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Back to the forum  Query: 2017-05-27 19:28 CEST (UTC+2h)
 
javier
Junior

Spain,
2017-03-16 17:49

Posting: # 17158
Views: 747
 

 differents half life values [PK / PD]

Dear All

Reading about nivolumab, in the EPAR, there is a confusing information regarding the half life, im wondering if you dont mind to use your expertise to answer this question,
in the single dose pk study (with full pk sampling ) the half life was reported in 17 days, while in the multiple dose study (with sparse sampling) the half life was reported in 26 days, How could it be possible? How would you calculate the steady state in this situation?

I quote the exact word of the EPAR

"the mean terminal elimination half-life of nivolumab ranged between 17 and 27.5 days following single dose (study MDX1106-01) and Q2W administration (MDX1106-03) across the range of 0.1 to 10 mg/kg dose."

Thanks in advance for your time and dedication answering it

Best Regards

Javier


Edit: EPAR linked and category changed; see also this post #1. [Helmut]
Helmut
Hero
Homepage
Vienna, Austria,
2017-03-17 13:09

@ javier
Posting: # 17160
Views: 608
 

 artifact?

Hi javier,

» in the single dose pk study (with full pk sampling ) the half life was reported in 17 days, while in the multiple dose study (with sparse sampling) the half life was reported in 26 days, How could it be possible?

First of all I don’t think that half lives are normal distributed. Hence, I don’t like the reported arithmetic means. ;-) There were different number of patients enrolled in the cohorts. Therefore, you should use weighted means which are 22.0 days (single dose) and 26.1 days (multiple dose). Such a difference does not worry me. Furthermore, half lives in the SD study were obtained by NCA and in the MD study by a two-compartment PopPK model. Since there is substantial accumulation it might be possible that in the SD study the terminal phase was not completely “visible” – especially after low doses and NCA underestimated the true (i.e., higher) value.

» How would you calculate the steady state in this situation?

What do you mean by that?

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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nobody
Senior

2017-03-17 16:35

@ Helmut
Posting: # 17163
Views: 582
 

 artifact?

btw nice example why I don't like discussions based on t1/2. If you ever determined it yourself you know what kind of mess this parameter is, not to speak of the pain trying to compare results from different trials (SD/MD, sampling times/duration, non-comp./comp. models, etc. pp...).

Kindest regards, nobody
javier
Junior

Spain,
2017-03-20 12:56

@ Helmut
Posting: # 17168
Views: 487
 

 artifact?

Hi Helmut

» » How would you calculate the steady state in this situation?
»
» What do you mean by that?

first, thank you for your swift and ilustrated response, regarding the steady state question, I was wondering about how to calculate the steady state of a drug when you have two different values of half life (If I understand correctly the steady state of a drug takes 3-5 half lives)

thanks again and best regards
Helmut
Hero
Homepage
Vienna, Austria,
2017-03-20 14:40

@ javier
Posting: # 17170
Views: 477
 

 Understanding the PK of a drug

¡Hola Javier!

» I was wondering about how to calculate the steady state of a drug when you have two different values of half life

See this post (especially the last sentence) and the warfarin example (slides 21–22). ;-)
If you extrapolate from SD to MD you have to rely on assumptions (linear PK, no saturation/induction/inhibition/capacity-limited excretion).

» (If I understand correctly the steady state of a drug takes 3-5 half lives)

It depends on how one defines sufficiently ‘close’ to true steady state (at t = ∞!). For a one-compartment model, IV administration

i  % SS
1  50
2  75
3  87.5
4  93.75
5  96.875

where i = number of half lives and % SS = 100(1 – ½i ). For EV (and more important: other models) this approach is only approximate.
Coming back to your OP: I would trust the results of the MD study’s PopPK-model more than the SD study’s results derived by NCA.

[image]All the best,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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