Desipramine, substrate for CYP2D6 activity: population pharmacokinetic model and design elements of drug-drug interaction trials.
OBJECTIVE
To develop a population pharmacokinetic model to describe the pharmacokinetics of desipramine in healthy subjects, after oral administration of a 50mg dose. Additional objectives were to develop a semi-mechanistic population pharmacokinetic model for desipramine, which allowed simulation of CYP2D6-mediated inhibition, when using desipramine as a probe substrate, and to evaluate certain study design elements, such as duration of desipramine pharmacokinetic sampling, required sample size and optimal pharmacokinetic sampling schedule for intermediate, extensive and ultrarapid metabolizers of CYP2D6 substrates.


RESULTS
The mean population estimates of the first order absorption rate constant (k(a) ), apparent clearance (CL/F) and apparent volume of distribution at steady state (V(ss) /F) were 0.15h(-1) , 111 lh(-1) and 2950 l, respectively. Further, using the proposed semi-mechanistic hepatic intrinsic clearance model with Bayesian inference, mean population desipramine hepatic intrinsic clearance was estimated to be 262 lh(-1) with between-subject variability of 84%. d-optimal PK sampling times for intermediate metabolizers were calculated to be approximately 0.25, 24, 75 and 200h. Similar sampling times were found for ultrarapid and extensive metabolizers except that the second d-optimal sample was earlier at 14 and 19h, respectively, compared with 24h for intermediate metabolizers. This difference in sampling times between the three genotypes can be attributed to the different intrinsic clearances and elimination rates.


CONCLUSIONS
A two compartment population pharmacokinetic model best described desipramine disposition. The semi-mechanistic population model developed is suitable to describe the pharmacokinetic behaviour of desipramine for the dose routinely used in drug-drug interaction (DDI) studies. Based on this meta-analysis of seven trials, a sample size of 21 subjects in cross-over design is appropriate for assessing CYP2D6 interaction with novel compounds.
Gueorguieva
Ivelina
I
Lilly Research Laboratories,Department of Drug Disposition, Lilly Research Laboratories, SunninghillRoad,Windlesham, Surrey, UK. gueorguieva_ivelina@lilly.com
Jackson
Kimberley
K
Wrighton
Steven A
SA
Sinha
Vikram P
VP
Chien
Jenny Y
JY
D000284:Administration, Oral; D000328:Adult; D001499:Bayes Theorem; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003891:Desipramine / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010641:Phenotype
D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D019389:Cytochrome P-450 CYP2D6; D003891:Desipramine