Delamanid at all dosages was safe, well tolerated and demonstrated significant exposure-dependent EBA over 14 days, supporting further investigation of its pharmacokinetics and anti-tuberculosis activity.

IntroductionElevated interleukin (IL)-6 occurs in patients with active rheumatoid arthritis (RA), which has been shown to lead to a decrease in cytochrome P450 (CYP) enzyme activity and alterations in drug concentrations metabolized by CYP. IL-6 signaling blockade by IL-6 receptor (IL-6R) antagonists may reverse this effect of IL-6 and restore CYP activity. This study evaluated the pharmacokinetic profile of simvastatin (a CYP3A4 substrate) before and 1 week after a single dose of sarilumab (a human monoclonal antibody [mAb] blocking the IL-6Rα) in patients with RA, to assess potential interaction.MethodsNineteen patients with active RA received oral simvastatin 40 mg 1 day before and 7 days after subcutaneous injection of sarilumab 200 mg. The pharmacokinetic parameters of simvastatin and its primary metabolite, β-hydroxy-simvastatin acid, were calculated using noncompartmental analysis.ResultsCompared with simvastatin alone, single-dose simvastatin administration 7 days after single-dose sarilumab administration in patients with RA resulted in reduced simvastatin and β-hydroxy-simvastatin acid exposure in plasma. Mean effect ratios (90 % confidence interval) for simvastatin peak plasma concentration (C max) and area under the concentration–time curve extrapolated to infinity (AUC∞) were 54.1 % (42.2–69.4 %) and 54.7 % (47.2–63.3 %), respectively. No changes occurred in time to C max or half-life for either simvastatin or β-hydroxy-simvastatin acid after sarilumab administration.ConclusionsSarilumab treatment resulted in a reduction in exposure of simvastatin, consistent with reversal of IL-6-mediated CYP3A4 suppression in patients with active RA, as was reported for tocilizumab with simvastatin and for sirukumab with midazolam.Clinical trial registration numberNCT02017639.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-016-0462-8) contains supplementary material, which is available to authorized users.

The binding of docetaxel to human plasma proteins was studied by ultrafiltration at 37 degrees C and pH 7.4. Docetaxel was extensively (> 98%) plasma protein bound. At clinically relevant concentrations (1-5 micrograms/ml), the plasma binding was concentration-independent. Lipoproteins, alpha1-acid glycoprotein and albumin were the main carriers of docetaxel in plasma, and owing to the high interindividual variability of alpha1-acid glycoprotein plasma concentration, particularly in cancer, it was concluded that alpha1-acid glycoprotein should be the main determinant of docetaxel plasma binding variability. Drugs potentially coadministered with docetaxel (cisplatin, dexamethasone, doxorubicin, etoposide, vinblastine) did not modify the plasma binding of docetaxel. In blood, docetaxel was found to be mainly located in the plasma compartment (less than 15% associated to erythrocytes).

Objective Safety and efficacy of mAbs blocking the IL-6 receptor have been established in RA. This is the first analysis examining safety and tolerability of sarilumab and tocilizumab administered as single or multiple doses in patients with RA within the same study. Methods In ASCERTAIN, patients were randomized 1: 1: 2 to 24 weeks’ double-blind sarilumab 150 or 200 mg every 2 weeks s.c. or tocilizumab 4 mg/kg every 4 weeks i.v., increased to 8 mg/kg if clinically indicated. In Study 1309, patients were randomized 1: 1: 1: 1 to single-dose open-label sarilumab 150 or 200 mg s.c. or tocilizumab 4 or 8 mg/kg i.v. Results In ASCERTAIN, incidence of treatment-emergent adverse events was similar between sarilumab and tocilizumab. The most common treatment-emergent adverse events were the following: sarilumab: neutropenia [6 patients (12.2%) in the 150 mg group and 8 (15.7%) in the 200 mg group], nasopharyngitis [6 (12.2%) and 3 (5.9%)], and injection-site erythema [4 (8.2%) and 4 (7.8%)]; tocilizumab: accidental overdose [9 (8.8%)], upper respiratory tract infection [7 (6.9%)] and nausea [7 (6.9%)]. Laboratory changes in both studies included decreased neutrophils and platelets and increased transaminases and lipids. In Study 1309, incidence of absolute neutrophil count <1.0 giga/l was similar between sarilumab and tocilizumab, and occurred more frequently in the higher dose groups. No association between decrease in absolute neutrophil count and increased incidence of infection was observed in either study. Conclusion No clinically meaningful differences in treatment-emergent adverse events were observed between sarilumab and tocilizumab. Laboratory changes with sarilumab were within the same range as those with tocilizumab. Trial registration numbers ASCERTAIN (NCT01768572); Study 1309 (NCT02097524).

First-line cemiplimab (anti-programmed cell death-1 (PD-1)) monotherapy has previously shown significant improvement in overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with advanced non-small cell lung cancer (aNSCLC) and PD-ligand 1 (PD-L1) expression ≥50%. EMPOWER-Lung 3 (NCT03409614), a double-blind, placebo-controlled, phase 3 study, examined cemiplimab plus platinum-doublet chemotherapy as first-line treatment for aNSCLC, irrespective of PD-L1 expression or histology. In this study, 466 patients with stage III/IV aNSCLC without EGFR, ALK or ROS1 genomic tumor aberrations were randomized (2:1) to receive cemiplimab 350 mg (n = 312) or placebo (n = 154) every 3 weeks for up to 108 weeks in combination with four cycles of platinum-doublet chemotherapy (followed by pemetrexed maintenance as indicated). In total, 57.1% (266/466 patients) had non-squamous NSCLC, and 85.2% (397/466 patients) had stage IV disease. The primary endpoint was OS. The trial was stopped early per recommendation of the independent data monitoring committee, based on meeting preset OS efficacy criteria: median OS was 21.9 months (95% confidence interval (CI), 15.5–not evaluable) with cemiplimab plus chemotherapy versus 13.0 months (95% CI, 11.9–16.1) with placebo plus chemotherapy (hazard ratio (HR) = 0.71; 95% CI, 0.53–0.93; P = 0.014). Grade ≥3 adverse events occurred with cemiplimab plus chemotherapy (43.6%, 136/312 patients) and placebo plus chemotherapy (31.4%, 48/153 patients). Cemiplimab is only the second anti-PD-1/PD-L1 agent to show efficacy in aNSCLC as both monotherapy and in combination with chemotherapy for both squamous and non-squamous histologies.