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Purpose: To describe patient characteristics, treatment patterns, and the burden of illness among adult migraine patients in Canada prescribed migraine prophylactics. Little is known about the relative persistence of treatments in the real-world setting and the impact of migraine prophylactic therapy on patients. As a result, migraine care in Canada continues to inadequately serve patients suffering from frequent headache days, reflecting a large unmet need. Methods: This retrospective study used Reformulary Group’s longitudinal prescription claims database. Private payer data were analyzed to identify 2007 migraine prophylactic naïve patients, with a prior history of acute therapy, for tracking over 24 months to determine treatment patterns and costs. Patient flow is summarized in a Sankey diagram visualizing persistence and switching across different timepoints. Results: Patient persistence to migraine prophylactic medications was low at 24.9% (n=500); Switching from index medications to another prophylactic medication was common (27%), however 50% of patients discontinued without switching. It was observed that acute treatment and opioid use were much lower when patients established and maintained therapy on migraine prophylactics. Overall, angiotensin receptor blockers and CGRP antagonists had high persistence but were underutilized therapies while the inverse was true for antidepressants and anticonvulsants. Conclusion: In a real-word setting, recognizing that many patients may discontinue preventative treatment completely after their first therapy, there is a need to employ migraine-specific prophylactics and/or tolerable medications early. Treatment guidelines aligned to costs savings and/or requiring step therapy may be inadvertently failing patients. Further, the impact of migraine on the day-to-day lives of patients and high societal costs such as its impact on productivity should be weighed in considering migraine’s burden of illness and the benefits of treatment.

Chronic kidney disease (CKD) is an important health issue that affects ~ 9.1% of the world adult population. Serum creatinine is the most commonly used biomarker for assessing kidney function and is utilized in different equations for estimating creatinine clearance or glomerular filtration rate (GFR). The Cockcroft-Gault formula for adults and "original" Schwartz formula for children have been the most commonly used equations for estimating kidney function during the last 3-4 decades. Introduction of standardized serum creatinine bioanalytical methodology has reduced interlaboratory variability but is not intended to be used with Cockcroft-Gault or original Schwartz equations. More accurate equations (for instance, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) for adults and bedside Schwartz or Chronic Kidney Disease in Children Schwartz equation for children) based on standardized serum creatinine values (and another biomarker-cystatin C) have been introduced and validated in recent years. Recently, the CKD-EPI equation refitted without a race variable was introduced. Clinical practice guidance in nephrology advocates a shift to these equations for managing health care of patients with CKD. The guidance also recommends use of albuminuria in addition to GFR for CKD diagnosis and management. Significant research with large data sets would be necessary to evaluate whether this paradigm would also be valuable in drug dose adjustments. This article attempts to highlight some important advancements in the field from a clinical pharmacology perspective and is a call to action to industry, regulators, and academia to rethink the current paradigm for assessing kidney function to enable dose recommendation in patients with CKD.

Mobocertinib (TAK‐788) is an investigational oral tyrosine kinase inhibitor targeting epidermal growth factor receptor and human epidermal growth factor 2. A phase 1 open‐label, 2‐period, fixed‐sequence, 2‐part study ({"type":"clinical-trial","attrs":{"text":"NCT03928327","term_id":"NCT03928327"}}NCT03928327) characterized effects of a strong CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on the pharmacokinetics (PK) of mobocertinib and its active metabolites, AP32960 and AP32914. Healthy volunteers (n = 12 per part) received a single dose of mobocertinib alone (20 mg, part 1; 160 mg, part 2) and with multiple doses of itraconazole 200 mg once daily (part 1) or rifampin 600 mg once daily (part 2). Coadministration of itraconazole with mobocertinib increased the combined molar area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐∞) of mobocertinib, AP32960, and AP32914 by 527% (geometric least‐squares mean [LSM] ratio, 6.27; 90% confidence interval [CI], 5.20‐7.56). Coadministration of rifampin with mobocertinib decreased the combined molar AUC0‐∞ of mobocertinib, AP32960, and AP32914 by 95% (geometric LSM ratio, 0.05; 90%CI, 0.04‐0.07). Based on these results, the strong CYP3A inhibitor itraconazole and inducer rifampin significantly influenced the PK of mobocertinib and its active metabolites. Coadministration of mobocertinib with moderate and strong CYP3A inhibitors or inducers is not recommended in ongoing clinical trials.

Mobocertinib (TAK‐788) is a tyrosine kinase inhibitor under investigation for treatment of non–small cell lung cancer with activating EGFR exon 20 insertions. This study examined the safety; tolerability; pharmacokinetics (PK), including food effects; and bioavailability of mobocertinib in healthy volunteers. In part 1, fasted volunteers were randomized to placebo or mobocertinib in single‐ascending‐dose cohorts (20‐160 mg). In part 2, mobocertinib (120/160 mg) was administered on day 1 of periods 1 and 2 under fasted or low‐fat meal conditions (2‐period, 2‐sequence crossover design). In part 3, fasted volunteers received mobocertinib 160 mg in 1 of 2 capsule products on day 1 of periods 1 and 2 with 7‐day washout. Safety and PK parameters were assessed. Sixty‐nine volunteers were enrolled (mean age, 29 years; 75% male). The most common adverse events (AEs; ≥10% of volunteers) were gastrointestinal AEs (25%‐50%) and headache (8%‐31%). No serious AEs were reported. A low‐fat meal did not affect the PK of mobocertinib or its active metabolites. The geometric mean terminal disposition phase half‐life (20 hours) supported once‐daily dosing. The 2 capsule products were bioequivalent. These data guided dosing and supported administration of mobocertinib without regard to low‐fat meal intake in ongoing and planned clinical studies.

Mobocertinib is an oral tyrosine kinase inhibitor approved for treatment of patients with locally advanced or metastatic non-small cell lung cancer (mNSCLC) with epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20ins) mutations previously treated with platinum-based chemotherapy. These exposure-response analyses assessed potential relationships between exposure and efficacy or safety outcomes in platinum-pretreated patients with EGFRex20ins-positive mNSCLC who received mobocertinib 160 mg once daily (q.d.) in a pivotal phase I/II study. A statistically significant relationship between the independent review committee-assessed objective response rate and molar sum exposure to mobocertinib and its active metabolites (AP32960 and AP32914) was not discernable using a longitudinal model of clinical response driven by normalized dynamic molar sum exposure or a static model of best clinical response based on time-averaged molar sum exposure. However, the longitudinal model suggested a trend for decreased probability of response with the change in mobocertinib molar sum exposure between the 160- and 120-mg doses (odds ratio: 0.78; 95% confidence interval: 0.55-1.10; P = 0.156). Time-averaged molar sum exposure was a significant predictor of the rate of grade ≥ 3 treatment-emergent adverse events (AEs). Taken together, these exposure-efficacy and exposure-safety results support a favorable benefit-risk profile for the approved mobocertinib 160-mg q.d. dose and dose modification guidelines for patients experiencing AEs.

Summary This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1 mg oral solution dose of [14C]-ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled ixazomib (4 mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35. Blood, urine, and fecal samples were collected during Part A to assess the mass balance (by accelerator mass spectrometry), excretion, and PK of ixazomib. During Part B of the study, patients received non-radiolabeled ixazomib (4 mg capsules) on days 1, 8, and 15 of 28-day cycles. After oral administration, ixazomib was rapidly absorbed with a median plasma Tmax of 0.5 h and represented 70% of total drug-related material in plasma. The mean total recovery of administered TRA was 83.9%; 62.1% in urine and 21.8% in feces. Only 3.23% of the administered dose was recovered in urine as unchanged drug up to 168 h post dose, suggesting that most of the TRA in urine was attributable to metabolites. All patients experienced a treatment-emergent adverse event, which most commonly involved the gastrointestinal system. These findings suggest that ixazomib is extensively metabolized, with urine representing the predominant route of excretion of drug-related material. Trial ID: ClinicalTrials.gov # NCT01953783.

Background The oral proteasome inhibitor ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE-MM1 study. Objective The objective of this study was to quantitatively characterize the benefit–risk profile of ixazomib in relapsed/refractory MM in support of the approved dose and schedule. Methods We report early-phase study data and exposure–response analyses of TOURMALINE-MM1 data that support the selection of the recommended ixazomib dose and schedule. Results Single-agent ixazomib studies showed a favorable efficacy/safety profile with weekly versus twice-weekly dosing; a phase I/II study of ixazomib in combination with lenalidomide and dexamethasone (IRd) identified a weekly ixazomib dose that offered an acceptable efficacy/safety profile. In IRd exposure–response analyses from TOURMALINE-MM1, ixazomib systemic exposure was not a significant predictor of progression-free survival or probability of response. Significant associations were observed between ixazomib exposure and the probability of grade ≥3 anemia and thrombocytopenia, and grade ≥2 diarrhea, fatigue, nausea, peripheral neuropathy, and rash. Additionally, higher ixazomib exposure was associated with lower lenalidomide relative dose intensity. Conclusions These analyses support a favorable benefit–risk profile for weekly ixazomib 4.0 mg on days 1, 8, and 15 of 28-day cycles, which was selected for the phase III TOURMALINE registration program. Trial Registration Numbers ClinicalTrials.gov NCT00932698, NCT00963820, NCT01217957, NCT01564537 Electronic supplementary material The online version of this article (doi:10.1007/s11523-017-0524-3) contains supplementary material, which is available to authorized users.

Purpose BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. This phase I–IIa study was designed to identify the maximum tolerated dose (MTD) and assess safety, antitumour activity, pharmacokinetics and pharmacodynamics of BMS-690514. Patients and methods In phase I, patients with advanced solid tumours received escalating doses of once-daily BMS-690514. In phase IIa, erlotinib-naive (cohort A) or erlotinib-resistant (cohort B) patients with advanced non-small-cell lung cancer (NSCLC) received BMS-690514 once-daily at the MTD. Results In phase I ( n =28), the MTD was determined to be 200mg daily. BMS-690514 was rapidly absorbed and highly metabolised after repeated oral administration with minimum drug accumulation. In phase IIa ( n =62), the most frequent treatment-related adverse events were diarrhoea and acneiform rash. Adverse events that led to >1 discontinuation were diarrhoea ( n =4; 4%) and rash ( n =2; 2%). Disease control (⩾4months) and objective response rates, respectively, were 43.3% and 3.3% (cohort A) and 22.6% and 3.2% (cohort B). Six of 21 (29%) NSCLC patients with wild-type EGFR achieved disease control versus seven of 10 (70%) patients with EGFR mutations (including T790M). At MTD, BMS-690514 modulated pharmacodynamic biomarkers associated with inhibition of VEGFR- and EGFR-signalling pathways. Conclusion This phase I–IIa study suggests that BMS-690514 has manageable safety profile and antitumour activity in patients with NSCLC at 200mg/d, including those with EGFR mutations conferring resistance to erlotinib.

A phase I dose escalation study was performed to determine the maximum tolerated dose (MTD) of intercalated dosing of BMS-690514, a reversible oral panHER/VEGF receptor inhibitor, combined with paclitaxel/carboplatin (PC) in advanced solid tumors. Secondary endpoints included safety, pharmacokinetics (PK), exploratory pharmacodynamics (PD), and preliminary efficacy. Patients received fixed doses of P (200 mg/m2) and C (AUC 6 mg/mL min) q21 days with intercalated BMS-690514 (Days 4–19) starting at 100 mg/day and increasing by 50 mg/day using a 3 + 3 dose escalation design until the MTD was reached. Twenty additional patients were enrolled in the expansion cohort at the recommended phase II dose (RP2D). The MTD was reached at 150 mg/day. DLTs included grade 3 thrombosis at 100 mg (1 patient) and grade 3 diarrhea at 150 mg (1 patient) and 200 mg (2 patients). Serious adverse events (AEs) occurring in 20/37 patients included neutropenia (n = 5), diarrhea (n = 4), pulmonary embolism (n = 3), and simultaneous dehydration, acute renal failure, and febrile neutropenia (n = 2). BMS-690514-related AEs included diarrhea (97 %), acneiform rash (60 %), fatigue (43 %), nausea (30 %), and anorexia (30 %). There were no treatment-related deaths. Sequential intermittent administration of PC did not affect the PK of BMS-690514. Of the 32 patients evaluable for efficacy, there were 12 partial responses including five patients with non-small-cell lung cancer and 12 patients with stable disease. The MTD of intercalated BMS-609514 combined with PC was 150 mg/day. This approach was tolerable with manageable toxicities and antitumor activity in a variety of solid tumor types.

Dry eye disease (DED) is a common ocular disorder associated with inflammation of the lacrimal gland and ocular surface. The interaction of the integrin lymphocyte function-associated antigen-1 (LFA-1) with its cognate ligand intercellular adhesion molecule-1 (ICAM-1) is known to have important roles in the interaction of a variety of cells involved in immune responses and inflammation, including those prominent in ocular surface inflammation. Lifitegrast, an LFA-1 antagonist that blocks binding of ICAM-1 to LFA-1, has recently been approved in the United States for the treatment of signs and symptoms of DED. In this review, we evaluate research findings to explore the potential role of LFA-1/ICAM-1 interaction in the pathophysiology of DED, and the evidence supporting LFA-1/ICAM-1 interaction as a rational therapeutic target in DED. The results of our review suggest that LFA-1/ICAM-1 interaction may play important roles in the cell-mediated immune response and inflammation associated with DED, including facilitating the homing of dendritic cells to the lymph nodes, interaction of dendritic cells with T cells and subsequent T cell activation/differentiation, migration of activated CD4+ T cells from the lymph nodes to the ocular surface, reactivation of T cells by resident antigen-presenting cells at the ocular surface, and recruitment and retention of LFA-1-expressing T cells in the conjunctival epithelium. Based on the available evidence, inhibition of LFA-1/ICAM-1 interaction represents a rational targeted approach in treating DED. Notably, inhibition of LFA-1/ICAM-1 binding with lifitegrast offers a novel approach to reducing ocular surface inflammation in this condition.

What is already known about this subject • Several clinical studies have shown that the toxicity of tipifarnib in cancer patients is acceptable. • However, previous exposure vs. toxicity analyses have been only performed for a limited range of toxic effects and were based on a single study involving a limited number of patients. What this study adds • This study represents the first comprehensive and large-scale exposure vs. response analysis based on five clinical studies, involving more than 600 patients and evaluating more than 10 different toxicities. • The results have defined the relationship between haematological toxicities and tipifarnib exposure in patients with solid tumours. The occurrence of exposure-related nonhaematological toxicities was low regardless of tumour type. Aims To explore the potential relationship between systemic exposure to tipifarnib and the incidence of toxicity in cancer patients. Methods Data from 673 subjects (540 receiving tipifarnib and 133 receiving placebo) were included in the analysis. Tipifarnib was administered in doses ranging from 100 mg to 850 mg twice daily under fed conditions for 21 days in a 28 day cycle. Univariate and multivariate logistic regression models were used to evaluate the relationships between tipifarnib exposure and haematological (neutropenia and thrombocytopenia) and nonhaematological toxicities. Tipifarnib exposure was quantified as the area under the curve during the first cycle of chemotherapy (AUC), the maximum plasma concentration (Cmax), the time above plasma tipifarnib concentrations of 400 (T400) and 600 ng ml−1 (T600), the cumulative area under the curve (AUCT), and the area under the curve density (AUCD), defined as the ratio AUCT to the duration of treatment. The nonhaematological toxicities measured were elevation of AST, ALT, bilirubin and serum creatinine, the occurrence of a skin rash, CNS or peripheral neuropathy, nausea and vomiting, diarrhoea and inflammation of the gastrointestinal tract. Odds ratios (OR) associated with drug exposure were used to measure the effect of the drug. Results Tipifarnib AUC exhibited a positive and significant association with neutropenia grade ≥3 (OR 1.69, 95% CI 1.47, 1.95) and thrombocytopenia grade ≥3 (OR 1.41, 95% CI 1.21, 1.63) in patients with solid tumours, but not in refractory or relapsed AML patients. The incidence of exposure-related nonhaematological toxicity is small regardless of tumour type. No association was found between tipifarnib AUC and the elevation of AST, ALT and total bilirubin, and nausea and vomiting. There was a weak relationship between tipifarnib AUC and serum creatinine elevation (OR 1.18, 95% CI 1.11, 1.26), CNS (OR 1.05, 95% CI 1.01, 1.10) and peripheral neurotoxicity (OR 1.10, 95% CI 1.03, 1.18), diarrhoea (OR 1.14, 95% CI 1.08, 1.21), gastrointestinal tract inflammation (OR 1.13, 95% CI 1.07, 1.19), and skin rash (OR 1.10, 95% CI 1.04, 1.17). Conclusions In those patients who develop severe toxicity, dose reduction may improve the tolerability of tipifarnib. However, an exposure-guided approach to dosage adjustment to limit haematological and nonhaematological toxicity is not warranted.

BACKGROUND To evaluate the toxicity and pharmacological and biological properties of the farnesyl protein transferase (FPTase) inhibitor, tipifarnib (R115777, ZARNESTRAtrade mark) and capecitabine administered for 14 days every 3 weeks. PATIENTS AND METHODS Patients with advanced cancers received twice daily tipifarnib (100-500 mg) and capecitabine (1000-1125 mg/m(2)) for 14 days every 3 weeks. Pharmacokinetics of tipifarnib, capecitabine and 5-fluorouracil (5-FU) were determined. Peripheral blood mononuclear cells were analyzed for farnesylation of the HDJ2 chaperone protein and FPTase activity. RESULTS Forty-one patients received 185 courses of treatment. Diarrhea and palmar-plantar erythrodysesthesia were dose limiting at 300 mg tipifarnib/1125 mg/m(2) capecitabine b.i.d. When the capecitabine dose was fixed at 1000 mg/m(2) b.i.d., neutropenia was dose limiting at 400 and 500 mg b.i.d. of tipifarnib. Capecitabine did not affect the pharmacology of tipifarnib at 100-300 mg b.i.d., although tipifarnib significantly increased the C(max) of 5-FU at 400 mg b.i.d. HDJ2 farnesylation and FPTase activity decreased between 200 and 400 mg b.i.d. doses of tipifarnib, without a dose-response relationship. Five patients demonstrated partial remissions and 11 patients maintained prolonged stable disease. CONCLUSIONS Tipifarnib and capecitabine are well tolerated at 300 mg/1000 mg/m(2) b.i.d., respectively, resulting in biologically relevant plasma concentrations and antitumor activity. The recommended dose for further disease-focused studies is 300 mg b.i.d. tipifarnib and 1000 mg/m(2) b.i.d. capecitabine, given for 14 days every 3 weeks.

The primary objective of this study was to identify intravenous regimens of tipifarnib that would mimic the systemic exposure obtained after the current twice-daily oral administration of tipifarnib. After determination of an intravenous dose that 6 subjects with advanced cancer could tolerate, another 26 subjects were randomly assigned to receive 3 consecutive 4-day regimens of tipifarnib with different treatment sequences: a 100-mg 2-hour intravenous infusion, 200-mg oral administration twice daily, and a 200-mg/d continuous intravenous infusion. The systemic exposure to tipifarnib was comparable among these 3 regimens. The plasma concentration-time profile of 2-hour intravenous infusion more closely resembled the oral administration than did the continuous infusion. Glucuronidation is a metabolic pathway for tipifarnib with concentrations of the glucuronide conjugate greatly exceeding the parent compound after oral and intravenous administration. Analysis of plasma metabolites indicated that tipifarnib also undergoes dealkylation and loss of the imidazole group.

Aims To characterize the population pharmacokinetics of tipifarnib. Methods A total of 1083 subjects treated orally with a solution, capsule or tablet formulations of tipifarnib, given as a single dose or as multiple twice-daily doses (range 25-1300 mg) were combined with data from 1, 2 and 24 h intravenous infusions. A total of 3445 concentrations in the index data set were fitted by an open three-compartment linear disposition model with sequential zero-order input into the depot compartment, followed by a first-order absorption process, and lag time, using NONMEM V. The effect of patient covariates on tipifarnib pharmacokinetics was explored. The model was evaluated using goodness of fit plots and relative error measurements for 3894 concentrations in the test data set. Computer simulations were undertaken to evaluate the effect of covariates on tipifarnib pharmacokinetics. Results Tipifarnib oral bioavailability (26.7%) did not differ between the formulations. The absorption rate from the solution was faster than from the solid forms. Whereas the absorption rate and systemic clearance were more rapid in healthy subjects, the extent of absorption and the steady-state volume of distribution were comparable in cancer patients and healthy subjects. Systemic clearance in cancer patients (21.9 l h-1) exhibited a statistically significant relationship with total bilirubin. The typical volume of the central compartment in cancer patients (54.6 l 70 kg-1) was directly proportional to body weight. The clinical relevance of these covariates in cancer patients is questionable as there was a substantial overlap in simulated concentration-time profiles across a wide range of covariate values. Conclusions A population PK approach has been used to integrate data gathered during clinical development and to characterize the pharmacokinetics of tipifarnib. Individualization of dose based on body weight or total bilirubin concentration in adult cancer patients is not warranted.

The aims of this study were to determine the maximum-tolerated dose (MTD), toxicity profile, and pharmacokinetics of irinotecan given with oral R115777 (tipifarnib), a farnesyl protein transferase inhibitor. Patients were treated with escalating doses of irinotecan with interval-modulated dosing of R115777 (continuously or on days 1-14, and repeated every 21 days). In total, 35 patients were entered onto the trial for a median duration of treatment of 43 days (range, 5-224 days). Neutropenia and thrombocytopenia were the dose-limiting toxicities; other side effects were mostly mild. The MTD was established at R115777 300 mg b.i.d. for 14 consecutive days with irinotecan 350 mg x m(-2) given every 3 weeks starting on day 1. Three patients had a partial response and 14 had stable disease. In the continuous schedule, the area under the curves of irinotecan and its active metabolite SN-38 were 20.0% (P=0.004) and 38.0% (P

(R,R)-formoterol is a beta-agonist for inhalation. Aqueous instability suggested the need for a reconstitutable lyophilized dosage form. The objective of these studies was to devise a stable, rapid-dissolving, therapeutically compatible dosage form. The effects of diluents and residual moisture on the stability of thermally stressed formoterol formulations were investigated. Drug and various excipients (acetate, lactose, and mannitol) were lyophilized and placed in humidity chambers (0 to 90% relative humidity) at 25 to 50 degrees C. Stability was characterized by time-dependent changes using HPLC, pH, and XRD. Residual moisture were determined by Karl Fisher methods. Regression models were developed to quantify the effects of formulation and environmental variation on drug stability. Solid-state instability was observed as a function of high residual moisture and diluent type. Although the residual moisture in mannitol formulations were typically below 1%, the degradation rate (50 degrees C) varied from 2 to 10 mcg/day, which was 1.3- to 20-fold high than observed for lactose formulations under the same relative humidity conditions. At high relative humidity, the presence of acetate significantly increased the degradation rate (p0.04). The critical residual moisture content for lactose formulations was 3%. The amount of lactose was optimized by evaluating the degradation over the temperature range 25 to 50 degrees C. Mannitol and acetate were shown to be unsuitable excipients, and an optimal lactose amount was 50 mg for vials containing 50 mcg of drug.

Greater scrutiny is being placed on developing a full understanding of potential cardiotoxicity of therapeutic agents, especially on the potential to prolong the QTc interval which can lead to arrhythmias such as torsade de pointes and sudden death. This trial was designed to specifically evaluate the effect, if any, of cetuximab on the QTc interval in patients with advanced solid tumors.Cetuximab was administered as an initial dose of 400 mg/m(2) on day 1 (week 1) followed by a maintenance dose of 250 mg/m(2) weekly thereafter. ECG monitoring was performed at screening, baseline (week 1 preceding dosing), and during week 1 to 5 of treatment. Cetuximab concentration-to-QTc relationship was evaluated based on cetuximab serum samples obtained at the time of each ECG measurement to allow for accurate correlation between any observed QT/QTc changes and cetuximab serum concentration.At the recommended dose (400 mg/m(2) on day 1 followed by 250 mg/m(2) weekly), cetuximab had no clinically meaningful effect on QTc interval, PR or QRS intervals, or heart rate and there was no apparent concentration-dependent effect of cetuximab on any of these electrocardiogram parameters. Safety observations in patients treated with cetuximab in this study were consistent with the agent's known safety profile.These results suggest that cetuximab can be safely administered as a single agent without risk of effect on QTc interval.

The PK of unchanged drug and the pseudo-PK parameters of total radioactivity (TRA) must be estimated in human ADME studies. With multiple PK samples collected in plasma and excreta, the PK parameters that represent the extent of a drug in or clearance from the circulation system are readily determined using a noncompartment approach that can be executed quickly in routine and traditional PK data analysis without assumption on disposition of drug in the body. Mechanism- or compartment-based PK models contain specific expression to characterize, in a quantitative manner, processes on the causal path from absorption, distribution, and metabolism to elimination. Data analysis using modeling will provide information on not only the extent of a drug in the body but also the rate of a drug transferring through different parts of the body. Pooling PK data from a human ADME together with the data from the other studies of the same molecule can help scientists build a more robust population PK model, which can be used in interpreting or predicting the underlying physiological or pathological processes that drugs act on and for optimizing therapy with drugs that have a complex disposition. Keywords: pharmacokinetics; absorption kinetics; distribution kinetics; metabolism kinetics; elimination kinetics; mass balance; radioactivity; noncompartmental analysis; compartmental analysis

To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of dasatinib, an inhibitor of the Src family kinase proteins, with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, among recurrent malignant glioma patients. Once daily dasatinib was escalated in successive cohorts while erlotinib was administered daily at established doses based on concurrent CYP3A-inducing anticonvulsant (EIAEDS) use. Dasatinib pharmacokinetic analyzes were performed. Forty-seven patients enrolled including 37 (79 %) with grade IV and 10 (21 %) with grade III malignant glioma. Thirty patients (64 %) were at ≥second recurrence, while 27 (57 %) had received prior bevacizumab. The dasatinib MTD was 180 mg when combined with either 150 mg of erlotinib for patients not on EIAEDs, or 450 mg of erlotinib for patients on EIAEDs. The most common DLTs were diarrhea and fatigue, while most adverse events were grade 2. Pharmacokinetic data suggests that dasatinib exposure increased with increased dasatinib dose and concurrent erlotinib administration, while concurrent EIAED use diminished dasatinib exposure. No radio-graphic responses were observed, and only one patient (2 %) remained progression-free at 6 months. We demonstrate that dasatinib plus erlotinib can be safely co-administered on a continuous, daily dosing schedule with erlotinib, and established the recommended dose level of this combination.

We studied the effect of food on pharmacokinetics, safety, and tolerability of BMS-690514. Two open-label, randomized, single-dose, 2-treatment, 2-period crossover studies were performed in healthy subjects. In study 1 (N = 26), a single oral dose of BMS-690514, 200 mg, was administered while fasting or after a high-fat meal, and in study 2 (N = 17), a single oral dose of BMS-690514, 200 mg, was administered while fasting or after a light meal. Compared with fasting, the adjusted geometric mean maximum observed plasma concentration (C(max)), area under the plasma concentration-time curve from time zero to time of last quantifiable concentration (AUC(0-T)), area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC(INF)) of BMS-690514 increased by 55%, 33%, and 34%, respectively, following a high-fat meal (951 kcal, 52% fat) and by 41%, 20%, and 20%, respectively, following a light meal (336 kcal, 75% carbohydrate). BMS-690514 was well tolerated in both studies. Most frequently occurring adverse events were diarrhea and acne in study 1 and rash, dry skin, and diarrhea in study 2. Systemic exposure of highly soluble BMS-690514 was increased when given along with a meal, probably through inhibition of intestinal first-pass metabolism and/or efflux transporters by food. These studies also demonstrated a tolerable safety profile of BMS-690514 in the absence and presence of food.

BMS-690514, a selective inhibitor of the ErbB and vascular endothelial growth factor receptors, has shown antitumor activity in early clinical development. The compound is metabolized by multiple enzymes, with CYP3A4 responsible for the largest fraction (34%) of metabolism. It is also a substrate of P-glycoprotein (P-gp) in vitro. To assess the effect of ketoconazole on BMS-690514 pharmacokinetics, 17 healthy volunteers received 200 mg BMS-690514 alone followed by 100 mg BMS-690514 with ketoconazole (400 mg once daily for 4 days). The AUC(∞) of 100 mg BMS-690514 concomitantly administered with ketoconazole was similar to that of 200 mg BMS-690514 alone. The dose-normalized C(max) and AUC(∞) of BMS-690514 from the 100-mg BMS-690514/400-mg ketoconazole treatment increased by 55% and 127%, respectively, relative to those from 200 mg BMS-690514 alone. Prediction of the drug-drug interaction (DDI) using a population-based simulator (Simcyp) indicated that, in addition to CYP3A4 inhibition, the inhibition of P-gp by ketoconazole in the intestine, liver, and kidneys must be invoked to fully account for the DDI observed. This finding suggests that the inhibition of P-gp by ketoconazole, along with its effect on CYP3A4, needs to be considered when designing a DDI study of ketoconazole with a victim drug that is a dual substrate.

Purpose: BMS-641988 is an androgen receptor antagonist with increased potency relative to bicalutamide in both in vitro and in vivo prostate cancer models. A first-in-man phase I study was conducted to define the safety and tolerability of oral BMS-641988 in patients with castration-resistant prostate cancer (CRPC). Experimental Design: Doses were escalated from 5 to 150 mg based on discrete pharmacokinetic parameters in cohorts of three to six subjects. After establishing safety with 20 mg of BMS-641988 in the United States, a companion study was opened in Japan to assess differences in drug metabolism between populations. Results: Sixty-one men with CRPC were treated with daily BMS-641988. The pharmacokinetics (PK) of BMS-641988 and its active metabolites were proportional to dose. One patient experienced an epileptic seizure at a dose of 60 mg administered twice. Despite achieving target drug exposures, antitumor activity was limited to one partial response. Seventeen of 23 evaluable patients (74%) exhibited stable disease on imaging (median 15 weeks; range 8–32), and 10 of 61 patients (16%) achieved a ≥30% decline in levels of prostate-specific antigen (PSA). Partial agonism was seen within the context of this study upon removal of the drug as evidenced by a decrease in PSA. Conclusions: Although the clinical outcomes of predominantly stable disease and partial agonism were similar to what was observed in the preclinical evaluation of the compound, the limited antitumor activity of BMS-641988 at therapeutic dose levels coupled with an episode of seizure activity led to study closure. Clin Cancer Res; 17(4); 880–7. ©2010 AACR.

(3R,4R)-4-Amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-3-piperidinol (BMS-690514), an oral selective inhibitor of human epidermal growth factor receptors 1 (or epidermal growth factor receptor), 2, and 4, and vascular endothelial growth factor receptors 1, 2, and 3, is being developed as a treatment for patients with non-small-cell lung cancer and metastatic breast cancer. The disposition of [(14)C]BMS-690514 was investigated in nine healthy male subjects (group 1, n = 6; group 2, n = 3) after oral administration of a 200-mg dose. Urine, feces, and plasma were collected from all subjects for up to 12 days postdose. In group 2 subjects, bile was collected from 3 to 8 h postdose. Across groups, approximately 50 and 34% of administered radioactivity was recovered in the feces and urine, respectively. An additional 16% was recovered in the bile of group 2 subjects. Less than 28% of the dose was recovered as parent drug in the combined excreta, suggesting that BMS-690514 was highly metabolized. BMS-690514 was rapidly absorbed (median time of maximum observed concentration 0.5 h) with the absorbed fraction estimated to be approximately 50 to 68%. BMS-690514 represented ≤7.9% of the area under the concentration-time curve from time 0 extrapolated to infinite time of plasma radioactivity, indicating that the majority of the circulating radioactivity was from metabolites. BMS-690514 was metabolized via multiple oxidation reactions and direct glucuronidation. Circulating metabolites included a hydroxylated rearrangement product (M1), a direct ether glucuronide (M6), and multiple secondary glucuronide conjugates. None of these metabolites is expected to contribute to the pharmacology of BMS-690514. In summary, BMS-690514 was well absorbed and extensively metabolized via multiple metabolic pathways in humans, with excretion of drug-related radioactivity in both bile and urine.

Purpose This study explored the feasibility of treating patients with impaired hepatic function with tipifarnib. The safety profile, pharmacokinetics, and relationship between the pharmacokinetics and toxicities were evaluated. Patients and Methods Patients with mildly or moderately impaired hepatic function (Child-Pugh classification) were treated with tipifarnib bid on days 1 to 5 of cycle 1. Further dosing was based on the individual day 5 pharmacokinetic data and absolute neutrophil count. For patients with normal hepatic function, tipifarnib was dosed on days 1 to 14, followed by 1 week of rest. For all patients, in subsequent cycles, tipifarnib was administered for 21 consecutive days out of every 28 days. Results Twenty-eight patients were included in the normal (n = 16), mild (n = 9), and moderate (n = 3) impairment groups. The most important grade 3 to 4 hematologic toxicity was leukocytopenia/neutropenia, which was mostly observed in patients with moderate impairment. Common nonhematologic toxicities were fatigue, nausea, and vomiting. The pharmacokinetic data showed higher plasma concentrations of tipifarnib in patients with liver impairment compared with patients with normal hepatic function. Conclusion In patients with mildly impaired hepatic function, tipifarnib can be administered safely at a starting dose of 200 mg bid, but it is not safe to treat patients with moderate hepatic impairment.

Background: R115777 (tipifarnib, Zarnestra™) is a farnesyl transferase inhibitor that blocks the farnesylation of proteins involved in signal transduction pathways critical for cell proliferation and survival. This multicenter phase II study was conducted to determine the efficacy, tolerability and pharmacokinetics of R115777 in patients with relapsed small-cell lung cancer (SCLC). Patients and methods: Patients who had a partial or complete response to their initial chemotherapy regimen, followed by at least 3 months off treatment before relapse (sensitive relapse) were eligible. R115777 was administered in 3-week cycles at a dose of 400 mg orally twice daily for 14 consecutive days followed by 7 days off treatment. Results: Twenty-two patients were enrolled. The median progression-free survival was 1.4 months and median overall survival was 6.8 months. Non-hematological toxicities were predominantly grade 1–2 and included nausea (64%) and fatigue (60%). Grade 3–4 granulocytopenia and thrombocytopenia occurred in 27% and 23% of patients, respectively. Febrile neutropenia was not observed. Pharmacokinetic studies demonstrated peak plasma concentrations of R115777 2.6–4.5 h after oral dosing and no significant drug accumulation. The trial was terminated because no objective responses were observed in 20 patients evaluable for response. Conclusions: R115777 showed no significant antitumor activity as a single agent in sensitive-relapse SCLC.

Abstract 3993 Background: Aberrant hedgehog (HH) pathway signaling has been suggested to play a role in the development and progression of multiple myeloma (MM). BMS-833923 is a oral, small molecule antagonist of the HH signaling component Smoothened (SMO). Methods: The trial is designed to identify a maximum tolerated dose (MTD) and evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-833923 administered in escalating dose cohorts as monotherapy or in combination with lenalidomide plus dexamethasone or with bortezomib in subjects with relapsed or refractory MM. The study consists of three treatment arms: i) BMS-833923 alone; ii) BMS-833923 in combination with lenalidomide (25 mg daily [QD] for 21 days of a 28 day cycle) plus dexamethasone (40 mg once weekly); and iii) BMS-833923 in combination with bortezomib (1.3 mg/m2on Days 1, 4, 8, and 11 for a 21 day cycle). A 3-plus-3 design was followed using drug related CTCAEs (v3.0) to inform dose escalation increments. In the first two dose cohorts of the single agent arm, a loading dose was employed during the first week of dosing, followed by a continuation dose. The starting dose was 60 mg QD for 7 days followed by a 30 mg QD continuation dose. Patients who developed progressive disease after 2 cycles or had stable disease after 3 cycles could add on either lenalidomide plus dexamethasone or bortezomib, which allowed for the exploration of the effect of the standard of care agents on BMS-833923 exposures, safety in combination, and clinical activity. The PK parameters of BMS-883923 co-administered with lenalidomide/dexamethasone or bortezomib was evaluated using noncompartmental PK analysis. Results: As of June 20, 2011, 19 patients have been treated at six dose levels in the single agent arm: 60/30 mg (n=3), 120/60 mg (n=3), 90 mg (n=5), 135 mg (n=3), 270 mg (n=3), and 500 mg (n=2); 6 of these patients added lenalidomide plus dexamethasone and 4 patients added bortezomib; and 1 patient has been treated in the combination arm with 90 mg QD of BMS-833923 plus lenalidomide and dexamethasone. This dose range includes dose levels of BMS-833923 with demonstrated anti-tumor activity in patients with advanced or metastatic basal cell carcinoma. In the current study, treated patients had a median age of 62 (range 41–71) and ECOG performance status of 0–2. No DLTs have been observed. The most common drug related AEs (>10%) include muscle spasms, dysgeusia, ageusia, lipase increased, alopecia, decreased appetite, nausea, and fatigue. All the common AEs (> 10%) were Grade 1 or 2 with the exception of a Grade 3 muscle spasms and Grade 3 elevated lipase. Other drug related Grade 3 AEs included thrombocytopenia, sinusitis, streptococal bacteraemia, and otitis media. In the single agent treatment arm, for patients that did not add on standard of care therapies, the median duration of treatment with BMS-833923 was 31 days (range 10–49 days). Median duration of BMS-833923 single agent treatment for patients that added on standard therapy was 90 days (42–175 days). Preliminary analysis of BMS-833923 exposures determined that the geometric mean Cmax ratio of BMS-833923 (dose range of 30 mg/day to 135 mg/day) with or without lenalidomide and dexamethasone was 0.99 (n=4). Similarly, the geometric mean Cmax ratio of 135 mg/day BMS-833923 with or without bortezomib was 0.92 (n=2). Clinical response data is being collected and will be presented. Conclusion: BMS-833923 is generally tolerated at the dose levels tested. Disclosures: Huff: Bristol-Myers Squibb: Honoraria, Research Funding. Padmanabhan:Bristol-Myers Squibb: Research Funding. Somlo:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zonder:Bristol-Myers Squibb: Research Funding. Fischer:Bristol-Myers Squibb: Employment. Lang:Bristol-Myers Squibb: Employment. Zhang:Bristol-Myers Squibb: Employment. Gestone:Bristol-Myers Squibb: Employment. Bennett:Bristol-Myers Squibb: Employment.

Neuropathic pain is a complex disorder resulting from injury to the nerve, spinal cord or brain. Current therapies for neuropathic pain using small-molecule drugs are limited by a range of drug-related side effects, primarily due to their lack of specificity in targeting the receptor/channel of choice. Gene therapy approaches to the treatment of neuropathic pain address this problem in two ways. Firstly, the difficulty in selectively targeting key biologically validated pain receptors at the protein level is circumvented by treatments that can derive specificity at the DNA level and drive the regulation of the target gene. Secondly, the effector molecule can be coupled to a delivery vector that specifically targets the organ of interest |[ndash]| in this case the dorsal root ganglia (DRG) |[ndash]| thus creating a more |[ldquo]|local|[rdquo]| treatment.

Phospholamban (PLN) is a critical regulator of cardiac calcium homeostasis and muscle contractility. Recent studies have demonstrated that ablation or inhibition of PLN function can improve cardiac contractile properties in animal models of congestive heart failure (CHF), suggesting that PLN is an attractive target for treatment of CHF. Because of its use of a large, relatively flat interaction surface when docking with its regulation target (Sarcoplasmic Reticulum Ca2+ ATPase 2 isoform A (SERCA2a)), the development of small-molecule inhibitors of PLN function is expected to be extremely challenging. Therefore, approaches that aim to block the expression of PLN may provide a superior means of achieving the desired therapeutic effect.