Abemaciclib is a selective and potent small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) being investigated for treatment of refractory hormone-receptor positive (HR+) advanced or metastatic breast cancer. In vitro, CYP3A is responsible for >99% of the CYP-mediated microsomal metabolism of abemaciclib and its active metabolites. Three clinical studies evaluated the disposition and metabolism and drug interaction potential of abemaciclib in the presence of a strong CYP3A-inducer, rifampin, or a strong CYP3A-inhibitor, clarithromycin. Abemaciclib disposition and metabolism were determined following a single oral 150 mg dose of [14C]-abemaciclib in healthy subjects (N = 6). In the rifampin interaction study, abemaciclib was administered as a single oral 200 mg dose in healthy subjects (N = 24) on 2 occasions: alone on Day 1 of Period 1 and in combination with 600 mg rifampin on Day 7 of Period 2, after 6 days of rifampin once daily (QD) dosing; rifampin continued QD for 7 days after abemaciclib. In the clarithromycin interaction study, abemaciclib was administered as a single oral 50 mg dose in patients with advanced cancer (N = 26) on 2 occasions: alone in Period 1 and on Day 5 of clarithromycin dosing (500 mg BID) in Period 2 followed by an additional 7 days of clarithromycin. Abemaciclib was extensively metabolized, with less than 10% of parent drug recovered unchanged in feces. Parent drug and 3 active metabolites; (LSN2839567 [M2], LSN3106729 [M18], and LSN3106726 [M20]) were detected in plasma. The mean t1/2 in healthy subjects was 29.0, 104.0, 55.9, and 43.1 hours for abemaciclib, M2, M18, and M20, respectively. Coadministration with rifampin compared to abemaciclib alone decreased abemaciclib AUC(0-?) and Cmax by 95% and 92%, respectively, and decreased AUC(0-?) and Cmax of total active species (abemaciclib + M2 + M18+ M20) by 77% and 45%, respectively. Coadministration with clarithromycin compared to abemaciclib alone increased abemaciclib AUC(0-?) and Cmax by 237% and 30%, respectively; and increased the total active species AUC(0-?) by 119% and decreased Cmax by 7%. The mean abemaciclib t1/2 was prolonged from 28.8 to 63.6 hours. No clinically significant safety concerns were observed following single doses of abemaciclib in healthy subjects or in patients with advanced cancer based on vital signs, clinical laboratory evaluations, and electrocardiogram data. The human absorption, distribution, metabolism and excretion study indicated that abemaciclib was cleared primarily by hepatic metabolism, and the clinical drug-drug interaction studies with strong CYP3A inducer and inhibitor substantiated the major role of CYP3A in the metabolism of abemaciclib. Due to significant changes in abemaciclib and active-metabolite exposure in the presence of strong CYP3A inducers and inhibitors, concomitant use with abemaciclib should be avoided, or abemaciclib dose may require adjustment. Citation Format: Palaniappan Kulanthaivel, Daruka Mahadevan, P. Kellie Turner, Jane Royalty, Wee Teck Ng, Ping Yi, Jessica Rehmel, Kenneth Cassidy, Jill Chappell. Pharmacokinetic drug interactions between abemaciclib and CYP3A inducers and inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT153.

Abemaciclib is an oral, selective, and potent small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) being investigated for the treatment of patients with refractory hormone-receptor positive (HR+) advanced or metastatic breast cancer. The absolute bioavailability and effect of food on pharmacokinetics (PK) following a single 200-mg oral dose of abemaciclib in healthy subjects were evaluated in three studies (Table 1). Abemaciclib plasma concentrations were measured serially pre-dose through 192 hours post-dose. Non-compartmental analysis was used to calculate PK parameters, and a mixed-effects model was used for statistical inference. In Study 1 the absolute bioavailability of a 200-mg dose of abemaciclib was 45% (90% CI: 40%, 51%). In Study 2 the ratios of AUC0-? after a high-fat or standard meal compared to fasting showed no effect (90% CIs within 0.80, 1.25). However, Cmax increased by 24% and 25% following high-fat and standard meals, respectively, compared to fasting (upper 90% CIs >1.25). No differences were found in the AUC0-? and Cmax of abemaciclib following a high-fat meal compared to a standard meal (90% CI within 0.80, 1.25). The median tmax was delayed by 2 hours following a high-fat meal compared to fasting (p = 0006). However, there was no difference in median tmax between the standard meal and fasting (p = .7197). Abemaciclib terminal half-life was similar across fed and fasted conditions. The late-breaking Study-3 results will be presented. In conclusion, abemaciclib oral bioavailability is sufficient to achieve therapeutic exposure. Food with abemaciclib does not reduce or increase the inter-individual PK variability and does not have a clinically-relevant impact on the PK of abemaciclib. Therefore, abemaciclib may be administered without regard to food. Table 1Designs for three open-label clinical studies of abemaciclib as a single 200-mg oral dose administered to healthy subjectsStudy ParametersNCT02327143a (Study 1)I3Y-MC-JPBSNCT02059148a (Study 2)I3Y-MC-JPBGNCT02482935a (Study 3)I3Y-MC-JPBUCompleted subjects (N)82329Overall designs and formulationsAbsolute bioavailability, 4 x 50-mg (25% w/w) capsules and tracer IVbPilot food effect, randomized crossover 3 period, 6 sequence 4 x 50-mg (50% w/w) capsulesPivotal food effect, randomized crossover 2 period, 2 sequence 2 x 100-mg (25% w/w) capsulesMeal conditionFastedFastedStandard mealHigh-fat, high-calorie mealFastedHigh-fat, high-calorie meal Citation Format: Kellie Turner, Jill Chappell, Palaniappan Kulanthaivel, Wee Teck Ng, Jane Royalty. Food effect on the pharmacokinetics of 200-mg abemaciclib in healthy subject. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT152.

Early and sustained HbA control between 6.5 and <7.0% appears to be an important modifiable factor that helps reduce CV risk in patients with newly-diagnosed T2DM in real-world clinical practice.

Olaratumab (Olara), a fully human monoclonal antibody that selectively binds human platelet-derived growth factor receptor alpha and blocks ligand binding, shows encouraging efficacy in combination with Dox in STS. Patients with metastatic or locally advanced STS not amenable to treatment with surgery or curative radiotherapy, aged ?18 years with an ECOG PS of 0-2 and documented LVE fraction ?50% were included. The primary objective was to assess the effect of Olara on the PK of Dox. Secondary objectives were to further characterize the PK and safety profiles of Olara alone and in combination with Dox. Drug-drug interaction (DDI) was assessed in 21-day cycles, where patients received each drug alone (Cycle 1) then in combination (Cycle 2). In Cycles 3-8, patients with clinical benefit could continue treatment with Olara+Dox. 15-mg/kg Olara was given IV over ∼60 min; 75-mg/m2 Dox was given IV over ∼15 min. Overall, 25 patients (10 male and 15 female, aged 27-83 years) received at least one dose of study drug; as planned, 15 patients were evaluable for PK and DDI assessment. The AUC and Cmax for Dox were similar with or without Olara; the 90% CIs for the ratios of geometric LS means for AUC were within the standard no-effect boundary (0.8, 1.25); the 90% CI for Cmax was only slightly out of the boundary but with a Cmax ratio close to unity (0.984). After the first infusion of Olara alone (Cycle 1, Day 10), a mean Olara Cmax of 293μg/mL was achieved at ∼2h post start of infusion, with a mean t1/2 of ∼157h. The mean Olara CL was 0.0259L/h. After the second infusion (Cycle 2, Day 1, Olara+Dox), Olara serum concentration had a median tmax of ∼2.8h post start of infusion, and the mean Cmax was higher (393μg/mL), due to the residual Olara serum concentrations from cycle 1. The mean t1/2 (∼131h) and CL (0.0218L/h) were, however, similar to those obtained after the first infusion. These Olara PK results are consistent with those previously reported. No deaths occurred. The most common treatment-emergent AE reported during the study were nausea (48%) and fatigue (44%). One Grade 4 IRR was observed; there was no evidence of QT prolongation. IV infusion of Olara did not have a clinically relevant effect on systemic exposure to Dox when both agents were given in combination. The PK of Olara alone and with Dox was consistent with previously reported data. Olara+Dox had an acceptable safety profile Citation Format: Victor Villalobos, Mark Agulnik, Seth M. Pollack, Daniel A. Rushing, Arun Singh, Brian A. Van Tine, Chukwuemeka Okereke, Wee Teck Ng, Damien M. Cronier. A phase I open-label study to evaluate the effect of olaratumab on the pharmacokinetics (PK) of doxorubicin (Dox) in patients with advanced soft tissue sarcoma (STS). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT145.

Background Smoking is a significant risk factor for periodontal disease and tooth loss, as shown in several clinical studies comparing smokers and nonsmokers. Although only a few longitudinal studies have assessed the outcome of periodontal disease after smoking cessation, they indicated that recovery after nonsurgical treatment was more successful in those who had quit smoking. As part of tobacco harm reduction strategies, substituting cigarettes with alternative, less harmful tobacco products is an approach complementary to cessation for smokers who would otherwise continue to smoke. The Tobacco Heating System (THS), developed by Philip Morris International (commercialized as IQOS), is part of the heat-not-burn product category. The IQOS device electrically heats tobacco instead of burning it, at much lower temperatures than cigarettes, thereby producing substantially lower levels of harmful and potentially harmful constituents, while providing the nicotine, taste, ritual, and a sensory experience that closely parallel those of cigarettes. Phillip Morris International has published the results from a broad clinical assessment program, which was established to scientifically substantiate the harm reduction potential of the THS among adult healthy smokers switching to the THS. The program is now progressing toward including adult smokers with smoking-related diseases. Objective The goal of this study is to demonstrate favorable changes of periodontal endpoints in response to mechanical periodontal therapy in patients with generalized chronic periodontitis who completely switched to THS use compared with continued cigarette smoking. Methods This is a randomized controlled two-arm parallel-group multicenter Japanese study conducted in patients with chronic generalized periodontitis who switch from cigarettes to THS compared with smokers continuing to smoke cigarettes for 6 months. The patients were treated with mechanical periodontal therapy as per standard of care in Japan. The primary objective of the study is to demonstrate the beneficial effect of switching to THS use compared with continued cigarette smoking on pocket depth (PD) reduction in all sites with an initial PD≥4 mm. The secondary objectives include evaluation of other periodontal parameters (eg, clinical attachment level or gingival inflammation) and overall oral health status upon switching to THS. Safety was monitored throughout the study. Results In total, 172 subjects were randomized to the cigarette (n=86) or THS (n=86) groups, and all 172 completed the study. The conduct phase of the study is completed, while data cleaning and analyses are ongoing. Conclusions This study is the first to test a heat-not-burn tobacco product in smokers with an already established disease. The results should further strengthen the evidence that switching to THS can significantly reduce the risk of smoking-related diseases if favorable changes in the evolution of chronic generalized periodontitis after mechanical therapy are found when compared with continued cigarette smoking. Trial Registration ClinicalTrials.gov NCT03364751; https://clinicaltrials.gov/ct2/show/NCT03364751 International Registered Report Identifier (IRRID) DERR1-10.2196/15350