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Dear all,
I have a lead compound, mouse T1/2 (p.o) is 60 min.
I have done a preliminary test and choose 20,80 and 160mg/kg dose level. all
formulation is in solution.
the single dose AUC is 207884, 1597952(7.6 fold), 2626265(12.6fold).
the chronic dose (qd for 14days) AUC is 147757, 1269248( 8.6
fold),1090548(7.4fold).
my question is
1 why dose increase from 20 to 80 (4folds) while the AUC increase nearly 8
folds?
2 why single dose study have a good Dose -Exposure relation while Chronic dose
not?
3 how to choose a toxicology dose for a Lead compound ? (for our lead, the
highest dose is 160mg/kg due to the solubility)
4 The in vivo efficacy dose is 20mg.kg, in vitro study shows the lead works at
5 fM, shoud we to lower the dose to like 5mg/kg to repeat in vivo efficacy
study?
sorry for the overwhilming data, and do not know if I explain it accurately!
Thanks for your help!
chang
Department of Biochemistry
UT Southwestern Medical Center
5323 Harry Hines Boulevard
Dallas, Texas 75390-9038
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The following message was posted to: PharmPK
Chang,
It seems that the increases in exposure is not proportional to the dose in
both the single and multiple dosing studies. Generally, there could be
several reasons for this, including decreased first-pass effect leading to
increased bioavailability, which in turn can have several reasons, or an
inhibition of the metabolizing enzymes. In your case, I would guess that the
1st-pass effect is changed (decreased) from one dose to another since you
see it both after the single and multiple dosing. Maybe an efflux
transporter or an enzyme is saturated, allowing more drug to be absorbed at
higher doses?
Does the half-life stay relatively constant across doses?
One good way to describe the observation would be to model the data,
especially if you can add a couple of more doses. A PK model would enable
you to estimate exposure even at doses you have not tested. It will also
allow you to connect the dots between dose-exposure-effect much more
efficiently.
Toufigh
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Toufigh
Thanks for your kind reply!
the multiple dose half life seems longer than that of single dose.
so I think there must be somthing happened after 14days dose. even the halflife is short.
you mentioned that fist pass effect is decreased,
however the exposure did not doubled while increase dose from 80 to 160.
I attached the PK parameters for your review.
Thank you
happy weekend
chang
Single dose 20mg/kg 80mg/kg 160mg/kg
Rsq 0.99 0.95 0.98
No_points_lambda_z 3
4
5
Lambda_z 1/min 0.017
0.01
HL_Lambda_z min 38.77
98.89
63.05
Tmax min 60
60
30
Cmax ng/ml 2580
13900
22050
AUClast min*ng/ml 207884
1597952
2626265
AUC_%Extrap_obs % 0.19 0.63 0.045
Vz_F_obs ml/kg 5371 7096 5539
Cl_F_obs ml/min/kg 96 49 60
AUMClast min*min*ng/ml 14826672 1.91E+08 2.76E+08
MRTlast min 71.32 119.42 105.18
Multiple dose 20mg/kg 80mg/kg 160mg/kg
Rsq 0.65 0.57 0.97
No_points_lambda_z 4 4 3
Lambda_z 1/min 0.001966 0.003924 0.004023
HL_Lambda_z min 352 176 172
Tmax min 60 30 60
Cmax ng/ml 2030 12475 12200
AUClast min*ng/ml 147757 1269248 1090548
AUC_%Extrap_obs % 0.81 0.08 0.03
Vz_F_obs ml/kg 68306 16049 36458
Cl_F_obs ml/min/kg 134 62 146
AUMClast min*min*ng/ml 22667184 1.12E+08 1.10E+08
MRTlast min 153 88 101
chang
Department of Biochemistry
UT Southwestern Medical Center
5323 Harry Hines Boulevard
Dallas, Texas 75390-9038
Email:chg-wang.-at-.hotmail.com
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