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Dear all,
I'd like to get some feedback on whether there are any guidelines (or
rule of thumb) for deciding the infusion time in clinical trials,
particularly of oncology drugs. For example, it is unclear (to me)
why people use infusion times varying from several minutes to several
hours because the reason/rationale is often not specifically
discussed in (journal) articles (and one assumes there is a
rationale). In addition, it appears that there is a disconnect
between common pre-clinical practice (bolus injections or (very)
short infusions) and drug administration in human trials.
Regards,
Frederik Pruijn
Frederik B. Pruijn PhD MSc (Senior Research Fellow)
Experimental Oncology Group
Auckland Cancer Society Research Centre
Faculty of Medical and Health Sciences
The University of Auckland
Private Bag 92019
Auckland
New Zealand
E-mail: f.pruijn.aaa.auckland.ac.nz
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The following message was posted to: PharmPK
Frederik,
I have yet to see any pharmacologically based rationale for deciding
on an optimal infusion duration, or the spacing between doses in a
treatment cycle or the number of treatment cycles.
I know of a couple of examples of dose individualization based on
aiming for a target AUC (methotrexate, carboplatin), but while this
is better than the one dose for everyone approach, both of these pay
no attention to duration of infusion or timing of doses because the
AUC approach necessarily removes any influence, or understanding, of
time.
I would really like to see if anyone reading this list can give an
example of a pharmacologically rational means of determining an
optimum dosing regimen for treatment of cancer in humans.
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.-a-.auckland.ac.nz
www.health.auckland.ac.nz/pharmacology/staff/nholford
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Dear Frederik, Nick
Infusion duration in oncology is often a trade off between the incidence
of side-effects, patient discomfort and practicality. A longer infusion
could, for instance, reduce the incidence of nausea/vomiting, as these
side-effects are often Cmax related. If the infusion duration is
prolonged, patients have to stay longer in the hospital.
Treatment schedules (spacing between doses, dose levels, cycles ) are
often also guided by side effects. Proper spacing allows the patient to
recover from hematological side-effects.
Classical anti-cancer drugs bind often irreversible to their target and
the effect is longer lasting. Therefore, the effect is amount or AUC
driven. Indeed, time is less important.
However, more and more anti-cancer drugs bind reversible to their
target, e.g inhibition of a certain key enzyme, and need to be given on
a daily basis. Dose levels are guided by target concentrations, e.g.
IC50 or IC90s. Treatment schedules (spacing) are also guided by the
side-effects.
I hope this helps.
Best regards,
Kees
Kees Bol, Ph.D.
--
Kinesis Pharma BV > Consultants in Drug Development
BREDA, The Netherlands
www.kinesis-pharma.com
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Dear Frederik,
As I understand clinical practice in this area, anticancer drugs are
often infused at the highest tolerable rate, restricted by the damage
and pain caused to the vein and limb which is catheterised. The high
concentration at the point of infusion before mixing of the drug with
systemic blood is responsible for "collateral" damage. For this reason,
long term treatment is often given through a "central line" into a
larger blood vessel. Other restraints are the number of hours in a
working day, which becomes an issue for combination regimes which are
administered consecutively because they are not tolerated or not
compatible together. Finally there are formulation issues - some drugs
are so insoluble that a large volume infusion is required, once more
increasing the duration of infusion.
There are other PK differences to consider. Courses of some anticancer
drugs (platins) are given with large volumes of water (up to 2 litres)
to dilute the drug excreted in urine and reduce the damage to the
kidneys.
There is usually some guidance (with a range of conditions) for treating
patients in the drug datasheets.
Nick's comment on the spacing between doses in a cycle is also very
interesting and I am interested to know if it based on anything more
than the time taken to recovery from side-effects.
Best regards.
Ted
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Hi,
The current level of mathematical modeling and analysis in
biomedicine, and especially in its field known as pharmacokinetics,
enables to adjust drug infusions at constant and/or time-varying
rates (infusion time and drug dose), using mathematical models and
computer-controlled infusion pumps.
The aims of such dosing are:
a) to achieve and to maintain required drug concentration-time
profiles in patients;
b) to be safe, cost effective, and patient specific, see e.g. works
(1,2).
1.Durisova, M., et al. Pharmacokinetics of Factor VIII in
hemophilia A patients assessed by frequency response method. Meth
Find Exper Clin Pharmacol, 20, 1998, 217-226.
2.Durisova, M., Dedik, L. A system-approach method for the adjustment
of time-varying continuous drug infusion in individual patients. A
simulation study. J Pharmacokin Pharmacodyn, 29, 2002, 427-444.(Full
text)
With best regards,
Maria Durisova
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