Peter Stopfer - Academia.edu (original) (raw)
Papers by Peter Stopfer
Journal of Clinical Oncology, Jun 20, 2006
3025 Background: BIBW 2992 is a highly selective, potent, irreversible tyrosine inhibitor of EGFR... more 3025 Background: BIBW 2992 is a highly selective, potent, irreversible tyrosine inhibitor of EGFR and HER2. A phase 1 study of orally administered BIBW 2992 was performed to determine its safety, PK and PD. Methods: Patients (pts) with advanced solid malignancies received BIBW 2992 once daily (OD) for 2 weeks, in 4 week cycles. Adverse events were evaluated according to CTCv3.0 and tumor response according to RECIST. In cycle 1 and 2, BIBW 2992 plasma PK analysis was performed. Before and after cycle 1, biomarkers involved in EGFR activation were assessed in skin biopsies. Results: 38 pts received 10 mg (n=3), 20 mg (n=3), 30 mg (n=3), 45 mg (n=3), 70 mg (n=18), 100 mg (n=2) and 85 mg (n=6) OD. At 100 mg dose-limiting toxicities (DLTs) consisted of grade 3 skin rash (n=1) and grade 3 diarrhea despite loperamide (n=1). At the dose level of 85 mg, DLTs were seen in 2 pts (diarrhea in both). An additional 12 pts were subsequently enrolled at 70 mg. A total of 3 DLTs was seen in the 18 pts treated at 70 mg (all 3 diarrhea, in one case with additional grade 3 nausea and ALT increase). In other pts, diarrhea was controllable with loperamide, whereas skin events could be ameliorated with minocycline. The dose of 70 mg BIBW 2992 OD was therefore set as the recommended phase 2 dose. Exposure (AUC0-∞ and AUCτ,ss range 82–2080 ng·h/mL) and peak plasma concentrations (Cmax and Cmax,ss range 7–150 ng/mL) increased with increasing doses. High interpatient variability in all PK parameters was found, but was within the range expected for an orally administered drug. The volume of distribution (Vz/F) ranged from 800–2900 L, indicating high tissue distribution. Median tmax values ranged between 1–4 h. The gMean terminal t1/2 ranged between 13–32 h. Accumulation ratio based on AUC was between 2–2.9. Steady state was reached around day 8. After cycle 1, a >20% reduction in Ki-67 (range 20–83%), reflecting inhibition of keratinocyte proliferation, was seen in paired skin biopsies of 31 pts. Ki-67 positive cells (mean ± SD) decreased from 14 ± 4.5% pre-treatment to 7.9 ± 4.5% on day 13 (p<0.0001). SD lasting ≥4 cycles occurred in 8 pts. Conclusions: 70 mg BIBW 2992 OD can be safely administered in a 2 week on, 2 week off schedule. Further evaluation in phase 2 trials in warranted. [Table: see text]
Annals of Oncology, Jun 1, 2011
Background: To assess the efficacy, safety, tolerability and pharmacokinetics of BIBF 1120 in pat... more Background: To assess the efficacy, safety, tolerability and pharmacokinetics of BIBF 1120 in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC). Methods: Patients with locally advanced or metastatic relapsed NSCLC in whom first-or second-line platinumbased chemotherapy failed were randomly allocated to daily 250 mg BIBF 1120 b.i.d. or 150 mg BIBF 1120 b.i.d. Primary end points were progression-free survival (PFS) and objective tumour response (RECIST). Incidence and severity of adverse events (AEs) were reported. Results: Seventy-three patients received BIBF 1120. Median PFS was 6.9 weeks, with no significant difference between treatment arms. Median overall survival (OS) was 21.9 weeks. Eastern Cooperative Oncology Group (ECOG) 0-1 patients (n = 56) had a median PFS of 11.6 weeks and a median OS of 37.7 weeks. Tumour stabilisation was achieved in 46% of patients (ECOG 0-1 patients: 59%), with one confirmed partial response (250 mg b.i.d.). Most commonly reported drug-related AEs were nausea (57.5%), diarrhoea (47.9%), vomiting (42.5%), anorexia (28.8%), abdominal pain (13.7%) and reversible alanine transaminase (13.7%) and aspartate aminotransferase elevations (9.6%). BIBF 1120 displayed dose-linear pharmacokinetic characteristics. Conclusion: Continuous treatment with BIBF 1120 was well tolerated, with no difference in efficacy between treatment arms. PFS and objective response with single-agent treatment in advanced disease warrants further exploration.
PubMed, Jul 15, 2002
Growth of solid fibrosarcoma tumors in mice was inhibited by the release of a solublelymphotoxin-... more Growth of solid fibrosarcoma tumors in mice was inhibited by the release of a solublelymphotoxin-beta receptor inhibitor (LTbetaR-immunoglobulin fusion protein) from the tumor cells. Tumor growth arrest in mice deficient in the ligand LTalpha1beta2 demonstrated the requirement for activation of the LTbetaR on the tumor cells by host cell-derived LTalpha1beta2. Activation of the LTbetaR resulted in enhanced release of macrophage inflammatory protein-2. Blocked angiogenesis was revealed in LTbetaR inhibitor-producing tumor nodules by immunohistochemistry and in vivo microscopy. The growth arrest of LTbetaR inhibitor-producing fibrosarcomas was overcome by forced MIP-2 expression in the tumor cells. Thus, LTbetaR activation on tumor cells by activated host lymphocytes can initiate a novel proangiogenic pathway leading to organized tumor tissue development.
Langenbecks Archiv für Chirurgie, 2004
Background: The lymphotoxin-β receptor (LTβR) pathway is critical for maintenance of organized ly... more Background: The lymphotoxin-β receptor (LTβR) pathway is critical for maintenance of organized lymphoid structures and involved in development of colitis as shown in different mouse colitis models. Thus, the mechanisms by which LTβR activation contributes to the pathology the chronic form of DSS-colitis was investigated. Moreover, it was demonstrated that mucosal addressin cell adhesion molecule-1 (MadCAM-1), which is strongly expressed in inflamed intestinal mucosa, plays a significant role in development of chronic DSS-colitis [1, 2]. Material and Methods: Acute colitis was induced in Balb/c mice (20 ± 0.4g; n = 10 per group) by oral administration of 5% dextran sodium sulfate (DSS) dissolved in drinking water for 4 cycles of treatment [3]. Two weeks after completion of 4 cycles of DSS treatment, mice in the therapy group received 100 µg i.p. of a monoclonal antibody against LTβR for 6 days. Mice of the control group received 100µg of an isotyp antibody. To prepare mice for cell injection, a venous and arterial catheter was implanted in anaesthetized animals. The colon was then mobilized and extriorized for in vivo microscopy. Leukocyte-endothelium interaction in collecting and postcapillary venules was visualized and quantified by epiillumination at a 680-fold magnification. For in vivo microscopy of the mucosa the colon was incised and leukocyte extravasation was calculated. Then tissue was taken out for histological and immunohistochemical tests. Results: Treatment of chronic form of DSS-induced colitis with LTβR-Ig significantly attenuated the development and histological manifestation of the disease. The expression of the proinflammatory cytokines TNF, IL-Iβ and IL-6 was clearly reduced by LTβR-Ig treatment in the chronic form of colitis. Moreover LTβR-Ig treatment significantly downregulated MadCAM-1 expression, leading to reduced leucocyte endothelium interaction. Additionally, reduced extravasation of leucocytes to intestinal mucosa was observed. MadCAM expression was semi-quantitatively detected by immunhistochemistry. Conclusions: Our results show, that LTβR pathway inhibition leads to a downregulation of MadCAM-1 expression. This leads to a significant reduction of leucocyte-endothelium interaction, extravasation of lymphocytes and also to a better histological score. This study verifies the pathophyiological role of LTβR pathway inhibition in the rise of inflammatory bowel disease, that is mediated by MadCAM-1.
The Journal of Clinical Pharmacology, Oct 6, 2016
Nintedanib, a triple angiokinase inhibitor, has undergone clinical investigation for the treatmen... more Nintedanib, a triple angiokinase inhibitor, has undergone clinical investigation for the treatment of solid tumors and idiopathic pulmonary fibrosis. Nintedanib (Vargatef R) plus docetaxel is approved in the EU for the treatment of patients with adenocarcinoma non-small cell lung cancer (NSCLC) after first-line chemotherapy, and as monotherapy (Ofev R) in the United States and EU for the treatment of patients with idiopathic pulmonary fibrosis. Pharmacokinetics (PK) of nintedanib after oral single and multiple doses and intravenous (IV) administration were assessed using 3 data sets: (1) an absolute bioavailability trial that enrolled 30 healthy volunteers; (2) a pooled data analysis of 4 studies that enrolled a total of 107 healthy volunteers; and (3) a pooled data analysis of 4 studies that enrolled a total of 149 patients with advanced cancer. In the absolute bioavailability trial of healthy volunteers, nintedanib showed a high total clearance (geometric mean 1390 mL/min) and a high volume of distribution at steady state (V ss = 1050 L). Urinary excretion of IV nintedanib was about 1% of dose; renal clearance was about 20 mL/min and therefore negligible. There was no deviation from dose proportionality after IV administration in the dose range tested. Absolute bioavailability of oral nintedanib (100 mg capsule) relative to IV dosing (4-hour infusion, 6 mg) was slightly below 5%. Nintedanib was quickly absorbed after oral administration. It underwent rapid and extensive first-pass metabolism and followed at least biphasic disposition kinetics. In advanced cancer patients, steady state was reached at the latest at 7 days for twice-daily dosing. Nintedanib's PK was time-independent; accumulation after repeated administration was negligible.
Clinical Pharmacology & Therapeutics, Aug 4, 2023
Endogenous biomarkers are discussed as tools for detection of drug‐drug interactions (DDIs) media... more Endogenous biomarkers are discussed as tools for detection of drug‐drug interactions (DDIs) mediated by renal transport proteins, such as organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1 and MATE2‐K) and organic anion transporters (OAT1 and OAT3). Whereas sensitivity of some endogenous biomarkers against at least one clinical transporter inhibitor has frequently been shown, intra‐study comparisons of the extent of effects of inhibitors on different biomarkers are frequently lacking. Moreover, in vivo specificity of such discussed biomarkers has frequently not been studied. We therefore investigated changes of 10 previously described putative biomarkers for inhibition of OCT2/MATEs, as well as 15 previously described putative biomarkers for OATs in human plasma and urine samples of healthy volunteers in response to treatment with 4 inhibitors of transport proteins [verapamil (P‐glycoprotein), rifampin (organic anion transporting polypeptides), cimetidine (OCT2/MATEs), and probenecid (OATs)]. Two of the putative biomarkers had been suggested for both OCT2/MATEs and OATs. All substances were unequivocally identified in an untargeted metabolomics assay. The OCT2/MATE biomarkers choline and trimethylamine N‐oxide were both sensitive and specific (median log2‐fold changes −1.18 in estimated renal elimination and −0.85 in urinary excretion, respectively). For renal OATs, indoleacetyl glutamine and indoleacetic acid (median log2‐fold changes −3.77 and −2.85 in estimated renal elimination, respectively) were the candidates for sensitive and specific biomarkers with the most extensive change, followed by taurine, indolelactic acid, and hypoxanthine. This comprehensive study adds further knowledge on sensitivity and specificity of 23 previously described biomarkers of renal OCT2/MATE‐ and OAT‐mediated DDIs.
Annals of Oncology, Sep 1, 2012
Acquired-resistance to EGFR inhibitors may result from the activation of HER3 and/ or HER2, which... more Acquired-resistance to EGFR inhibitors may result from the activation of HER3 and/ or HER2, which share overlapping the signaling pathways. U3-1287 is a fully human anti-HER3 monoclonal antibody that has demonstrated anticancer activity in preclinical models. In a preceding US phase I study, the tolerability of U3-1287 was evaluated up to the dose of 20 mg/kg without dose-limiting toxicities (DLTs). In this study, we evaluated the tolerability, pharmacokinetics (PK) and potential antitumor activities of U3-1287 in Japanese patients with solid tumors up to the dose of 18 mg/kg. Methods: Patients received U3-1287 at a dose of 9 mg/kg or 18 mg/kg intravenously every 3 weeks (q3w). Tumor response, incidence of anti-U3-1287 antibodies (HAHA), and level of soluble HER3 (sHER3) were also evaluated. Results: Nine patients, 3 at 9 mg/kg and 6 at 18 mg/kg, were enrolled. Five patients were male and median (range) age of 67 (50-69) years. Tumor types were lung (2), colorectal (2), esophageal (2), breast (1), cervical (1), and sarcoma (1). No DLTs were reported. U3-1287-related AEs were ALT increase (3 patients), thrombocytopenia, diarrhea, stomatitis, cheilitis, rash, and AST increase (2 each). Plasma disappearance was bi-phasic and terminal half-life at the dose of 18 mg/kg was approximately 9 days. PK profiles were similar to those in the US phase I study. Four patients had best responses of stable disease. All patients tested were negative for HAHA formation. Level of sHER3 unexpectedly increased about four times in all patients. Mean sHER3 concentrations at baseline and day 15 were 3.8 ng/mL and 16.5 ng/mL, respectively. These changes did not correlate with clinical response (at day15 in SD and PD patients; 16.7 ng/mL and 16.9 ng/ml, respectively). Conclusions: U3-1287 was well tolerated up to 18 mg/kg in Japanese patients with solid tumors. These data support a dosing regimen of 18 mg/kg q3w in future studies.
PubMed, Sep 6, 2003
Activation of the lymphotoxin beta-receptor (LTbetaR), a member of the tumor necrosis factor rece... more Activation of the lymphotoxin beta-receptor (LTbetaR), a member of the tumor necrosis factor receptor family, plays a crucial role in lymphoid organogenesis and tumor development. Lymphotoxin alpha(1)beta(2) (LTalpha(1)beta(2)) and LIGHT have been identified as membrane anchored ligands for the LTbetaR. While LTbetaR is expressed on a wide range of cell types e.g. fibroblasts and monocytes, the ligands are expressed only on activated lymphocytes and NK cells. In order to characterize LTbetaR expression and the biological consequences of LTbetaR activation rat anti-mouse LTbetaR monoclonal antibodies were generated. These antibodies recognized a mouse LTbetaR-Ig fusion protein as well as endogenous LTbetaR on a variety of mouse fibroblast and fibrosarcoma cell lines. Specificity was demonstrated by the lack of binding to LTbetaR-deficient embryonic fibroblasts. Competitive binding studies revealed that three different epitopes were recognized by the monoclonal antibodies. Two of the monoclonals activated the LTbetaR and induced activation of NFkappaB and secretion of MIP-2 and IL-6 in L929 mouse fibroblast cells. MIP-2 and IL-6 secretion was NFkappaB-dependent because IkappaB-transfected cells released significantly reduced amounts of both mediators.
Pharmaceutical Research, Oct 1, 2021
active efflux by BCRP and Pgp, metabolism by CYP2C9 and passive glomerular filtration. The availa... more active efflux by BCRP and Pgp, metabolism by CYP2C9 and passive glomerular filtration. The available clinical rifampicin, gemfibrozil and probenecid DDI studies were modeled using in vitro inhibition constants without adjustments. The good prediction of DDIs was demonstrated by simulated rosuvastatin plasma profiles, DDI AUC last ratios (AUC last during DDI/AUC last without co-administration) and DDI C max ratios (C max during DDI/C max without co-administration), with all simulated DDI ratios within 1.6-fold of the observed values. Conclusions A whole-body PBPK model of rosuvastatin was built and qualified for the prediction of rosuvastatin pharmacokinetics and transporter-mediated DDIs. The model is freely available in the Open Systems Pharmacology model repository, to support future investigations of rosuvastatin pharmacokinetics, rosuvastatin therapy and DDI studies during model-informed drug discovery and development (MID3). KEYWORDS Physiologically based pharmacokinetic modeling (PBPK) • Rosuvastatin • Drug-drug interactions (DDIs) • Organic anion transporting polypeptide 1B1/1B3 (OATP1B1/1B3) • Model-informed drug discovery and development (MID3) ABBREVIATIONS ADME Absorption, distribution, metabolism and excretion AUC Area under the plasma concentration-time curve AUC last AUC from the time of drug administration to the last measured concentration
Journal of Clinical Oncology, Jun 20, 2006
2074 Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of both... more 2074 Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of both EGFR and HER2 receptor tyrosine kinases with IC50 values of 0.5 and 14 nM, respectively. Methods: BIBW 2992 was administered orally as a continuous once daily dose starting at 10 mg daily and doubled in successive cohorts until observation of drug-related adverse events (AE) ≥ CTC grade 2. Thereafter, escalation steps of no more than 50% were allowed. All pts underwent pharmacokinetic sampling. The enrolled patient population included a variety of advanced solid malignancies, historically known to express EGFR and/or HER2. After reaching DLT, the MTD dose group was expanded to a total of 18 treated at that dose level. Results: To date in this continuing study, twenty-two patients have been included (13 M/ 9 F). Median age: 61.5 (range: 34–80). Administered doses (patients) were 10 (5), 20 (3), 40 (11), and 60 (3) mg in a once daily schedule. Ten pts who completed the initial 28 treatment days were eligible to continue treatment beyond the first treatment cycle. Duration of treatment is up to 7 cycles so far in this ongoing study. A total of three dose-limiting toxicities (DLT) were observed. DLT events were diarrhea (CTC grade 3) and patients recovered fully upon cessation of the drug. The 60 mg dose level was considered dose-limiting with the occurrence of two DLT. The dose level below (40 mg) was expanded to a total of 18 patients. A pharmacokinetic interim analysis (9 pts) showed, in general, increasing exposure to BIBW 2992 with increasing doses at steady state. A high inter-patient variability in all PK parameters was detected. Conclusions: BIBW 2992, in an oral once daily administration of 40mg, is well tolerated with an acceptable toxicity profile. The further evaluation of BIBW 2992 in Phase II clinical trials is warranted. [Table: see text]
British Journal of Cancer, Nov 20, 2007
To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the... more To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the dual epidermal growth factor receptor (EGFR) 1 and 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule of once-daily (OD) BIBW 2992 for 14 days followed by 14 days off medication was explored. Thirty-eight patients were enrolled. Dose levels were 10, 20, 30, 45, 70, 85, and 100 mg. At 100 mg dose-limiting toxicity (DLT) (common toxicity criteria grade 3 skin rash and grade 3 diarrhoea despite treatment with loperamide) occurred in two patients. In the next-lower dose of 70 mg, DLT (grade 3 fatigue and ALAT elevation) occurred in one of six patients. An intermediate dose level of 85 mg was studied. Here DLT occurred in two patients (grade 3 diarrhoea despite treatment and grade 2 diarrhoea lasting more than 7 days despite treatment). An additional 12 patients were treated at 70 mg. BIBW 2992 PK after single and multiple doses revealed moderately fast absorption, and no deviation from dose proportionality. Pharmacodynamics analysis in skin biopsies did not show significant changes in EGFR-associated biomarkers. However, a significant inhibitory effect on the proliferation index of epidermal keratinocytes was observed. No partial or complete responses were observed, stable disease lasting more than four cycles was seen in seven patients. The recommended dose for studies with BIBW 2992 for 14 days followed by 14 days off medication is 70 mg OD.
Clinical Pharmacokinectics, Apr 23, 2019
Nintedanib is an oral, small-molecule tyrosine kinase inhibitor approved for the treatment of idi... more 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. Key Points Nintedanib has a straightforward and time-independent pharmacokinetic profile that is consistent across a range of patient populations.
Journal of Clinical Oncology, Jun 20, 2006
2074 Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of both... more 2074 Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of both EGFR and HER2 receptor tyrosine kinases with IC50 values of 0.5 and 14 nM, respectively. Methods: BIBW 2992 was administered orally as a continuous once daily dose starting at 10 mg daily and doubled in successive cohorts until observation of drug-related adverse events (AE) ≥ CTC grade 2. Thereafter, escalation steps of no more than 50% were allowed. All pts underwent pharmacokinetic sampling. The enrolled patient population included a variety of advanced solid malignancies, historically known to express EGFR and/or HER2. After reaching DLT, the MTD dose group was expanded to a total of 18 treated at that dose level. Results: To date in this continuing study, twenty-two patients have been included (13 M/ 9 F). Median age: 61.5 (range: 34–80). Administered doses (patients) were 10 (5), 20 (3), 40 (11), and 60 (3) mg in a once daily schedule. Ten pts who completed the initial 28 treatment days were eligible to continue treatment beyond the first treatment cycle. Duration of treatment is up to 7 cycles so far in this ongoing study. A total of three dose-limiting toxicities (DLT) were observed. DLT events were diarrhea (CTC grade 3) and patients recovered fully upon cessation of the drug. The 60 mg dose level was considered dose-limiting with the occurrence of two DLT. The dose level below (40 mg) was expanded to a total of 18 patients. A pharmacokinetic interim analysis (9 pts) showed, in general, increasing exposure to BIBW 2992 with increasing doses at steady state. A high inter-patient variability in all PK parameters was detected. Conclusions: BIBW 2992, in an oral once daily administration of 40mg, is well tolerated with an acceptable toxicity profile. The further evaluation of BIBW 2992 in Phase II clinical trials is warranted. [Table: see text]
Annals of Oncology, Feb 1, 2010
Background: The purpose of the phase I dose-escalation study was to evaluate the maximum tolerate... more Background: The purpose of the phase I dose-escalation study was to evaluate the maximum tolerated dose (MTD) of BIBF 1120, an oral triple angiokinase inhibitor of vascular endothelial growth factor, platelet derived growth factor and fibroblast growth factor receptors, combined with paclitaxel and carboplatin. Patients and methods: Patients with advanced gynecological malignancies received BIBF 1120 twice-daily (b.i.d.) continuously at 100, 150, 200 or 250 mg, combined with paclitaxel (175 mg/m 2) and carboplatin (area under the curve 5 minÁmg/ml) every 3 weeks. The MTD, safety, pharmacokinetics (PK) and clinical activity were evaluated. Results: Twenty-two patients were treated. Three experienced dose-limiting toxic effects in the first treatment cycle: 1 of 13 at 200 mg b.i.d. BIBF 1120 [diarrhea, common terminology criteria for adverse events (CTCAE) grade 3]; two of two at 250 mg b.i.d. BIBF 1120 (elevated alanine aminotransferase and aspartate aminotransferase, CTCAE grade 3/4). The MTD was defined as 200 mg b.i.d. Principal adverse events were gastrointestinal disorders. No clinically relevant drug-drug interaction was observed after 20 days treatment with 200 mg b.i.d. BIBF 1120 on the PK of paclitaxel or carboplatin and vice versa. Conclusions: The MTD of BIBF 1120 in a 20-day continuous dosing regimen with standard-dose paclitaxel and carboplatin was 200 mg b.i.d. This combination had an acceptable safety profile and no clinically relevant drug-drug interactions. Further evaluation of this combination is warranted in this indication.
Clinical Pharmacokinectics, Jul 28, 2016
Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains... more Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2-5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to afatinib. Over the clinical dose range of 20-50 mg, afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5-to 3.4-fold based on area under the plasma concentration-time curve (AUC) after multiple dosing. The pharmacokinetic profile of afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to afatinib. Renal function is correlated with afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug-drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of afatinib. At a dose of 50 mg, afatinib does not have proarrhythmic potential. Key Points Afatinib is an irreversible ErbB family blocker that is well absorbed, with maximum plasma concentration attained at 2-5 h. Afatinib demonstrates high apparent clearance after oral administration and is eliminated primarily as unchanged drug by faecal excretion. Afatinib has a favourable and time-independent pharmacokinetic profile that is consistent across a range of patient populations. Afatinib has a low potential for drug-drug interactions via cytochrome P450; coadministration of drugs that are potent inhibitors or inducers of P-glycoprotein should be undertaken with care. Intrinsic factors such as age, ethnicity, and hepatic function do not affect the pharmacokinetics of afatinib. Effects of sex, weight and renal function status are within the variability range of afatinib exposure.
Pharmaceutics, Jun 16, 2020
The calcium channel blocker and antiarrhythmic agent verapamil is recommended by the FDA for drug... more The calcium channel blocker and antiarrhythmic agent verapamil is recommended by the FDA for drug-drug interaction (DDI) studies as a moderate clinical CYP3A4 index inhibitor and as a clinical Pgp inhibitor. The purpose of the presented work was to develop a mechanistic whole-body physiologically based pharmacokinetic (PBPK) model to investigate and predict DDIs with verapamil. The model was established in PK-Sim ® , using 45 clinical studies (dosing range 0.1-250 mg), including literature as well as unpublished Boehringer Ingelheim data. The verapamil Rand S-enantiomers and their main metabolites R-and S-norverapamil are represented in the model. The processes implemented to describe the pharmacokinetics of verapamil and norverapamil include enantioselective plasma protein binding, enantioselective metabolism by CYP3A4, non-stereospecific Pgp transport, and passive glomerular filtration. To describe the auto-inhibitory and DDI potential, mechanism-based inactivation of CYP3A4 and non-competitive inhibition of Pgp by the verapamil and norverapamil enantiomers were incorporated based on in vitro literature. The resulting DDI performance was demonstrated by prediction of DDIs with midazolam, digoxin, rifampicin, and cimetidine, with 21/22 predicted DDI AUC ratios or C trough ratios within 1.5-fold of the observed values. The thoroughly built and qualified model will be freely available in the Open Systems Pharmacology model repository to support model-informed drug discovery and development.
Journal of Clinical Oncology, May 20, 2008
3567 Background: BIBF 1120 is a potent, orally available tyrosine kinase inhibitor (VEGFR 1/2/3, ... more 3567 Background: BIBF 1120 is a potent, orally available tyrosine kinase inhibitor (VEGFR 1/2/3, PDGFR α/β and FGFR 1/3) that suppresses tumor growth by angiogenesis inhibition. Recently, the combi...
European Journal of Drug Metabolism and Pharmacokinetics, Jul 6, 2017
Background In a recently described probe drug cocktail for clinically relevant drug transporters ... more Background In a recently described probe drug cocktail for clinically relevant drug transporters containing digoxin, furosemide, metformin and rosuvastatin, mutual interactions were essentially absent except for increases in the systemic exposure of rosuvastatin. To optimize the cocktail, we further examined the dose dependence of the effects of metformin and furosemide on rosuvastatin pharmacokinetics. Methods This was a randomized, open label, single center, six-treatment, six-period, six-sequence crossover trial. Eighteen healthy male subjects received 10 mg rosuvastatin as reference treatment and, as test treatments, 10 mg rosuvastatin combined with 10, 50 or 500 mg metformin (T1, T2 and T3) or with 1 or 5 mg furosemide (T4 and T5). Primary pharmacokinetic endpoints were rosuvastatin C max (maximum plasma concentration) and AUC 0-tz (area under the plasma concentration-time curve from time zero to the last quantifiable concentration). Results The relative bioavailability of rosuvastatin was essentially unchanged when administered with metformin in T1 and T2, but in T3 it increased to 152% for AUC 0-tz (90% CI 135-171%) and 154% for C max (90% CI 132-180%). Coadministration with furosemide did not change rosuvastatin relative bioavailability in T4, but in T5 it increased slightly to 116% for AUC 0-tz (90% CI 102-132%) and 118% for C max (90% CI 98-142%). Conclusion The increased systemic exposure of rosuvastatin when administered as part of the proposed transporter cocktail is most likely attributable to metformin and only to a minor degree to furosemide. Reduction of the doses of metformin and furosemide is expected to eliminate the previously described interaction. EudraCT no. 2015-003052-46, ClinicalTrials.gov identifier NCT02574845.
Molecular Immunology, 2008
The lymphotoxin beta receptor (LTR) signalling pathway is involved in the development of seconda... more The lymphotoxin beta receptor (LTR) signalling pathway is involved in the development of secondary lymphoid organs and the maintenance of organized lymphoid tissues. Additionally, previous studies clearly demonstrated the involvement of the LTR interaction with its ligands in promoting intestinal inflammation. In order to dissect the role of LTR activation in the mouse model of acute DSS-induced colitis we treated mice with a functional inhibitor of LTR activation (LTR:Ig) and compared it to disease in LTR-deficient and LT␣-deficient mice. All these modes of LTR signalling ablation resulted in significant aggravation of the disease and in release of inflammatory cytokines such as TNF, IL-6, and IFN␥. Finally, using mice with conditionally ablated expression of membrane bound LT on T or B cells, respectively, distinct and opposite contributions of surface LT expressed on T or B cells was found. Thus, activation of LTR by LT␣ mainly expressed on T lymphocytes is crucial for the down regulation of the inflammatory response in this experimental model.
Journal of Clinical Oncology, Jun 20, 2006
3025 Background: BIBW 2992 is a highly selective, potent, irreversible tyrosine inhibitor of EGFR... more 3025 Background: BIBW 2992 is a highly selective, potent, irreversible tyrosine inhibitor of EGFR and HER2. A phase 1 study of orally administered BIBW 2992 was performed to determine its safety, PK and PD. Methods: Patients (pts) with advanced solid malignancies received BIBW 2992 once daily (OD) for 2 weeks, in 4 week cycles. Adverse events were evaluated according to CTCv3.0 and tumor response according to RECIST. In cycle 1 and 2, BIBW 2992 plasma PK analysis was performed. Before and after cycle 1, biomarkers involved in EGFR activation were assessed in skin biopsies. Results: 38 pts received 10 mg (n=3), 20 mg (n=3), 30 mg (n=3), 45 mg (n=3), 70 mg (n=18), 100 mg (n=2) and 85 mg (n=6) OD. At 100 mg dose-limiting toxicities (DLTs) consisted of grade 3 skin rash (n=1) and grade 3 diarrhea despite loperamide (n=1). At the dose level of 85 mg, DLTs were seen in 2 pts (diarrhea in both). An additional 12 pts were subsequently enrolled at 70 mg. A total of 3 DLTs was seen in the 18 pts treated at 70 mg (all 3 diarrhea, in one case with additional grade 3 nausea and ALT increase). In other pts, diarrhea was controllable with loperamide, whereas skin events could be ameliorated with minocycline. The dose of 70 mg BIBW 2992 OD was therefore set as the recommended phase 2 dose. Exposure (AUC0-∞ and AUCτ,ss range 82–2080 ng·h/mL) and peak plasma concentrations (Cmax and Cmax,ss range 7–150 ng/mL) increased with increasing doses. High interpatient variability in all PK parameters was found, but was within the range expected for an orally administered drug. The volume of distribution (Vz/F) ranged from 800–2900 L, indicating high tissue distribution. Median tmax values ranged between 1–4 h. The gMean terminal t1/2 ranged between 13–32 h. Accumulation ratio based on AUC was between 2–2.9. Steady state was reached around day 8. After cycle 1, a >20% reduction in Ki-67 (range 20–83%), reflecting inhibition of keratinocyte proliferation, was seen in paired skin biopsies of 31 pts. Ki-67 positive cells (mean ± SD) decreased from 14 ± 4.5% pre-treatment to 7.9 ± 4.5% on day 13 (p<0.0001). SD lasting ≥4 cycles occurred in 8 pts. Conclusions: 70 mg BIBW 2992 OD can be safely administered in a 2 week on, 2 week off schedule. Further evaluation in phase 2 trials in warranted. [Table: see text]
Annals of Oncology, Jun 1, 2011
Background: To assess the efficacy, safety, tolerability and pharmacokinetics of BIBF 1120 in pat... more Background: To assess the efficacy, safety, tolerability and pharmacokinetics of BIBF 1120 in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC). Methods: Patients with locally advanced or metastatic relapsed NSCLC in whom first-or second-line platinumbased chemotherapy failed were randomly allocated to daily 250 mg BIBF 1120 b.i.d. or 150 mg BIBF 1120 b.i.d. Primary end points were progression-free survival (PFS) and objective tumour response (RECIST). Incidence and severity of adverse events (AEs) were reported. Results: Seventy-three patients received BIBF 1120. Median PFS was 6.9 weeks, with no significant difference between treatment arms. Median overall survival (OS) was 21.9 weeks. Eastern Cooperative Oncology Group (ECOG) 0-1 patients (n = 56) had a median PFS of 11.6 weeks and a median OS of 37.7 weeks. Tumour stabilisation was achieved in 46% of patients (ECOG 0-1 patients: 59%), with one confirmed partial response (250 mg b.i.d.). Most commonly reported drug-related AEs were nausea (57.5%), diarrhoea (47.9%), vomiting (42.5%), anorexia (28.8%), abdominal pain (13.7%) and reversible alanine transaminase (13.7%) and aspartate aminotransferase elevations (9.6%). BIBF 1120 displayed dose-linear pharmacokinetic characteristics. Conclusion: Continuous treatment with BIBF 1120 was well tolerated, with no difference in efficacy between treatment arms. PFS and objective response with single-agent treatment in advanced disease warrants further exploration.
PubMed, Jul 15, 2002
Growth of solid fibrosarcoma tumors in mice was inhibited by the release of a solublelymphotoxin-... more Growth of solid fibrosarcoma tumors in mice was inhibited by the release of a solublelymphotoxin-beta receptor inhibitor (LTbetaR-immunoglobulin fusion protein) from the tumor cells. Tumor growth arrest in mice deficient in the ligand LTalpha1beta2 demonstrated the requirement for activation of the LTbetaR on the tumor cells by host cell-derived LTalpha1beta2. Activation of the LTbetaR resulted in enhanced release of macrophage inflammatory protein-2. Blocked angiogenesis was revealed in LTbetaR inhibitor-producing tumor nodules by immunohistochemistry and in vivo microscopy. The growth arrest of LTbetaR inhibitor-producing fibrosarcomas was overcome by forced MIP-2 expression in the tumor cells. Thus, LTbetaR activation on tumor cells by activated host lymphocytes can initiate a novel proangiogenic pathway leading to organized tumor tissue development.
Langenbecks Archiv für Chirurgie, 2004
Background: The lymphotoxin-β receptor (LTβR) pathway is critical for maintenance of organized ly... more Background: The lymphotoxin-β receptor (LTβR) pathway is critical for maintenance of organized lymphoid structures and involved in development of colitis as shown in different mouse colitis models. Thus, the mechanisms by which LTβR activation contributes to the pathology the chronic form of DSS-colitis was investigated. Moreover, it was demonstrated that mucosal addressin cell adhesion molecule-1 (MadCAM-1), which is strongly expressed in inflamed intestinal mucosa, plays a significant role in development of chronic DSS-colitis [1, 2]. Material and Methods: Acute colitis was induced in Balb/c mice (20 ± 0.4g; n = 10 per group) by oral administration of 5% dextran sodium sulfate (DSS) dissolved in drinking water for 4 cycles of treatment [3]. Two weeks after completion of 4 cycles of DSS treatment, mice in the therapy group received 100 µg i.p. of a monoclonal antibody against LTβR for 6 days. Mice of the control group received 100µg of an isotyp antibody. To prepare mice for cell injection, a venous and arterial catheter was implanted in anaesthetized animals. The colon was then mobilized and extriorized for in vivo microscopy. Leukocyte-endothelium interaction in collecting and postcapillary venules was visualized and quantified by epiillumination at a 680-fold magnification. For in vivo microscopy of the mucosa the colon was incised and leukocyte extravasation was calculated. Then tissue was taken out for histological and immunohistochemical tests. Results: Treatment of chronic form of DSS-induced colitis with LTβR-Ig significantly attenuated the development and histological manifestation of the disease. The expression of the proinflammatory cytokines TNF, IL-Iβ and IL-6 was clearly reduced by LTβR-Ig treatment in the chronic form of colitis. Moreover LTβR-Ig treatment significantly downregulated MadCAM-1 expression, leading to reduced leucocyte endothelium interaction. Additionally, reduced extravasation of leucocytes to intestinal mucosa was observed. MadCAM expression was semi-quantitatively detected by immunhistochemistry. Conclusions: Our results show, that LTβR pathway inhibition leads to a downregulation of MadCAM-1 expression. This leads to a significant reduction of leucocyte-endothelium interaction, extravasation of lymphocytes and also to a better histological score. This study verifies the pathophyiological role of LTβR pathway inhibition in the rise of inflammatory bowel disease, that is mediated by MadCAM-1.
The Journal of Clinical Pharmacology, Oct 6, 2016
Nintedanib, a triple angiokinase inhibitor, has undergone clinical investigation for the treatmen... more Nintedanib, a triple angiokinase inhibitor, has undergone clinical investigation for the treatment of solid tumors and idiopathic pulmonary fibrosis. Nintedanib (Vargatef R) plus docetaxel is approved in the EU for the treatment of patients with adenocarcinoma non-small cell lung cancer (NSCLC) after first-line chemotherapy, and as monotherapy (Ofev R) in the United States and EU for the treatment of patients with idiopathic pulmonary fibrosis. Pharmacokinetics (PK) of nintedanib after oral single and multiple doses and intravenous (IV) administration were assessed using 3 data sets: (1) an absolute bioavailability trial that enrolled 30 healthy volunteers; (2) a pooled data analysis of 4 studies that enrolled a total of 107 healthy volunteers; and (3) a pooled data analysis of 4 studies that enrolled a total of 149 patients with advanced cancer. In the absolute bioavailability trial of healthy volunteers, nintedanib showed a high total clearance (geometric mean 1390 mL/min) and a high volume of distribution at steady state (V ss = 1050 L). Urinary excretion of IV nintedanib was about 1% of dose; renal clearance was about 20 mL/min and therefore negligible. There was no deviation from dose proportionality after IV administration in the dose range tested. Absolute bioavailability of oral nintedanib (100 mg capsule) relative to IV dosing (4-hour infusion, 6 mg) was slightly below 5%. Nintedanib was quickly absorbed after oral administration. It underwent rapid and extensive first-pass metabolism and followed at least biphasic disposition kinetics. In advanced cancer patients, steady state was reached at the latest at 7 days for twice-daily dosing. Nintedanib's PK was time-independent; accumulation after repeated administration was negligible.
Clinical Pharmacology & Therapeutics, Aug 4, 2023
Endogenous biomarkers are discussed as tools for detection of drug‐drug interactions (DDIs) media... more Endogenous biomarkers are discussed as tools for detection of drug‐drug interactions (DDIs) mediated by renal transport proteins, such as organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1 and MATE2‐K) and organic anion transporters (OAT1 and OAT3). Whereas sensitivity of some endogenous biomarkers against at least one clinical transporter inhibitor has frequently been shown, intra‐study comparisons of the extent of effects of inhibitors on different biomarkers are frequently lacking. Moreover, in vivo specificity of such discussed biomarkers has frequently not been studied. We therefore investigated changes of 10 previously described putative biomarkers for inhibition of OCT2/MATEs, as well as 15 previously described putative biomarkers for OATs in human plasma and urine samples of healthy volunteers in response to treatment with 4 inhibitors of transport proteins [verapamil (P‐glycoprotein), rifampin (organic anion transporting polypeptides), cimetidine (OCT2/MATEs), and probenecid (OATs)]. Two of the putative biomarkers had been suggested for both OCT2/MATEs and OATs. All substances were unequivocally identified in an untargeted metabolomics assay. The OCT2/MATE biomarkers choline and trimethylamine N‐oxide were both sensitive and specific (median log2‐fold changes −1.18 in estimated renal elimination and −0.85 in urinary excretion, respectively). For renal OATs, indoleacetyl glutamine and indoleacetic acid (median log2‐fold changes −3.77 and −2.85 in estimated renal elimination, respectively) were the candidates for sensitive and specific biomarkers with the most extensive change, followed by taurine, indolelactic acid, and hypoxanthine. This comprehensive study adds further knowledge on sensitivity and specificity of 23 previously described biomarkers of renal OCT2/MATE‐ and OAT‐mediated DDIs.
Annals of Oncology, Sep 1, 2012
Acquired-resistance to EGFR inhibitors may result from the activation of HER3 and/ or HER2, which... more Acquired-resistance to EGFR inhibitors may result from the activation of HER3 and/ or HER2, which share overlapping the signaling pathways. U3-1287 is a fully human anti-HER3 monoclonal antibody that has demonstrated anticancer activity in preclinical models. In a preceding US phase I study, the tolerability of U3-1287 was evaluated up to the dose of 20 mg/kg without dose-limiting toxicities (DLTs). In this study, we evaluated the tolerability, pharmacokinetics (PK) and potential antitumor activities of U3-1287 in Japanese patients with solid tumors up to the dose of 18 mg/kg. Methods: Patients received U3-1287 at a dose of 9 mg/kg or 18 mg/kg intravenously every 3 weeks (q3w). Tumor response, incidence of anti-U3-1287 antibodies (HAHA), and level of soluble HER3 (sHER3) were also evaluated. Results: Nine patients, 3 at 9 mg/kg and 6 at 18 mg/kg, were enrolled. Five patients were male and median (range) age of 67 (50-69) years. Tumor types were lung (2), colorectal (2), esophageal (2), breast (1), cervical (1), and sarcoma (1). No DLTs were reported. U3-1287-related AEs were ALT increase (3 patients), thrombocytopenia, diarrhea, stomatitis, cheilitis, rash, and AST increase (2 each). Plasma disappearance was bi-phasic and terminal half-life at the dose of 18 mg/kg was approximately 9 days. PK profiles were similar to those in the US phase I study. Four patients had best responses of stable disease. All patients tested were negative for HAHA formation. Level of sHER3 unexpectedly increased about four times in all patients. Mean sHER3 concentrations at baseline and day 15 were 3.8 ng/mL and 16.5 ng/mL, respectively. These changes did not correlate with clinical response (at day15 in SD and PD patients; 16.7 ng/mL and 16.9 ng/ml, respectively). Conclusions: U3-1287 was well tolerated up to 18 mg/kg in Japanese patients with solid tumors. These data support a dosing regimen of 18 mg/kg q3w in future studies.
PubMed, Sep 6, 2003
Activation of the lymphotoxin beta-receptor (LTbetaR), a member of the tumor necrosis factor rece... more Activation of the lymphotoxin beta-receptor (LTbetaR), a member of the tumor necrosis factor receptor family, plays a crucial role in lymphoid organogenesis and tumor development. Lymphotoxin alpha(1)beta(2) (LTalpha(1)beta(2)) and LIGHT have been identified as membrane anchored ligands for the LTbetaR. While LTbetaR is expressed on a wide range of cell types e.g. fibroblasts and monocytes, the ligands are expressed only on activated lymphocytes and NK cells. In order to characterize LTbetaR expression and the biological consequences of LTbetaR activation rat anti-mouse LTbetaR monoclonal antibodies were generated. These antibodies recognized a mouse LTbetaR-Ig fusion protein as well as endogenous LTbetaR on a variety of mouse fibroblast and fibrosarcoma cell lines. Specificity was demonstrated by the lack of binding to LTbetaR-deficient embryonic fibroblasts. Competitive binding studies revealed that three different epitopes were recognized by the monoclonal antibodies. Two of the monoclonals activated the LTbetaR and induced activation of NFkappaB and secretion of MIP-2 and IL-6 in L929 mouse fibroblast cells. MIP-2 and IL-6 secretion was NFkappaB-dependent because IkappaB-transfected cells released significantly reduced amounts of both mediators.
Pharmaceutical Research, Oct 1, 2021
active efflux by BCRP and Pgp, metabolism by CYP2C9 and passive glomerular filtration. The availa... more active efflux by BCRP and Pgp, metabolism by CYP2C9 and passive glomerular filtration. The available clinical rifampicin, gemfibrozil and probenecid DDI studies were modeled using in vitro inhibition constants without adjustments. The good prediction of DDIs was demonstrated by simulated rosuvastatin plasma profiles, DDI AUC last ratios (AUC last during DDI/AUC last without co-administration) and DDI C max ratios (C max during DDI/C max without co-administration), with all simulated DDI ratios within 1.6-fold of the observed values. Conclusions A whole-body PBPK model of rosuvastatin was built and qualified for the prediction of rosuvastatin pharmacokinetics and transporter-mediated DDIs. The model is freely available in the Open Systems Pharmacology model repository, to support future investigations of rosuvastatin pharmacokinetics, rosuvastatin therapy and DDI studies during model-informed drug discovery and development (MID3). KEYWORDS Physiologically based pharmacokinetic modeling (PBPK) • Rosuvastatin • Drug-drug interactions (DDIs) • Organic anion transporting polypeptide 1B1/1B3 (OATP1B1/1B3) • Model-informed drug discovery and development (MID3) ABBREVIATIONS ADME Absorption, distribution, metabolism and excretion AUC Area under the plasma concentration-time curve AUC last AUC from the time of drug administration to the last measured concentration
Journal of Clinical Oncology, Jun 20, 2006
2074 Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of both... more 2074 Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of both EGFR and HER2 receptor tyrosine kinases with IC50 values of 0.5 and 14 nM, respectively. Methods: BIBW 2992 was administered orally as a continuous once daily dose starting at 10 mg daily and doubled in successive cohorts until observation of drug-related adverse events (AE) ≥ CTC grade 2. Thereafter, escalation steps of no more than 50% were allowed. All pts underwent pharmacokinetic sampling. The enrolled patient population included a variety of advanced solid malignancies, historically known to express EGFR and/or HER2. After reaching DLT, the MTD dose group was expanded to a total of 18 treated at that dose level. Results: To date in this continuing study, twenty-two patients have been included (13 M/ 9 F). Median age: 61.5 (range: 34–80). Administered doses (patients) were 10 (5), 20 (3), 40 (11), and 60 (3) mg in a once daily schedule. Ten pts who completed the initial 28 treatment days were eligible to continue treatment beyond the first treatment cycle. Duration of treatment is up to 7 cycles so far in this ongoing study. A total of three dose-limiting toxicities (DLT) were observed. DLT events were diarrhea (CTC grade 3) and patients recovered fully upon cessation of the drug. The 60 mg dose level was considered dose-limiting with the occurrence of two DLT. The dose level below (40 mg) was expanded to a total of 18 patients. A pharmacokinetic interim analysis (9 pts) showed, in general, increasing exposure to BIBW 2992 with increasing doses at steady state. A high inter-patient variability in all PK parameters was detected. Conclusions: BIBW 2992, in an oral once daily administration of 40mg, is well tolerated with an acceptable toxicity profile. The further evaluation of BIBW 2992 in Phase II clinical trials is warranted. [Table: see text]
British Journal of Cancer, Nov 20, 2007
To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the... more To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the dual epidermal growth factor receptor (EGFR) 1 and 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule of once-daily (OD) BIBW 2992 for 14 days followed by 14 days off medication was explored. Thirty-eight patients were enrolled. Dose levels were 10, 20, 30, 45, 70, 85, and 100 mg. At 100 mg dose-limiting toxicity (DLT) (common toxicity criteria grade 3 skin rash and grade 3 diarrhoea despite treatment with loperamide) occurred in two patients. In the next-lower dose of 70 mg, DLT (grade 3 fatigue and ALAT elevation) occurred in one of six patients. An intermediate dose level of 85 mg was studied. Here DLT occurred in two patients (grade 3 diarrhoea despite treatment and grade 2 diarrhoea lasting more than 7 days despite treatment). An additional 12 patients were treated at 70 mg. BIBW 2992 PK after single and multiple doses revealed moderately fast absorption, and no deviation from dose proportionality. Pharmacodynamics analysis in skin biopsies did not show significant changes in EGFR-associated biomarkers. However, a significant inhibitory effect on the proliferation index of epidermal keratinocytes was observed. No partial or complete responses were observed, stable disease lasting more than four cycles was seen in seven patients. The recommended dose for studies with BIBW 2992 for 14 days followed by 14 days off medication is 70 mg OD.
Clinical Pharmacokinectics, Apr 23, 2019
Nintedanib is an oral, small-molecule tyrosine kinase inhibitor approved for the treatment of idi... more 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. Key Points Nintedanib has a straightforward and time-independent pharmacokinetic profile that is consistent across a range of patient populations.
Journal of Clinical Oncology, Jun 20, 2006
2074 Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of both... more 2074 Background: BIBW 2992 is a novel, potent, orally bioavailable irreversible inhibitor of both EGFR and HER2 receptor tyrosine kinases with IC50 values of 0.5 and 14 nM, respectively. Methods: BIBW 2992 was administered orally as a continuous once daily dose starting at 10 mg daily and doubled in successive cohorts until observation of drug-related adverse events (AE) ≥ CTC grade 2. Thereafter, escalation steps of no more than 50% were allowed. All pts underwent pharmacokinetic sampling. The enrolled patient population included a variety of advanced solid malignancies, historically known to express EGFR and/or HER2. After reaching DLT, the MTD dose group was expanded to a total of 18 treated at that dose level. Results: To date in this continuing study, twenty-two patients have been included (13 M/ 9 F). Median age: 61.5 (range: 34–80). Administered doses (patients) were 10 (5), 20 (3), 40 (11), and 60 (3) mg in a once daily schedule. Ten pts who completed the initial 28 treatment days were eligible to continue treatment beyond the first treatment cycle. Duration of treatment is up to 7 cycles so far in this ongoing study. A total of three dose-limiting toxicities (DLT) were observed. DLT events were diarrhea (CTC grade 3) and patients recovered fully upon cessation of the drug. The 60 mg dose level was considered dose-limiting with the occurrence of two DLT. The dose level below (40 mg) was expanded to a total of 18 patients. A pharmacokinetic interim analysis (9 pts) showed, in general, increasing exposure to BIBW 2992 with increasing doses at steady state. A high inter-patient variability in all PK parameters was detected. Conclusions: BIBW 2992, in an oral once daily administration of 40mg, is well tolerated with an acceptable toxicity profile. The further evaluation of BIBW 2992 in Phase II clinical trials is warranted. [Table: see text]
Annals of Oncology, Feb 1, 2010
Background: The purpose of the phase I dose-escalation study was to evaluate the maximum tolerate... more Background: The purpose of the phase I dose-escalation study was to evaluate the maximum tolerated dose (MTD) of BIBF 1120, an oral triple angiokinase inhibitor of vascular endothelial growth factor, platelet derived growth factor and fibroblast growth factor receptors, combined with paclitaxel and carboplatin. Patients and methods: Patients with advanced gynecological malignancies received BIBF 1120 twice-daily (b.i.d.) continuously at 100, 150, 200 or 250 mg, combined with paclitaxel (175 mg/m 2) and carboplatin (area under the curve 5 minÁmg/ml) every 3 weeks. The MTD, safety, pharmacokinetics (PK) and clinical activity were evaluated. Results: Twenty-two patients were treated. Three experienced dose-limiting toxic effects in the first treatment cycle: 1 of 13 at 200 mg b.i.d. BIBF 1120 [diarrhea, common terminology criteria for adverse events (CTCAE) grade 3]; two of two at 250 mg b.i.d. BIBF 1120 (elevated alanine aminotransferase and aspartate aminotransferase, CTCAE grade 3/4). The MTD was defined as 200 mg b.i.d. Principal adverse events were gastrointestinal disorders. No clinically relevant drug-drug interaction was observed after 20 days treatment with 200 mg b.i.d. BIBF 1120 on the PK of paclitaxel or carboplatin and vice versa. Conclusions: The MTD of BIBF 1120 in a 20-day continuous dosing regimen with standard-dose paclitaxel and carboplatin was 200 mg b.i.d. This combination had an acceptable safety profile and no clinically relevant drug-drug interactions. Further evaluation of this combination is warranted in this indication.
Clinical Pharmacokinectics, Jul 28, 2016
Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains... more Afatinib is an oral, irreversible ErbB family blocker that covalently binds to the kinase domains of epidermal growth factor receptor (EGFR), human EGFRs (HER) 2, and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Studies in healthy volunteers and patients with advanced solid tumours have shown that once-daily afatinib has time-independent pharmacokinetic characteristics. Maximum plasma concentrations of afatinib are reached approximately 2-5 h after oral administration and thereafter decline, at least bi-exponentially. Food reduces total exposure to afatinib. Over the clinical dose range of 20-50 mg, afatinib exposure increases slightly more than dose proportional. Afatinib metabolism is minimal, with unchanged drug predominantly excreted in the faeces and approximately 5 % in urine. Apart from the parent drug afatinib, the major circulation species in human plasma are the covalently bound adducts to plasma protein. The effective elimination half-life is approximately 37 h, consistent with an accumulation of drug exposure by 2.5-to 3.4-fold based on area under the plasma concentration-time curve (AUC) after multiple dosing. The pharmacokinetic profile of afatinib is consistent across a range of patient populations. Age, ethnicity, smoking status and hepatic function had no influence on afatinib pharmacokinetics, while females and patients with low body weight had increased exposure to afatinib. Renal function is correlated with afatinib exposure, but, as for sex and body weight, the effect size for patients with severe renal impairment (approximately 50 % increase in AUC) is only mildly relative to the extent of unexplained interpatient variability in afatinib exposure. Afatinib has a low potential as a victim or perpetrator of drug-drug interactions, especially with cytochrome P450-modulating agents. However, concomitant treatment with potent inhibitors or inducers of the P-glycoprotein transporter can affect the pharmacokinetics of afatinib. At a dose of 50 mg, afatinib does not have proarrhythmic potential. Key Points Afatinib is an irreversible ErbB family blocker that is well absorbed, with maximum plasma concentration attained at 2-5 h. Afatinib demonstrates high apparent clearance after oral administration and is eliminated primarily as unchanged drug by faecal excretion. Afatinib has a favourable and time-independent pharmacokinetic profile that is consistent across a range of patient populations. Afatinib has a low potential for drug-drug interactions via cytochrome P450; coadministration of drugs that are potent inhibitors or inducers of P-glycoprotein should be undertaken with care. Intrinsic factors such as age, ethnicity, and hepatic function do not affect the pharmacokinetics of afatinib. Effects of sex, weight and renal function status are within the variability range of afatinib exposure.
Pharmaceutics, Jun 16, 2020
The calcium channel blocker and antiarrhythmic agent verapamil is recommended by the FDA for drug... more The calcium channel blocker and antiarrhythmic agent verapamil is recommended by the FDA for drug-drug interaction (DDI) studies as a moderate clinical CYP3A4 index inhibitor and as a clinical Pgp inhibitor. The purpose of the presented work was to develop a mechanistic whole-body physiologically based pharmacokinetic (PBPK) model to investigate and predict DDIs with verapamil. The model was established in PK-Sim ® , using 45 clinical studies (dosing range 0.1-250 mg), including literature as well as unpublished Boehringer Ingelheim data. The verapamil Rand S-enantiomers and their main metabolites R-and S-norverapamil are represented in the model. The processes implemented to describe the pharmacokinetics of verapamil and norverapamil include enantioselective plasma protein binding, enantioselective metabolism by CYP3A4, non-stereospecific Pgp transport, and passive glomerular filtration. To describe the auto-inhibitory and DDI potential, mechanism-based inactivation of CYP3A4 and non-competitive inhibition of Pgp by the verapamil and norverapamil enantiomers were incorporated based on in vitro literature. The resulting DDI performance was demonstrated by prediction of DDIs with midazolam, digoxin, rifampicin, and cimetidine, with 21/22 predicted DDI AUC ratios or C trough ratios within 1.5-fold of the observed values. The thoroughly built and qualified model will be freely available in the Open Systems Pharmacology model repository to support model-informed drug discovery and development.
Journal of Clinical Oncology, May 20, 2008
3567 Background: BIBF 1120 is a potent, orally available tyrosine kinase inhibitor (VEGFR 1/2/3, ... more 3567 Background: BIBF 1120 is a potent, orally available tyrosine kinase inhibitor (VEGFR 1/2/3, PDGFR α/β and FGFR 1/3) that suppresses tumor growth by angiogenesis inhibition. Recently, the combi...
European Journal of Drug Metabolism and Pharmacokinetics, Jul 6, 2017
Background In a recently described probe drug cocktail for clinically relevant drug transporters ... more Background In a recently described probe drug cocktail for clinically relevant drug transporters containing digoxin, furosemide, metformin and rosuvastatin, mutual interactions were essentially absent except for increases in the systemic exposure of rosuvastatin. To optimize the cocktail, we further examined the dose dependence of the effects of metformin and furosemide on rosuvastatin pharmacokinetics. Methods This was a randomized, open label, single center, six-treatment, six-period, six-sequence crossover trial. Eighteen healthy male subjects received 10 mg rosuvastatin as reference treatment and, as test treatments, 10 mg rosuvastatin combined with 10, 50 or 500 mg metformin (T1, T2 and T3) or with 1 or 5 mg furosemide (T4 and T5). Primary pharmacokinetic endpoints were rosuvastatin C max (maximum plasma concentration) and AUC 0-tz (area under the plasma concentration-time curve from time zero to the last quantifiable concentration). Results The relative bioavailability of rosuvastatin was essentially unchanged when administered with metformin in T1 and T2, but in T3 it increased to 152% for AUC 0-tz (90% CI 135-171%) and 154% for C max (90% CI 132-180%). Coadministration with furosemide did not change rosuvastatin relative bioavailability in T4, but in T5 it increased slightly to 116% for AUC 0-tz (90% CI 102-132%) and 118% for C max (90% CI 98-142%). Conclusion The increased systemic exposure of rosuvastatin when administered as part of the proposed transporter cocktail is most likely attributable to metformin and only to a minor degree to furosemide. Reduction of the doses of metformin and furosemide is expected to eliminate the previously described interaction. EudraCT no. 2015-003052-46, ClinicalTrials.gov identifier NCT02574845.
Molecular Immunology, 2008
The lymphotoxin beta receptor (LTR) signalling pathway is involved in the development of seconda... more The lymphotoxin beta receptor (LTR) signalling pathway is involved in the development of secondary lymphoid organs and the maintenance of organized lymphoid tissues. Additionally, previous studies clearly demonstrated the involvement of the LTR interaction with its ligands in promoting intestinal inflammation. In order to dissect the role of LTR activation in the mouse model of acute DSS-induced colitis we treated mice with a functional inhibitor of LTR activation (LTR:Ig) and compared it to disease in LTR-deficient and LT␣-deficient mice. All these modes of LTR signalling ablation resulted in significant aggravation of the disease and in release of inflammatory cytokines such as TNF, IL-6, and IFN␥. Finally, using mice with conditionally ablated expression of membrane bound LT on T or B cells, respectively, distinct and opposite contributions of surface LT expressed on T or B cells was found. Thus, activation of LTR by LT␣ mainly expressed on T lymphocytes is crucial for the down regulation of the inflammatory response in this experimental model.