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Hello Forum,
In a study having 19 time points, for the last 9 of which the subjects
are ambulatory, a subject is injured (while ambulatory) after the 15th
time point and admitted as an inpatient. He is on a wide variety of
medications. What would be the impact (ethical, pharmacokinetic,
analytical etc) of collecting the remaining samples and using the data
for a BE study.
Nisha K.R.
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Dear Nisha,
There are a number of issues to consider.
A simple change from ambulatory to sedentary in itself is likely to
reduce the rate of absorption (if not already complete) due to altered
posture and reduced heart rate. Reduced heart rate would also
potentially reduce CL of high extraction ratio drugs.
Then there is the effect of the injury itself. This will depend on the
extent of the injury, which you do not allude to. If the injury is
severe and results in high systemic cytokine levels these can alter the
CL of drugs. There may also be changes in protein binding during the
acute phase response.
You mention the patient taking multiple drugs - if the drugs that the
patient is taking have changed because of the injury then this is also a
potential influence on the PK profile of your drug under investigation.
So - a number of potential influences on the PK of a drug due to the
injury.
Ethics - not sure if you are referring to the ethics of chasing down
injured participants for extra blood samples, or the ethics of including
these samples in your analysis. Either way, you could be on shaky
ground, depending on the extent of the injury.
Analytical - the only thing that I can think of is the potential for
altered plasma protein binding influencing your results.
Hope this helps your deliberations
Andrew
Dr Andrew Davey
School of Pharmacy and Medical Sciences
University of South Australia.
GPO Box 2471
Adelaide SA 5001
Tel: (0) 8 8302 1127
Fax: (0) 8 8302 2389
email: andrew.davey.at.unisa.edu.au
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Hi Nisha,
An injury followed by inpatient hospitalisation will be classified as
Serious Adverse Event (SAE). Collection of further samples have to be
discontinued and the subject has to be withdrawn from the study. A
report on the SAE has to be submitted to the IRB and the regulatory
agency at the earliest.
Regards
M.M.Ganesh
Senior Research Scientist
Ranbaxy Research Laboratories
New Delhi, INDIA
Web Page: www.geocities.com/ganaish/gans
Tel: 91-9891532434
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Dear Nisha
I think you had taken some of subjects as stand by because in this nine
(9) samples are ambulatory so you had to kept minimum 4 standby
subjects for study. Go to your point you can't take remaining samples
because this will affect your drug's metabolism by liver enzyme. So its
will affect you pK data. Second point ethically you can't take more
sample because that subject is admitted in the hospital for treatment
of injury and that Independent Ethics Committee (IEC) can't permit you
for taking blood sample from there patient. Third thing he will getting
some of the drugs which may be change pK of your study drug.
thanks and regards
Dr. Ilesh
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Dear Mr V.Radhakrishna
According to my experience in bioequivalence studies there might be
cases where AUCinf cannot be detected when terminal elimination phase
cannot be obtained from the available data but the AUC0-t should be
obtained.
In bioequivalence studies only 2 cases are described in the FDA
guideline regarding deletion of subject data: in case of vomiting (if
vomiting occurs at or before 2 times median Tmax.) or If the predose
value is greater than 5 percent of Cmax, the subject should be dropped
from all BE study evaluations.
In my opinion, the whole data for that specific period should be
evaluated .also the type of the drug whether long half life or not and
how much the absorption or terminal elemination phase is affected by
this missing data. and what is the percentage of the missing data to
the whole data.
It is also important that an internal operating procedure is present to
describes this issue.
Isra' Admour, M.Sc Pharm
Regualtory Affairs Director
International Pharmaceutical Research Center (IPRC)
Tel: +962-6-5627651/52/48 (ext. 213)
PO Box 963166, Amman11196, Jordan
www.iprc.com.jo
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Dr Andrew Davey, M.M.Ganesh and Dr Ilesh Changela,
Thank you for your views on this topic.
I am interested in knowing how the situation will change if
1. the subject's injury is minor for which he is treated, prescribed
some medication and discharged the same day.
2. the subject alternatively turns up and misses the remaining 4 time
points. I.e., misses 2 and turns up for 2.
3. the drug level is almost nil before injury and/or sufficient points
are available for elimination data calculation.
What would be the impact (ethical, pharmacokinetic, analytical etc) of
including this subject?
Is it still a SAE?
Thank you in advance,
Nisha K.R.
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The following message was posted to: PharmPK
Common sense: If the vomiting is related to the drug or the formulation
(Oral), then we might include the subject in the BE.
D. Paccaly,
Syngenor
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