin (AZT), Given as a Single Dose Approved oral regimens were: 500 mg followed by 250 mg/day x 4 (5D) and 500 mg q. day x 3 (3D) Experimental regimen, using a sustained release formulation, was a single dose of 1500 mg (SR); feasible due to long AZT T1/2? Animal infection model: Mongolian gerbils with acute otitis media infections due to Haemophilus influenzae Adaptive study design; humanization of AZT PK profiles Oral Dose Gut TLag, ka Vps Vc CLds CLt CLdf Vpf PK model is linear, 3 cmpt, in humans 1 and gerbils Regimens for gerbils were humanized by giving small supplemental doses designed, in this study, to mimic time-course of human free drug AUC (fauc) 1 Amsden GW et al. Clinical Drug Investigations 1997; 13(3):

8 AZT Pharmacokinetic Parameters Parameter (units) Humans Gerbils Vc (L/kg) Vpf (L/kg) Vps (L/kg) CLdf (L/h/kg) CLds (L/h/kg) CLt (L/h/kg) T½ (h)

9 Azithromycin Regimens in Humans 5D: mg q. day x 4 3D: 500mg q. day x 3 SR: 1500mg SR x 1

10 Humanized Azithromycin Regimens 5 Day Human and Gerbil PK Profile 3D Human and Gerbil Profile Conc ( g/ml) 0.2 Conc ( g/ml) D Gerbil Conc 5D Human Conc Time (hrs) D Gerbil Conc 3D Human Conc Time (hrs) 0.35 SR Human and Gerbil PK Profile Conc ( g/ml) D Gerbil Conc 1D Human Conc Time (hrs)

11 IMPACT OF EXPOSURE SHAPE : Same Exposure Administered Three Ways In dose partitioning experiments, AZT PD was best associated with AUC/MIC The 3 regimens considered below all achieve the SAME AUC (Shape matters!) AZT regimens, in gerbils, were humanized Azithromycin (500 mg load, then 250 mg/day or 500 mg QD x 3 days or 1500 mg x 1 dose) against H. influenzae in a Mongolian gerbil acute otitis media infection model Okusanya OO, et al Presented at 106th American Society for Clinical Pharmacology and Therapeutics, 2005

12 Conc (mg/l) % of Baseline Kd Conc (mg/l) % of Baseline Kd Simulations Results for Strain 1100 SR Conc vs. Time Plot SR % of Baseline Kd Time (h) 3d Conc vs. Time Plot Log CFU Log CFU Time (h) 3d % of Baseline Kd Log CFU Log CFU Time (h) Time (h)

13 AZT Summary and Conclusions Front-loading the AUC with the SR resulted in a more rapid and complete bacterial kill compared to the 3D and 5D PD was best modeled as enhancing Kd (Emax ~4.7-fold increase from baseline, which is small, for an AUCdependent drug) Concentrations at near-emax, during the first 24 h, resulted in greater kill, for both the sensitive and resistant subpopulations (reduced probability of emergence of resistance and treatment failure) 1500 mg AZT, as regular release, is not tolerable and would be less effective ( wasted AUC at high concentrations) By the way, single-dose SR AZT works DESPITE its long terminal T1/2, NOT because of it! - Results were similar in mice, with faster AZT clearance than gerbils, without humanization of AZT profiles

14 ORI and Staph aureus Pneumonia (SAP): Translation from Mouse to Man PK (including ELF) and PD of SAP, in neutropenic mice, and PK (including ELF), in human volunteers, were studied SS AUC targets in murine ELF were characterized The ratios, of SS AUC in ELF to AUC in plasma, were similar in mouse and in man (not a requirement for translation) The corresponding target SS AUC in plasma should be achievable and tolerable, in humans 400 mg once daily, in man, predicted to provide the desired SS drug concentration in ELF Traditional analysis would approve a pneumonia trial Predicted time course of PK/PD must also be considered! 14

15 Log CFU/mL ORITAVANCIN IN VITRO TIME-KILL STUDY AUC-Dependent Killing Time (minutes) Growth Control Vancomycin, 16 g/ml Oritavancin, 0.5 g/ml Oritavancin, 2 g/ml Oritavancin, 4 g/ml Oritavancin, 8 g/ml 1 ORI PD was also modeled as increased Kd; Emax was much larger than AZT; compared to AZT, ORI PD is better related to AUC, less sensitive to shape S. aureus NRS127 (LIN-NS MRSA); McKay et al th ECCMID. Poster P-544; and Data on file, The Medicines Company

16 Log 10 CFU/Thigh or Lung after 24 hrs of Therapy STEP 1 RESULTS Non-Clinical Exposure-Response Relationship for ORI Against S. aureus Lung Thigh Starting CFU S. aureus Smith strain MIC old = 1.0 mg/l Dose (mg/kg/24h) Free-Drug AUC 0-24 (mg/l h) AUC 0-24 Exposure Targets Endpoint Dose (mg/ kg) 1. Dose-response relationship for ORI is based on data from Craig WA, Andes DR. ICAAC 2004, abstract A Murine PK data are based on data from Bhavnani SM et al. ICAAC 2007, abstract A-51. Freedrug plasma AUC 0-24 stasis log kill log kill ~

17 Oritavancin and Staph. aureus Pneumonia: From Mouse to Man V2 ELF CL2 Kin Kout Dose Rate Vc CLt CL3 V3 Data were best fit by a 3 -compartment model with a zero-order rate input and linear clearance; the ELF was modeled as a biophase compartment Bhavnani SM, et al. ICAAC 2008, Abstract A

18 ORITAVANCIN POPULATION PK MODEL Predicted Concentration-Time Profile in Man 400 mg PO every 24 hour; no loading dose given Terminal T1/2 seen only in slow accumulation & washout Rubino CM et al. Oritavancin population pharmacokinetics in healthy subjects and patients with complicated skin and skin structure infections or bacteremia.. Antimicrobials Agents and Chemotherapy 2009, in press.

19 CONFOUNDING VARIABLE Differing Inter-Compartmental Rate Constants Bhavnani SM, et al. ICAAC 2008, Abstract A-51. Oritavancin pharmacokinetics were studied in both murine and human serum and epithelial lining fluid (ELF) Outcomes in mice at 24 hours are used to forecast outcomes in humans In this simulation, mice & humans were given identical serum profiles but speciesspecific equilibration between serum and ELF In humans, it takes (at least) 96 hours to reach the ELF exposures associated with efficacy, in mice at 24 hours These data suggest that very large initial doses (for pneumonia) would be needed in humans to match the early exposures in animals Oritavancin pneumonia program targeting S. aureus halted due to these data

20 ORI for SAP, Front Loaded Regimen 800 mg Q12 X 2; Then 400 mg Q24 X 13 Doses 4000 Plasma 240 ELF 3000 Daily AUC plasma Daily AUC elf Day Day Note: many cases still take 3-7 days to achieve the target fauc in ELF 20

21 Oritavancin: Complicated Skin and Skin Structure Infections Oritavancin had been in late-stage clinical development for nearly 10 years with multiple sponsors o Primary indication sought was complicated skin and skin structure infections o Phase 3 dose regimen was 200 mg IV once daily for 3-5 days Late in the game, Sponsor and ICPD scientists asked two questions: o Could oritavancin be dosed in a manner that would result in improved efficacy? o If so, how could we demonstrate it pre-clinically to support future clinical development? Bhavnani SM et al. Use of pharmacokinetics-pharmacodynamics to support oritavancin dose selection for patients with complicated skin and skin-structure infection: clinical confirmation of proof of concept. ICAAC 2009, Poster A

22 STEP 1 RESULTS Comparison of Daily Free-Drug AUC Values Rubino CM et al. Use of pharmacokinetic-pharmacodynamic principles for decisions for short-course oritavancin dosing regimens for complicated skin and skin structure infections. 18 th European Congress of Clinical Microbiology and Infectious Diseases.

23 STEP 2 METHODS Neutropenic Murine Infection Model Based upon population PK in mice and humans, humanized ORI dosing regimens for mice were designed to mimic 2 human oral regimens: 200 mg/day and a single 1200 mg dose Staphylococcus aureus was the challenge pathogen; study duration was 3 days PK and PK-PD modeling was done using Monte Carlo Parametric Expectation Maximization as implemented in S-ADAPT 1.53 Again, the one dose regimen (regular release, in this case) was more active than the traditional regimen

24 ORITAVANCIN NOVEL DOSE REGIMENS A Phase 2 Study Phase 2 study, international, multi-center, randomized, double-blind, controlled study in patients with csssi presumed or proven to be caused by gram-positive pathogen(s) The study consisted of 3 treatment arms: o o 200 mg oritavancin IV daily for a minimum of 3 days up to a maximum of 7 days, A single dose of 1200 mg oritavancin IV, or o A single dose of 800 mg oritavancin IV, with a further dose of 400 mg IV on Day 5 at the discretion of the attending physician Dunbar LM, et al. Efficacy of oritavancin at single or infrequent doses for the treatment of complicated skin and skin structure infections. 19 th European Congress of Clinical Microbiology and Infectious Diseases. Helsinki, Finland, May, 2009.

25 ORITAVANCIN NOVEL DOSE REGIMENS A Phase 2 Study Dunbar LM, et al. Efficacy of oritavancin at single or infrequent doses for the treatment of complicated skin and skin structure infections. 19 th European Congress of Clinical Microbiology and Infectious Diseases. Helsinki, Finland, May, 2009.

26 Dalbavancin (DAL) Modeled with linear 3 compartment model T 1/2 : alpha phase = 2.5 hours, beta phase = 8.5 days, terminal phase = 14 days Fraction bound: 93% Free-drug AUC /MIC = primary PD index Approved regimen: 1000 mg followed by 500 mg on day 8 Trial planned to compare efficacy of the approved dosing regimen to a single 1500 mg dose regimen Sparse sampling strategy needed Lakota E et al.. Determination of optimal sparse pharmacokinetic sampling times for a Phase 3 dalbavancin trial. Poster presented at 54th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC. September 5-9, 2014

27 Methods Using developed population PK model, Monte Carlo Simulation of 2000 subjects was performed Wide range of PK variability 20 randomly selected subjects PK profile displayed on right To determine optimal sampling times, stepwise linear regression with bidirectional selection was performed AUC 0- was the dependent variable DAL concentrations at selected time points from 0 to 1344 hours (8 weeks) represented the independent variables Lakota E et al.. 54th ICAAC. Washington, DC. September 5-9, 2014

28 Sampling Strategy for AUC 0- Optimal sampling strategy to estimate AUC 0- is displayed below All suggested samples occur at or after 120 hours, indicating that most PK variability occurs after day 5 The portion of total AUC which occurred after 120 hours ranged from 21.3% to 92.2%, with a median of 65.9% # of samples Suggested time point of samples (h) Precision * 64.0% 2 144, % 3 144, 1008, 1344 ** 79.9% 4 144, 192, 1008, % 5 120, 144, 192, 1008, % *1008 h = 6 weeks, **1334 h = 8 weeks Lakota E et al.. 54th ICAAC. Washington, DC. September 5-9, 2014

29 Sampling Strategy for AUC 0-120h AUC 0-120h is the PK/PD index most closely related to DAL efficacy Linear stepwise regression performed again AUC 0-120h as the dependent variable and concentrations at time points ranging from hours as the independent variables Optimal sampling strategy to estimate AUC 0-120h is displayed below # of samples Suggested time point of samples (h) Precision AUC % 2 18, % 3 18, 23, % 4 5, 18, 23, % 5 5, 18, 23, 36, % Lakota E et al.. 54th ICAAC. Washington, DC. September 5-9, 2014

30 Sampling Strategy for Precision of PK Parameters Optimal sampling theory using D-optimality Minimizes overall uncertainty in parameter estimates Sampling times(h): 1.8, 10, 124, 412, 894, 1344 PK Parameter Predicted CV% CL 4.8 Vc 40 Vp1 13 Vp2 45 CLd1 34 CLd2 8.5 Lakota E et al.. 54th ICAAC. Washington, DC. September 5-9, 2014

31 Sampling Strategies are Complicated Even with overlapping objectives, optimal sampling strategy is very dependent on goal of the study Lakota E et al.. 54th ICAAC. Washington, DC. September 5-9, 2014

32 Take Home Messages Optimal regimens for all antibacterials require insightful consideration of population PK, range of relevant MICs, site of infection, and PD characteristics such as bacterial heterogeneity, main PD driver and targets, rates of net kill, probability of (new) random point mutations and PD of toxic effects Drugs with very long terminal T1/2 present some interesting challenges and opportunities but the long T1/2 is rarely useful (rarely, if ever, favorable PK) Drugs with long T1/2 can accumulate throughout the course (daily doses with no load) and/or persist long periods at low concentrations (raising safety and resistance concerns) 32