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The JTpeak interval has been proposed as a new biomarker to demonstrate mixed ion channel effects, potentially leading to reduced late-stage electrocardiogram (ECG) monitoring for mildly QT-prolonging drugs. ECG waveforms from the IQ-CSRC study were used. Twenty healthy subjects were enrolled with 6 subjects on placebo and 9 subjects on each of 5 mildly QT-prolonging drugs - moxifloxacin, dofetilide, ondansetron, dolasetron, and quinine - and 1 negative drug, levocetirizine. A vector magnitude lead was derived from 12-lead ECGs, and measurements were made on a median beat from three 10-second replicates. Data were analyzed using a linear concentration-response model with QTcF and heart rate corrected JTpeak (JTpeak_c) as dependent variables. For moxifloxacin, dofetilide, and ondansetron, all pure hERG blockers, slopes of the concentration (C)-QTcF and C-JTpeak_c relationships were positive and statistically significant. With the prespecified linear model, the predicted effects on ΔΔQTcF and ΔΔJTpeak_c were 11.4 and 9.4 milliseconds for moxifloxacin at the geometric mean Cmax on day 1, 9.0 and 11.7 milliseconds for dofetilide and 11.5, and 7.9 milliseconds for ondansetron, respectively. In contrast, dolasetron and quinine, both with additional ion channel effects, prolonged QTcF with a positive C-ΔQTcF slope and predicted ΔΔQTcF effect on day 1 of 6.2 and 11.4 milliseconds, whereas the C-ΔJTpeak_c slope and the predicted ΔΔJTpeak on day 1 were negative (-0.3 and -7.5 milliseconds per ng/mL). Pure hERG-blocking drugs prolonged both the QTc and the JTpeak_c intervals, whereas drugs with mixed ion channel effects, including peak sodium inhibition, prolonged QTcF but not the JTpeak_c interval.

PURPOSE This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody–drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin. PATIENTS AND METHODS This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week. RESULTS Forty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non–small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity. CONCLUSION Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.

background Monoclonal antibodies have become attractive clinical anti-cancer drugs in the last 3 decades due to their targeting specificity and suitable pharmacokinetic properties. Mesothelin is a tumor-associated antigen with limited expression in normal tissues. It is frequently over-expressed on the cell membrane of a number of epithelial malignancies (e.g. mesothelioma, pancreatic, ovarian, lung, triple negative breast and gastric cancers). Methods Mesothelin is validated as a suitable antibody target for cancer therapy. A number of novel antibody therapeutics targeting mesothelin in development are compared and their mechanisms of action are also discussed. Both basic science and clinical data are provided to give a complete veiw of how an agent is developed from bench to bedside. Results Novel antibody therapeutics, including unconjugated monoclonal antibodies, recombinant immunotoxins and antibody-drug conjugates, targeting mesothelin exert anti-tumor activities by different mechanisms of action. Based on the convincing preclinical data generated with these molecules, the antibody therapeutics have been brought into early clinical evaluation where initial promising results were obtained. Conclusion These antibody therapeutics directed against mesothelin are expected to have different safety profiles, based on their different mechanism of action. Further clinical development will reveal which of these molecules shows the best efficacy and widest therapeutic window and thus is best suited to bring benefit to the patients.

3515 Background: PEN-866 is a miniature drug conjugate which links a HSP90 binding small molecule to a SN-38 cytotoxic payload. HSP90 is highly expressed in advanced malignancies. PEN-866 targets and binds to activated tumor HSP90 protein, releases its cytotoxic payload, and results in complete tumor regressions in multiple xenograft models. This first-in-human study assessed safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of PEN-866. Methods: Patients (pts) with progressive, advanced solid malignancies were enrolled in escalating cohorts of 2-9 pts. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of PEN-866 given weekly (3 out of 4 weeks in a 28-day cycle). Results: 30 pts were treated in 8 cohorts (range 30-360 mg flat dosing or 150–200 mg/m2 BSA-based dosing). As of 9Jan20, the total median/mean exposure was 7.05/12.4 weeks. No dose limiting toxicities (DLTs) occurred in the first 4 cohorts (30-240 mg; 14 pts). In cohort 5 (360 mg), 1 of 3 pts had a DLT of grade (G) 3 transient diarrhea, and 2 other pts had G3 uncomplicated transient neutropenia. A change to BSA-based dosing was instituted for cohort 6 (175 mg/m2), on which no DLTs were observed, although 1 pt experienced G3 uncomplicated transient neutropenia. At 200 mg/m2, 2 of 5 pts experienced DLTs (G5 dehydration, G3 fatigue). The MTD and RP2D were determined to be 175 mg/m2. The most frequent (≥20% pts) related adverse events were nausea (50%), fatigue (43%), diarrhea (40%), vomiting (27%), and anemia (23%). PK was nonlinear. Plasma exposures increased greater than dose proportionally. Median t1/2 ~7 h. Cleaved SN38 never exceeded 3% of PEN-866 plasma AUC at all dose levels. Tissue PK confirmed tumor accumulation and retention of both the conjugate and released payload. As of 9Jan20, 26 pts were evaluable for response. 11 pts had stable disease at 8 weeks, of which 7 lasted 12–58 weeks. One pt with anal squamous cell carcinoma achieved a confirmed partial response. Decreased target lesion size was observed in 6 additional pts. Conclusions: PEN-866 was well tolerated and demonstrated preliminary evidence of antitumor activity. PEN-866 will be evaluated in Phase 2a expansion cohorts enrolling multiple solid tumors (NCT03221400). Clinical trial information: NCT03221400 .

RG7112, the first selective small-molecule MDM2 antagonist in clinical testing, is a non-genotoxic oral p53 activator. To optimize its dose and schedule, a number of clinical pharmacology characteristics were explored in this multicenter trial in patients with advanced solid tumors. In part 1, the impact of high-energy/high-fat meal and formulations (crystalline and amorphous) on relative bioavailability was examined in single-dose crossover designs. In part 2, schedule optimization (4 schedules of drug administration under fasting condition and 2 cohorts with liquid supplementation) was investigated in parallel, dose escalation designs. Clinical endpoints were pharmacokinetics (PK), pharmacodynamics (PD) including MIC-1 elevation and platelet reduction, and safety/tolerability. With a single-dose treatment, a high-fat/high-energy meal and a new formulation under fasting condition, respectively, enhanced overall bioavailability of RG7112 slightly over twofold. Following multiple-dose administrations, all four schedules yielded the comparable per-cycle (28-d) exposure (AUC), as designed; liquid supplements also enhanced bioavailability. High-dose treatments of consecutive daily dosing for 5 and 3 days resulted in higher on-treatment-day exposure to RG7112 than both weekly and low-dose/long-duration (20-day) daily schedules. Serum MIC-1 and blood platelet profiles showed similar patterns to those of PK when the clinical pharmacology conditions were varied, suggesting the relative importance of treatment-day exposure than overall per-cycle AUC. Food (both high-fat and low-fat meals) and new formulation enhanced bioavailability. High-dose consecutive daily treatment for 3–5 days is superior to weekly and low-dose/long-duration (20-day) daily schedules in yielding the sufficiently high drug exposure and PD effects potentially required for cancer treatment efficacy.

Axitinib is a potent and selective inhibitor of vascular endothelial growth factor receptors 1–3, approved for second-line treatment of advanced renal cell carcinoma (RCC). Preclinical studies did not indicate potential for axitinib-induced delayed cardiac repolarization. The effect of axitinib on corrected QT (QTc) prolongation was evaluated with one-stage concentration–QTc response modeling using data from a definitive randomized crossover QT phase I study in healthy volunteers administered one single 5-mg axitinib dose alone or in the presence of steady-state ketoconazole (400 mg once daily). Axitinib and ketoconazole had opposite effects on heart rate: Axitinib lowered it, ketoconazole raised it. The final analysis showed a flat relationship between QTc and axitinib concentration (slope −0.0314 ms·mL/ng) for axitinib alone. Mean highest placebo-matched change from baseline in QTc was −3.0 [90 % confidence interval (CI) −5.4, −0.6] ms. At supratherapeutic axitinib exposures achieved with potent cytochrome P450 3A4/5 inhibition by ketoconazole, the model predicted mean QTc change of 6.5 (90 % CI 4.4–8.5) ms. The slope population mean estimate was −0.331 (95 % CI −0.860, 0.198) ms·mL/µg for ketoconazole alone and 0.0725 (0.0445–0.1005) ms·mL/ng for axitinib in the presence of ketoconazole. The results were then compared with those obtained based on more widely used Fridericia’s, Bazett’s, and study-specific correction methods. Since axitinib plasma concentrations observed in this study exceeded the range of concentrations observed in patients with RCC at the highest approved clinical dose (10 mg twice daily), axitinib was not associated with clinically significant QTc prolongation in target populations.

Aim To study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women. Methods Continuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration–QTc analyses were performed using a linear mixed effects model. Results Rac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QTcI) most effectively removed the heart rate dependency of the QTc interval. Mean QTcI was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QTcI in both genders. The largest mean change in QTcI (ΔQTcI) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean Cmax 1.8 μg ml−1 (range 1.1–2.8) vs. 1.4 μg ml−1 (range 0.9–1.9), P = 0.0009). The slope of the concentration–ΔQTcI relationship was steeper in women (30 ms per μg ml−1 vs. 23 ms per μg ml−1 in men; P = 0.0135). Conclusions The study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization.

A collaboration between the Consortium for Innovation and Quality in Pharmaceutical Development and the Cardiac Safety Research Consortium has been formed to design a clinical study in healthy subjects demonstrating that the thorough QT (TQT) study can be replaced by robust ECG monitoring and exposure-response (ER) analysis of data generated from First-in-Man single ascending dose (SAD) studies. Six marketed drugs with well-characterized QTc effects were identified in discussions with FDA; five have caused QT prolongation above the threshold of regulatory concern. Twenty healthy subjects will be enrolled in a randomized, placebo-controlled study designed with the intent to have similar power to exclude small QTc effects as a SAD study. Two doses (low and high) of each drug will be given on separate, consecutive days to 9 subjects. Six subjects will receive placebo. Data will be analyzed using linear mixed-effects ER models. Criteria for QT-positive drugs will be the demonstration of an upper bound (UB) of the 2-sided 90% confidence interval (CI) of the projected QTc effect at the peak plasma level of the lower dose above the threshold of regulatory concern (currently 10 ms) and a positive slope of ER relationship. The criterion for QT-negative drug will be an UB of the CI of the projected QTc effect of the higher dose

How does one define the discipline of clinical pharmacology? This has been a subject for much debate in recent literature [1–5]. The historical discipline of clinical pharmacology is one of integrating information across disciplines, requiring a broad knowledge base in several areas and the ability to synthesize and apply a ‘full picture’ from the parts. Can a discipline whose strength comes from cross-discipline knowledge survive when the complexity of disciplines over which one must integrate information is rapidly expanding?

This study characterized the multiple-dose pharmacokinetics of vemurafenib 240–960 mg twice daily (bid) in BRAF V600E mutation-positive metastatic melanoma patients, using the commercial formulation (240-mg microprecipitated bulk powder film-coated tablets). Melanoma patients (N = 52) were randomly allocated to four vemurafenib dose cohorts (240, 480, 720, or 960 mg bid for 14 days). After the day 15 morning dose, doses were interrupted until day 22, at which point patients were restarted on vemurafenib. Serial pharmacokinetic samples were collected after the morning dose on days 1, 9, and 15; trough pharmacokinetic samples were collected on day 2. Vemurafenib concentration increased with multiple doses to steady state at day 15; C max, AUC0–8h, and AUC0–168h increased between 3.3- and 3.8-fold across the fourfold dose range tested. Statistical analysis indicated dose proportionality across the dose range of 240–960 mg bid. Day 15 mean accumulation ratios (ratio of AUC0–8h on day 15/AUC0–8h on day 1) ranged from ~19 to 25 across cohorts. At steady state, the peak-to-trough ratio for vemurafenib exhibited a relatively flat concentration–time profile throughout the bid dosing interval. During dose interruption (days 15–22), mean vemurafenib trough concentrations decreased to minimal levels; vemurafenib exhibited a mean terminal phase half-life of 31.5–38.4 h. Vemurafenib plasma concentration accumulates with multiple bid doses of 240 mg. Vemurafenib exposure (AUC and C max) is dose proportional over the 240- to 960-mg bid dose range and exhibits constant drug levels over the bid dosing interval.

Cardiac proarrhythmia due to drug-induced QTc interval prolongation is an important concern in oncology since novel therapies can result in prolonged survival of cancer patients already predisposed to cardiotoxicity, and a number of anticancer agents, such as some of the tyrosine kinase inhibitors, are known to cause this risk. While not specifically requested by the ICH E14 guidance, a certain degree of QTc assessment in preapproval trials has emerged as the regulatory expectation with novel anticancer agents, particularly those that are small molecule chemical entities. This chapter reviews the challenges of evaluating QTc effect in oncology and proposes three integrated approaches to QTc risk assessment of anticancer agents (i.e., a “classic ICH E14-type” scenario, a “front-loaded” scenario, and a “full-development” scenario), which can be customized to different development plans and be evaluated using quantitative outcome criteria.

7580Background: MT-3724 is a novel recombinant fusion protein consisting of a CD20 binding variable fragment (scFv) fused to Shiga-like toxin-I A1. The SLT-I A1 forces MT-3724 internalization and i...

2568Background: Evofosfamide (Evo) is a prodrug of Br-IPM that is preferentially activated under hypoxic conditions. Hypoxia in locally advanced unresectable pancreatic ductal adenocarcinoma (PDAC)...

Background: Phase I study with the antibody-drug conjugate anetumab ravtansine demonstrated promising safety and efficacy as monotherapy in mesothelin-expressing tumors, and in particular for patients with advanced metastatic malignant pleural mesothelioma. Pemetrexed in combination with cisplatin is standard for first-line treatment of patients with metastatic mesothelioma and NSCLC. We therefore conducted a phase Ib study to determine the safety, tolerability, and maximum tolerated dose (MTD) of anetumab ravtansine in combination with pemetrexed/cisplatin (Pem/Cis) in subjects with mesothelin-expressing predominantly epithelial mesothelioma or nonsquamous NSCLC. Methods: Patients with histologically confirmed, unresectable, locally advanced or metastatic, mesothelin-expressing predominantly epithelial pleural or peritoneal mesothelioma or nonsquamous NSCLC, who previously failed ≤3 prior lines of chemotherapy, were eligible. Patients were prescreened based on obligatory tumor staining for mesothelin as determined by the Ventana MSLN (SP74) immunohistochemistry assay. Anetumab ravtansine was administered by 1-hour IV infusion on day 1 of every 21-day treatment cycle (Q3W). Pem (500 mg/m2) and Cis (75 mg/m2) were administered as IV infusions Q3W. Serial plasma samples were collected and analyzed for anetumab ravtansine and its components, pemetrexed, total and free platinum. Response to therapy was assessed by RECIST 1.1 and modified RECIST criteria for mesothelioma. Results: As of June 12, 2017, 17 patients had been treated and had received ≥2 cycles of treatment, including 7 patients with pleural mesothelioma, 9 with peritoneal mesothelioma, and 1 with NSCLC. Three patients were treated with anetumab ravtansine 5.5 mg/kg in combination with Pem/Cis with no dose-limiting toxicity (DLT). Six patients were then treated with anetumab ravtansine 6.5 mg/kg in combination with Pem/Cis, again without DLTs. This dose in combination was deemed as the MTD. An additional 8 patients were enrolled in an MTD expansion cohort. Anetumab ravtansine-related adverse events were mainly grade (G)1 and G2. G1/G2 eye toxicities were possibly more frequent with the combination than in historical data. There was one G3 corneal microcystic event and one G3 hypertension. There was a 50% overall response rate (all partial responses) from 16 evaluable patients. Of 13 patients treated at the 6.5 mg/kg MTD dose of anetumab ravtansine in combination with Pem/Cis, the overall response rate was 46%. Based on comparisons to historical data and within-subject comparisons in small number of subjects, clinically relevant PK interaction was not observed. Conclusions: Anetumab ravtansine at 6.5 mg/kg dosed Q3W in combination with standard dosing of Pem/Cis had a manageable toxicity profile without evidence of PK interaction and with early signs of clinical efficacy. Anetumab ravtansine at 6.5 mg/kg in combination with Pem 500 mg/m2 and Cis 75 mg/m2, all administered in a Q3W regimen, is thus feasible and the recommended dose for future study. Citation Format: Raffit Hassan, Ding Wang, John Wrangle, Anish Thomas, Angus Byars, Lianne Asschert, Rolando Atienza, Prabhu Rajagopalan, Annette Walter, Jun Zhang, Nenad Sarapa, Hedy Kindler. Phase Ib study of anetumab ravtansine in combination with pemetrexed and cisplatin in patients with mesothelin-expressing epithelial mesothelioma or nonsquamous non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A095.

Background Improved automated methods for electrocardiographic (ECG) analysis are needed, particularly for drug development purposes. Objectives This study compared a novel fully automated method for ECG analysis (QTinno; NewCardio, Santa Clara, CA) to 2 semiautomated digital methods: global measurement from the earliest QRS onset to the latest T-wave offset on representative superimposed beats (global) and tangent measurement on 3 consecutive beats in one lead (tangent). Methods All 3 methods were used to determine uncorrected and rate-corrected QT interval duration (QT and QTcF) and related metrics in 1422 digital 12-lead ECGs from a phase 1 drug study. Global and tangent annotations were manually adjusted by the same 3 cardiologists wherever necessary. No adjustments were made in QTinno determinations. Results QTinno returned QTcF change from time-matched baseline (ΔQTcF) that differed minimally from both global and tangent methods (mean pairwise difference: 0.1 millisecond between QTinno and global, 1.1 milliseconds between QTinno and tangent). The average absolute QT and QTcF intervals by QTinno were approximately 5 milliseconds longer than global and 25 milliseconds longer than by tangent. QTinno had lower intrinsic variability for ΔQTcF than either global or tangent (between-subject SD: QTinno 4.0 milliseconds, global 5.6 milliseconds, tangent 6.4 milliseconds; within-subject SD: QTinno 4.8 milliseconds, global 7.4 milliseconds, tangent 10.6 milliseconds). All methods were robust in detecting the largest placebo-adjusted mean time-matched ΔQTcF (15-25 milliseconds) induced by study drug. Conclusions The methods show good agreement for drug-induced QTc prolongation. Lower intrinsic variability of ΔQTcF by QTinno could facilitate smaller sample sizes or increase study power in thorough QTc studies.

Background: Continuous 12‐lead ECG monitoring (Holter) in early‐phase pharmaceutical studies is today widely used as an ideal platform to extract discrete ECGs for analysis. The extraction process is typically performed manually by trained readers using commercial Holter processing systems. Methods: Antares, a novel method for automatic 12‐lead extraction from continuous Holter recordings applying minimal noise criteria and heart‐rate stability conditions is presented. A set of 12‐lead Holter recordings from healthy subjects administered with sotalol is used to compare ECG extractions at fixed time points with ECG extractions generated by Antares optimizing noise and heart rate inside 5 minute windows centered around each expected time point of interest. Results: Global, low‐ and high‐frequency noise content of extracted ECGs was significantly reduced via optimized approach by Antares. Heart rate was also slightly reduced (from 69 ± 13 to 64 ± 13 bpm, P < 0.05). Similarly, the corrected QT interval from optimized extractions was significantly reduced (QTcB from 414 ± 32 to 402 ± 30 ms, P < 0.05). Using only baseline data, and after adjusting for intersubject variability, the standard deviation (SD) of QT intervals was highly reduced with optimized extraction (SD of QTcF from 11 ± 8 to 7 ± 2 ms, P < 0.05). Conclusions: Extraction of discrete 12‐lead ECG strips from continuous Holter generates less noisy and more stable ECGs leading to more robust QTc data, thereby potentially facilitating the assessment of ECG effects on clinical trials.

A novel fully automated method for wave identification and extraction from electrocardiogram (ECG) waveforms is presented. This approach implements the combined use of a new machinelearning algorithm and of specified parameterized functions called Gaussian mesa functions (GMFs). Individual cardiac cycle waveforms are broken up into GMFs using a generalized orthogonal forward regression algorithm; each individual GMF is subsequently identified (wave labeling) and analyzed for feature and morphologic extraction. The GMF associated with the repolarization waveform of the main vector lead, based on principal components analysis, was analyzed, and a set of morphologic parameters were derived under 2 experimental settings: first, in 100 digital 12-lead ECG Holter recordings acquired during three 24-hour periods (baseline and after 160 and 320 mg of sotalol) from 38 healthy subjects; second, in drug-free 12-lead resting ECGs from 100 genotyped long QT syndrome (LQTS) patients (50 each with LQT1 and LQT2). QTinterval duration was measured using an on-screen method applied to the global representative beats and reviewed by a senior cardiologist. QTci (individual correction) was used for analysis. All parameters in the sotalol test showed highly significant differences between the time of peak plasma concentration (Tmax) and baseline ECGs; however, the dynamic pattern of individual parameters followed different patterns. The LQTS test confirmed the results of the sotalol test, showing that GMF-based repolarization parameters were strongly modified as compared with healthy controls. In particular, T-wave width and descending phase of repolarization were more prolonged in LQT2 compared to LQT1. © 2008 Elsevier Inc. All rights reserved.

Background: The dissociation between a drug-induced increase of the QT interval prolongation and an increased risk for ventricular arrhythmias has been suggested by academic investigators and regulatory agencies. Yet, there are no alternative or complimentary electrocardiographic (ECG) techniques available for assessing the cardiotoxicity of novel compounds. In this study, we investigated a set of novel ECG parameters quantifying the morphology of the T-loop. In a group of healthy individuals exposed to sotalol, we compared their drug-induced changes to the drug-induced prolongations of the QTc, QTc apex and T-peak to T-end intervals. Methods: We implemented a set of parameters describing the morphology of the T loop in its preferential plane. These parameters measure the time interval needed for the heart vector amplitude to change from its maximum value to a time when its amplitude has been reduced by 30%, 50%, and 70%. These measurements are called early repolarization duration (ERD) when they are located before the T-wave apex and late repolarization duration (LRD) when measured after the apex. They depend on both the speed of the repolarization process and the morphology of the T loop. Thirty-nine healthy individuals were exposed to sotalol in a crossover-design study. Sixteen ECGs were recorded per day during 3 days. The first day (day 0) was baseline; a single dose of sotalol (160 mg) was given during day 1, and a double dose was given during day 2 (320 mg). The plasma concentration of the drug was measured just before the ECG recordings. Results: The values of all investigated parameters revealed a dose-dependent effect of sotalol (in average between parameters, ρ = 0.9, P b .001). Our investigations described profound and statistically significant changes in the morphology of the vectorial T loop for day 1 (peak effect of sotalol: ΔERD50% = 23 ± 6 msec, P b.05; ΔLRD50% = 8 ± 3 msec, P = .05) and day 2 (peak effect of sotalol: ΔERD50% = 51 ± 14 msec, P b .05; ΔLRD50% = 20 ± 12 msec, P = .05). When investigating the timing of peak drug concentration and peak effect of the drug on the various repolarization parameters, we found asynchrony between ERDs/LRDs (≥3.5 hours after dosing) and QTc/QTc apex profiles (b3.5 hours after dosing), suggesting that the time of maximum prolongation on the repolarization process was not synchronized with the time of maximum drug-induced heterogeneity of repolarization. Conclusion: This study describes the sotalol-induced changes of the T-loop morphology in healthy individuals based on novel vectocardiographic parameters. These observations might help in improving the next generation of ECG markers for the evaluation of drug cardiotoxicity.

The FDA mandates that digital electrocardiograms (ECGs) from 'thorough' QTc trials be submitted into the ECG Warehouse in Health Level 7 extended markup language format with annotated onset and offset points of waveforms. The FDA did not disclose the exact Warehouse metrics and minimal acceptable quality standards. The author describes the Warehouse scoring algorithms and metrics used by FDA, points out ways to improve FDA review and suggests Warehouse benefits for pharmaceutical sponsors. The Warehouse ranks individual ECGs according to their score for each quality metric and produces histogram distributions with Warehouse-specific thresholds that identify ECGs of questionable quality. Automatic Warehouse algorithms assess the quality of QT annotation and duration of manual QT measurement by the central ECG laboratory.

The absolute bioavailability of nelfinavir was determined in 6 healthy volunteers following simultaneous administration of 1250 mg oral nelfinavir and an intravenous infusion of (14)C-nelfinavir mesylate on day 1 and at steady state. Nelfinavir oral bioavailability decreased from 0.88 to 0.47 over the 11-day study period. The moderate bioavailability of nelfinavir was due to significant first-pass metabolism rather than low absorption, limiting the potential of formulation improvement to decrease pill burden. Human absolute bioavailability studies with accelerator mass spectrometry microdosing, in which an intravenous microdose is given along with a conventional oral dose of the same drug, can differentiate between gastrointestinal absorption and the first-pass metabolism of new drug candidates. Accelerator mass spectrometry allowed a several thousand-fold dose reduction of (14)C-nelfinavir relative to that required for liquid scintillation counting. Accelerator mass spectrometry microdosing reduces potential safety issues around dosing radioactivity to humans and prevents the need to formulate high intravenous doses.

In this study, we investigated the validity of T wave area-based parameters for the identification of drug-induced changes of repolarization. Based on electrocardiograms from 39 healthy patients, we computed the stability of repolarization measurements and compared the sotalol-induced repolarization changes when measured with area-based parameters and traditional QT interval techniques (manual and automatic). Also, we evaluated the effect of different types of heart rate correction on these repolarization measurements. The results show that the stability of the automatic repolarization measurements is higher when measured using computer algorithm than using manual QT measurement. By using a population-based heart rate correction, the area-based parameters reveal significant modification of the overall shape of the T wave in its early, middle, and final part. In conclusion, morphological parameters of T wave are able to identify the changes in repolarization interval induced by sotalol. These parameters are more stable and thus more reliable than the traditional QT interval measurements.

MAG-camptothecin (MAG-CPT) is the lead compound of a novel drug delivery system in which an active cytotoxic moiety, camptothecin (CPT), is covalently linked to a soluble polymeric carrier (MAG) to form an inactive prodrug. The mechanism of action of CPT remains unaltered, but the delivery system is thought to allow the carrier-bound drug to accumulate in tumor tissues and release the active CPT locally. This proof-of-concept clinical study was designed to determine whether MAG-CPT was preferentially delivered to or retained in tumor tissue compared to adjacent normal tissue or plasma, and to estimate the degree of intratissue release of CPT.This was an open, non-randomized study in ten adult patients scheduled for elective surgery for colorectal cancer. Patients received a single dose of 60 mg/m2 (CPT equivalent) of MAG-CPT 24 h, 3 days or 7 days prior to surgery. Plasma, tumor, and adjacent normal tissue samples were collected simultaneously at the time of surgery and analyzed for MAG-bound and released CPT concentrations.MAG-bound and free CPT concentrations in plasma, tumor, and normal tissue achieved equilibrium by 24 h after dosing, declining in parallel up to 7 days after dosing. MAG-bound CPT was delivered to similar levels to tumor and normal tissue. At 24 h after dosing, the mean+/-SD MAG-bound CPT concentrations were 861+/-216 ng/g in tumor and 751+/-215 ng/g in adjacent normal tissue, and free CPT concentrations were lower in tumor than in normal tissue (12.2+/-4.7 ng/g and 21.9+/-6.7 ng/g, respectively). At 24 h after dosing, mean+/-SD ratios of MAG-bound and free CPT in tumor and plasma were 0.13+/-0.03 and 0.22+/-0.09, respectively, and the ratios did not change for up to 7 days after dosing, indicating a lack of preferential retention of MAG-bound CPT or release of free CPT in tumor. These results are in marked contrast to previous data from animal tumor xenograft studies, where MAG-CPT levels were higher in tissue than in plasma at 3 and 7 days after a single i.v. dose.Delivery of CPT to the target tumor tissue is achievable by means of the MAG-CPT polymer-bound delivery system, with the equilibrium between plasma and tumor tissue concentrations of released CPT being established within 24 h after dosing. However, preferential retention of MAG-bound or released CPT in the tumor relative to normal tissue or plasma was not detected during the 7 days after dosing. The methods employed in our study could be of use in making "go/no-go" decisions on further development of anticancer drugs.

This double-blind, four-way crossover study assessed the effect of valdecoxib on the QTc interval duration in 25 male and 9 female healthy adults. Subjects received placebo or 40 mg, 80 mg, or 120 mg valdecoxib once daily for 5 days. Serial ECGs were obtained for 24 hours before the first treatment (baseline) and on the 5th day of each treatment. The study was statistically powered to detect a difference of > or = 5.6 ms in the average daily QTc change from baseline and a > or = 7.8-ms difference in the average maximal daily change from baseline. No QTc prolongation versus placebo (Fridericia's or Bazett's correction) was observed for any valdecoxib dose. A 22% greater than proportional increase in valdecoxib AUC0-24 was observed over the 40- to 120-mg dose range, supporting the conclusiveness of the negative QTc risk assessment even at supratherapeutic doses (up to three times the maximum recommended dose of 40 mg per day) and concentrations. In conclusion, repeated administration of doses up to 120 mg valdecoxib had no effect on cardiac repolarization in healthy volunteers, suggesting that chronic administration of valdecoxib to patients would not increase the risk from cardiac arrhythmia associated with QT prolongation.

Categorizations of best response observed at week 8 (between week 3 and 14) of first-line treatment in two studies of bevacizumab plus chemotherapy in Western (878 patients) and Chinese (198 patients) patients with non-small cell lung cancer were assessed together with baseline prognostic factors in multivariate parametric models to predict overall survival (OS) and progression free survival (PFS). Predictive performances of the models were assessed by simulating multiple replicates of the studies. Disease control rate (DCR) was the best response categorization to predict OS and PFS. In the OS model, DCR fully captured bevacizumab effect. For PFS, DCR did not fully capture bevacizumab treatment effect. The models adequately predicted OS and PFS distributions in each arm as well as bevacizumab hazard ratio (HR) for OS and PFS, for example, in Western patients (model prediction [95% prediction interval]: 0.84 [0.71-0.98] vs. observed: 0.77 for OS and 0.59 [0.49-0.72] vs. observed: 0.58 for PFS). Covariates in the models captured endpoint differences seen in Chinese patients. There was no impact of Chinese ethnicity on the DCR relationship to OS or PFS. DCR predicted OS benefit with bevacizumab in first-line NSCLC patients. Western data can be used to inform design of studies in Chinese patients.

Purpose To assess new metrics of tumor-size response to predict overall survival (OS) in colorectal cancer (CRC) in Western and Chinese patients. Patients and Methods Various metrics of tumor-size response were estimated using longitudinal tumor size models and data from two phase III studies that compared bevacizumab plus chemotherapy versus chemotherapy as first-line therapy in Western (n = 923) and Chinese (n = 203) patients with CRC. Baseline prognostic factors and tumor-size metrics estimates were assessed in multivariate models to predict OS. Predictive performances of the models were assessed by simulating multiple replicas of the phase III studies. Results Time to tumor growth (TTG) was the best metric to predict OS. TTG fully captured bevacizumab effect. Chinese ethnicity had no impact on OS or on the TTG-OS relationships. The model correctly predicted OS distributions in each arm as well as bevacizumab hazard ratio (model prediction, 0.75 v 0.68 observed in Western patients; 95% prediction interval, 0.62 to 0.91). Conclusion TTG captured therapeutic benefit with bevacizumab in first-line CRC patients. Chinese ethnicity had no impact. Longitudinal tumor size data coupled with model-based approaches may offer a powerful alternative in the design and analysis of early clinical studies.

2509Background: AR (BAY 94-9343) comprises a novel fully human anti-mesothelin IgG1 antibody conjugated to the maytansinoid tubulin inhibitor DMR. A phase I study was conducted in patients (pts) with advanced solid tumors. Methods: Eligible pts with solid tumors refractory to standard treatment, adequate organ function, and ECOG performance status (PS) ≤ 1 were enrolled. AR was administered IV on 2 schedules: every 21 days (q3w) in 45 pts (21 mesothelioma [Meso], 9 pancreatic, 5 breast, 4 ovarian cancer [OC], 6 other) at doses ranging from 0.15 to 7.5 mg/kg and in an expansion cohort at 6.5 mg/kg (12 Meso and 20 OC); and weekly (qw) in 71 pts (31 Meso and 40 OC) randomized to either 1.8 mg/kg or 2.2 mg/kg. Pts were assessed for AEs weekly C1-C3 and on D1 in subsequent cycles. Tumor response was assessed q6w C1-C8 and q12w thereafter. Mesothelin expression in archival tumor samples was assessed by IHC (SP74, Ventana). Results: A total of 147 pts were evaluable: 64% female, mean age 61 yrs (range 18-88), PS...

Background: Drug-induced QTc prolongation is becoming increasingly important in oncology since novel therapies result in prolonged survival of cancer patients already predisposed to cardiotoxicity. Methods: We review the challenges of implementing the ICH E14 guidance in oncology and propose an integrated approach to QTc risk assessment of nonadjuvant anticancer agents (NAAs), with quantitative outcome criteria. Results: We recommend informed use of non-clinical cardiac safety pharmacology results, some degree of robust ECG assessments in early phase studies, a dedicated QTc study in cancer patients conducted at the appropriate time pre-, peri-, or post-approval (with the design and timing agreed upon with regulatory agencies), and ECG monitoring in late-phase studies commensurate with the outcome of previous QTc studies. Conclusion: The proposed approach would facilitate risk–benefit assessment for NAAs during clinical development and regulatory review, and enable adequate labeling for safe and effective...

The US Food and Drug Administration recommends submission of digital electrocardiograms in the standard HL7 XML format into the electrocardiogram warehouse to support preapproval review of new drug applications. The Food and Drug Administration scrutinizes electrocardiogram quality by viewing the annotated waveforms and scoring electrocardiogram quality by the warehouse algorithms. Part of the Food and Drug Administration warehouse is commercially available to sponsors as the E-Scribe Warehouse. The authors tested the performance of E-Scribe Warehouse algorithms by quantifying electrocardiogram acquisition quality, adherence to QT annotation protocol, and T-wave signal strength in 2 data sets: "reference" (104 digital electrocardiograms from a phase I study with sotalol in 26 healthy subjects with QT annotations by computer-assisted manual adjustment) and "test" (the same electrocardiograms with an intentionally introduced predefined number of quality issues). The E-Scribe Warehouse correctly detected differences between the 2 sets expected from the number and pattern of errors in the "test" set (except for 1 subject with QT misannotated in different leads of serial electrocardiograms) and confirmed the absence of differences where none was expected. E-Scribe Warehouse scores below the threshold value identified individual electrocardiograms with questionable T-wave signal strength. The E-Scribe Warehouse showed satisfactory performance in detecting electrocardiogram quality issues that may impair reliability of QTc assessment in clinical trials in healthy subjects.

Background: Restitution through intracardiac pacing has been used to assess arrhythmia vulnerability. We examined whether analyses of sequential beat‐to‐beat QT and TQ interval measures can be used to quantify ECG restitution changes under normal sinus rhythm. Methods: The QT, R‐R and TQ intervals were examined 22.5 hour Holter monitoring before and after oral sotalol in normal male and female volunteers. Additionally, comparisons were made to those observed in the time‐matched dataset prior to torsades de pointes in a heart diseased patient that received a single dose of sotalol. Results: Sotalol increased QT, R‐R and TQ intervals 71, 101, and 125 ms after 160 mg (n = 38) and 194, 235, and 135 ms after 320 mg (n = 19) during maximum plasma concentrations, respectively. The percentage of beats with a QT/TQ ratio >1 was reduced 25% over the entire 22.5 hours after sotalol and the lower TQ interval boundary (5th quantile) was increased 22–30%. In contrast, 99% of the beats prior to torsades de pointes had a QT/TQ ratio > 1 and the median TQ interval was below the lower 98% confidence bounds of normals before and after sotalol. Conclusions: ECG restitution changes are quantifiable under varying states (nocturnally, beta‐adrenergic blockade, QT prolongation) in healthy subjects.

Ever since it was introduced in routine clinical cardiology practice (1), the continuous ambulatory electrocardiogram (Holter ECG) has been routinely used for diagnostic assessment of patients with different types of heart disease like cardiac arrhythmias, transient ischemic episodes and silent myocardial ischemia. The incidence of cardiac arrhythmia and myocardial ischemia, as well as the assessment of heart rate variability on Holter ECG acquired continuously over 24 h or longer have been useful for predicting clinical disease outcomes (2, 3, 4, 5). Likewise, Holter ECG is often used in clinical drug research for the monitoring of general cardiac safety of novel drugs under development, particularly during the early phase I trials. In contrast, Holter ECG has only rarely been used in drug development for the formal assessment of drug-induced effects on cardiac repolarization, and the experience of central ECG laboratories in measuring ECG intervals on Holter is limited. Pharmaceutical sponsors and patients alike would benefit if reliable QT/QTc assessment were possible by Holter ECG, whereby the continuous ambulatory digital 12-lead ECG would be used to substitute for standard resting supine 12-lead ECGs in the assessment of drug-induced QT/QTc prolongation.

INTRODUCTION The QTc interval prolongation is not a perfect surrogate marker of the presence of an increased risk for arrhythmic events. In the search for alternative markers, we investigated the T-amplitude and QT interval adaptation to heart rate (HR) in patients with the congenital long QT syndrome (LQTS) and individuals with sotalol-induced QT prolongation. METHODS AND RESULTS Our investigation is based on the analysis of continuous 12-lead digital Holter recordings in: 49 LQT1 carriers, 25 LQT2 carriers, 37 healthy individuals off drugs and on 160 mg of sotalol, and 21 of them also on 320 mg of sotalol. The Holter recordings were used to investigate repolarization parameters and their HR dependency. A loss of HR dependency of the T-amplitude was found as a common feature in individuals with impaired I(kr) kinetics: LQT2 carriers and subjects on sotalol. The T-amplitude/RR slope was significantly (P < 0.05) flatter in LQT2 (0.31 +/- 0.27 microV/ms) than in both LQT1 (0.62 +/- 0.40 microV/ms) and healthy individuals (0.55 +/- 0.29 microV/ms). A dose-dependent reduction of the T-amplitude/RR slope was also observed in subjects on sotalol (160 mg dose: 0.26 +/- 0.19 microV/ms; 320 mg dose: 0.21 +/- 0.14 microV/ms). The QT/RR slope was less effective than T-amplitude/RR slope in differentiating between congenital and drug-induced repolarization delay. CONCLUSIONS Impaired adaptation of T-amplitude to changing HR is a common electrocardiographic feature associated with KCNH2 mutation and I(kr) blockade by sotalol. This ECG marker may play an important role in the future of the assessment of the penetrance of KCNH2 mutation and the identification of a drug effect on the I(kr) kinetics.

DX-619 is a novel des-fluoro(6)-quinolone with activity against a broad range of bacterial strains, including methicillin-resistant Staphylococcus aureus . The effects of DX-619 on the glomerular filtration rate (GFR) were evaluated because drug-related increases in serum creatinine levels were observed in studies with healthy volunteers. Forty-one healthy subjects were randomized to receive intravenous DX-619 at 800 mg or placebo once daily for 4 days, and the GFR was directly measured by determination of the clearance of a bolus iohexol injection in 33 subjects who completed the study per protocol. DX-619 was noninferior to placebo for the GFR on the basis of a criterion for a clinically significant difference of −12 ml/min/1.73 m 2 . The mean GFRs on day 4 were 101.1 ± 14.2 ml/min/1.73 m 2 and 100.2 ± 15.6 ml/min/1.73 m 2 for the volunteers receiving placebo and DX-619, respectively. On day 4 the mean serum creatinine concentration for volunteers receiving DX-619 increased by 30 to 40%, with a corresponding decrease in mean creatinine clearance. Both parameters normalized within 7 days after the cessation of DX-619 treatment. Nonclinical studies suggest that DX-619 increases the serum creatinine concentration by inhibiting excretory tubular transporters. In conclusion, DX-619 administered intravenously at 800 mg once a day for 4 days did not affect the GFR in healthy volunteers. Glomerular toxicity is not expected to present a risk to patients receiving DX-619 in clinical trials, but monitoring of the renal function, with an emphasis on the serum creatinine concentration, is still warranted.

Well-specified recommendations have yet to be established on how electrocardiogram (ECG) interval measurement should be performed by digital on-screen caliper systems to assess drug-induced effect on cardiac repolarization in pharmaceutical clinical trials with adequate precision and reproducibility. Since 1997, the industry has followed the European Committee for Proprietary Medicinal Products Points to Consider by using fully manual measurement of 3 consecutive sinus rhythm PQRST complexes in 1 lead only (typically limb lead II). More recently, semiautomatic measurement performed on representative (median) beats and based on the global leads has been considered. The International Conference on Harmonization E14 guidance (June 2005) advocates development of quality standards for centralized ECG interval measurement and allows all methods "whether or not assisted by computer" but includes no recommendations on how to perform the measurement. We provide an overview of the currently available methods for digital ECG interval measurement and the implications of between-method differences on quality of ECG interval measurements. We applied 4 methods most commonly used to assess QT prolongation (applied on 3 raw beats in limb lead II or by global measurement on 1 or 12 superimposed representative beats). QT, QTc Fridericia, and RR interval durations were measured on resting 12-lead digital ECGs obtained in 26 healthy volunteers predose and at 1, 2, and 3 hours after dosing with a single 160 mg oral dose of sotalol. Absolute interval durations and changes from baseline were compared between the 4 measurement methods. A better understanding of the implications from different measurement methodologies will facilitate more informed choice of the appropriate method for ECG interval measurement on clinical trials.

Background: Careful assessment of QT interval prolongation is required before novel drugs are approved by regulatory authorities. The choice of the most appropriate method of electrocardiogram (ECG) acquisition and QT/RR interval measurement in clinical trials requires better understanding of the differences among currently available approaches. This study compared standard and Holter-derived 12-lead ECGs for utility in detecting sotalol-induced QT/QTc and RR changes. Manual methods (digitizing pad and digital on-screen calipers) were compared for precision of QT and RR interval measurement. Methods and Results: Sixteen hundred pairs of serial 12-lead digital ECGs were recorded simultaneously by standard resting ECG device and by continuous 12-lead digital Holter over 3 days in 39 healthy male and female volunteers. No therapy was given on the 1st day followed by 160 mg and 320 mg of sotalol on the 2nd and 3rd day, respectively. Holter-derived and standard ECGs produced nearly identical sotalol-induced QT/QTc and RR changes from baseline, as did the manual digipad and on-screen caliper measurements. The variability of on-screen QT measurement in this study was greater than that of digipad. Conclusions: Digital 12-lead Holter and standard 12-lead ECG recorders, as well as the manual digitizing pad and digital on-screen calipers, are of equal utility for the assessment of drug-induced change from baseline in QT and RR interval, although the variability of the on-screen method in this study was greater than of the digipad.

MDM2 is overproduced as a mechanism to impair p53 function in many cancers. By reactivating p53, antagonists of p53-MDM2 interaction could offer a novel approach to treatment of solid tumors and leukemias. RG7112, the first potent and selective small-molecule MDM2 antagonist in clinical testing, is an oral p53 activator and is currently in phase I. To optimize its dose and schedule, a number of clinical pharmacology characteristics were explored in this multi-center trial in patients (pts) with advanced solid tumors. In Part I, the impact of high-energy/high-fat meal and formulation (crystalline versus amorphous) was examined in cross-over design. In Part II, schedule optimization (4 schedules of drug adm under fasting condition and 1 cohort with liquid supplementation) was investigated in parallel, dose escalation design. Clinical endpoints were PK/PD and safety/tolerability including platelet reduction (a potential target-mediated hematological toxicity indicator). A total of 76 pts (42F and 34M, mean age 60 yr) participated in the study. In their first-cycle treatment, 36 pts received weekly x3 (26 with food/formulation evaluation), 15 pts daily x5, 6 pts daily x20, and 19 pts daily x3 (3 with food evaluation) doses; daily doses ranged from 500-4500 mg. The most commonly reported AEs (> 20%) were GI-related. Twelve pts have reported 21 SAEs, of which, 4 events in 2 pts (1 pt with G4 thrombocytopenia, anemia, and neutropenia; 1 pt with G3 delirium) were related to study treatment. A high-energy (∼1000 kcal)/high-fat (∼60 g) meal and a reduced energy (∼500 kcal)/fat (∼30 g) liquid supplementation both enhanced overall bioavailability (BA) of tested formulations by 2-fold, with inter-pt variability reduced by half. At steady-state, amorphous formulation also reduced PK variability by half from the crystalline formulation. High-dose consecutive daily dosing for 5 and 3 d yielded highest drug concentrations on the last day of treatment. On the other hand, both weekly and low-dose/long-duration (20-day) schedules yielded lower peak concentrations (note that the per-cycle exposure was comparable to, or higher than, high-dose 5x and 3x daily schedules). Serum profiles of MIC-1, a secreted protein that is strongly induced by activated p53, showed similar patterns to the PK when the clinical pharmacology conditions were varied. The first-cycle platelet profiles indicate that the weekly schedule didn't cause platelet reduction, while the daily schedules showed a trend of dose- and length-dependent platelet reduction with daily x 5 at high doses being the most pronounced (1 pt resulted in G-4 thrombocytopenia). In conclusion, RG7112 is well tolerated with or without food in the therapeutically relevant dose range, food enhanced BA with reduced variability, and high-dose consecutive daily for 3-5 d is superior in yielding sufficiently high PK exposure and PD effects potentially required for cancer treatment efficacy. Citation Format: Amita Patnaik, Anthony Tolcher, Muralidhar Beeram, John Nemunaitis, Glen Weiss, Gwen Nichols, Steven Middleton, Nenad Sarapa, Anna Beryozkina, Jianguo Zhi. Clinical pharmacology characterization of RG7112, an MDM2 antagonist, in patients with advanced solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-201. doi:10.1158/1538-7445.AM2013-LB-201

The pharmacokinetics of furosemide (frusemide) in patients with oedema have been relatively well studied, but in many studies it is unclear whether the disease or the oedema per se has the major effect. The rate of absorption of oral furosemide in patients with oedema was decreased, but total bioavailability was almost unchanged. The peak serum concentration (Cmax) and time taken to achieve Cmax were either decreased or unchanged. Binding of furosemide to plasma proteins is lower in patients with congestive heart failure (CHF), decompensated liver cirrhosis (DLC) and nephrotic syndrome, probably as a result of hypoalbuminaemia. The elimination half-life (t1/2) can be unchanged (CHF, DLC) or prolonged (chronic renal failure: CRF). Plasma and renal clearance are reduced in patients with CRF and nephrotic syndrome, but are almost unchanged in CHF and DLC. Disease-induced disorders are mainly responsible for the alterations of furosemide pharmacokinetics in oedematous conditions, while the influence of oedema per se is probably not clinically relevant. The pharmacokinetics of digoxin have been studied in a small number of studies only. In patients with CHF, considerable interindividual differences have been found. Because digoxin has a narrow therapeutic window, this drug should be administered cautiously to oedematous patients. Theophylline has higher bioavailability in patients with oedema, with a significantly higher Cmax in patients with hepatic cirrhosis and CHF than in healthy volunteers (29 and 22%, respectively). Furthermore, clearance decreases and t1/2 increases in these patients. Angiotensin converting enzyme (ACE) inhibitors are often administered as prodrugs, and their pharmacokinetic profile could be influenced by the diseases that accompany oedematous states. However, the effect of oedema is difficult to discriminate from that of the disease. Individual ACE inhibitors are affected differently, but importantly the dosage of perindopril should be reduced in patients with CHF, while for most other ACE inhibitors the changes in pharmacokinetic parameters are clinically irrelevant. In conclusion, studies on pharmacokinetic changes in oedema are limited. Besides affecting absorption (after oral administration) and conversion of the prodrug to the active form, probably as a result of the associated disease, oedema has not been proven to cause any clinically relevant changes in pharmacokinetic parameters for individual drugs. However, further studies of this aspect of pharmacokinetics are needed.

Summary Objective Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, is metabolized primarily by cytochrome P450 (CYP) 3A with minor contributions from CYP1A2, CYP2C19, and glucuronidation. Co-administration with CYP inhibitors may increase systemic exposure to axitinib and alter its safety profile. This study evaluated changes in axitinib plasma pharmacokinetic parameters and assessed safety and tolerability in healthy subjects, following axitinib co-administration with the potent CYP3A inhibitor ketoconazole. Methods In this randomized, single-blind, two-way crossover study, 32 healthy volunteers received placebo, followed by a single 5-mg oral dose of axitinib, administered either alone or on the fourth day of dosing with oral ketoconazole (400 mg/day for 7 days). Results Axitinib exposure was significantly increased in the presence of ketoconazole, with a geometric mean ratio for area under the plasma concentration–time curve from time zero to infinity of 2.06 (90% confidence interval [CI]: 1.84–2.30) and a geometric mean ratio for maximum plasma concentration (Cmax) of 1.50 (90% CI: 1.33–1.70). For axitinib alone or with ketoconazole, Cmax occurred 1.5 and 2.0 h after dosing, respectively. Adverse events were predominantly mild; the most commonly reported treatment-related adverse events were headache and nausea. Conclusions Axitinib plasma exposures and peak concentrations were increased following concurrent administration of axitinib and ketoconazole in healthy volunteers. Axitinib alone and in combination with ketoconazole was well tolerated. These findings provide an upper exposure for expected axitinib plasma concentrations in the presence of potent metabolic inhibition.