Bioequivalence and Bioavailability Forum 18:45 CEST

Main page Policy/Terms of Use Abbreviations Latest Posts

 Log in |  Register |  Search


2015-11-24 08:13

Posting: # 15658
Views: 3,160

 Cumulation detec­tion [PK / PD]

Hi All,

Is it possible to detect cumulation of a substance using "classic" PK-parameters (AUC, Cmax, Tmax, etc)?

Maybe additional metrics to be calculated? :confused:
Vienna, Austria,
2015-11-24 13:41

@ BE-proff
Posting: # 15662
Views: 2,574

 Cumulation detection

Hi BE-proff,

» Is it possible to detect cumulation of a substance using "classic" PK-parameters (AUC, Cmax, Tmax, etc)?

Not sure what you mean. According to the “Superposition Principle” linear pharmacokinetics could be tested by a comparison of AUC0-τ (steady state) with AUC0-∞ (single dose). Generally this is done in a study where after the single dose profile the drug is administered until steady state is reached.*

The comparison is done by a paired test – which assumes no period effects. I have never seen a crossover in 35 years… Would be a logistic nightmare.
If the 90% CI of AUC0-τ/AUC0-∞ is outside the acceptance range, nonlinear PK is proven. See also this lengthy thread.
The superposition principle is applicable to AUCs only (that’s why Friedrich Hartmut Dost called it “Gesetz der kor­res­pondierenden FlächenLaw of Corresponding Areas back in 1953).
Comparisons of Css,max/Cmax and tss,max–tmax are possible but of doubtful value.

» Maybe additional metrics to be calculated? :confused:

Whichever you might think of. ;-) A common one is the “Accumulation Index”:
   R = 1/(1 – 2ε), where ε = τ/t½.
Phoenix/WinNonlin uses a different formula
   R = 1/(1 – ℯλz·τ), which gives the same result (homework: why?).
R gives you an idea how much higher average concentrations in steady state are if compared to a single dose. Example: Half-life 12 h (λz 0.05776) and dosing interval 24 h ⇒ R 1.333 (i.e., con­centrations in steady state will be ⅓ higher than after a single dose). If you decrease the dosing interval to t½, R will be 2.

I’m not a big fan of R since it might be difficult to obtain a reasonably good estimate of λz / t½ in steady state. In the BE-context we don’t sample beyond τ. If you are interested in a good estimate of λz (e.g., in phase I studies of new drugs) you might sample longer.
Further­more, R is strictly valid only for the one-compartment model. For more compartments it is appro­xi­mate (since based on the elimination phase only).

  • “True” steady state is reached at t = ∞. Too long for us mortals. However, most people are happy by ad­mi­nistering for five to seven half-lives. IIRC, only ANVISA requires ten half-lives.
     n   % ss
     1  50.00
     2  75.00
     3  87.50
     4  93.75
     5  96.88
     6  98.44
     7  99.22

     8  99.61
     9  99.80
    10  99.90
    11  99.95
    12  99.98
    13  99.99

    Formula: % ss = 100(1 – ½n )

Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Back to the forum Activity
 Thread view
Bioequivalence and Bioavailability Forum |  Admin contact
18,700 posts in 3,984 threads, 1,241 registered users;
online 13 (0 registered, 13 guests [including 12 identified bots]).

When puzzled, it never hurts to read the primary documents –
a rather simple and self-evident principle that has, nonetheless,
completely disappeared from large sectors
of the American experience.    Stephen Jay Gould

BEBAC Ing. Helmut Schütz