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Background and Objective Increased glycine availability at the synaptic cleft may enhance N-methyl-D-aspartate receptor signalling and provide a promising therapeutic strategy for cognitive impairment associated with schizophrenia. These studies aimed to assess the pharmacokinetics of BI 425809, a potent glycine-transporter-1 inhibitor, when co-administered with a strong cytochrome P450 3A4 (CYP3A4) inhibitor (itraconazole) and inducer (rifampicin). Methods In vitro studies using recombinant CYPs, human liver microsomes, and human hepatocytes were conducted to determine the CYP isoforms responsible for BI 425809 metabolism. In addition, two open-label, fixed-treatment period, phase I studies in healthy male volunteers are described. Period 1: participants received oral BI 425809 25 mg (single dose) on day 1; period 2: participants received multiple doses, across 10 days, of oral itraconazole or rifampicin combined with a single dose of oral BI 425809 25 mg on day 4/7 of the itraconazole/rifampicin treatment, respectively. Pharmacokinetic and safety endpoints were assessed in the absence/presence of itraconazole/rifampicin and included area under the concentration-time curve (AUC) over the time interval 0–167 h (AUC0‒167; itraconazole), 0–168 h (AUC0‒168; rifampicin), or 0–infinity (AUC0-∞; rifampicin and itraconazole), maximum measured concentration (Cmax) of BI 425809, and adverse events. Results In vitro results suggested that CYP3A4 accounted for ≥ 90% of the metabolism of BI 425809. BI 425809 exposure (adjusted geometric mean ratio [%]) was higher in the presence of itraconazole (AUC0‒167: 265.3; AUC0−∞: 597.0; Cmax: 116.1) and lower in the presence of rifampicin (AUC0‒168: 10.3; AUC0−∞: 9.8; Cmax: 37.4) compared with BI 425809 alone. Investigational treatments were well tolerated. Conclusions Systemic exposure of BI 425809 was altered in the presence of strong CYP3A4 modulators, corroborating in vitro results that CYP3A4 mediates a major metabolic pathway for BI 425809. Trial Registration Number NCT02342717 (registered on 15 January 2015) and NCT03082183 (registered on 10 March 2017) Supplementary Information The online version contains supplementary material available at 10.1007/s13318-021-00723-y.

Contains fulltext : 248967.pdf (Publisher’s version ) (Open Access) BACKGROUND AND OBJECTIVES: Nintedanib is a tyrosine kinase inhibitor approved for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD), idiopathic pulmonary fibrosis, and other chronic fibrosing ILDs with a progressive phenotype. As nintedanib may cause foetal harm, patients taking nintedanib should avoid pregnancy. The objective of this study was to investigate the effect of nintedanib co-administration on the pharmacokinetics of Microgynon (ethinylestradiol and levonorgestrel) in female patients with SSc-ILD. METHODS: This was an open-label, two-period, fixed-sequence, drug-drug interaction study. Female patients with SSc and ≥ 10% extent of fibrotic ILD on a high-resolution computed tomography scan were eligible to participate. In Period 1, patients received one Microgynon tablet (ethinylestradiol 30 μg and levonorgestrel 150 μg) ≥ 3 days before the first administration of nintedanib in Period 2. In Period 2, patients received one Microgynon tablet following intake of nintedanib 150 mg twice daily for ≥ 10 consecutive days. The primary pharmacokinetic endpoints were the areas under the plasma concentration-time curve of ethinylestradiol and levonorgestrel over the time interval from 0 to the last quantifiable data point (AUC(0-tz)) and the maximum measured concentrations of ethinylestradiol and levonorgestrel in plasma (C(max)). The secondary pharmacokinetic endpoint was the area under the plasma concentration-time curve of ethinylestradiol and levonorgestrel over the time interval from 0 extrapolated to infinity (AUC(0-∞)). The relative exposures of ethinylestradiol and levonorgestrel when administered alone and in combination with nintedanib were assessed using an ANOVA model. RESULTS: Seventeen patients were treated. Pharmacokinetic data from 15 patients were analysed. Plasma concentration-time profiles of ethinylestradiol and levonorgestrel were similar following administration of Microgynon before and after administration of nintedanib for ≥ 10 consecutive days. Adjusted geometric mean (gMean) ratios [90% confidence intervals (CIs)] for AUC(0‒tz) (101.4% [92.8, 110.7]) and AUC(0‒∞) (101.2% [94.0, 109.1]) indicated that there was no difference in total ethinylestradiol exposure when Microgynon was administered before or after administration of nintedanib. The adjusted gMean ratio for C(max) of ethinylestradiol (116.7% [90% CI 107.6, 126.5]) indicated an increase in peak exposure in the presence of nintedanib. Adjusted gMean ratios [90% CIs] for AUC(0-tz) (96.4% [91.5, 101.6]) and C(max) (100.9% [89.9, 113.2]) indicated that there was no difference in total or peak levonorgestrel exposure when Microgynon was administered before or after administration of nintedanib. The adjusted gMean ratio for AUC(0‒∞) of levonorgestrel indicated a decrease in total exposure in the presence of nintedanib (88.1% [90% CI 80.0, 97.0]). CONCLUSION: Pharmacokinetic data indicate that there is no relevant effect of nintedanib on plasma exposure to ethinylestradiol and levonorgestrel in female patients with SSc-ILD. TRIAL REGISTRATION: Clinicaltrials.gov NCT03675581.

Nintedanib is an oral, small-molecule tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis and patients with advanced non-small cell cancer of adenocarcinoma tumour histology. Nintedanib competitively binds to the kinase domains of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF). Studies in healthy volunteers and in patients with advanced cancer have shown that nintedanib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of nintedanib are reached approximately 2–4 h after oral administration and thereafter decline at least bi-exponentially. Over the investigated dose range of 50–450 mg once daily and 150–300 mg twice daily, nintedanib exposure increases are dose proportional. Nintedanib is metabolised via hydrolytic ester cleavage, resulting in the formation of the free acid moiety that is subsequently glucuronidated and excreted in the faeces. Less than 1% of drug-related radioactivity is eliminated in urine. The terminal elimination half-life of nintedanib is about 10–15 h. Accumulation after repeated twice-daily dosing is negligible. Sex and renal function have no influence on nintedanib pharmacokinetics, while effects of ethnicity, low body weight, older age and smoking are within the inter-patient variability range of nintedanib exposure and no dose adjustments are required. Administration of nintedanib in patients with moderate or severe hepatic impairment is not recommended, and patients with mild hepatic impairment should be monitored closely and the dose adjusted accordingly. Nintedanib has a low potential for drug–drug interactions, especially with drugs metabolised by cytochrome P450 enzymes. Concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of nintedanib. At an investigated dose of 200 mg twice daily, nintedanib does not have proarrhythmic potential.

BI 425809 is a potent and selective glycine transporter 1 (GlyT1) inhibitor being developed for the treatment of cognitive impairment in Alzheimer disease and schizophrenia. Translational studies evaluated the effects of BI 425809 on glycine levels in rat and human cerebrospinal fluid (CSF). Oral administration of BI 425809 in rats induced a dose‐dependent increase of glycine CSF levels from 30% (0.2 mg/kg, not significant) to 78% (2 mg/kg, P

Background and Objective Schizophrenia and Alzheimer’s disease are characterised by abnormalities in glutamatergic pathways related to N-methyl-d-aspartate receptor hypofunction. Glycine is an N-methyl-d-aspartate receptor co-agonist; inhibition of glycine transporter 1 may improve N-methyl-d-aspartate receptor function. This phase I, randomised, two-part study evaluated the safety, tolerability and pharmacokinetic profile of BI 425809, a novel glycine transporter 1 inhibitor, in healthy male and female volunteers. Methods Part 1 evaluated BI 425809 10, 25, 50 or 75 mg once daily or 75 mg twice daily in young subjects, and 25 mg or 50 mg once daily in elderly subjects. Each dose group comprised 12 subjects who received BI 425809 (n = 9) or placebo (n = 3) for 14 days (day 1: single dose; days 4–14: multiple dosing). Part 2 compared pharmacokinetic profiles in 12 subjects who received a single dose of BI 425809 25 mg in the morning and evening. Results Pharmacokinetic profiles were similarly shaped for all dose groups. Median time to maximum plasma concentration was 3.0–4.5 h with steady state being reached between days 6 and 10. Pharmacokinetic parameters demonstrated dose linearity at the predicted therapeutic exposure range of BI 425809 ≤ 25 mg once daily, but increased less than dose proportionally for ≥ 50 mg once daily. All reported adverse events were of mild-to-moderate intensity, 51/84 (61%; part 1) subjects had one or more treatment-related adverse event, no serious adverse events occurred and no dose dependency was observed. Conclusions Pharmacokinetic properties support both morning and evening dosing. BI 425809 was generally well tolerated at all tested doses. Clinicaltrials.gov identifier NCT02337283. Electronic supplementary material The online version of this article (10.1007/s40261-018-0660-2) contains supplementary material, which is available to authorized users.

Background and objectives Schizophrenia and Alzheimer’s disease are characterised by glutamatergic pathway abnormalities related to N-methyl-d-aspartate (NMDA) receptor hypofunction and cognitive impairment. Glycine is an NMDA receptor co-agonist; inhibition of glycine transporter 1 (GlyT1) should improve NMDA receptor hypofunction. This study evaluated safety and pharmacokinetic properties of BI 425809—a potent and selective GlyT1 inhibitor. Methods In the single-rising dose (SRD) component of this study, subjects were randomised to a single dose of BI 425809 [doses (mg): 0.5, 1, 2, 5, 10, 25, 50, 100 and 150], or placebo. The bioavailability/food effect (BA/FE) component investigated BI 425809 pharmacokinetics following single dosing (25-mg tablet) after overnight fasting or with a high-calorie meal or as solution (25 mg) after overnight fasting. Results Overall, 33/83 (39.8%) subjects had ≥ 1 treatment-related adverse event (AE); there were no deaths or serious AEs. Reported SRD part AEs trended towards dose dependency, occurring at the higher doses (mostly central nervous system related). BI 425809 plasma concentration–time profiles were similarly shaped across all doses and plasma exposure increased proportional to dose. In the BA/FE component, geometric mean ratios for the area under the concentration–time curve from time zero to the last measurable concentration and the maximum plasma concentration for tablet fasted versus solution fasted were 80.5 and 50.0%, respectively, and for tablet fed versus fasted were 125.9 and 142.1%, respectively. Conclusion BI 425809 was generally well-tolerated at doses expected to be clinically relevant. The AE profile suggested possible GlyT1-inhibiting effects. Clinical trial identifier NCT02068690.

Afatinib is an oral irreversible ErbB-Family Blocker indicated for treatment of patients with EGFR mutation positive advanced non-small cell lung cancer. This trial assessed whether renal impairment influences the pharmacokinetics and safety of afatinib. This was an open-label, single-dose study. Pharmacokinetic parameters after afatinib 40 mg were investigated in subjects with moderate (n = 8) or severe (n = 8) renal impairment (estimated glomerular filtration rate 30–59 mL/min/1.73 m2 and 15–29 mL/min/1.73 m2, respectively) and healthy matched controls (n = 14). Plasma and urine samples were collected before and up to 14 days after dosing for pharmacokinetic and plasma protein-binding assessment. Primary endpoints were area under the plasma concentration–time curve from time zero to the last quantifiable concentration (AUClast) and maximum plasma concentration (C max) between subjects with renal impairment and healthy matched controls. Pharmacokinetic profiles and plasma protein binding were similar in all groups. The extent of exposure, as indicated by AUClast and C max, was generally similar between the matched treatment groups, with the exception of the geometric mean ratio of AUClast for subjects with severe renal impairment, which showed a trend towards a higher value compared with matched healthy subjects (150.0 % [90 % CI 105.3–213.7]) Inter-individual variability was moderate (geometric mean coefficient of variation 28–39 % for moderate impairment, 34–42 % for severe impairment). Afatinib was well tolerated and urinary excretion was minimal. Moderate-to-severe renal impairment had a minor influence on the pharmacokinetics of afatinib that was within the observed inter-individual variability, suggesting that afatinib treatment can be considered in this patient population. Registered at ClinicalTrials.gov as NCT02096718.

Nintedanib and pirfenidone are approved treatments for idiopathic pulmonary fibrosis (IPF). This open-label, two-group trial investigated the pharmacokinetic drug–drug interaction between these two drugs in patients with IPF.Subjects not treated with antifibrotics at screening (group 1, n=20) received a single nintedanib dose (150 mg) followed by pirfenidone (titrated to 801 mg thrice daily) for 3 weeks, with a further single nintedanib dose (150 mg) on the last day (day 23). Subjects treated with pirfenidone at screening (group 2, n=17) continued to receive pirfenidone alone (801 mg thrice daily) for 7 days, then co-administered with nintedanib (150 mg twice daily) for a further 7 days, before single doses of both treatments on day 16.In group 1, adjusted geometric mean (gMean) ratios (with/without pirfenidone) were 88.6% and 80.6% for nintedanib area under the plasma concentration–time curve (AUC) and maximum plasma concentration (Cmax), respectively. In group 2, gMean ratios (with/without nintedanib) were 97.2% and 99.5% for pirfenidone AUC and Cmax, respectively. For all parameters, the 90% confidence intervals included 100%, suggesting similar exposure for administration alone and when co-administered. Both treatments were well tolerated.These data indicate there is no relevant pharmacokinetic drug–drug interaction between nintedanib and pirfenidone when co-administered in IPF patients.

This population pharmacokinetic model was developed to characterize the pharmacokinetics of the oral irreversible ErbB family blocker afatinib in patients with solid tumors and to investigate the impact of selected intrinsic and extrinsic factors.Data from 927 patients (4,460 plasma concentrations) with advanced solid tumors in 7 Phase II or III studies were analyzed. Afatinib was administered orally in continuous 3 or 4 week cycles (starting dose 20, 40 or 50 mg once-daily). Plasma concentration-time data for up to 7 months dosing were analyzed using nonlinear mixed-effects modeling.The pharmacokinetic profile of afatinib was best described by a two-compartment disposition model with first-order absorption and linear elimination. There was a slightly more than proportional increase in exposure with increasing dose, accounted for by a dose-dependent relative bioavailability. For the therapeutic dose of 40 mg, the estimated apparent total clearance and distribution volume at steady state were 734 mL/min and 2,370 L, respectively. While food intake, body weight, gender, Eastern Cooperative Oncology Group performance score, renal function, and the level of alkaline phosphatase, lactate dehydrogenase or total protein were statistically significant covariates influencing afatinib exposure, none resulted in a proportional change in exposure of more than 27.8 % in a typical patient at model extremes (2.5th and 97.5th percentiles of baseline values for continuous covariates). In simulations of the individual covariate effects, none caused a change in the typical profile exceeding the observed variability range (90 % prediction interval) of afatinib.This population pharmacokinetic model adequately described the pharmacokinetics of afatinib in different cancer patient populations and therefore can be used for simulations exploring covariate effects and possible dose adaptations. The effect size for each of the individual covariates is not considered clinically relevant.

Afatinib is a potent, irreversible, ErbB family blocker in clinical development for the treatment of advanced non-small cell lung cancer, metastatic head and neck cancer, and other solid tumours. As afatinib is a substrate for the P-glycoprotein (P-gp) pump transporter the three studies presented here investigated the pharmacokinetics of afatinib in the presence of a potent inhibitor (ritonavir) or inducer [rifampicin (rifampin)] of P-gp.We conducted phase I, open-label, single-centre studies in healthy male volunteers who received a single once-daily oral dose of afatinib (20 or 40 mg) together with either ritonavir or rifampicin; two studies had a randomised, two- and three-way crossover design and the third was a non-randomised, two-period sequential study.When afatinib 20 mg was administered 1 h after ritonavir, afatinib geometric mean (gMean) maximum plasma concentration (C max) and area under the plasma concentration-time curve from time zero to infinity (AUC∞) increased by 38.5 and 47.6 %, respectively. Coadministration of ritonavir either simultaneously or 6 h later than afatinib 40 mg resulted in minimal increase in the afatinib gMean C max and AUC∞ (4.1 and 18.6 % for simultaneous administration with AUC∞ not completely within the bioequivalence limits; 5.1 and 10.8 % for timed administration within the bioequivalence limits). Administration of afatinib 40 mg in the presence of rifampicin led to reduction in C max and AUC∞ by 21.6 and 33.8 %, respectively. In all studies, P-gp modulation mainly affected the extent of absorption of afatinib; there was no change in the terminal elimination half-life. The overall safety profile of afatinib was acceptable.Coadministration of potent P-gp modulators had no clinically relevant effect on afatinib exposure. Effects of potent P-gp inhibitors were minimal at higher afatinib doses and can be readily managed by the timing of concomitant therapy. As afatinib is not a relevant modulator or substrate of cytochrome P450 enzymes, the drug-drug interaction potential is considered to be low.

Afatinib is a potent, irreversible, ErbB family blocker in clinical development for the treatment of a variety of solid tumours. This study evaluated the pharmacokinetics of afatinib (10–100 mg once daily) in cancer patients. Data from 221 patients with advanced solid tumours in four phase I and one phase II trial were analysed using non-compartmental methods. Within each dose group, the shape of the geometric mean plasma concentration–time profiles after single and multiple doses were comparable. Maximum plasma concentration (C max) values were achieved 2–5 h after dosing and thereafter declined at least bi-exponentially. Steady-state plasma concentrations were attained within 8 days after the start of dosing. The geometric mean terminal elimination half-life at steady state was about 37 h. Repeated dosing resulted in a 2.77-fold accumulation based on the area under the plasma concentration–time curve (AUC), and 2.11-fold accumulation based on C max values. A slightly more than dose-proportional increase in afatinib exposure was observed. There was moderate intra-individual variability in afatinib trough concentration values (the geometric coefficient of variation (gCV) ranged from 22.2 to 67.5 %). The inter-patient variability in plasma concentrations was moderate to high (e.g. at the 40 mg dose, the gCVs ranged from 35.6 to 221 %). The exposure to afatinib (as measured by AUC and C max) correlated with the severity of the most common adverse events of afatinib—diarrhoea and rash. The pharmacokinetic profile of afatinib supports a once-daily dosage regimen. As expected for this patient population, the pharmacokinetic parameters of afatinib showed moderate to high inter-patient variability. Afatinib exhibits non-linear pharmacokinetics.

Background Afatinib 40mg/day is approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). In the case of drug-related grade ≥3 or selected prolonged grade 2 adverse events (AEs), the dose can be reduced by 10mg decrements to a minimum of 20mg. Here, we evaluate the influence of afatinib dose reduction on AEs, pharmacokinetics and progression-free survival (PFS) in the phase III LUX-Lung 3 and 6 (LL3/6) trials. Patients and methods Treatment-naive patients with advanced EGFR mutation-positive NSCLC in LL3 (global) and LL6 (China, Thailand, South Korea) were randomized to afatinib or chemotherapy. All afatinib-treated patients (LL3, n = 229; LL6, n = 239) were included in the post hoc analyses. Incidence and severity of common AEs before and after afatinib dose reduction were assessed. Afatinib plasma concentrations were compared in patients who reduced to 30mg versus those remaining at 40mg. PFS was compared between patients who dose reduced within the first 6 months of treatment and those who did not. Results Dose reductions occurred in 53.3% (122/229) and 28.0% (67/239) of patients in LL3 and LL6, respectively; most (86.1% and 82.1%) within the first 6 months of treatment. Dose reduction led to decreases in the incidence of drug-related AEs, and was more likely in patients with higher afatinib plasma concentrations. On day 43, patients who dose reduced to 30mg (n = 59) had geometric mean afatinib plasma concentrations of 23.3 ng/ml, versus 22.8 ng/ml in patients who remained on 40mg (n = 284). The median PFS was similar in patients who dose reduced during the first 6 months versus those who did not {LL3: 11.3 versus 11.0 months [hazard ratio (HR) 1.25]; LL6: 12.3 versus 11.0 months (HR 1.00)}. Conclusions Tolerability-guided dose adjustment is an effective measure to reduce afatinib-related AEs without affecting therapeutic efficacy. Clinical trial registration Clinicaltrials.gov identifiers: NCT00949650 and NCT0112393.

Arterial hypertension is associated with increased levels of reactive oxygen species, which may scavenge endothelium-derived NO and thereby diminish its vasorelaxant effects. However, the quantitatively relevant source of reactive oxygen species is unclear. Thus, this potential pathomechanism is not yet pharmacologically targetable. Several enzymatic sources of reactive oxygen species have been suggested: uncoupled endothelial NO synthase, xanthine oxidase, and NADPH oxidases. Here we show that increased reactive oxygen species formation in aortas of 12- to 14-month–old spontaneously hypertensive rats versus age-matched Wistar Kyoto rats is inhibited by the specific NADPH oxidase inhibitor VAS2870 but neither by the xanthine oxidase inhibitor oxypurinol nor the NO synthase inhibitor N G -nitro- l -arginine methyl ester. NADPH oxidase activity, as well as protein expression of its catalytic subunits, NOX1 and NOX2, was increased in the aortas of spontaneously hypertensive rats, whereas the expression of NOX4 protein, the most abundant NOX isoform, was not significantly changed. Impaired acetylcholine-induced relaxation of spontaneously hypertensive rat aortas was significantly improved by VAS2870. In conclusion, NOX1 and NOX2 but not NOX4 proteins are increased in aged spontaneously hypertensive rat aortas. Importantly, these NOX isoforms, in particular, ectopic expression of NOX1 in endothelial cells, appear to affect vascular function in an NADPH oxidase inhibitor-reversible manner. NADPH oxidases may, thus, be a novel target for the treatment of systemic hypertension.

ABSTRACT Aims: To evaluate the safety and maximum tolerated dose (MTD) of afatinib combined with nintedanib. Materials & methods: Patients received afatinib 10–20 mg daily plus nintedanib 150–200 mg twice daily (28-day cycle). Dose escalation followed a 3+3 design. Results: Patients received afatinib/nintedanib: 10/150 mg (n = 11); 10/200 mg (n = 13; MTD); 20/200 mg (n = 4). Four patients had dose-limiting toxicities (all grade 3): increased alanine aminotransferase (afatinib/nintedanib: 10/150 mg), diarrhea (10/200 mg), dehydration (20/200 mg), diarrhea with elevated liver enzymes (20/200 mg). Frequent treatment-related adverse events were diarrhea, nausea, anorexia, fatigue and vomiting. In total, 14 patients (46.2%) had objective responses at the MTD. Conclusion: The MTD, afatinib 10 mg daily plus nintedanib 200 mg twice daily, had a manageable safety profile, but was considered subtherapeutic for Phase II evaluation.

Background Afatinib 40 mg/day is approved for the first-line treatment of pts with EGFR mutation-positive NSCLC. The dose can be adjusted based on individual tolerability. Post-hoc analyses assessed the impact of afatinib dose adjustment on adverse events (AEs), pharmacokinetics (PK) and progression-free survival (PFS) in LL3 and LL6. Methods All afatinib-treated pts in LL3 (n = 229) and LL6 (n= 239) were included. In case of drug-related grade 3 or selected prolonged grade 2 AEs with afatinib 40 mg, the dose could be reduced by 10 mg decrements to a minimum of 20 mg. We analysed the incidence and severity of common AEs before and after dose reduction and compared PK data collected as part of the standard visit schedule on Day 43 in pts who reduced to 30 mg vs those remaining at 40 mg. PFS in pts who dose reduced within the first 6 months of treatment was compared with those who remained on afatinib 40 mg/day. Results Dose reductions occurred in 53% (122/229) and 28% (67/239) of pts in LL3 and LL6, respectively; the majority (86% and 82%, respectively) within the first 6 months of treatment. Dose reduction led to decreases in the incidence and severity of EGFR-mediated drug-related AEs (table). Combined PK analysis of LL3 and LL6 suggested that dose reduction was more likely in pts with higher plasma concentrations of afatinib. On Day 43, pts who had dose reduced to 30 mg (n = 59) had geometric mean plasma afatinib concentrations of 23.3 ng/mL, vs 22.8 ng/mL in pts who remained on the 40 mg dose (n = 284). Median PFS was similar in pts who dose reduced during the first 6 months of treatment vs those who did not in LL3 (11.3 vs 11.0 months [HR = 1.25; 95% CI, 0.91–1.72]) and LL6 (12.3 vs 11.0 months [HR = 1.00; 95% CI, 0.69–1.46]). Conclusions Tolerability-guided dose adjustment of afatinib reduced treatment-related AEs without adversely affecting efficacy.

8073 Background: Afatinib 40 mg/day (oral) is approved for the treatment of pts with advanced EGFRm+ NSCLC. Dose adjustment is recommended according to pre-defined tolerability criteria. We perform...

Temozolomide plus radiotherapy is standard treatment for newly diagnosed glioblastoma (GBM) patients.1 Recent attempts to improve front-line treatment with bevacizumab2,3 or cilengitide4 have failed to improve survival when combined with standard treatment. Following front-line treatment, nearly all GBMs recur, and there are no effective treatments with durable benefit for recurrent GBM.5 Recurrent GBM has an extremely poor prognosis, with a median overall survival (OS) of ∼9 months and a 12-month OS of 14%.5 Treatment failure is associated with the development of resistance to temozolomide and is primarily mediated by overexpression of specific proteins (O[6]-methylguanine methyltransferase [MGMT] and O[6]-alkylguanine-DNA-alkyl-transferase [AGAT]).6 Nevertheless, temozolomide is well tolerated and may have activity despite prior exposure if novel dose schedules are used.7,8 For example, protracted, low-dose (metronomic) temozolomide may deplete MGMT and AGAT9 and restore temozolomide sensitivity in the recurrent setting. Activation of the ErbB family of receptors, including the epidermal growth factor receptor (EGFR), can initiate downstream signaling pathways involved in cell growth and proliferation.10 ErbB pathway regulation plays an important role in glioma progression, and certain germline EGFR polymorphisms may contribute to the glioma pathogenesis.11 EGFR is amplified and overexpressed in ∼50%–60% of GBMs, and multiple EGFR gene mutations occur in GBM tumors.12,13 The EGFRvIII mutation is expressed in 30% of GBMs, including 41%–60% of those with EGFR amplification.12 HER2 (ErbB2) is a possible low-penetrance gene candidate associated with GBM development.11 The high frequency of EGFR pathway alterations in GBM has triggered interest in therapeutically targeting the ErbB family, including EGFR. EGFR inhibition in vitro has activity against GBM; however, reversible EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have had limited impact on survival of recurrent GBM patients, either as monotherapy or in combination with other agents.14–26 Afatinib is a potent, orally bioavailable ErbB family blocker that irreversibly binds to the ATP binding pocket of the ErbB family of receptors, inhibiting the activity of EGFR (including the EGFRvIII variant), HER, and ErbB4 and blocks transphosphorylation of ErbB3.27,28 Afatinib is active against ErbB family-driven tumors, including lung cancer.29–31 In vitro, afatinib inhibits cells harboring mutations that are frequently found in GBM, including EGFRvIII and EGFR R108K.28,32 Furthermore, unlike erlotinib and gefitinib, cytochrome P450 metabolism of afatinib is negligible.33 Phase I of this study aimed to establish the maximum tolerated dose (MTD) and pharmacokinetics (PKs) of afatinib plus temozolomide among recurrent malignant glioma patients. Phase II assessed the efficacy and safety of afatinib (±temozolomide) versus temozolomide monotherapy in patients with recurrent GBM.

Afatinib (BIBW 2992) is an ErbB-family blocker that irreversibly inhibits signaling from all relevant ErbB-family dimers. Afatinib has demonstrated preclinical activity in human epidermal growth factor receptor HER2 (ErbB2)-positive and triple-negative xenograft models of breast cancer, and clinical activity in phase I studies. This was a multicenter phase II study enrolling patients with HER2-negative metastatic breast cancer progressing following no more than three lines of chemotherapy. No prior epidermal growth factor receptor-targeted therapy was allowed. Patients received 50-mg afatinib once daily until disease progression. Tumor assessment was performed at every other 28-day treatment course. The primary endpoint was clinical benefit (CB) for ≥4 treatment courses in triple-negative (Cohort A) metastatic breast cancer (TNBC) and objective responses measured by Response Evaluation Criteria in Solid Tumors in patients with HER2-negative, estrogen receptor-positive, and/or progesterone receptor-positive breast cancer (Cohort B). Fifty patients received treatment, including 29 patients in Cohort A and 21 patients in Cohort B. No objective responses were observed in either cohort. Median progression-free survival was 7.4 and 7.7 weeks in Cohorts A and B, respectively. Three patients with TNBC had stable disease for ≥4 treatment courses, one of them for 12 courses (median 26.3 weeks; range 18.9-47.9 weeks). The most frequently observed afatinib-associated adverse events (AEs) were gastrointestinal and skin-related side effects, which were manageable by symptomatic treatment and dose reductions. Afatinib pharmacokinetics were comparable to those observed in previously reported phase I trials. In conclusion, afatinib had limited activity in HER2-negative breast cancer. AEs were generally manageable and mainly affected the skin and the gastrointestinal tract., Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

A large body of literature suggest that vascular reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidases are important sources of reactive oxygen species. Many studies, however, relied on data obtained with the inhibitor apocynin (4′-hydroxy-3′methoxyacetophenone). Because the mode of action of apocynin, however, is elusive, we determined its mechanism of inhibition on vascular NADPH oxidases. In HEK293 cells overexpressing NADPH oxidase isoforms (Nox1, Nox2, or Nox4), apocynin failed to inhibit superoxide anion generation detected by lucigenin chemiluminescence. In contrast, apocynin interfered with the detection of reactive oxygen species in assay systems selective for hydrogen peroxide or hydroxyl radicals. Importantly, apocynin interfered directly with the detection of peroxides but not superoxide, if generated by xanthine/xanthine oxidase or nonenzymatic systems. In leukocytes, apocynin is a prodrug that is activated by myeloperoxidase, a process that results in the formation of apocynin dimers. Endothelial cells and smooth muscle cells failed to form these dimers and, therefore, are not able to activate apocynin. Dimer formation was, however, observed in Nox-overexpressing HEK293 cells when myeloperoxidase was supplemented. As a consequence, apocynin should only inhibit NADPH oxidase in leukocytes, whereas in vascular cells, the compound could act as an antioxidant. Indeed, in vascular smooth muscle cells, the activation of the redox-sensitive kinases p38-mitogen-activate protein kinase, Akt, and extracellular signal–regulated kinase 1/2 by hydrogen peroxide and by the intracellular radical generator menadione was prevented in the presence of apocynin. These observations indicate that apocynin predominantly acts as an antioxidant in endothelial cells and vascular smooth muscle cells and should not be used as an NADPH oxidase inhibitor in vascular systems.

Background Afatinib (BIBW 2992) is an oral, irreversible ErbB Family Blocker. It was found to be mainly excreted via faeces and is highly protein bound. To define the impact of different degrees of hepatic impairment (HI) on the pharmacokinetics (PK) and safety of afatinib, a dedicated Phase I trial was conducted. Table: 468P 50 mg afatinib, mild HI (N = 8) 50 mg afatinib, HV matched to mild HI (N = 8) 50 mg afatinib, moderate HI (N = 8) 50 mg afatinib, HV matched to moderate HI (N = 8) Parameter Unit gMean gCV [%] gMean gCV [%] gMean gCV [%] gMean gCV [%] AUC0-∞ [ng*h/mL] 886 53.7 956 22.7 934 31.0 985 32.3 Cmax [ng/mL] 33.7 51.7 30.7 33.7 39.5 40.1 31.1 46.0 AUC0-tz [ng*h/mL] 842 50.8 930 22.5 904 31.4 956 33.3 Methods This single-dose, open-label, dose-escalation study in a matched group design included male or female subjects with HI (mild: Child Pugh A, score 5 or 6; moderate: Child Pugh B, score 7 to 9) and healthy volunteers (HV) matched to the HI subjects based on age, weight, sex and creatinine clearance. Dose escalation of afatinib from 30 to 50 mg was performed depending on tolerability and PK. Plasma and urine sampling was performed for up to 240 hours (h) and 72 h after afatinib administration, respectively. Primary endpoints were comparison of AUC0-∞ and Cmax of afatinib between subjects with HI and matched healthy subjects. For all other parameters, descriptive statistics were calculated. Additionally, blood samples were drawn to determine in vitro plasma protein binding of afatinib. Results Thirty-five subjects entered the trial: 3 subjects with mild HI received single-dose 30 mg afatinib and 32 subjects received single-dose 50 mg afatinib. Tolerability of afatinib was good, with 6/35 subjects showing AEs, which were related to afatinib in 3/35 subjects. Main PK parameters are given in Table 1. After a single dose of 50 mg, PK parameters were similar between patients with HI and their matched HV controls. Conclusions Mild and moderate HI had no influence on the PK and tolerability of a single dose of 50 mg afatinib. Table 1: Comparison of main PK parameters after single-dose administration of 50 mg afatinib. Disclosure D. Schnell: Employee of SocraMetrics / Boehringer Ingelheim. S. Buschke: Employee of Boehringer Ingelheim. H. Fuchs: Employee of Boehringer Ingelheim. R. Goldner: Employee of Boehringer Ingelheim. M. Uttenreuther-Fischer: Employee of Boehringer Ingelheim. P. Stopfer: Employee of Boehringer Ingelheim. S. Wind: Employee of Boehringer Ingelheim. A. Halabi: Employee of CRS Clinical Research Services / Boehringer Ingelheim. R. Koenen: Employee of Boehringer Ingelheim.

2585 Background: Afatinib (BIBW 2992) is an oral irreversible ErbB family blocker with activity in a wide range of tumor cell lines dependent on erbB signaling. Vinorelbine, a semi-synthetic vinca alkaloid, interferes with tubulin polymerization and spindle formation during metaphase. Additive or supraadditive activity of afatinib or EGFR TKI with vinorelbine has been demonstrated in preclinical models in vitro and in vivo. Methods: This is a dose-escalation study to define the MTD and characterize the pharmacokinetics (PK), pharmacodynamics and safety profile of afatinib with i.v. weekly vinorelbine. Eligible patients (pts) were ≥18 years of age with advanced or metastatic tumors, refractory to standard therapies, ECOG 0-1, and adequate organ and bone marrow function. In each 28-day treatment course, a fixed dose of vinorelbine (25 mg/m2) was administered weekly on days 1, 8, 15 and 22 with escalating afatinib daily doses of 20 mg, 40 mg and 50 mg given orally. Results: The study treated 15 patients (7 M...

Afatinib, an oral irreversible ErbB family blocker, undergoes minimal metabolism by non-enzyme-catalysed adduct formation with proteins or nucleophilic small molecules and is predominantly non-renally excreted via the entero-hepatic system. This trial assessed whether mild or moderate hepatic impairment influences the pharmacokinetics of afatinib. This was an open-label single-dose study. Pharmacokinetic parameters after afatinib 50 mg were investigated in subjects with mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh A and B) and healthy controls (n = 16) matched for age, weight and gender. Plasma and urine samples for pharmacokinetic assessment were collected before and up to 10 days after dosing. Additional blood samples were drawn to determine ex vivo plasma protein binding of afatinib. Primary endpoints were comparisons of afatinib C max and AUC0–∞ between subjects with hepatic impairment and healthy matched controls. Study progression was based on drug-related toxicity (CTCAE v. 3.0) and C max of afatinib. Afatinib pharmacokinetic profiles and plasma protein binding were similar in subjects with impaired liver function and healthy controls. Compared with matched controls, the afatinib-adjusted geometric mean ratio for AUC0–∞ was 92.6 % (90 % CI 68.0–126.3 %) and C max was 109.5 % (90 % CI 82.7–144.9 %) for subjects with mild hepatic impairment, and 94.9 % (90 % CI 72.3–124.5 %) and 126.9 % (90 % CI 86.0–187.2 %), respectively, for subjects with moderate hepatic impairment. For all parameters, the 90 % CI included 100 %. Afatinib was generally well tolerated with no serious adverse events reported. Mild to moderate hepatic impairment had no clinically relevant effect on the pharmacokinetics of a single 50 mg dose of afatinib, implying that adjustments to the starting dose of afatinib are not considered necessary in this patient population.

Afatinib is an oral, ErbB family blocker, which covalently binds and irreversibly blocks all kinase-competent ErbB family members. This phase II, open-label, single-arm study explored afatinib activity in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients progressing after trastuzumab treatment. Patients had stage IIIB/IV HER2-positive metastatic breast cancer, with progression following trastuzumab or trastuzumab intolerance and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Patients received 50 mg afatinib once-daily until disease progression. Primary endpoint was objective response rate (Response Evaluation Criteria in Solid Tumors 1.0), with tumor assessments every 8 weeks. Forty-one patients were treated. Patients had received a median of three prior chemotherapy lines (range, 0–15) and 68.3% had received trastuzumab for >1 year. Four patients (10% of 41 treated; 11% of evaluable patients) had partial response. Fifteen patients (37% of 41) had stable disease as best response and 19 (46% of 41) achieved clinical benefit. Median progression-free survival was 15.1 weeks (95% confidence interval [CI]: 8.1–16.7); median overall survival was 61.0 weeks (95% CI: 56.7–not evaluable). Most frequent common terminology criteria for adverse events grade 3 treatment-related adverse events were diarrhea (24.4%) and rash (9.8%). Afatinib monotherapy was associated with promising clinical activity in extensively pretreated HER2-positive breast cancer patients who had progressed following trastuzumab treatment. Electronic supplementary material The online version of this article (doi:10.1007/s10549-012-2003-y) contains supplementary material, which is available to authorized users.