Bioequivalence and Bioavailability Forum • Capecitabine: 2 slopes

mittyri
★★

Russia,
2013-11-01 09:30
(4208 d 09:13 ago)

Posting: # 11854
Views: 10,121

Capecitabine: 2 slopes [PK / PD]

Dear All,

I would ask you about the concentration/time curve in capecitabine study.
Here's an example from M. Mackean et al. "Phase I and Pharmacologic Study of Intermittent Twice-Daily Oral Therapy With Capecitabine in Patients With Advanced and/or Metastatic Cancer" Journal of Clinical Oncology, Vol 16, No 9, 1998: pp 2977-2985
[image]

As you can see capecitabine and 5-FU curves have 2 slopes. What is the reason of such curve shapes? fed condition or something else?
In our study we have similar results.

Edit: Category changed. [Helmut]

—
Kind regards,
Mittyri

Helmut
★★★

Vienna, Austria,
2013-11-01 16:11
(4208 d 02:32 ago)

@ mittyri
Posting: # 11856
Views: 8,267

Enterohepatic recirculation

Post reply

Hi Miityri,

❝ As you can see capecitabine and 5-FU curves have 2 slopes. What is the reason of such curve shapes?

Capecitabine is partly excreted unchanged into the bile and known to undergo enterohepatic recirculation; such profiles are common.

Capecitabine → 5’-dFCR → 5’-dFUR → 5-FU → DHFU → FUPA → FBAL

Note that the primary metabolite 5’-dFCR does not show first-order elimination between 1–4 hours as well (concave semilog-plot). C_max of the secondary 5’-dFUR is actually due to the reabsorbed fraction. If you walk the metabolization-chain further ‘downstream’ peaks merge and are shifted to later times.

❝ fed condition or something else?

See above – but in fasting state you would see a shift of the second peak towards later times (emptying of the gall bladder triggered by food). However, administration after food is the labeled use of Xeloda.

❝ In our study we have similar results.

As expected. Nothing to worry about in BE (that’s the drug, not the formulation).

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

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mittyri
★★

Russia,
2013-11-21 13:23
(4188 d 05:20 ago)

@ Helmut
Posting: # 11934
Views: 6,364

Enterohepatic recirculation

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Hi Helmut,

Thank you for exhaustive explanation!
The information from this forum is very helpful.

I've one more question following up upon this topic.

One of the subjects has actual data:
[image]

All points are BQL after last visible point.
So the question is: how to calculate the AUC part from tlast to infinity in this case with Winnonlin (what kind of points to collect for lambda z calculation & hl)?

—
Kind regards,
Mittyri

Helmut
★★★

Vienna, Austria,
2013-11-21 15:18
(4188 d 03:25 ago)

@ mittyri
Posting: # 11936
Views: 6,912

WinNonlin: λz

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Hi Mittyri,

❝ So the question is: how to calculate the AUC part from tlast to infinity in this case with Winnonlin (what kind of points to collect for lambda z calculation & hl)?

What did you state in the protocol?

Generally it is not a good idea to include C_max/t_max in the estimation of λ_z, since absorption is not complete. That’s the reason why Phoenix’ default “Best Fit” would not give you an estimate (only two data points >t_max). On the other hand WinNonlin ≤5.3 would happily give you an R²_adj of ~0.999 – in log-scale the last part of the profile looks nice.
Some ideas:
- Overrule Phoenix’ default and use the last three data points. You could justify that by the almost identical λ_z obtained from the last two.
- According to the Russian GL the main PK metric for extent of absorption is AUC_t (if AUC_t > 80% AUC_∞). If you cannot demonstrate that according to the protocol (e.g., three data points after t_max required), consider excluding the subject from the comparison of AUC_t. That should no hurt in terms of power because the critical PK metric is C_max (likely higher CV).

PS: Excel’s xy-plot with the “smooth line” option sucks.

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

The quality of responses received is directly proportional to the quality of the question asked. 🚮
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mittyri ★★ Russia, 2013-11-22 09:25 (4187 d 09:18 ago) @ Helmut Posting: # 11941 Views: 6,266	WinNonlin: λz Post reply
	Hi Helmut, Thank you for advice! ❝ What did you state in the protocol? I didn't state in the protocol anything about this situation. Now I have a plan&experience Could you give a cue in the same situation: Last point is BLQ. What do you think about this case? How to calculate λz? — Kind regards, Mittyri