Bioequivalence and Bioavailability Forum

Pharmacokinetic metrics CL, Vd and F [Regulatives / Guidelines]

posted by Helmut  – Vienna, Austria, 2017-05-06 14:14 (2539 d 23:56 ago) – Posting: # 17309
Views: 10,045

Hi MMW,

❝ As per the Guideline, for CFDA submissions, …

This one (page 17)?

F = 100×AUC_T/AUC_R.

If the drug exhibits linear PK and different doses are administered a correction is suggested

F = 100×(AUC_T×D_R)/(AUC_R×D_T).

❝ … pharmacokinetic parameters CL, Vd and F needs to be submitted.

<nitpicking>

pharmacokinetic modeling → PK parameters
noncompartmental analysis → PK metrics

</nitpicking>

❝ Can we calculate these parameters in Phoenix software?

If you have a Phoenix/WinNonlin license, please RTFM.

To calculate ƒ (absolute bioavailability after an extravascular dose) you need a crossover study with EV vs. IV doses. Better is simultaneous administration of EV and stable isotope labeled IV – which requires cGMP of the IV dose (that’s a big obstacle). Then

ƒ = (AUC_∞,EV×D_IV)/(AUC_∞,IV×D_EV) and
F (%) = 100ƒ.

Note that ƒ calculated from a crossover study assumes constant inter-occasion clearances, which might not be correct (especially for highly variable drugs*).
CL and V_d are only accessible after an intravenous dose, where

CL = D/AUC_∞ and
V_d = D/C₀.

Without ƒ (i.e., only EV dosing) you get just CL/ƒ and V_d/ƒ, which IMHO is of limited value since ƒ is unknown. Both are given in the standard output of Phoenix/WinNonlin. Report them to make the CFDA happy (irrelevant in BE) but please not as CL and V.

---

• If the study is sufficiently large, ƒ might still be usable though the subjects show extreme variability in PK.

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! 
Helmut Schütz


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Complete thread:

• Pharmacokinetic parameters CL, Vd and F mmw 2017-05-06 11:07 [Regulatives / Guidelines] 
  • Pharmacokinetic metrics CL, Vd and FHelmut 2017-05-06 12:14
    • Pharmacokinetic metrics CL, Vd and F Shuanghe 2017-05-08 16:16
      • CFDA 2016 BE-GL Helmut 2017-05-09 13:52
        • CFDA 2016 BE-GL Shuanghe 2017-05-10 13:03
          • nonlinear PK: highest dose ⇔ strength Helmut 2017-05-10 15:17
            • highest dose ⇔ strength for dummies d_labes 2017-05-10 15:41
              • highest dose ⇔ strength for dummies Helmut 2017-05-10 15:45
                • highest dose ⇔ strength for dummies d_labes 2017-05-10 16:20
                  • highest dose ⇔ strength for dummies Helmut 2017-05-10 16:28
                    • highest dose ⇔ strength for dummies d_labes 2017-05-11 16:31
                    • highest dose ⇔ strength for dummies mmw 2017-05-15 06:53