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Dear all
Can somebody help explain some, to me at least, peculiar PK findings
we observed in a first-into-man study?
The study tested a single dose of a novel drug which was administered
as an oral solution to groups of 6 healthy male subjects at dose
levels ranging from 0.5 mg to 16 mg. Subjects participated in more
than one treatment period. Thus, subjects treated with a single dose
of 0.5 mg also received a single dose 2 mg and 8 mg (after an
appropriate wash-out period). Likewise, subjects treated with a single
dose of 1 mg also received a single dose 4 mg and 16 mg.
A non-compartmental PK analysis indicated that the increase in AUC was
dose-proportional. However, to my surprise the NCA also indicated that
the increase in AUC0-24h and Cmax were "supra-dose-proportional" and
that the terminal half-life was shorter at increasing doses.
Does anyone have any explanations for these results (dose-proportional
increase in AUC; supra-dose-proportional increase in AUC0-24h and
Cmax; shorter terminal half-life at increasing doses)?
I have added a bit more information below including the results of the
NCA [mean (SD)] for Cmax, Cmax/D, AUC, AUC/D, AUC0-24h, AUC0-24h/D and
t\0x00 below:
Dose (mg) Cmax (ng/mL) Cmax/D (ng/mL/mg)
0.5 1.6 ( 0.8) 3.3 (1.6)
1 3.5 ( 0.7) 3.5 (0.7)
2 11.3 ( 5.2) 5.7 (2.6)
4 30.9 (10.4) 7.7 (2.6)
8 71.9 (16.7) 9.0 (2.1)
16 170.5 (42.4) 10.7 (2.6)
Dose (mg) AUC (ng*h/mL) AUC/D ((ng*h/mL)/mg)
0.5 51.9 ( 13.8) 103.8 (27.5)
1 96.6 ( 19.5) 96.6 (19.5)
2 215.2 ( 50.7) 107.6 (25.3)
4 446.5 (134.3) 111.6 (33.6)
8 912.0 (179.5) 114.0 (22.4)
16 2046.7 (625.1) 127.9 (39.1)
Dose (mg) AUC0-24h (ng*h/mL) AUC0-24h/D ((ng*h/mL)/mg)
0.5 10.4 ( 3.7) 20.8 ( 7.5)
1 32.0 ( 7.4) 32.0 ( 7.4)
2 100.3 ( 24.5) 50.2 (12.2)
4 268.5 ( 66.1) 67.1 (16.5)
8 600.0 (116.9) 75.0 (14.6)
16 1360.8 (271.2) 85.1 (17.0)
Dose (mg) t 1/2 (h)
0.5 95.4 (31.9)
1 68.1 ( 9.3)
2 64.9 (16.8)
4 60.7 ( 4.8)
8 52.4 ( 6.5)
16 46.5 ( 7.1)
The drug was rapidly absorbed with tmax within 1-2 hours after
administration.
The plasma concentration versus time profiles indicated that the
sampling schedule was adequate for accurately estimating the AUC and
terminal half-life. Cmax was generally observed already at the second
or third post dose sample suggesting that the determination of Cmax
(and tmax) could possibly benefit from one or two more samples being
drawn early after dosing.
Following Cmax the plasma concentrations, in general, declined in
multi-phasic manner.
I thank you very much in advance.
Best regards,
Torben Balchen
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Torben,
The supra-proportional increase may possibly be due to saturation of
elimination pathway (renal excretion?). The increase in half life at
higher doses can be due to metabolite inhibiting the biotransformation
of parent drug and increasing its half-life or your assay may not be
sensitive enough to detect drug levels at low doses. Do you see any
changes in Vd with doses?
Ganesh Mugundu
--
Ganesh M Mugundu
PhD Candidate
Departmentof Pharmacokinetics & Biopharmaceutics,
College of Pharmacy
University of Cincinnati
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The following message was posted to: PharmPK
Torben,
This data would be best explored by modeling, rather than
non-compartmental analysis. But generally this sounds more like
saturation of distribution rather than saturation of elimination. With
this, less than proportional amount of drug would leave the circulation
to tissues as dose increases resulting in higher than proportional Cmax
and lower non-compartmental estimate of Vd. If clearance is not affected
(i.e. is linear), AUC would still be dose-proportional, and half-life
would appear lower at higher doses.
Regards,
Katya
--
Ekaterina Gibiansky
Senior Director, PKPD, Modeling & Simulation
ICON Development Solutions
Ekaterina.Gibiansky.-at-.iconplc.com
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The following message was posted to: PharmPK
Dear Torben,
If the terminal half life is decreasing with an increase in dose, for
drugs
with long residence times (i.e., the absorption phase is certainly
complete), then the apparent linearity of drug exposures from 0-inf is
an
artifact of competing nonlinear processes.
Deciphering which nonlinear processes are at play is speculation,
which I
wouldn't recommend.
That said, you come to the board not for problems, but solutions:
The nonlinearity in Cmax with a relatively short Tmax suggests a
saturated
efflux process, .. on the flip side, the long residence times are
consistent
with a saturated first pass effect, ... no bias towards either.
At the same time, the shorter terminal half lives at higher doses
suggest
that higher exposures from nonlinear drug input are competing with
saturated
protein binding (which can reduce exposure).
In the final analysis, lean towards extracting physiological phenomena
that
commonly may not show up during the preclinical trials, when
recommending
additional, more mechanistic data collection. Reviewing the drug
structure,
and any data from analogs, can usually lead you in a safe direction.
Emphasis on usually!
Regards,
Shawn D. Spencer, Ph.D., R.Ph.
Assistant Professor of Biopharmaceutics
Florida A&M College of Pharmacy
Tallahassee, FL 32307
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What did the clinical chemistry profiles look like on this study, were
there any concomitant therapeutic agents on board form the PT
histories. Any unusual findings
--
Sanjeev Thohan, PhD
SARx Consulting
SARxconsult.aaa.Gmail.com
http://www.linkedin.com/in/sanjeevthohan
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The following message was posted to: PharmPK
Hi Balchen,
According to your PK data, it seems that the sampling time is not long
enough. This could result in an inaccurate estimation of PK parameters.
In addition, you mentioned that you observed a "supra-dose-proportional"
AUC0-24h because this drug was not really in terminal stage at 24 hrs.
One more thing is that your quantitative assay may need to do some
modification to increase its sensitivity.
Regards,
Wang Lingzhi (PhD)
Cancer Science Institute, Singapore
National University of Singapore
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The following message was posted to: PharmPK
Dear Torben,
It seems to me that clearance is constant over this dose range, so that
rules out saturable gut metabolism, and if the extent of absorption is
constant then you probably don't have a solubility problem. Also, at
these small doses, I would be amazed if you can have saturable binding
to anything other than the pharmacological target.
I wonder if your compound is a P-gp substrate with a low Km. At low
doses, absorption of the drug is incomplete in the upper intestine but
is completed later, probably in the colon, from 24 to 48 hours. At high
doses, the efflux pump in the gut is defeated by high luminal
concentration and so most absorption happens in 0-24 hours. This would
also explain why the changes don't continue as dose size increases even
more.
Interestingly, these substrates are hard to detect in Caco-2 studies
because most assays use a high donor concentration for convenient
detection (eg 10 micromolar). Try running Caco-2 at < 1 micromolar (and
get the analysts to crank up the mass spec!) and see if there is efflux.
If this is difficult, then take a look at the polar surface area; this
is calculated from the structure so doesn't cost any time or money
(though you have to reveal the structure obviously). 120 square
angstroms is usually considered a cut-off, but slightly lower values -
say 110 - can apply to compounds which are moderately permeable and
efflux pumped.
From the development point of view, you have to hope that the effective
dose is not in the region of 2mg where this transition takes place; if
it is higher, you might be ok for consistent delivery.
Regards.
Ted
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Torben
What is the estimated half life of the drug from the lowest to highest
dose? Also fit the data using compartmental analysis.
Manish Issar, Ph.D
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Dear Torben,
What do you know about metabolism (stability, CYPs involved,
extraction ratio) and inhibition/induction potential of this compound?
One speculative interpretation is that this drug is both substrate and
inhibitor of 3A4 and also is metabolized by at least one more CYP
which is inducible. So autoinhibition in gut results in more than dose
proportional increase in Cmax and AUC0-24 while (Tmax remains the
same) but at higher dose also cause enzyme induction resulting in
shorter t1/2. Your t1/2 ranges from 6 to 12 days and most likely you
did not have long enough sampling time to characterize the terminal
elimination t1/2 and therefore some of your calculations may not be
accurate. Would you please share your metabolism data and provide a
representative PK profile along with LLOQ? Do you have PB data at
different drug conc?
Rostam
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