Bioequivalence and Bioavailability Forum

thirupathireddy alla ☆ 2010-09-02 08:36 (5763 d 05:41 ago) Posting: # 5873 Views: 5,339	ambulatory sample [Regulatives / Guidelines] Post reply
	Dear HS and other members, We have to plan for withdrawal of ambulatory sample with the window period of plus 30 min to schedule time with NO Protocol deviation (e.g. for 08:00 clock amb. sample, if the sample withdrawn at 08:29/30 we will consider 08:00 clock sample). Is this samples are impact on the value of AUCt/other? With Best Regards, Thirupathi Reddy.alla ACL-HYD — Regards, ATR-INDIA

Ohlbe
★★★

France,
2010-09-02 12:25
(5763 d 01:52 ago)

@ thirupathireddy alla
Posting: # 5874
Views: 4,422

Sampling time deviations

Post reply

Dear Thirupathi,

There are two different aspects that should not be mixed up:

first, is a sampling time deviation a protocol deviation. If you define a 30 minute window in your protocol, sampling time deviations of less than 30 minutes are not protocol deviations, but sampling time deviations of more than 30 minutes will be considered as protocol deviations and would need to be reported in that section of the trial report;
second, should sampling time deviations be considered for AUC calculations. The new EMA guideline is clear (§ 4.1.5, Pharmacokinetic parameters):
Actual time of sampling should be used in the estimation of the pharmacokinetic parameters
My interpretation of this would be that if a sample was taken at 48 hours and 30 minutes, the sampling time should be considered to be 48.5 and not 48, even if it is still within the 30-minute window defined in your protocol.

Regards
Ohlbe

—
Regards
Ohlbe

Helmut
★★★

Vienna, Austria,
2010-09-02 14:46
(5762 d 23:31 ago)

@ thirupathireddy alla
Posting: # 5875
Views: 4,393

ambulatory sample

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Dear Thirupathi!

❝ We have to plan for withdrawal of ambulatory sample with the window period of plus 30 min to schedule time with NO Protocol deviation (e.g. for 08:00 clock amb. sample, if the sample withdrawn at 08:29/30 we will consider 08:00 clock sample).

First I agree with Ohlbe. Experienced CROs define ‘time allowance windows’ (based on the PK of the drug: narrower in the earlier parts of the profile and wider in the later parts) where deviations don’t have to be commented (!) in the CRF and/or EDCS. However, all deviations are recorded. Some ideas behind:

Large deviations are unlikely in the early parts where mainly a venflon is used.
Deviations are more likely in the later part; clotting of tubes may occur, or repetitive venipuncture may be applied.
The window for recording a protocol deviation should be set realistically! It is by far more important to record the exact time point, than to write down a detailed explanation. If the personnel introduces further delays in the clinical performance just recording reasons for delays, such a practice is counterproductive.

❝ Is this samples are impact on the value of AUCt/other?

Sure. No good idea. Let’s see an example (i.v. administration, one-compartment open model): C = 100e^{–ln(2)/8 × t}, theoretical AUCs: AUC_∞ = 100/[ln(2)/8] = 1154.2, AUC_t = AUC_∞ – AUC_∞ × e^{–ln(2)/8 × t} (48 h: 1136.1, 48.5 h: 1136.9).

dataset           1.                  2.                  3.

time            s i m u l a t e d   c o n c e n t r a t i o n 

 0              100                 100                 100

 2               84.0896             84.0896             84.0896

 4               70.7107             70.7107             70.7107

 8               50                  50                  50

16               25                  25                  25

24               12.5                12.5                12.5

48                1.5625                                  1.4963

48.5                                  1.4963

t½    (%bias)     8.0000 (±0.0)       8.0000 (±0.0)       7.8676 (-1.7)

lin-trapezoidal rule

AUCt  (%bias)  1199.1 (+5.5)       1201.8 (+5.7)       1198.3 (+5.5)

AUC∞  (%bias)  1217.1 (+5.5)       1219.0 (+5.6)       1215.3 (+5.3) 

log-trapezoidal rule

AUCt  (%bias)  1136.1 (±0.0)       1136.9 (±0.0)       1134.3 (-0.2)

AUC∞  (%bias)  1154.2 (±0.0)       1154.2 (±0.0)       1151.3 (-0.2)

The log-trapezoidal (or lin-up/log-down for extravascular data) rule is the better choice.

The original dataset with no deviations. t_1/2 from the last three values is estimated with 8 hours (unbiased); correct AUC_t and AUC_∞.
A delay of 30 minutes at 48 hours and the actual time point is used: Unbiased estimate of t_1/2; correct AUCs.
Delayed sampling treated as scheduled (48.5 → 48): Biased estimate of t_1/2 with 7.87 hours; underestimated AUCs.

—
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Helmut Schütz

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thirupathireddy alla ☆ 2010-09-03 15:33 (5761 d 22:44 ago) @ Helmut Posting: # 5882 Views: 4,197	ambulatory sample Post reply
	Thank You Mr. Ohlbe and HS for good reply Edit: Full quote removed. Please delete anything from the text of the original poster which is not necessary in understanding your answer; see also this post! [Ohlbe] — Regards, ATR-INDIA

patilatu
☆

2010-09-22 08:57
(5743 d 05:20 ago)

@ thirupathireddy alla
Posting: # 5929
Views: 7,923

ambulatory sample

Post reply

Actual time of sampling should be used in the estimation of the pharmacokinetic parameters. In studies to determine bioequivalence after a single dose, AUC(0-t), AUC(0-∞), residual area, Cmax and tmax should be determined. In studies with a sampling period of 72 h, and where the concentration at 72 h is quantifiable, AUC(0-∞) and residual area do not need to be reported; it is sufficient to report AUC truncated at 72h, AUC(0-72h).

Edit: Full quote removed. Please delete anything from the text of the original poster which is not necessary in understanding your answer; see this post! [Helmut]

ambulatory sample [Regulatives / Guidelines]

Sampling time deviations

ambulatory sample

ambulatory sample

ambulatory sample