Clinical Assessment of Mocravimod As a Victim of Drug-Drug Interactions Via CYP3A Metabolism and Transporters
Authors: Huntjens Dymphy , Oehen Stephan , Kueenburg Elisabeth 
Published: December 2024

Background

Mocravimod (MOC), a novel sphingosine-1-phosphate receptor (S1PR) modulator is predominantly metabolized via the CYP3A4 pathway based upon in vitro data. The potential therapeutic effect of MOC is retention of lymphocytes in lymphoid organs and thus reduction of circulating lymphocytes. MOC is in phase 3 development as an adjuctive and maintenance therapy in patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (allo-HCT), MOC and its active metabolite mocravimod-phosphate (MOC-P) is a victim of BCRP but not of OAPT1B1 or OATP1B3 transporters. Preliminary pharmacokinetic (PK) modeling of phase 1b data suggested that CYP3A4 inhibitors and cyclosporin (CsA) could increase exposure to MOC significantly. Given the co-administration of MOC with CYP3A4 inhibitors (e.g. azoles and CsA) in allo-HCT patients, two phase 1 studies were conducted to evaluate the drug-drug interactions (DDI) of MOC in combination with itraconazole (ITZ) or CsA.

Methods

Two phase 1, open-label fixed sequence studies were conducted in healthy volunteers (HV) to assess the effects of multiple dosing of a strong cytochrome P450 (CYP) 3A4 and P-glycoprotein (gP) inhibitor ITZ and multiple dosing of a strong CYP3A4, P-gp and BCRP inhibitor CsA on the single-dose pharmacokinetics of MOC. The studies consisted of 2 treatment periods and a washout period of at least 4 weeks. In the first treatment period, participants were administered MOC 3 mg alone in a single administration, and in the second treatment period participants were administered MOC 3 mg in a single administration with CsA 100 mg b.id. for 7 days or ITZ 200 mg QD for 14 days. All investigational medicinal products were administered orally in fed conditions. Blood samples were collected to determine MOC and MOC-P. MOC and MOC-P have long half-lives and therefore AUC0-inf was determined using non-linear mixed effect modeling1. Ratios of geometric least square (LS) means and 90% CIs were constructed for AUC0-inf and Cmax. Additionally, safety and tolerability of MOCwere monitored.

Results

ITZ co-administration with MOC did not affect the MOC and MOC-P Cmax; geometric mean ratio (GMR) of 0.92 [0.85-1.01] and 0.99 [0.92-1.08] fold, respectively. AUC0-inf was similar and independent of ITZ co-administration; GMR of 1.04 [0.97-1.11] and 1.11 [1.04-1.18] for MOC and MOC-P, respectively. CsA co-administration with MOC had a minor effect on MOC and a moderate effect MOC-P Cmax; geometric mean ratio (GMR) of 1.15 [1.10-1.20] and 1.87 [1.66-2.11] fold, respectively. A minor effect was observed on AUC0-inf ; GMR of 1.31 [1.24-1.38] and 1.46 [1.35-1.59] for MOC and MOC-P, respectively. PK modeling showed no effect of ITZ or CsA on the clearance of MOC or MOC-P, indicating limited CYP3A4 inhibition. Modeling indicated a potential small effect of BCRP inhibition by CsA on the absorption phase of MOC and MOC-P. Based on the pharmacological mechanism of action of S1PR modulators bradycardia is a potential adverse event (AE) class effect as well as lymphopenia. In these studies, bradycardia, 88%/84% of HV in ITZ study (with/without ITZ) and 100%/100% in CsA study (with/without CsA) and lymphocyte count decreases 76%/68% in ITZ study and 43%/53% in CsA study were the most common AEs. AEs were generally mild, and treatment emergent AEs were similar with or without co-administration of ITZ or CsA.

Conclusions

MOC, ITZ and CsA were generally well tolerated when administered alone or in combination. The PK of MOC and MOC-P are bioequivalent with or without co-administration of multiple doses of the strong CYP3A4 inhibitor ITZ and a minor interaction is observed when co-administered with CsA. Taken together, MOC can be co-administered with CYP3A4 inhibitors such as azoles or CsA without dosage adjustments.

References

1Svensson EM, C Acharya, B Clauson, KE Dooley, and MO Karlsson, 2016, Pharmacokinetic Interactions for Drugs With a Long Half-Life - Evidence for the Need of Model-Based Analysis, AAPS J, 18(1):171-179.