Vincristine Sulfate Liposome Injection with Bendamustine and Rituximab as First-Line Therapy for B-Cell Lymphomas: A Phase I Study.

BACKGROUND: We conducted an investigator-initiated, phase I trial of vincristine sulfate liposomal injection (VSLI) in combination with bendamustine and rituximab (BR) for indolent B-cell (BCL) or mantle cell lymphoma. METHODS: Participants received 6 cycles of standard BR with VSLI at patient-specific dose determined by the Escalation with Overdose Control (EWOC) model targeting 33% probability of dose-limiting toxicity (DLT). Maximum tolerated dose (MTD) was the primary endpoint; secondary endpoints included rates of adverse events (AEs), overall response rate (ORR), and complete response (CR). Vincristine sulfate liposomal injection is FDA approved for the treatment of patients with recurrent Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL). RESULTS: Among 10 enrolled patients, VSLI was escalated from 1.80 to 2.24 mg/m2, with one DLT (ileus) at 2.04 mg/m2. Two patients discontinued VSLI early. The most common AE included lymphopenia (100%), constipation, nausea, infusion reaction (each 60%), neutropenia, and peripheral neuropathy (50%). Grade 3/4 AE included lymphopenia (90%), neutropenia (20%), and ileus (10%), with prolonged grade ≥2 lymphopenia observed in most patients. Calculated MTD for VSLI was 2.25 mg/m2 (95% Bayesian credible interval: 2.00-2.40). Overall response was 100% with 50% CR. With median follow-up 26 months, 4/10 patients experienced recurrence and 1 died. CONCLUSION: Vincristine sulfate liposomal injection at 2.25 mg/m2 can be safely combined with BR for indolent B-cell lymphoma, but given observed toxicities and recurrences, we did not pursue an expanded cohort.Clinical Trials Registration Number: ClinicalTrials.gov identifier NCT02257242.

In vitro metabolism of CP-122,721 ((2S,3S)-2-phenyl-3-[(5-trifluoromethoxy-2-methoxy)benzylamino]piperidine), a non-peptide antagonist of the substance P receptor.

The metabolism of CP-122,721, a neurokinin-1 antagonist, has been examined in vitro using hepatic microsomes from human and animal species, and recombinant heterologously expressed P450 enzymes. Metabolism occurs primarily via O-demethylation and N-dealkylation reactions. In human liver microsomes, O-demethylation was shown to be catalyzed by CYP2D6 with a low K(M) value. N-dealkyation was shown to be catalyzed primarily by CYP3A4. When scaled to in vivo, in vitro intrinsic clearance data yielded a reasonable correlation across species. CP-122,721 was shown to be metabolized by parallel pathways to 5-trifluoromethoxysalicylic acid, which had been observed as a major circulating metabolite in humans after oral administration of CP-122,721. The involvement of CYP1A2, CYP3A4, and MAO-B was demonstrated in the pathways leading to 5-trifluoromethoxysalicylic acid. The O-desmethyl metabolite of CP-122,721 was shown to undergo a P450 catalyzed O-detrifluoromethylation reaction yielding a p-hydroquinone metabolite. The reaction was shown to be catalyzed by CYP3A4. Incubation under (18)O(2) yielded the hydroquinone containing O-18, consistent with this reaction occurring via an ispo substitution mechanism. Combined, these findings provide a comprehensive understanding of the metabolism of this new agent.

Impact of nonspecific binding to microsomes and phospholipid on the inhibition of cytochrome P4502D6: implications for relating in vitro inhibition data to in vivo drug interactions.

The effects of microsomal concentration on the inhibitory potencies of four compounds--fluoxetine, quinidine, imipramine, and ezlopitant--on heterologously expressed recombinant CYP2D6-catalyzed bufuralol 1'-hydroxylase activity were determined. Increasing microsomal concentration from 0.0088 to 2.0 mg/ml, using additional microsomes not containing cytochrome P450, resulted in a marked increase in IC(50) and K(I) values for fluoxetine, ezlopitant, and imipramine, when inhibition constants were calculated using the nominal concentration of inhibitor added to the incubation mixture. The extent of nonspecific binding of these inhibitors to microsomes was determined using equilibrium dialysis. The extent of binding increased with increasing microsomal concentration. Binding was greatest for ezlopitant, followed by fluoxetine, imipramine, and quinidine. Correcting inhibition constants for the extent of nonspecific binding resulted in greater consistency of these values with differing microsomal protein concentrations. This effect was also studied with added phospholipid. Inhibition constants increased with increasing phospholipid, and nonspecific binding was also observed for these four drugs to phospholipid. This suggests that the phospholipid component of microsomes possesses some or all of the responsibility for nonspecific binding, and its effect on inhibitors of drug-metabolizing enzymes. These findings suggest that inhibition constants for drugs as inhibitors of microsomal drug-metabolizing enzymes, such as cytochrome P450, should be corrected for the extent of nonspecific binding to components of the in vitro matrix. The implications of this on the prediction of drug-drug interactions from in vitro data are discussed.