RE: Modeling variability in absorption and clearance (Auto induction)
Dear Shankar Lanke,
you can try modeling variable absorption with a chain of transit
compartments and estimating the mean absorption and to account for
interoccasion variability in relative oral bioavailability (e.g.
F1=1*EXP(ETA(1)).
Other things that you should account for with efavirenz in my opnion are
1.The liquid formulation of efavirenz has a lower bioavailability.
2. slow metabolizers may exist due to CYP2B6 polymorphism. If you do not
have genotype data available, you could try mixture modeling of multiple
subpopulations.
3. weight is a known covariate on clearance and volume of distribution
4. CYP3A4 autoinduction of efavirenz is debatable.
Cheers,
Rob ter Heine
------
R. ter Heine, PhD, PharmD
Hospital pharmacist i.t.
Meander Medical Center, Amersfoort, The Netherlands
T: +31-33-8502335
E: [email protected]
________________________________
Quoted reply history
Van: [email protected] [mailto:[email protected]]
Namens Shankar Lanke
Verzonden: maandag 14 mei 2012 17:33
Aan: nmusers
Onderwerp: [NMusers] Modeling variability in absorption and clearance
(Auto induction)
Dear All,
I am working on Efavirenz (NNRTI dosed at 600 mg/day oral) population
pharmacokinetic data analysis (70 patients, 800 samples). Intense
sampling data on day 1 and 14. Individual day 1 and 14 analysis shows an
increased absorption in few patients plus increased clearance (auto
induction) in some of these patients and other patients (who revealed no
change in absorption). It is shown in earlier clinical studies that fed
state results in increased bioavailability. I have no covariate
information which may support this (available info Wt, Sex, total
protein and TBR). Moreover the absorption profiles are very haphazard
with troughs and peaks in the absorption phase, similar to what Bulitta
et.al 2009, Pg 3462-3471 showed(Antimicrobial agents and
chemotherapy). I have tried this Michaelis-Menton model in absorption
with and without lag time ( run fails).
NONMEM runs for one C.M. with no variability in absorption and
clearance as an OBF value of 1498, 2CM 1390 (Vd is low 68 liters cv% 7
and Vd perip CV% 64 ). 2 CM with autoinduction model (for all
patients)is OBV 1284 (run fails).
Efavirenz preclinical trials shows that dose variability results in non
linearity in absorption (Balani et.al 1998, vol 27, No.1), no clinical
trials supporting this info and dose is 600 mg/day in my data. Auto
induction was shown in clinical trials (zhu et.al). I have identified
the patients who have clearance and absorption variability and created
two columns in data sheet.Runs including the variability in absorption
and clearance for some patients completely fails with Vd as low as 30
and perip as high as 400 liters.
My questions to NM community are
1. How to handle this data if we dont have any covariate information for
absorption and clearance variability.
2. Any references to model the data without crashing the runs
Your suggestions are appreciated.
Thank you very much in advance.
Regards,
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