Low Potential of Basimglurant to Be Involved in Drug-Drug Interactions: Influence of Non–Michaelis-Menten P450 Kinetics on Fraction Metabolized

Abstract

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 (K) and S 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.

Population Pharmacokinetic and Exposure–dizziness Modeling for a Metabotropic Glutamate Receptor Subtype 5 Negative Allosteric Modulator in Major Depressive Disorder Patients

“…The elimination of basimglurant is mainly mediated by oxidative metabolism; in vitro enzyme phenotyping and kinetics studies have demonstrated that at the concentrations attained clinically, basimglurant metabolic clearance is catalyzed mainly by CYP1A212; this was confirmed in a clinical study using a CYP1A2 inhibitor, fluvoxamine, and lack of effect with a CYP3A4 inhibitor, ketoconazole. It is therefore not surprising that the covariates affecting CL/F directly, i.e., smoking status and gender and indirectly via the relative bioavailability, i.e., Asian ethnicity, are related to this metabolic pathway.…”

“…12 A dual inhibitor of CYP1A2 and CYP3A4, fluvoxamine, increased basimglurant plasma concentrations. 12 Ketoconazole (CYP3A4 inhibitor) had a modest to no impact on exposure of basimglurant. 11 This article describes the population modeling approach used to characterize the pharmacokinetics (PK) of basimglurant administered orally using an MR formulation in healthy subjects and MDD patients, to estimate the between-subject variability (BSV) and to quantify the effects of possible covariates on the PK of basimglurant.…”

“…The elimination of basimglurant is mainly mediated by cytochrome P450 (CYP) oxidative metabolism, followed by renal and fecal excretion with negligible parent drug found in urine. Carbamazepine decreased basimglurant plasma concentrations, likely by induction of CYP1A2 and/or CYP3A4 activity 12. A dual inhibitor of CYP1A2 and CYP3A4, fluvoxamine, increased basimglurant plasma concentrations 12.…”

“…Carbamazepine decreased basimglurant plasma concentrations, likely by induction of CYP1A2 and/or CYP3A4 activity 12. A dual inhibitor of CYP1A2 and CYP3A4, fluvoxamine, increased basimglurant plasma concentrations 12. Ketoconazole (CYP3A4 inhibitor) had a modest to no impact on exposure of basimglurant 11…”

In vitro and in vivo methods to assess pharmacokinetic drug– drug interactions in drug discovery and development

“…If reaction phenotyping information is not available or incorrect, it may lead to safety concerns, as subjects on the potent inhibitor/inducer drugs or PMs/UMs might not be excluded from clinical studies. In some cases, clinical DDI study might be conducted based on the wrong enzymes, e.g., it should have been a CYP1A2 DDI study rather than a CYP3A DDI study (Fowler et al, ). When there is a disconnect between in vitro f m and in vivo DDI results, it will require much more work to figure out the reasons through experiments, modeling and simulations.…”