Changes in the defined daily dose; CYP2D6/CYP3A metabolism as an indicator for dose-setting problems.
OBJECTIVE
Interindividual variability is common at all stages of drug absorption, distribution, pharmacodynamics, metabolism and elimination. In this study, we focused on two enzymes involved in phase-I drug metabolism as markers of pharmacological variability: the CYP3A and CYP2D6 subsystems of cytochrome P450. The main aim of our study was to determine whether substrate drugs for CYP2D6 and/or CYP3A enzymes, showing high interindividual matabolic variability, are more prone to postmarketing adjustments of defined daily dose (DDD).


METHODS
A case-control design was used. We identified all DDD changes between 1982 and May 2004 through the website of the WHO Collaborating Centre for Drug Statistics Methodology. Cases were drugs with a DDD change and controls were other drugs with unchanged DDDs. Information about metabolism pathway, introduction year, literature exposure and administration route was retrieved.


RESULTS
We included 88 cases and 176 controls. Of the 88 cases, 51 were dosage decreases (58.0%). Overall, DDD changes were not associated with CYP2D6/CYP3A metabolism (OR 1.92; 95%CI 0.78-4.72). However, DDD decreases were associated with CYP2D6/CYP3A metabolism (OR 3.21; 95%CI 1.25-8.26). Adjusting for introduction year weakened this effect (OR 2.78; 95%CI 0.98-7.90).


CONCLUSIONS
Our study indicates that CYP2D6 and CYP3A substrates are more likely to require a DDD decrease after granting of market authorisation. However, this effect was diminished by adjusting for period of introduction. The implication of this finding is that variability indicators, as is demonstrated in this study for CYP2D6/CYP3A metabolism, can exert their influence on a wide variety of drug measures, such as the DDD.
Stolk
P
P
Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute for Pharmaceutical Sciences, P.O. Box 80082, 3508, TB Utrecht, The Netherlands.
Heerdink
E R
ER
Leufkens
H G M
HG
D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism
D015415:Biomarkers; D004364:Pharmaceutical Preparations; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A