Liangang Liu

Pomalidomide: evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects.

Pomalidomide offers an alternative for patients with relapsed/refractory multiple myeloma who have exhausted treatment options with lenalidomide and bortezomib. Little is known about pomalidomides potential for drug–drug interactions (DDIs); as pomalidomide clearance includes hydrolysis and cytochrome P450 (CYP450)‐mediated hydroxylation, possible DDIs via CYP450 and drug‐transporter proteins were investigated in vitro and in a clinical study. In vitro pomalidomide was neither an inducer nor inhibitor of CYP450, nor an inhibitor of transporter proteins P glycoprotein (P‐gp), BCRP, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3. Oxidative metabolism of pomalidomide was predominately mediated by CYP1A2 and CYP3A4, and pomalidomide was shown to be a P‐gp substrate. In healthy males, co‐administration of oral (4 mg) pomalidomide with ketoconazole (CYP3A/P‐gp inhibitor) or carbamazepine (CYP3A/P‐gp inducer) did not result in clinically relevant changes in pomalidomide exposure. Co‐administration of pomalidomide with fluvoxamine (CYP1A2 inhibitor) in the presence of ketoconazole approximately doubled pomalidomide exposure. Pomalidomide appears to have low potential for clinically relevant DDI and is unlikely to affect the clinical exposure of other drugs. Avoid co‐administration of strong CYP1A2 inhibitors unless medically necessary. Pomalidomide dose should be reduced by 50% if co‐administered with strong CYP1A2 inhibitors and strong CYP3A/P‐gp inhibitors.

Population pharmacokinetics of pomalidomide

A population pharmacokinetic (PPK) model of pomalidomide was developed and the influence of demographic and disease‐related covariates on PPK parameters was assessed based on data from 6 clinical trials of pomalidomide (dose range, 0.5–10 mg) in healthy participants (n = 96) and patients with multiple myeloma (MM; n = 144). PPK data described herein suggest that systemic clearance of pomalidomide is comparable between healthy study participants and patients with MM. However, apparent peripheral volume of distribution and apparent intercompartmental clearance between central and peripheral compartments were 8‐ and 3.7‐fold higher in patients with MM vs. healthy subjects, suggesting drug exposure is higher in peripheral compartments of patients with MM vs. healthy subjects. Covariate analysis suggested pomalidomide clearance is not affected by demographic factors except for gender, and it is unlikely this factor is clinically relevant. In addition, renal function as measured by creatinine clearance or renal impairment (RI) does not significantly affect clearance of pomalidomide. In conclusion, pomalidomide has robust pharmacokinetic exposure, not affected by demographic factors or renal impairment. Pomalidomide is preferentially taken up by tumors over healthy tissues in patients with MM.

A Phase I Study in Patients with Solid or Hematologic Malignancies of the Dose Proportionality of Subcutaneous Azacitidine and Its Pharmacokinetics in Patients with Severe Renal Impairment

To assess the dose proportionality of azacitidine pharmacokinetics (PK) after single subcutaneous (SC) doses of 25–100 mg/m2, and determine the effect of renal impairment on PK after single and multiple 75 mg/m2 SC azacitidine doses.

Evaluation of CYP3A‐mediated drug–drug interactions with romidepsin in patients with advanced cancer

Two multicenter, single‐arm, single‐infusion, open‐label studies were conducted to evaluate the effect of ketoconazole (a strong CYP3A inhibitor) or rifampin (a strong CYP3A inducer) daily for 5 days on the pharmacokinetics (PK) and safety of romidepsin (8 mg/m2 intravenous 4‐hour infusion for the ketoconazole study or a 14 mg/m2 intravenous 4‐hour infusion for the rifampin study) in patients with advanced cancer. Romidepsin coadministered with ketoconazole (400 mg) or rifampin (600 mg) was not bioequivalent to romidepsin alone. With ketoconazole, the mean romidepsin AUC and Cmax were increased by approximately 25% and 10%, respectively. With rifampin, the mean romidepsin AUC and Cmax were unexpectedly increased by approximately 80% and 60%, respectively; this is likely because of inhibition of active liver uptake. For both studies, romidepsin clearance and volume of distribution were decreased, terminal half‐life was comparable, and median Tmax was similar. Overall, the safety profile of romidepsin was not altered by coadministration with ketoconazole or rifampin, except that a higher incidence and greater severity of thrombocytopenia was observed when romidepsin was given with rifampin. The use of romidepsin with rifampin and strong CYP3A inducers should be avoided. Toxicity related to romidepsin exposure should be monitored when romidepsin is given with strong CYP3A inhibitors.

OP0119 The CRL4 Cereblon E3 Ubiquitin Ligase Modulator CC-220 Induces Degradation of the Transcription Factors Aiolos and Ikaros: Immunomodulation in Healthy Volunteers and Relevance to Systemic Lupus Erythematosus

Background CC-220 is an immunomodulatory compound that binds to cereblon (CRBN), part of the CRL4CRBN E3 ubiquitin ligase complex, which has been shown to ubiquitinate the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3). Polymorphisms at the IKZF1 and IKZF3 loci have been associated with risk of systemic lupus erythematosus (SLE). Objectives We explored CRBN, IKZF1, and IKZF3 gene expression in peripheral blood mononuclear cells (PBMC) from SLE patients; the effect of CC-220 on Ikaros and Aiolos protein levels and SLE autoantibody production in vitro; and the impact of CC-220 on immunological parameters in a double-blinded, placebo-controlled, single-ascending dose, healthy volunteer phase 1 clinical trial. Methods CRBN, IKZF1, and IKZF3 gene expression were measured by qRT-PCR. Ikaros and Aiolos protein levels were measured by western blot and flow cytometry. Anti-dsDNA and anti-phospholipid autoantibodies were measured from SLE PBMC cultures treated for 7 days with CC-220. In the phase 1 healthy volunteer study, 56 subjects were randomized and enrolled in 7 cohorts, with 6 subjects per cohort receiving a single oral dose of CC-220 (0.03-6 mg) and 2 subjects per cohort receiving placebo. CD19+ B cells, CD3+ T cells, and intracellular Aiolos were measured by flow cytometry. IL-2 and IL-1β production were stimulated with anti-CD3 or LPS, respectively, in the TruCulture ex vivo whole blood assay system. Results Compared to normal PBMC, SLE PBMC expressed significantly higher levels of CRBN (1.5-fold), IKZF1 (2.1-fold), and IKZF3 (4.1-fold). CC-220 treatment of whole blood significantly reduced Aiolos and Ikaros protein levels in B cells, T cells, and monocytes, but not in granulocytes. In cultures of SLE PBMC, CC-220 inhibited anti-dsDNA and anti-phospholipid autoantibody production with an IC50 of

In Vivo Assessment of the Effect of CYP1A2 Inhibition and Induction on Pomalidomide Pharmacokinetics in Healthy Subjects

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Cereblon modulator iberdomide induces degradation of the transcription factors Ikaros and Aiolos: immunomodulation in healthy volunteers and relevance to systemic lupus erythematosus

10 nM. Following administration of single doses of CC-220 to healthy volunteers, there was a treatment-related decrease in intracellular Aiolos, with minimum mean percent of baseline values of

The effects of apremilast on the QTc interval in healthy male volunteers: a formal, thorough QT study

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Pharmacokinetics and safety of apremilast (CC-10004) in subjects with hepatic impairment

12%>28% in B cells and 0%>33% in T cells, for 0.3-6 mg. There was also a treatment-related decrease in absolute CD19+ B cells and CD3+ T cells, with minimum mean percent of baseline values of

Pharmacokinetics and safety of Enasidenib following single oral doses in Japanese and Caucasian subjects

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