1. Old and Newer methods for Bayesian updating
Roger Jelliffe, M.D.
USC Lab of Applied Pharmacokinetics
11/14/2018
USC LAPK

2. Four types of Bayesian updating
Maximum Aposteriori Probability (MAP).
Multiple Model (MM) Bayesian updating.
Hybrid Bayesian (MAP + MM) updating.
Interacting Multiple Model (IMM) Bayesian updating
11/14/2018
USC LAPK

3. Maximum Aposteriori Probability (MAP).
Can reach out toward an unusual patient
But the MAP point misses the true patient
Held back toward the prior
Also, only 1 point. No graphic view of uncertainties.
What to do?
11/14/2018
USC LAPK

4. 11/14/2018
USC LAPK

5. 2. Multiple Model (MM) Bayesian updating.
Support points don’t change. Values of support points stay the same
Use Bayes’ theorem to compute the Bayesian posterior probability of each support point, given patient’s data
Problem: will not reach out beyond pop param ranges. May miss unusual patient. What to do?
11/14/2018
USC LAPK

6. Pop model has definite boundaries
11/14/2018
USC LAPK

7. 3. Hybrid Bayesian posterior updating
Start with MAP Bayesian. It reaches out, but not fully. Pop prior holds it back.
Add new support points nearby, inside and outside, to precondition the pop model for the new patient data.
Then do MM Bayesian on ALL the support points.
We are implementing this now. Out soon.
11/14/2018
USC LAPK

8. Test Case Probabilities calculated on a 4x4 grid about optimal
5 percent increase/decrease between grid points
11/14/2018
USC LAPK

9. 4. Bayesian for very unstable patients: interacting multiple model (IMM)
Limitation of all current Bayesian methods: assume only 1 set of fixed parameters to fit the data.
Sequential MAP or MM Bayesian same as fitting all at once.
Relax this assumption. Let the “true patient” change during data analysis if more likely to do so.
Hit evasive targets better. IMM.
11/14/2018
USC LAPK

10. 11/14/2018
USC LAPK

11. What individualized therapy has done
Digoxin
Lidocaine
Aminoglycosides
Vancomycin
Busulfan
Methotrexate
11/14/2018
USC LAPK

12. What individualized therapy has done
Digoxin
11/14/2018
USC LAPK

13. 11/14/2018
USC LAPK

14. 11/14/2018
USC LAPK

15. What individualized therapy has done
Lidocaine
11/14/2018
USC LAPK

16. 11/14/2018
USC LAPK

17. What individualized therapy has done
Aminoglycosides
11/14/2018
USC LAPK

18. 11/14/2018
USC LAPK

19. 11/14/2018
USC LAPK

20. 11/14/2018
USC LAPK

21. Vinks et al. Aminoglycoside therapy: 4 hospitals.(TDM 21:63-73, 1999)
Adaptive TDM (ATM) vs ordinary TDM
Patients
Inf on adm
Peak conc ±2.9 ug/ml 7.6±2.2 p<0.01
Trough conc ± ±1.3 p<.001
Mortality / /127 p=.26
Mort, inf on adm 1/ /62 p=.023
11/14/2018
USC LAPK

22. Other aminoglycoside outcomes
ATM TDM
Nephrotoxicity % % p<.01
Hospital stay ±1.4d ± p=.045
Inf on adm ±0.8d ± p<.001
Cost (DFL) ,125±9, ,882±17,721 p<.05
Inf on adm 8,883±3, ,743± 7,437 p<.001
11/14/2018
USC LAPK

23. What individualized therapy has done
Vancomycin
11/14/2018
USC LAPK

24. 11/14/2018
USC LAPK

25. Vanco IV Options
11/14/2018
USC LAPK

26. Vanco IV Options
11/14/2018
USC LAPK

27. What individualized therapy has done
Busulfan
11/14/2018
USC LAPK

28. Bleyzac et al. Busulfan in 29 Ped BMT Pts
Test Control
PTS
VOD % 24.1%*
Graft Failure % 12.0%
Survival % %
*p<.05
11/14/2018
USC LAPK

29. COST EFFECIVENESS STUDY OF CYCLOSPORIN BAYESIAN MONITORING IN PEDIATRIC BONE MARROW TRANSPLANTATION
Nathalie BLEYZAC, Emmanuelle SAVIDAN, Claire GALAMBRUN
Hôpital DEBROUSSE, Hospices Civils de Lyon
11/14/2018
USC LAPK

30. Context Bone marrow transplantation
Numerous complications including graft versus host disease (GVHD)
GVHD prophylaxis: Cyclosporine ± ATG
11/14/2018
USC LAPK

31. Bone marrow transplantation : Indications
Malignant diseases :
Leukemia (ALL, AML, CML, JMML), non Hodgkin lymphoma
Myelodysplastic syndromes
Non malignant diseases :
Bone marrow failure, hemoglobinopathies
Immunodeficiencies
Metabolic disorders
11/14/2018
USC LAPK

32. Cyclosporine: PK/PD No dose-effect relationship
Relationship between cyclosporine trough blood concentration and GVHD grades
Existence of cyclosporine target blood concentrations specific to each type of graft and each pathology
11/14/2018
USC LAPK

33. Cyclosporine therapeutic monitoring : Empirical strategy
YES NO
 or  doses by 5 to 10% increment if trough blood concentration differ from target values (Cmin between 100 et 200ng/ml)
new measure of trough
blood concentration to verify it is within target values range
More than one week is sometimes needed before finding the optimal dosage regimen
11/14/2018
USC LAPK

34. Cyclosporine therapeutic monitoring : MAP Bayesian monitoring strategy
Home-made PK populations
3 dose control per week / 2 first weeks
USCPACK: linear PK (≠ CsA)
+ “human neuronal network”
11/14/2018
USC LAPK

35. Methods (1) Strategies compared : Costs considered : Direct costs :
Strategy A: Bayesian monitoring (Debrousse hospital’s)
Strategy B: empirical monitoring (all other French centers)
Costs considered : Direct costs :
directly linked to GVHD treatment
costs of monitoring strategies
11/14/2018
USC LAPK

36. Methods (2): Efficacy of cyclosporine Bayesian TDM
Choice of efficacy endpoint :
→ Incidence of severe acute GVHD
(grades III and IV )
→ Relapses
11/14/2018
USC LAPK

37. Methods (3): Efficacy: data collection
Strategy A :
Data reported in a previous study: patients transplanted from Nov to Oct at Debrousse hospital
85 children
11/14/2018
USC LAPK

38. Methods (4): Efficacy: data collection
Strategy B :
Literature review : Medline request combining “bone marrow transplantation” AND “children” AND “GVHD” ; restriction on last 6 years
→ > 100 papers
Selection of studies showing criterion previously defined
11/14/2018
USC LAPK

39. Methods (5): Efficacy: data collection
Strategy B :
Selection criterion
Pediatric studies
≥ 15 patients
Incidence of moderate and severe acute GVHD clearly indicated
Exclusion criterion
Rare pathologies
Autologous graft
Peripheral stem cell graft or umbilical cord blood graft if no data about BMT
11/14/2018
USC LAPK

40. Methods (6): Efficacy: data collection
Strategy B :
9 studies
Warning : cohorts differ from ours for different reasons
Data synthesis
Median percentages about moderate and severe acute GVHD incidence calculated from percentages reported in each study
11/14/2018
USC LAPK

41. Methods (7): Costs considered
Cost saved by using strategy A
Overcost generated by the treatment of one severe GVHD :
Mean cost of treatment for a patient affected by severe GVHD – mean cost of treatment for a patient without GVHD or I-II
Cost of carrying out strategy A
11/14/2018
USC LAPK

42. Methods (8) : Costs considered
Cost of carrying out strategy A :
Cyclosporine blood samples and dosages :
Equivalent in both strategies
Bayesian monitoring :
Informatics material : insignificant
Staff : 0.6 “équivalent temps plein” (ETP) of hospital pharmacist and 1.5 ETP of resident
11/14/2018
USC LAPK

43. Methods (9) : Costs considered
Costs of treatment (severe acute GVHD / no GVHD) :
Cost of hospitalization
Cost of drugs used
Cost of stable and labile blood products
Parenteral nutrition
Biological and imaging investigations
Calculated from 10 patients’ files .
11/14/2018
USC LAPK

44. Results (1) : Strategy efficacy: incidence of GVHD
Strategy A :
Between 1999 and 2004 :
Grade I-II : 48.2 %
Grade III-IV : 8.2%
Strategy B :
Mean :
Grade I-II : 39.4%
Grade III-IV: 22.4%
11/14/2018
USC LAPK

45. Results (2) : Additional cost linked to severe GVHD
Number of patients concerned :
26 BMT / year at Debrousse hospital of which
26 x 8.2% = 2.1 patients affected by severe acute GVHD each year.
If cyclosporine was monitored according to classical strategy, it would be 26 × 22.4% = 5.8 patients affected by severe acute GVHD each year, i.e. 3.7 more.
11/14/2018
USC LAPK

46. Results (3) : Resources consumed (costs in euros)
The additional cost for one severe acute GVHD is approximately
euros
11/14/2018
USC LAPK

47. Results (4) : Costs avoided by cyclosporine Bayesian monitoring
Cost of severe GVHD saved (3.7 x ) :
euros
Cost of carrying out strategy A :
euros
Overall cost saved by using strategy A :
euros
11/14/2018
USC LAPK

48. Results (5): Sensitivity analysis
Strategy A remains cost-effective when resources varies:
Hospitalization cost : length of stay of 50 – 130 days
Quantity of stable and labile blood products administered : 2000 to euros
Severe GVHD incidence variance above 12.5%
11/14/2018
USC LAPK

49. Conclusion
Cyclosporin MAP Bayesian monitoring strategy is cost-effective as it allows :
about 14% less severe acute GVHD
about euros of cost saving per year
11/14/2018
USC LAPK