Duration of Absorption Time From Depot (Gut) as Covariate
Title: Paul R
I have been asked to look at data that suggest a dependence of AUC and
Cmax upon transit time in the gut. The elimination rates for the one
compartment model are quite similar, suggesting that the variability
lies in bioavailability. Preliminary data suggest that the absorption
of this drug from the gut is transporter-limited, and may be dependent
upon the duration of time that the drug is exposed to a specific
portion of the duodenum or jejunum. Drug is observed at the earliest
sampling time, so I am not including a Tlag at this point.
I have in vitro dissolution data for this (hopefully) extended release
formulation, which I am introducing to the gut compartment for the
human subject PK data as events of AMT and RATE corresponding to each
measured point in the dissolution curve. Thus I am fixing it as a
time-dependent inputs over the 12 hour period following the single dose
and during the plasma sampling. Because of the non-instantaneous input
function, I understand I cannot use Savik's TRANSIT model (2007).
I have tried the code below to try to turn off Ka after some time TOFF,
the point at which the drug is estimated to have moved past the section
of absorption. There is no change in the gradient for TOFF, and the
fit is not improved over a simple 1 compartment absorption model
(ADVAN2).
I cannot turn off compartment 1 (-1) in my INPUT, since I do not know
when to turn it off (I am trying to determine this in the model).
There is extensive first pass of the compound - I do not know of any
auto-inhibition of metabolism. I suppose that I could try to trip F1
to null at some TOFF, but tripping Ka to Null seems more physiologic.
Can anyone suggest a snippet of code that might close Ka based upon a
covariate THETA corresponding to the time required to move past the
intestinal segment of absorption?
Thanks very much.
Paul
$SUBROUTINES ADVAN2
; 1 COMPARTMENT MODEL, NO LAG, NO LIMIT TO ABSORPTION PERIOD
$PK
TVKA=THETA(1); ABSORPTION RATE FROM GUT
CL=THETA(2)*EXP(ETA(1)); CLEARANCE
V2=THETA(3)*EXP(ETA(2)); V2
TOFF=THETA(4)*EXP(ETA(3)); DURATION OF PRESENCE IN ABSORPTION SEGMENT
K=CL/V2
DOSE=5; MG TABLET
AUC=DOSE/CL
S2=V2/1000
FLAG=1
IF(TIME.GE.TOFF) FLAG=0.0001
KA=TVKA*FLAG
$ERROR
IPRE = F
W1=F
DEL = 0
IF(IPRE.LT.0.001) DEL = 1
IRES = DV-IPRE; NEGATIVE TREND IS OVERESTIMATING IPRED WRT DV
IWRE = IRES/(W1+DEL)
Y=F*(1+ERR(1))+ERR(2)
$THETA (0.1,1.23, 50); KAGUT
$THETA (0.10,97.8,1000); CL
$THETA (0.1,86.5,1000); V2
$THETA (0.001, 1, 24); DUR
;$OMEGA 0.3; KA
$OMEGA 0.5; CL
$OMEGA 0.3; V2
$OMEGA 0.6; TOFF
--
Paul R.
Hutson, Pharm.D.
Associate
Professor
UW School
of Pharmacy
777
Highland Avenue
Madison
WI 53705-2222
Tel 608.263.2496
Fax
608.265.5421
Pager
608.265.7000, p7856