Back to the Top
Hi
When we did a SAD and MAD study in cancer patients. The results indicate that both Cmax
and AUC0-inf decrease with increasing dose. The drug candidate is mainly metabolized by
CYP3A4.
Any suggestions?
Thanks,
S. Kumar
Back to the Top
The following message was posted to: PharmPK
Hi Shiva. One possibility is that the drug makes volunteers feel
nauseated with increasing dose, which delays gastric emptying, which
reduces rate of absorption and so Cmax Then constant removal by
whatever metabolic process is at work reduces AUCinf. Andrew Sutton
Back to the Top
The following message was posted to: PharmPK
Dear S. Kumar,
You said:
> When we did a SAD and MAD study in cancer patients. The results
indicate that both Cmax
> and AUC0-inf decrease with increasing dose. The drug candidate is
mainly metabolized by
> CYP3A4.
> Any suggestions?
That is very little information to go on; however, a simulation study
using GastroPlus(tm) (or SimCYP or PK-Sim) would help to determine the driving
mechanisms underlying the drug's (/formulation's?) behavior.
Walt Woltosz
Simulations Plus, Inc.
42505 10th Street West
Lancaster, CA 93534
Back to the Top
When you say AUC 0-inf and Cmax decrease with increasing dose, you don't
mean that AUC and Cmax after, e.g., a 100 mg dose are smaller than that
after a 50 mg dose, correct? I am assuming you mean dose-normalized
values decrease. In other words, if you double the dose, these
parameters increase by maybe 1.5 times instead of expected 2 times.
It is rather hard to be specific with suggestions based on the limited
information you provide. Assuming the drug is given orally, here are a
couple of other reasons for decreasing bioavailability with increasing
dose:
- Saturable solubility. If your compound has a low solubility high doses
may lead to saturated solubility in the gut.
- A saturable transporting system is involved. If your drug's uptake is
mainly through a transporter system with limited capacity, it may get
saturated at higher doses, resulting in lower F. I believe gabapentin is
an example of a drug behaving this way.
Toufigh
Toufigh Gordi, PhD
President, PK/PD and Clinical Pharmacology Services
Rosa & Co. LLC: www.rosaandco.com
E-mail: tgordi.-a-.rosaandco.com
Back to the Top
The following message was posted to: PharmPK
Dear Kumar,
Check for gut metabolism through calculation using hepatic extraction
and bioavailability, if iv clearance is available. If your compound is
sufficiently soluble and permeable and dose is low, then the assumption
of fraction absorbed = 1, needed for this calculation should be valid.
You can also look for systemic metabolites iv vs oral.
Kind regards,
Sheila
Back to the Top
The following message was posted to: PharmPK
Dear Shiva
The possibilities of decreased AUC could be:
1. Solubility limited absorption. Whts the solubility of ur comp.
2. The other reason could be saturation of uptake transporters
3. Also there is possibilty of saturation of protein binding leading to
increase in clearance and hence lower AUC.
Hope it helps.
Tausif Ahmed Ph.D
Piramal Life Sciences
Mumbai India
Back to the Top
Dear Shiva,
Whether the AUC/Cmax actually decreases with dose or it does not
increase in proportion to the dose, it is clear you have dose-dependent
PK, or it may be time-dependent if the higher doses were given to the
same patients after low dose.
This can be due to physical factors such as solubility, which may affet
rate of absorption and/or bioavailability, or it can be sue to
inhibition (autoinhibition) of one or more of the ADME processess such
as transporters, metabolizing enzymes, protein binding...etc.
You can learn a lot about possible underlying mechanisms using simple
and cheap in vitro systems.
Back to the Top
Dear Shiva,
Could be a limited solubility in GI fluid, as most of the cancer drugs are highly
lipophilic.
Jignesh S. Kotecha, Ph D.
AGM - Discovery Bioanalysis and ADME,
Torrent Pharmaceuticals Ltd | Reaserch Centre | PO Bhat | Gandhinagar - 382428 | Gujarat,
India
|
Want to post a follow-up message on this topic?
If this link does not work with your browser send a follow-up message to PharmPK@boomer.org with "Causes of non-linear PK" as the subject | Support PharmPK by using the |
Copyright 1995-2011 David W. A. Bourne (david@boomer.org)