I need the group's help on something. I have data from 2 studies whereBack to the Top
the drug was given by 30 minute intravenous infusion. PK sampling was
at 0.25 h, 0.5 h, 0.58 h, etc. The vast majority of subject
concentrations at 0.25 hours were greater than at 0.5 hours (sometimes
as high as 2-times higher),i.e., pre-end of infusion concentrations
were signficantly higher than end of infusion concentrations. Samples
were collected intravenously from the opposite arm as the infusion.
Can anyone think of any reason how this can occur besides the site
switched the tubes or the lab switched tubes. I could understand this
explanation for 1 or 2 subjects but not for most subjects across 2
different studies. Any thoughts?
Peter L. Bonate, PhD, FCP
4545 Horizon Hill Blvd
San Antonio, TX 78229
Dear Pete,Back to the Top
What is the pharmacology of the drug? Does it have an influence on
renal clearance (e.g through an increase in blood pressure) or diuretic
This may be a direction to look.
Head of Pharmacology and Preclinical Development
4SC AG Fon: +49 89 700763-0
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I have a couple of thoughts, but no real insights... did the infusion rate change over the course of drug administration or was part of the 30 minute infusion a saline flush of the line?Back to the Top
Human Genome Sciences, Inc
Hello,Back to the Top
One possible explanation may be that the 30-minute infusion was not
actually performed at a fixed rate. Theoretically, it may be possible that most
of the drug was given initially at a higher IV rate, and then, to
compensate this, a slower rate was placed until completing the 30-minute infusion. Even, the possibility of shorter than 30 minutes IV infusions may had
happened, but with the EOI PK samples drawn at the planned 30 minutes.
Short IV infusions at a planned fixed rate are difficult to establish
accurately, without mistakes, without a programmed pump. Was that the
Emiliano Calvo, MD, PhD
Institute for Drug Development
Cancer Therapy and Research Center
7979 Wurzbach, Zeller Building, 4th floor, Room #Z414H
San Antonio, Texas 78229
Telephone: (210) 616-5970
Fax: (210) 692-7502
I'd like to thank everyone for their comments on this problem. So farBack to the Top
here are some of the possible reasons for pre-end of infusion
concentrations being much higher than end of infusion concentrations:
- steady state has already been reached and what we are seeing is
fluctuation around steady state. I don't think so. Most of the pre-EOI
concentrations are much higher than EOI. The trend is too prominent.
- errors on infusion times. This seems unlikely as the phenomenon
happens in 2/3 of the patients across multiple centers and studies.
- delayed metabolism. This may be possible but I am unaware of any
drug that actually shows this.
- delayed distribution. Same as delayed metabolism.
- errors in collection times. Same as errors in infusion times.
Actual clock times on CRFs do not change matters.
- is the drug formulated in some type of liposomal formulation? No.
The drug is formulated in saline.
- the drugs pharmacology affects its pk. This is possible, but I am
unaware of the drug having affect on blood pressure. It may be
affecting transporters. Don't know yet.
- analytical error. This is possible. I am verifying with the lab.
I think the most likely explanation is delayed metabolism or
distribution. Is anyone aware of any other drugs that this might happen
We have experienced it in the past. The most probable reason for thatBack to the Top
is the EOI (30 min) sample drawn after the infusion is stopped. This
can be easily solved by drawing the EOI sample just prior to (say 2
min)the end of infusion to get the peak levels. In all the clinical
trials invoving drug infusions at our site we draw EOI samples 2 min
before the pump stops.
Ramesh Boinpally, PhD
Karmanos Cancer Institute
Wayne State University
Detroit, MI 48201
Pete:Back to the Top
By end of infusion do you mean, say, 5 minutes before the infusion
stopped, or after the end of the infusion. If the latter, how much
longer after the true EOI? The latter possibility of course suggests
an extremely rapid, high-capacity distribution phase, perhaps to
endothelium or receptors, possibly to tissue.
Paul Hutson, Pharm.D.
Associate Professor (CHS)
UW School of Pharmacy
777 Highland Avenue
Madison, WI 53705-2222
Tel: (608) 263-2496
FAX: (608) 265-5421
This frequently happen with drugs exhibiting rapid distribution. ABack to the Top
delay of 5 minutes after end of infusion would result in blood conc
more than half that just before end of infusion.
Dear All,Back to the Top
We have seen this phenomen with furosemide infusion in the patients.
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