Combinatorial Efficacy and Toxicity of an Engineered Toxin Body MT-3724 with Gemcitabine and Oxaliplatin in Relapsed or Refractory Diffuse Large B Cell Lymphoma.

MT-3724 is an engineered direct-kill immunotoxin comprised of a CD20-specific scFv fused to a Shiga-like toxin subunit. In this phase IIa study, eight patients with relapsed diffuse large B-cell lymphoma were treated with MT-3724 combined with gemcitabine and oxaliplatin (GEMOX). The objective response rate was 85.7%, with a median duration of response of 2.2 months. The 12-month overall survival and progression-free survival were 71.4% and 28.6%, respectively. Two patients experienced grade 2 capillary leak syndrome (CLS). Combination therapy with MT-3724 and GEMOX demonstrated an early efficacy signal but was limited by the incidence of CLS.

Exploratory effects of a strong CYP3A inhibitor (ketoconazole), a strong CYP3A inducer (rifampicin), and concomitant ethanol on piragliatin pharmacokinetics and pharmacodynamics in type 2 diabetic patients.

Piragliatin is a CYP3A substrate; its inactive metabolite M4, formed through cytosolic reductase, is reversibly metabolized back to piragliatin through CYP3A. The impact of concomitant CYP3A modifiers thus cannot be predicted. Drinking alcohol under fasting conditions is associated with a recognized glucose-lowering effect, which might be synergistic with piragliatin's hypoglycemic effect. Two exploratory studies were conducted to examine these potential interactions in type 2 diabetes (T2D) patients: 16 completed an open-label, sequential 2-way crossover, 2-arm (randomized to ketoconazole and rifampicin) CYP3A study; another 18 participated in a double-blind, placebo-controlled, randomized 3-way crossover ethanol study. Administration of piragliatin (100-mg single dose) resulted in a 32% Cmax and 44% area under the curve (AUC∞ ) increase in piragliatin exposure without affecting glucose AUC0-6h following ketoconazole (400 mg QD × 5 days); 30% Cmax and 72% AUC∞ decrease in piragliatin exposure with a 13% increase in glucose AUC0-6h following rifampicin (600 mg QD × 5 days); and, unexpectedly, a 32% Cmax and 23% AUC0-6h decrease (no change in AUC∞ ) in piragliatin exposure with a 13% increase in glucose AUC0-6h following alcohol (40-g single dose). In conclusion, a strong CYP3A modifier or concomitant alcohol could lead to a change in exposure to piragliatin with a potential alteration in glucose-lowering effect.

Lack of Potential Pharmacokinetic and Pharmacodynamic Interactions Between Piragliatin, a Glucokinase Activator, and Simvastatin in Patients With Type 2 Diabetes Mellitus.

To evaluate the potential pharmacokinetic (PK) and pharmacodynamic (PD, glucose-lowering effect) interaction between simvastatin and piragliatin, both CYP3A substrates, 30 patients with type 2 diabetes mellitus participated in this open-label, randomized, 6-sequence, 3-way crossover (William's design) study. During 3 periods, patients were randomized to receive a single dose of 80 mg simvastatin alone, a single dose of 100 mg piragliatin alone, as well as single doses of 80 mg simvastatin and 100 mg piragliatin together. Primary PK and PD parameters were AUCs on dosing days. The ratio of geometric means (90% confidence intervals) of the AUCinf of piragliatin coadministered with simvastatin compared with piragliatin alone was 0.98 (0.92-1.05), whereas that of the AUCinf of simvastatin acid (active metabolite) coadministered with piragliatin compared with simvastatin alone, was 1.02 (0.90-1.16), suggesting lack of pharmacokinetic interaction between piragliatin and simvastatin. Piragliatin's glucose-lowering effect was not affected by coadministration of simvastatin. Overall, administration of piragliatin with simvastatin was without additional clinically relevant adverse effects as well as abnormality in laboratory tests, vital signs, and electrocardiogram parameters. Concomitant administration of simvastatin and piragliatin, both CYP3A substrates, has no clinically relevant effect on the pharmacokinetics of either piragliatin or simvastatin or on the pharmacodynamics for piragliatin.

Pharmacokinetics and pharmacodynamics of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, following single-dose administration by subcutaneous and intravenous routes to healthy subjects.

OBJECTIVES: Tocilizumab, a humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody, given by intravenous (i.v.) infusion every 4 weeks has been approved for treatment of patients with rheumatoid arthritis. The objective of the study was to determine pharmacokinetics (PK) and pharmacodynamics (PD) of tocilizumab including absolute PK and PD bioavailabilities following subcutaneous (s.c.) administration. METHODS: The PK and PD of tocilizumab 162 mg or 81 mg after single s.c. and i.v. administration were evaluated in an open-label, 4-parallel group study involving 48 healthy subjects (n = 12/group). RESULTS: Following single-dose s.c. administration of tocilizumab, area under the serum concentration-time curve (AUC∞) increased by 6.4-fold, and maximum serum concentration (Cmax) increased by 4-fold, as the dose was doubled from 81 mg to 162 mg. Tocilizumab absolute PK bioavailability (AUC∞ ratio (s.c./i.v.)) was higher at 162 mg (48.8%) than at 81 mg (22.7%). Tocilizumab PD bioavailability for soluble IL-6R (sIL-6R) (AUClast ratio (s.c./i.v.)) was 109% at 162 mg and 80.9% at 81 mg. Tocilizumab PD bioavailability for C-reactive protein (CRP) effect was 98.2% (CRP AUC480h ratio) at 162 mg and 80.4% (AUC240h ratio (s.c./i.v.)) at 81 mg. Tocilizumab was well tolerated at both doses after s.c. and i.v. administration. CONCLUSIONS: Tocilizumab absolute PK bioavailability for s.c. vs. i.v. administration was low; however, the PD effects for sIL-6R and CRP levels were comparable after 162-mg s.c. and i.v. administration. Therefore, 162 mg s.c. dose is a comparable dose for 162 mg i.v. dose based on PD bioavailability.

Antiemetic care for patients with breast cancer: focus on drug interactions and safety concerns.

PURPOSE: The drug interactions and adverse events that should be considered when individualizing antiemetic therapy for patients undergoing treatment for breast cancer are reviewed. SUMMARY: A variety of antiemetic agents are available, including antihistamines, dopamine-receptor antagonists, serotonin-receptor antagonists, and neurokinin-receptor antagonists. To ensure optimal symptom control for each patient without unnecessarily prolonging treatment, patient- and treatment-specific risk factors must be considered. Neurokinin-receptor antagonists, the newest class of antiemetics, are effective in preventing acute and delayed chemotherapy-induced nausea and vomiting but must be used in combination with a serotonin-receptor antagonist and a corticosteroid. The serotonin-receptor antagonists have become the mainstay of antiemetic therapy, but current guidelines do not distinguish among the different agents in this class. However, there are distinct pharmacologic differences that may affect the potential for drug interactions and, ultimately, patient outcomes and the occurrence of adverse events. Therefore, the potential for drug interactions must be considered when selecting an antiemetic, particularly for patients who are taking multiple concomitant medications. Further, because a number of breast cancer therapies and some antiemetic agents carry cardiovascular warnings or precautions and since breast cancer patients may already be suffering from cardiovascular complications, the possible cardiotoxic effects of the antiemetic or chemotherapy agents or the combinations of these agents should be considered. CONCLUSION: Antiemetic treatment is essential for patients with breast cancer who are undergoing moderately to highly emetogenic cytotoxic treatment. When selecting an antiemetic, clinicians must select an agent that provides optimal protection against nausea and vomiting while avoiding drug-drug interactions and additional adverse events.