Basimglurant, a novel mGlu5-negative allosteric modulator under development for the treatment of
major depressive disorder, is cleared via
cytochrome P450 (P450)-mediated oxidative metabolism. Initial
enzyme phenotyping studies indicated that
CYP3A4/5 dominates
basimglurant metabolism and highlights a risk for
drug-drug interactions when it is comedicated with strong
CYP3A4/5 inhibitors or inactivators; however, a clinical
drug-drug interaction (DDI) study using the potent and selective
CYP3A4/5 inhibitor
ketoconazole resulted in an area under the curve (AUC) AUCi/AUC ratio of only 1.24. A further study using the
CYP3A4 inducer carbamazepine resulted in an AUCi/AUC ratio of 0.69. More detailed in vitro
enzyme phenotyping and kinetics studies showed that, at the low concentrations attained clinically,
basimglurant metabolic clearance is catalyzed mainly by
CYP1A2. The relative contributions of the
enzymes were estimated as 70:30
CYP1A2:
CYP3A4/5. Using this information, a clinical study using the
CYP1A2 inhibitor
fluvoxamine was performed, resulting in an AUCi/AUC ratio of 1.60, confirming the role of
CYP1A2 and indicating a balanced DDI risk profile.
Basimglurant metabolism kinetics show
enzyme dependency: CYP1A2-mediated metabolism follows Michaelis-Menten kinetics, whereas
CYP3A4 and
CYP3A5 follow sigmoidal kinetics [with similar constant (KM) and S50 values]. The interplay of the different
enzyme kinetics leads to changing fractional
enzyme contributions to metabolism with substrate concentration, even though none of the metabolic
enzymes is saturated. This example demonstrates the relevance of non-Michaelis-Menten
P450 enzyme kinetics and highlights the need for a thorough understanding of metabolism enzymology to make accurate predictions for human metabolism in vivo.