PK-guided prophylaxis

Jan Blatný

Dept. of Paediatric Haematology

CUH Brno

Czech Republic

Overview

• Theoretical background

• It really works!

– When/how to use PK profiling

• Case reports

• Summary

Theory

(Historical) Standard of care

• Prophylaxis is a gold standard of care for children with

severe haemophilia

• Increasing number of adults are taking the advantage of

prophylaxis as well

• On-demand treatment with pdF/rF is used for those, who

are not on prophylaxis

• Uniform, weight based dosing has been used most often

• “One size/dose fits all” policy dominated to haemophilia

treatment for decades

– And helped to improve the care significantly

Does “One size fits all” work?

• …perhaps, it is a time to shift our paradigm…..

Interindividual variability

• The effect of the prophylactic therapy (i.e. the time, when

patients have the factor level below critical level) is

dependent more on half-life (and thus the clearance) of the

factor and the frequency of administration, than on IVR (in

vitro recovery).

» Collins et al, JTH 2009

• This pattern is age dependent, as the decline in (FVIII)

clearence and increase in half-life with age could be

described as continuous function

» Bjorkmann et al., Thromb Haemost 2012

• Half-lives for FVIII could range between 7-20h (van den Berg,

JTH 2007), or even 6-28,8h (Fijnvandraat, BJH, 1995)

– Influenced mainly by vWF Ag level and BG

Interindividual variability

51 hours to FVIII =1% Half-life = 8.8h

FVIII below 1% Risk of bleed!

110 hours to FVIII =1% Half-life =15.4h

POSSIBLE VARIANCE Adolescents/Adults10-65 years old; e.g. 70kg, 30 IU/kg of the same FVIII product

59 hours of difference

~2.5 days

Collins PW et al. Heamophilia. 2011;17:2-10.

FV

III le

vel (%

)

Time (h)

Interindividual variability

Pharmacokinetics

What is the prophylaxis about?

(Using PK terms)

• Peak levels

– Correspond with IVR

– Are necessary (mainly) to stop eventual/potential/micro bleeds

which still may occur on prophylaxis

– Help to cover “high risk situations”

• AUC represented mainly by the half-life

– Corresponds with the overall efficacy of the prophylaxis

– Describes the time individual spends with sufficient level of the

factor

• Trough level

– Desired level of the factor we do not want the patient to go below

• All above mentioned could be “tweaked” and fitted to

anyone’s need with PK profiling!

Ways, how PK can help patient/treater

• Aiming for long intervals of application?

– PK can help you, but (trough) levels will be lower; less frequent peaks

– Good perhaps for those with sedentary life style

• Aiming for active life with no compromises?

– PK can help you, but the intervals be rather short

– Good perhaps for very active people

• Aiming for the compromise between above mentioned?

– PK can help you, indeed

– Keep your intervals and (trough) levels convenient enough and tailor

your acivities to your PK profile

Two ways how to use PK

• Tailor you dosing to your life-style

• Tailor your life-style/daily activities to your dosing/PK

profile

• Anyway, DO YOUR PK profile. It make sense!

Pharmacokinetics – is it difficult?

• Hemophilia A – < 30 min prior FVIII infusion

– 7 time-points post infusion in older kids

• 30min, 1, 3, 6, 12, 24, 48 hours

– At least 5 time-points in patients ≤ 6 years old

• Hemophilia B – 7 samples over a period of 72 hours

ISTH recommendation

Bayesian population PK modeling

• Three-compartment models are needed to characterize

the PK of both plasma-derived and recombinant

coagulation factors

• Simplification to one-compartment model is less

straightforward for FIX, than for FVII modeling

» Bjorkman, Haemophilia 2013

• Once the model is ready, the PK profiling is possible

with minimal sampling

– May suits small children or those, who from different reasons do

not want or cannot undergo their own full-PK

PK as a tool for reducing costs

• Certain number of patients on “standard” prophylaxis are

“overdosed”

– PK may help to find the most cost-effective way of treatment for

them, reducing costs

• Certain number of patients on “standard” prophylaxis are

“underdosed” – having more bleeds

– PK may help to find optimal regimen, lower the bleeding rate and

save resources

It really works (and helps)

CUH Brno paediatric guidelines for PK

profiling

• PK profiling must be offered to all children with haemophilia A/B

on prophylaxis after first 50 ED. Parents/patients are

encouraged to do so.

– Final decision made by family, though

– Should PK be requested by other patients/families we do our best to

accommodate such a request

• PK repeated every 2 years (if consent given by the

patient/family)

• Whenever changing the factor, PK on “old” and “new” factor is

offered/done to prove “non-inferiority” of the new medication

– Amount of vWF:Ag in patient (as well as in pdFVIII) may influence T1/2

– FL rFVIII is deemed to have longer T1/2 than BDD rFVIII

• FL (14.3 h; CI, 13.3-15.4 h) versus BDD (11.3 h; CI, 9.9-12.7 h). Interpret with caution!

– Gruppo et al, Haemophilia 2003, METAANALYSIS only

PK outcomes in CUH Brno

• Apart from outcome for treaters, we provide an outcome

for patients, which is understandable and useful for them

• Pre-designed form issued, showing

– PK raw data, including trough level, peak level and recovery

calculation. Correlation with clinical bleeding pattern is provided.

– Time (in hours post infusion of prophylactic factor dose) when:

• Factor level is <12%

• Factor level is <3%

• Factor level is <1% (should this happen)

– Information about the suggested change of treatment regimen,

should this happen, based on the recent PK study

– Narrative for the patient to clarify, what does it mean to him

and/or parents

Regular FUP visit

Sample of PK curve (M.D. YOB 1995)

Time (h) F VIII (%)

0 2,6

0,5 55

1 44

3 35

5 29

24 8

48 3,6

72 0

derivate: XXXXX

Dose(IU) Weight(kg)

Dose given in IU/kg: 1500 69 21,74

Calculated rise 43,5 %

Real rise: from 2,6 to 55 % 52,4 %

recovery 120,5 %

t ½ (logarithmic phase) 5,3 hod

y = -11,08ln(x) + 46,068 R² = 0,9936

-10

0

10

20

30

40

50

60

0 10 20 30 40 50 60 70 80

F V

III

(%)

čas (hod)

Why to switch to another product?

• Insufficient response to current medication?

– Bad clinical outcome/bleeding pattern

• Aiming for higher safety profile?

– Switch from pdF to rF

• Out of stock?

– End of registration

– End of clinical trial

• Other reasons?

– Family/patient wants it, etc…

• Do the PK to help you/patient to make a right decision!

Switching to a new product?

Prove “non-inferiority” M.R. YOB 1994

OLD product (pdFVIII) NEW product (rFVIII)

Time(h) F VIII (%)

0 0,4

0,5 97

1,75 46

3 44

5 59

24 16

48 6

recovery 183 %

čas (hod) F VIII (%)

0 1,2

0,5 70

1 61

3 47

5 42

24 16

48 6,5

72 2,5 recovery 122,2 %

y = -17,83ln(x) + 73,273 R² = 0,8606

0

20

40

60

80

100

120

0 10 20 30 40 50 60

F V

III

(%)

Time (h)

y = -13,92ln(x) + 61,537 R² = 0,9968

0

10

20

30

40

50

60

70

80

0 20 40 60 80

F V

III

(%)

Time (h)

Virtual case report

5 years old boy

• Severe Haemophilia A (FVIII<1%)

• No inhibitor

• 17 kg

• On prophylaxis with rFVIII 500 (29 IU/kg) twice weekly (We,

Sat)

• General interest in soccer

– Sport activities mainly on Tuesday afternoon

• Parents want to learn him skiing this winter (going to Alps)

• Back tooth extraction (primary tooth) awaited

Do a full PK in him

Time (h) F VIII (%)

čas (h) F VIII (%) recovery

0 0,5

0,5 77 1,309

1 60 1,020

3 45 0,765

5 38 0,646

24 18 0,306

48 5 0,085

72 1,6 0,027

derivate: XXXXX

Dose(IU) weight(kg)

Dose in IU/kg: 500 17 29,41 IU/kg

Calculated rise 58,8 %

Real rise: from 0,5 to77 % 76,5 %

recovery 130,1 %

y = -14,65ln(x) + 62,854 R² = 0,9927

0

10

20

30

40

50

60

70

80

90

0 10 20 30 40 50 60 70 80

F V

III

(%)

time (h)

What about soccer on Tuesday

• Being on We, Sat prophylaxis on Tuesday afternoon his

FVIII is <1%

• Suggest to change his dosing regimen to Tue, Fri or Tue

Sat (depending on weekend activities)

• When injecting before school (8 a.m.), during his regular

soccer training (4 p.m.) he still be over 30% of FVIII

• If any intense sport activity is to be commenced, it

should be ideally within 36 h after the injection, when his

levels are still above cca 12%.

– Otherwise consider “top-up” dose

What about the week he goes for his

first skiing to the Alps

• Temporary change of prophy regimen suggested

• Giving him dose every 48 hours will keep him within

levels for mild haemophilia

– will be always over 5%

• During the day-time (and thus during skiing) he is not

likely to drop below 12%

What about his tooth?

• This is going to be rather simple extraction than dental

surgery in 5 yrs old boy

• Pre op arrangements:

– His regular prophy gives him rise up to almost 80%

– Do it on the day of prophylaxis

– Keep him for 5 days on antifibrinolytics

– This arrangement should be enough for uncomplicated dental

extraction

• In case of dental surgery, keep him on a daily dose giving

him rise to 40 – 60% as clinically determined (often 3-5 days)

Summary

• PK is “doable” in anyone

– population PK modeling helps those, who might have concerns

• PK gives the confidence to the patient as well as to the

treater

– You know, how you treat/are treated

• PK helps to accommodate individual’s needs, behavior,

life-style and activities

• PK helps to make the treatment cost-effective

• PK helps to prevent break-through bleeds