Evaluation Of CYP450 and Transporter-Mediated Drug-Drug Interaction Potential Of Pomalidomide In Healthy Men and In Vitro
Authors: Kasserra Claudia , Assaf Mahmoud , Hoffmann Matthew , Li Yan , Liu Liangang , Wang Xiaomin , Kumar Gondi , Palmisano Maria 
Published: October 2019

Abstract

Introduction
Pomalidomide (POM) is an IMiD® immunomodulatory agent recently approved by the FDA for the treatment of patients with relapsed/refractory multiple myeloma. The prevalence of polypharmacy in disease treatment raises the possibilities of drug-drug interactions. Therapies that are CYP450 inhibitors, inducers, or transporter inhibitors, may alter the clinical exposure of substrates of these enzymes and transporters when they are administered concomitantly. POM is known to be predominantly metabolized via CYP450-mediated hydroxylation.1
The aim was to investigate the inhibition/induction potential of POM and its sensitivity as a CYP450 substrate in vitro, and to evaluate the impact of strong CYP450 inhibitors/inducers and a P-glycoprotein (P-gp) inhibitor on the pharmacokinetics (PK) of POM in healthy male subjects.

Methods
In vitro analyses were conducted using standard published methodologies.2-7
The in vitro data were followed up with a phase 1, open-label, non-randomized study in healthy men with single doses (SD) of POM. The study comprised a screening phase, 2 parallel treatment groups and a safety follow-up. Subjects in Part 1 received POM (4 mg SD) alone; ketoconazole (KETO 200 mg twice daily [BID] for 7 days) + POM (4 mg SD on day 5); and KETO (200 mg BID) + fluvoxamine (FLUV 50 mg BID) for 7 days + POM (4 mg SD on day 5) in three sequential periods to evaluate the effect of CYP3A4 and P-gp (KETO) and CYP1A2 (FLUV) inhibition on POM PK. Subjects in Part 2 received POM (4 mg SD) alone followed by carbamazepine (CARB 200 mg BID) for 11 days + POM (4 mg SD on day 10) in two sequential periods to evaluate the effect of CYP3A4 induction on POM PK. Serial blood samples were collected to determine the plasma concentrations of POM, FLUV, KETO, CARB and CARB-10, 11-epoxide by validated LC-MS/MS assay.
PK and safety data were summarized using descriptive statistics. An analysis of variance model was performed on natural log transformed PK data, and used to estimate the ratio of geometric means between POM and the other drugs with treatments as fixed effects and subjects as random effect.

Results
In vitro, POM did not inhibit or induce CYP450 enzymes, nor the transporters P-gp, BCRP, OAT1, OAT2, OAT3, OATP1B1, or OATP1B3. The in vitro oxidative metabolism of POM was predominately mediated by CYP3A4 and CYP1A2.
In the clinical trial, all 32 enrolled subjects (age 20–54 years; BMI 19.3–30.3 kg/m2) were included in the PK and safety analyses.
Statistical comparison showed that the mean exposure of POM administered after multiple doses of KETO was increased by ∼19% (AUC0-inf) and 7% (Cmax) compared to exposure of POM alone (Table). Addition of FLUV to the POM + KETO regimen increased mean exposure of POM by ∼107% (AUC0-inf) and 13% (Cmax) compared to POM + KETO. Overall, co-administration of POM + KETO + FLUV increased mean exposure of POM by ∼146% (AUC0-inf) and 21% (Cmax) compared to POM alone. The mean exposure of POM when administered after multiple doses of CARB decreased by ∼20% (AUC0-inf) and 25% (Cmax) compared to exposure of POM alone.
The mean estimated terminal half-life of POM was similar with or without KETO or CARB (range 5.85 to 6.77 h), but increased in the presence of KETO + FLUV (12.37 h), suggesting that the predominant interaction may be on the clearance (CL/F) rather than the absorption phase of POM.
POM CL/F was decreased by ∼16% in the presence of KETO (6.96 L/h), and decreased by ∼56% in the presence of KETO + FLUV (3.64 L/h), compared to POM alone (8.27 L/h). In contrast, POM + CARB increased POM CL/F compared to POM alone (9.49 versus 7.56 L/h).
POM 4 mg SD was generally well tolerated either alone or with the other drugs. The most common POM-related adverse event (AE) was nausea (6.3% of subjects). No deaths or serious AEs were reported.

Conclusions
POM appears to have a low potential for drug-drug interactions. POM is not a CYP450 inhibitor, inducer, or transporter inhibitor, in vitro and is therefore unlikely to affect the exposure of other drugs clinically. Co-administration of POM with the strong CYP3A4/5 and P-gp inhibitor KETO, or the strong CYP3A4/5 inducer CARB, had no clinically relevant effect on exposure to POM. Co-administration of POM with a strong CYP1A2 inhibitor (FLUV) will likely increase systemic exposure to POM and subjects receiving these concomitantly should be closely monitored for the occurrence of side-effects. POM 4 mg was generally well tolerated.

Disclosures:
Kasserra: Celgene: Employment, Equity Ownership. Assaf:Celgene Corporation: Employment, Equity Ownership. Hoffmann:Celgene Corporation: Employment, Equity Ownership. Li:Celgene Corporation: Employment, Equity Ownership. Liu:Celgene Corporation: Employment, Equity Ownership. Wang:Celgene Corporation: Employment, Equity Ownership. Kumar:Celgene Corporation: Employment, Equity Ownership. Palmisano:Celgene Corporation: Employment, Equity Ownership.