Publications by authors named "Christelle Darstein"

18 Publications

  • Page 1 of 1

Octreotide SC depot in patients with acromegaly and functioning neuroendocrine tumors: a phase 2, multicenter study.

Cancer Chemother Pharmacol 2019 02 8;83(2):375-385. Epub 2018 Dec 8.

Endocrinology, DiMI and CEBR, University of Genoa, Genoa, Italy.

Purpose: Octreotide SC depot is a novel, ready-to-use formulation administered via a thin needle. In a phase 1 study in healthy volunteers, this formulation provided higher bioavailability of octreotide with faster onset and stronger suppression of IGF-1 in healthy volunteers versus long-acting intramuscular (IM) octreotide. This phase 2 study evaluated the pharmacokinetics, efficacy, and safety of octreotide SC depot in patients with acromegaly and functioning NETs, previously treated with octreotide IM.

Methods: Adult patients with acromegaly or functioning NETs treated for ≥ 2 months with octreotide IM [10/20/30 mg every 4 weeks (q4w)] received the last dose of octreotide IM treatment in study period 0 and were randomized 28 days later to receive octreotide SC depot 10 mg q2w, or 20 mg q4w for 3 months (period 1). The primary objective was to characterize the PK profile of octreotide SC depot after each injection vs PK for octreotide IM (period 0).

Results: Twelve patients were randomized to receive octreotide SC depot 10 mg q2w (acromegaly n = 3; NET n = 1) or 20 mg q4w (acromegaly n = 4; NET n = 4). Plasma levels of octreotide were higher with octreotide SC depot as compared to octreotide IM. Adverse events were reported in 6 and 8 patients during period 0 and period 1, respectively; most common in period 1 were gastrointestinal disorders.

Conclusion: Octreotide SC depot provided higher exposure (AUC) than octreotide IM, maintained biochemical control in patients with acromegaly and symptom control in patients with functioning NETs, and was well tolerated with a safety profile consistent with octreotide IM. CLINICALTRIALS.

Gov Identifier: NCT02299089.
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http://dx.doi.org/10.1007/s00280-018-3734-1DOI Listing
February 2019

Drug Interaction Potential of Osilodrostat (LCI699) Based on Its Effect on the Pharmacokinetics of Probe Drugs of Cytochrome P450 Enzymes in Healthy Adults.

Clin Drug Investig 2017 May;37(5):465-472

Novartis Pharmaceuticals Corporation, 1 Health Plaza, Building 315, 04-4230E, East Hanover, NJ, 07936, USA.

Background And Objectives: Osilodrostat (LCI699) is an adrenal steroidogenesis inhibitor currently in late-phase clinical development as a potential treatment for Cushing's disease. This study evaluated the inhibitory effect of osilodrostat on the pharmacokinetics of probe substrates of the cytochrome P450 (CYP) enzymes CYP1A2, CYP2C19, CYP2D6, and CYP3A4.

Methods: Healthy adult volunteers received single-dose cocktail probe substrates [caffeine (100 mg), omeprazole (20 mg), dextromethorphan (30 mg), and midazolam (2 mg)] followed by a 6-day washout. Subjects then received a single dose of osilodrostat 50 mg followed by a single dose of cocktail probe substrates.

Results: Nineteen of twenty subjects (ten were male) completed the study. Mean age, body weight, and body mass index were 41.8 years, 73.0 kg, and 24.4 kg/m. Geometric mean ratio of the area under the concentration-time curve from time zero to the last measureable concentration and 90% confidence intervals of probe substrate exposure with osilodrostat were: caffeine (CYP1A2 probe substrate), 2.33 (2.10-2.59); omeprazole (CYP2C19), 1.91 (1.74-2.11); dextromethorphan (CYP2D6), 1.48 (1.34-1.63); and midazolam (CYP3A4/5), 1.50 (1.41-1.60). Corresponding values for geometric mean ratio of maximum plasma concentration (90% confidence interval) for the change in substrate exposure were 1.07 (0.988-1.15), 1.61 (1.40-1.84), 1.35 (1.21-1.50), and 1.47 (1.32-1.62).

Conclusions: Osilodrostat is a moderate inhibitor of CYP1A2 and CYP2C19 and a weak inhibitor of CYP2D6 and the most clinically important CYP enzyme, CYP3A4. Osilodrostat is unlikely to significantly increase the exposures of other medications cleared by CYP3A4. These findings are clinically relevant given that Cushing's disease is a chronic condition often requiring multiple medications and that most other therapies have significant drug interaction potential.
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http://dx.doi.org/10.1007/s40261-017-0497-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394143PMC
May 2017

Utility of Exposure-Response Analysis in Regulatory Decision on the Selection of Starting Dose of Pasireotide for Cushing Disease.

J Clin Pharmacol 2016 08 10;56(8):1035-8. Epub 2016 Feb 10.

Division of Pharmacometrics, Office of Clinical Pharmacology, Food and Drug Administration, Silver Spring, MD, USA.

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http://dx.doi.org/10.1002/jcph.694DOI Listing
August 2016

Effects of enzastaurin and its metabolites on the QT interval in cancer patients.

J Clin Pharmacol 2016 Jan 17;56(1):101-8. Epub 2015 Aug 17.

Comprehensive Cancer Center and Biotrial, Rennes, France.

Preclinical and interim results from a clinical pharmacology study in patients with cancer indicated that enzastaurin might have the potential to prolong the QT. Rather than undertake a formal thorough QT study, the effect of enzastaurin on the QT was assessed by combining the QT corrected for heart rate (QTc) intervals from 3 clinical pharmacology studies totaling 85 patients with cancer receiving multiple therapeutic or supratherapeutic doses of enzastaurin. Neither a placebo nor an active control was used. Serial, replicate, time-matched electrocardiograms were collected during a no-drug baseline day and when enzastaurin and its major active metabolite, LSN326020, had achieved steady state. Plasma concentrations of enzastaurin and LSN326020 were determined at each electrocardiogram point to enable concentration-QT analyses. The cross-study analysis showed that enzastaurin resulted in a statistically significant prolongation of the QTc at therapeutic and supratherapeutic doses. At an enzastaurin maximum plasma concentration (Cmax ) of 3660 nmol/L, the predicted QTc using Fridericia's formula (QTcF) interval and its 90% confidence interval was 17.72 milliseconds (16.52-18.92 milliseconds). Likewise, at an LSN326020 Cmax value of 1718 nmol/L, the predicted QTcF interval was 20.23 milliseconds (18.72-21.74 milliseconds). The concentration-QTcF slopes for enzastaurin and LSN326020 were positive and statistically significantly different from zero (all P < .05).
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http://dx.doi.org/10.1002/jcph.573DOI Listing
January 2016

Pharmacokinetics and safety of subcutaneous pasireotide and intramuscular pasireotide long-acting release in Chinese male healthy volunteers: a phase I, single-center, open-label, randomized study.

Clin Ther 2014 Aug 8;36(8):1196-210. Epub 2014 Jul 8.

Clinical Pharmacology Research Centre, Peking Union Medical College Hospital, Beijing, China. Electronic address:

Purpose: The purpose of this study was to assess the pharmacokinetic (PK) properties and safety of single and multiple doses of subcutaneous (SC) pasireotide and a single-dose intramuscular (IM) long-acting release (LAR) formulation of pasireotide in Chinese healthy volunteers (HVs) versus the PK properties in Western HVs (pooled from previous PK studies).

Methods: In this phase I, single-center, open-label study, 45 Chinese male HVs were evenly randomized to 1 to 9 treatment sequences: each volunteer received a single dose of 300, 600, or 900 μg of pasireotide SC on day 1, followed by administration of the same dose BID from day 15 to the morning of day 19, and then a single IM dose of 20, 40, or 60 mg of pasireotide LAR on day 33. The PK parameters were assessed with noncompartmental analysis. Statistical comparison of PK parameters, including AUC, Cmax, and CL/F from both formulations, was made for Chinese versus Western male HVs. The safety profile was also assessed. Metabolic parameters, including blood glucose, insulin, and glucagon, and measures that reflect the effects of pasireotide LAR on relatively long-term glucose control, lipid metabolism, and systemic concentrations of pancreatic enzymes and thyrotropin were evaluated.

Findings: Of the 45 randomized HVs, 42 completed the study per protocol, 1 withdrew his informed consent for personal reasons, and 2 prematurely discontinued the study because of adverse events (AEs). Concentration-time and safety profiles of both formulations were similar to those reported in Western HVs. Mean geometric mean ratios (GMRs) of Chinese versus Western HVs ranged from 0.79 to 1.42. For most primary PK parameters, 90% CIs for GMRs were within a predefined ethnic insensitivity interval (90% CI, 0.70-1.43). After considering age and weight as covariates in the statistical model, the GMRs and 90% CIs for other PK parameters were within the predefined interval (Cmax in single-dose SC administration) or significantly decreased (Cmin,ss in multiple BID SC doses and first peak Cmax in the single-dose LAR formulation). No serious AEs were reported. Both formulations were well tolerated; pasireotide SC caused transient changes in glucose metabolism. Owing to the differential binding affinity to the somatostatin receptor subtypes, pasireotide LAR elicited a concentration-dependent increase of fasting blood glucose, substantial reduction in triglyceride, and a mild decrease in cholesterol. The most frequently reported AEs after single-dose and multiple-dose pasireotide SC were injection site reaction, nausea, dizziness, and diarrhea; most HVs developed diarrhea with single-dose pasireotide LAR.

Implications: The pasireotide formulations had similar PK and safety profiles between Chinese and Western male HVs. Thus, no ethnic sensitivity was found for pasireotide SC or LAR.
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http://dx.doi.org/10.1016/j.clinthera.2014.06.006DOI Listing
August 2014

Management of hyperglycemia associated with pasireotide (SOM230): healthy volunteer study.

Diabetes Res Clin Pract 2014 Mar 25;103(3):458-65. Epub 2013 Dec 25.

Early Phase Clinical Unit - Berlin, Parexel International GmbH, Klinikum Westend - Haus 18, Spandauer Damm 130, 14050 Berlin, Germany. Electronic address:

Aims: Pasireotide, a multireceptor-targeted somatostatin analogue with efficacy in Cushing's disease and acromegaly, can affect glucose metabolism due to inhibition of insulin secretion and incretin hormone responses. A study was therefore conducted to evaluate different antihyperglycemic drugs in the management of pasireotide-associated hyperglycemia.

Methods: This was a 1-week, Phase I, open-label study. Healthy male volunteers were randomized to pasireotide 600 μg sc bid alone or co-administered with metformin 500 mg po bid, nateglinide 60 mg po tid, vildagliptin 50mg po bid, or liraglutide 0.6 mg sc qd. An oral glucose tolerance test (OGTT) was performed on days 1 and 7 to evaluate effects on serum insulin, plasma glucose and glucagon levels. Safety/tolerability and pharmacokinetic effects were also evaluated.

Results: Ninety healthy male volunteers were enrolled (n=18 per arm). After 7 days of treatment, plasma glucose AUC post-OGTT increased by 69% with pasireotide alone. The effect was reduced by 13%, 29%, 45% and 72% with co-administration of metformin, nateglinide, vildagliptin and liraglutide, respectively. On day 7, compared with pasireotide alone, the decrease in serum insulin was attenuated with nateglinide, metformin, liraglutide and vildagliptin co-administration (levels were 3%, 6%, 34% and 71% higher, respectively). Minimal changes in plasma glucagon were observed. Adverse events were consistent with the safety profiles of the drugs used.

Conclusions: Vildagliptin and liraglutide were most effective in minimizing pasireotide-associated hyperglycemia in healthy volunteers.
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http://dx.doi.org/10.1016/j.diabres.2013.12.011DOI Listing
March 2014

Effects of Subcutaneous Pasireotide on Cardiac Repolarization in Healthy Volunteers: a Single‐Center, Phase I, Randomized, Four‐Way Crossover Study.

J Clin Pharmacol 2014 Jan;54(1):75-86

The aim of this study was to evaluate the effects of subcutaneous pasireotide on cardiac repolarization in healthy volunteers. Healthy volunteers were randomized to one of four treatment sequences (n = 112) involving four successive treatments in different order: pasireotide 600 µg (therapeutic dose) or 1,950 µg (maximum tolerated dose) bid by subcutaneous injection (sc), placebo injection and oral moxifloxacin. Maximum ΔΔQTcI occurred 2 hours post-dose for both doses of pasireotide. Mean ΔΔQTcI was 13.2 milliseconds (90% CI: 11.4, 15.0) and 16.1 milliseconds (90% CI: 14.3, 17.9) for the 600 and 1,950 µg bid doses, respectively. Maximal placebo-subtracted change in QTcI from baseline for moxifloxacin was 11.1 (90% CI: 9.3, 12.9) milliseconds. Both pasireotide doses caused a reduction in heart rate: maximal heart rate change compared with placebo occurred at 1 hour for pasireotide 600 µg bid and at 0.5 hours for pasireotide 1,950 µg bid, with heart rate reductions of 10.4 and 14.9 bpm, respectively. At the therapeutic dose of 600 µg, pasireotide has a modest QT-prolonging effect. The relatively small increase of ∼3 milliseconds in ΔΔQTcI in the presence of a 3.25-fold increase in dose suggests a relatively flat dose–effect relationship of pasireotide on ΔΔQTcI in healthy volunteers. No safety concerns for pasireotide were identified during the study.
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http://dx.doi.org/10.1002/jcph.213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272414PMC
January 2014

Multiple once-daily subcutaneous doses of pasireotide were well tolerated in healthy male volunteers: a randomized, double-blind, placebo-controlled, cross-over, Phase I study.

Endocrine 2012 Oct 21;42(2):366-74. Epub 2012 Apr 21.

Division of Gastroenterology, University Hospital Basel, Basel, Switzerland.

A randomized, double-blind, placebo-controlled, cross-over, dose-escalating, single-center study was conducted to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple once-daily (qd) subcutaneous (sc) doses of pasireotide in healthy male subjects. Subjects received pasireotide 50, 200, or 600 μg sc qd for 14 days and placebo in separate sequences. Thirty-three subjects were randomized. The most frequently reported drug-related adverse events were injection-site reactions (n = 18), diarrhea (n = 14) and nausea (n = 10), which were mostly mild or moderate in intensity. Pasireotide 600 μg sc was associated with pre- and post-prandial elevations in glucose levels relative to placebo; however, this effect was less pronounced on day 14 compared with day 1. PK steady state appeared to be achieved after 3 days of dosing and PK exposures had a moderate accumulation of 20-40 % across doses. Pasireotide demonstrated fast absorption (T(max,ss): 0.25-0.5 h), low clearance (CL/F(ss): 8.10-9.03 L/h), long effective half-life (T(½,eff): ~12 h, on average between 9.7 and 13.1 h for 50, 200, and 600 μg sc qd), and large volume of distribution (V(z)/F(ss): 251-1,091 L) at steady state. Dose proportionality was confirmed for C(max,ss); other PK parameters (C(max), AUC(0-24 h) and AUC(tau)) were approximately dose proportional. Growth hormone inhibition was observed with pasireotide 200 and 600 μg sc qd. Gallbladder volume increased post-prandially with pasireotide 200 and 600 μg sc qd, which appeared to correlate with reduced levels of cholecystokinin at these doses. Pasireotide was generally well tolerated up to the tested dose of 600 μg qd, with a linear and time-independent PK profile after sc qd dosing in healthy subjects.
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http://dx.doi.org/10.1007/s12020-012-9668-1DOI Listing
October 2012

Carboplatin and paclitaxel in combination with oral enzastaurin in advanced ovarian or primary peritoneal cancer: results from a safety lead-in study.

Int J Gynecol Cancer 2009 Dec;19(9):1505-10

Department of Gynaecological Oncology, Division Obstetrics and Gynaecology, University Hospitals Leuven, Leuven, Belgium.

Introduction: This safety lead-in study examined the pharmacokinetic and adverse event profile of combining enzastaurin with paclitaxel plus carboplatin as first-line therapy for the treatment of advanced-stage ovarian cancer and primary peritoneal carcinoma. The specific objectives of this study were to assess safety and tolerability after 2 cycles of treatment, to determine if enzastaurin alters paclitaxel and carboplatin pharmacokinetics, and to determine if enzastaurin pharmacokinetics is affected by paclitaxel and carboplatin.

Methods: After debulking surgery, patients with previously untreated epithelial ovarian or primary peritoneal carcinoma received sequential paclitaxel (175 mg/m) and carboplatin (area under the curve, 5 mg x min/mL) on day 1 every 3 weeks for 6 cycles. Patients ingested an oral loading dose of 1125 mg enzastaurin on day 4 of cycle 1, followed by oral 500-mg enzastaurin daily until the end of therapy. Adverse events were graded according to the Common Terminology Criteria for Adverse Events v3.0.

Results: There were 5 serious adverse events in 4 of 11 patients: soft tissue injury, wound infection, intestinal fistula, clostridial infection, and anemia. Coadministration with enzastaurin did not significantly alter paclitaxel and carboplatin pharmacokinetics (area under the curve ratio of treatment comparison asymptotically equal to 1.05 and 1.06, respectively). Enzastaurin exposures were unchanged (Cav,ss ratio of treatment comparison asymptotically equal to 0.95 for average steady-state total analyte concentrations of enzastaurin and its metabolite).

Conclusions: Adding enzastaurin to paclitaxel plus carboplatin chemotherapy is feasible for advanced ovarian cancer after radical cytoreduction. Enzastaurin did not alter paclitaxel or carboplatin pharmacokinetics, and enzastaurin exposures were not significantly changed by carboplatin and paclitaxel.
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http://dx.doi.org/10.1111/IGC.0b013e3181bda1a7DOI Listing
December 2009

Evaluation of biomarkers for pharmacological activity.

J Biopharm Stat 2009 ;19(2):256-72

Center for Statistics, Hasselt University, Diepenbeek, Belgium.

In recent years the cost of drug development has increased the demands on efficiency in the selection of suitable drug candidates. Biomarkers for efficacy and safety could be a plausible strategy to improve this selection process. In the present work, we focus on the study and evaluation of different physiological variables as biomarkers for pharmacological activity. We proposed three different approaches using multivariate and univariate techniques. We note that even though one could argue that the multivariate procedure is more powerful than the other alternatives, the univariate methods also offer a great flexibility to answer interesting scientific questions. The three approaches were used to analyze a crossover study involving an opioid antagonist.
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http://dx.doi.org/10.1080/10543400802622386DOI Listing
June 2009

Pharmacokinetic evaluation of platinum derived from cisplatin administered alone and with pemetrexed in head and neck cancer patients.

Cancer Chemother Pharmacol 2009 Jul 15;64(2):233-41. Epub 2008 Nov 15.

Department of Medical Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650, Edegem, Belgium.

Purpose: This phase I study characterized the pharmacokinetics of free and total platinum derived from cisplatin administered alone and in combination with pemetrexed. Secondary objectives were to assess the pharmacokinetics of pemetrexed when it is combined with cisplatin as well as to evaluate the safety profile and document antitumor activity associated with this combination.

Methods: An open-label, two-arm, cross-over phase 1 study was performed in patients with squamous cell carcinoma of the head and neck, age > or =18 years, an Eastern Cooperative Oncology Group performance status of 0-2, and adequate organ function. Blood samples were taken and pharmacokinetics evaluated for the first two cycles using noncompartmental analysis. Patients received either pemetrexed (500 mg m(-2)) plus cisplatin (75 mg m(-2)) administered in cycle 1 followed by cisplatin alone in cycle 2; or in the reverse order (i.e., cisplatin alone in cycle 1 followed by pemetrexed plus cisplatin in cycle 2). Each treatment cycle was 21 days and patients received folic acid, vitamin B(12) supplementation, and dexamethasone prophylaxis. After the first two cycles, patients continued study treatment with pemetrexed plus cisplatin every 3 weeks up to a maximum of six total treatment cycles. Toxicities were graded by the investigators according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 3.0.

Results: A total of 13 patients were treated; one patient was discontinued from the study after cycle 1 for failure to meet baseline eligibility criteria for renal function. The ratios and 90% confidence intervals (CI) comparing the pharmacokinetics for cisplatin administered with pemetrexed to those for cisplatin administered alone for free platinum were: C(max) = 1.08 (CI: 0.92, 1.27) and AUC = 0.93 (CI: 0.82, 1.06); and, total platinum were: C(max) = 0.97 (CI: 0.88, 1.06) and AUC = 0.87 (CI: 0.81, 0.93). These results indicate that platinum pharmacokinetics (free and total) are similar, whether cisplatin is administered alone or combined with pemetrexed. The pemetrexed pharmacokinetic results were consistent with those from previous single-agent pemetrexed studies and a previous study of pemetrexed in combination with cisplatin. The combination of pemetrexed and cisplatin did not show any unexpected toxicities. Consistent with the platinum pharmacokinetic results, co-administration with pemetrexed did not appear to enhance cisplatin-related toxicities. Of the 13 treated patients, 11 had stable disease as the best overall response and 2 had progressive disease.

Conclusions: The pharmacokinetics of free platinum derived from cisplatin were not altered by co-administration with pemetrexed, and in agreement with this, no unexpected cisplatin-induced toxicities were observed when these drugs were combined.
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http://dx.doi.org/10.1007/s00280-008-0853-0DOI Listing
July 2009

Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects.

J Clin Pharmacol 2008 May 27;48(5):610-8. Epub 2008 Feb 27.

Lilly Research Laboratories, Lilly Corporate Center, DC 0730, Indianapolis, IN 46285, USA.

Tadalafil, an oral phosphodiesterase 5 (PDE5) inhibitor, is being investigated as a treatment for pulmonary arterial hypertension. Bosentan is an oral endothelin receptor antagonist widely used in the treatment of pulmonary arterial hypertension. Tadalafil is mainly metabolized by cytochrome P450 (CYP) 3A4, and as bosentan induces CYP2C9 and CYP3A4, a pharmacokinetic interaction is possible between these agents. This open-label, randomized study investigated whether any pharmacokinetic interaction exists between tadalafil and bosentan. Healthy adult men (n = 15; 19-52 years of age) received 10 consecutive days of tadalafil 40 mg once daily, bosentan 125 mg twice daily, and a combination of both in a 3-period, crossover design. Following 10 days of multiple-dose coadministration of bosentan and tadalafil, compared with tadalafil alone, tadalafil geometric mean ratios (90% confidence interval [CI]) for AUCtau and Cmax were 0.59 (0.55, 0.62) and 0.73 (0.68, 0.79), respectively, with no observed change in tmax. Following coadministration of bosentan with tadalafil, bosentan ratios (90% CI) for AUCtau and Cmax were 1.13 (1.02, 1.24) and 1.20 (1.05, 1.36), respectively. Tadalafil alone and combined with bosentan was generally well tolerated. In conclusion, after 10 days of coadministration, bosentan decreased tadalafil exposure by 41.5% with minimal and clinically irrelevant differences (<20%) in bosentan exposure.
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http://dx.doi.org/10.1177/0091270008315315DOI Listing
May 2008

A phase I safety, tolerability, and pharmacokinetic study of enzastaurin combined with capecitabine in patients with advanced solid tumors.

Anticancer Drugs 2008 Jan;19(1):77-84

Division of Medical Oncology, University of Colorado Cancer Center, Aurora, Colorado 80045, USA.

Enzastaurin, an oral inhibitor of protein kinase Cbeta, affects signal transduction associated with angiogenesis, proliferation, and survival. Capecitabine is converted to 5-fluoruracil by thymidine phosphorylase, a putative angiogenic factor. The all-oral combination of the two drugs offers the potential for targeting angiogenesis in capecitabine-sensitive tumors with nonoverlapping toxicities. Patients with advanced cancer initially received single-agent enzastaurin to achieve steady-state concentrations (cycle 1). In subsequent 21-day cycles, enzastaurin was given orally, once daily, on days 1-21 and capecitabine orally, twice daily (b.i.d.), on days 1-14 in three dose-level cohorts. Three dose-escalation cohorts were studied: cohort 1 (n=8), 350 mg of enzastaurin +capecitabine (750 mg/m2 b.i.d.); cohort 2 (n=7), enzastaurin (350 mg)+capecitabine (1000 mg/m2 b.i.d.); cohort 3 (n=12), 525-mg capsules or 500-mg enzastaurin+capecitabine (1000 mg/m2 b.i.d.). Further dose escalation was not pursued because of emerging data that enzastaurin systemic exposure did not increase at doses above 525 mg. Although a traditional toxicity-based maximum tolerated dose was not achieved, the highest dosing cohort represented a biologically relevant dose of enzastaurin, on the basis of preclinical data and correlative pharmacodynamic biomarker assays of protein kinase Cbeta inhibition in peripheral blood mononucleocytes, in combination with a standard dose of capecitabine. For the 500/525-mg dose, ratios of total enzastaurin analyte geometric means (i.e. enzastaurin alone versus enzastaurin with capecitabine) reflected a trend toward decreased enzastaurin exposure, but did not reach statistical significance. The pharmacokinetic parameters of capecitabine with enzastaurin were similar to those previously reported for single-agent capecitabine. The regimen was well tolerated, without any consistent pattern of drug-related grade 3 or grade 4 toxicities being observed. Although no objective tumor responses were documented, five patients maintained stable disease for >or=6 months (range: 6-9.7 months). The recommended phase II dose of this combination, based on the results of this study, is enzastaurin at a daily dose of 500 mg (tablet formulation) and capecitabine (1000 mg/m2, b.i.d.) on days 1-14 every 21 days. Further disease-directed studies are warranted, such as in malignancies in the treatment of which both capecitabine and inhibitors of angiogenesis have previously been benchmarked as being effective.
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http://dx.doi.org/10.1097/CAD.0b013e3282f077b3DOI Listing
January 2008

Hemodynamic interaction between a daily dosed phosphodiesterase 5 inhibitor, tadalafil, and the alpha-adrenergic blockers, doxazosin and tamsulosin, in middle-aged healthy male subjects.

J Clin Pharmacol 2007 Oct;47(10):1303-10

Aster-Cephac, Paris, France.

The hemodynamic interaction between tadalafil (5 mg/d) and doxazosin or tamsulosin was investigated in 2 randomized, double-blind, crossover phase 1 studies. Healthy men (n = 45) received tadalafil or placebo for 28 days and increasing doses of doxazosin (1, 2, and 4 mg/d) for the last 21 days of treatment. In the second study, participants (n = 39) received tadalafil or placebo for 14 days and tamsulosin (0.4 mg/d) for the last 7 days of treatment. Similar mean maximum postbaseline changes in standing systolic blood pressure were observed in subjects given tadalafil or placebo with 4 mg of doxazosin (-0.5 mm Hg; 95% confidence interval, -4 to 3.1 mm Hg) or with tamsulosin (0.9 mm Hg; 95% confidence interval, -1.4 to 3.2 mm Hg). Standing systolic blood pressure less than 85 mm Hg (blood pressure outlier) occurred in 1 subject treated with 4 mg of doxazosin plus tadalafil but was not reported in subjects treated with tamsulosin and tadalafil. Three subjects experienced moderate hypotensive events lasting less than 2 hours, 2 with syncope (after tadalafil alone or with 4 mg of doxazosin) and 1 without (after 4 mg of doxazosin with placebo). The incidence of hypotension was low in healthy men given increasing doses of doxazosin with chronically dosed tadalafil or placebo. Administration of tadalafil with tamsulosin was well tolerated in healthy men.
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http://dx.doi.org/10.1177/0091270007306559DOI Listing
October 2007

Safety, tolerability, QTc evaluation, and pharmacokinetics of single and multiple doses of enzastaurin HCl (LY317615), a protein kinase C-beta inhibitor, in healthy subjects.

J Clin Pharmacol 2007 Sep;47(9):1138-51

Eli Lilly and Company, Lilly Corporate Center DC 0734, Indianapolis, IN 46285, USA.

The safety, tolerability, and pharmacokinetics of orally administered enzastaurin were evaluated in 2 placebo-controlled, dose escalation studies in healthy subjects. In the first human dose study, single doses (2-400 mg) were evaluated, with 22 subjects receiving enzastaurin. The mean half-lives of enzastaurin and its metabolites ranged from approximately 12 to 40 hours. The longer half-life of the major circulating and pharmacologically active metabolite allowed once-a-day dosing and predicted that steady state would be achieved within 2 weeks of daily oral dosing in all subjects. In the multiple-dose study, daily doses (25-400 mg) were examined, with 24 subjects receiving at least 1 dose. The most common adverse events related to enzastaurin were headache, sleepiness, diarrhea, and nausea. No clinically significant changes in QTc intervals were observed. Overall, enzastaurin was well tolerated in healthy subjects, and the planned maximum dose was achieved in both studies.
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http://dx.doi.org/10.1177/0091270007304775DOI Listing
September 2007

Phase II study of enzastaurin, a protein kinase C beta inhibitor, in patients with relapsed or refractory diffuse large B-cell lymphoma.

J Clin Oncol 2007 May 26;25(13):1741-6. Epub 2007 Mar 26.

Indiana University Medical Center, Indianapolis, IN, USA.

Purpose: Protein kinase C beta (PKCbeta) was identified by gene-expression profiling, preclinical evaluation, and independent immunohistochemical analysis as a rational therapeutic target in diffuse large B-cell lymphoma (DLBCL). We conducted a multicenter phase II study of a potent inhibitor of PKCbeta, enzastaurin, in patients with relapsed or refractory DLBCL.

Patients And Methods: Enzastaurin was taken orally once daily until disease progression or unacceptable toxicity occurred. Study end points included freedom from progression (FFP) for > or= two cycles (one cycle = 28 days), objective response, and toxicity.

Results: Fifty-five patients (median age, 68 years) were enrolled. Patients had received a median number of two prior therapies (range, one to five); six patients relapsed after high-dose therapy and autologous stem-cell transplantation. Only one grade 4 toxicity (hypomagnesemia) occurred. Grade 3 toxicities included fatigue (n = 2), edema (n = 1), headache (n = 1), motor neuropathy (n = 1), and thrombocytopenia (n = 1). No grade 3 or 4 neutropenia occurred. No deaths or discontinuations due to toxicity were reported. Fifteen patients completed less than one cycle of therapy. Twelve of 55 patients (22%; 95% CI, 13% to 46%) experienced FFP for two cycles, and eight patients remained free from progression for four cycles (15%; 95% CI, 6% to 27%). Four patients (7%; 95% CI, 2% to 18%), including three complete responders and one patient with stable disease, continue to experience FFP 20+ to 50+ months after study entry.

Conclusion: Treatment with enzastaurin was well-tolerated and associated with prolonged FFP in a small subset of patients with relapsed or refractory DLBCL. Further studies of enzastaurin in DLBCL are warranted.
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http://dx.doi.org/10.1200/JCO.2006.09.3146DOI Listing
May 2007

Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease.

Eur Heart J 2006 May 18;27(10):1166-73. Epub 2006 Apr 18.

Department of Medical Sciences, Cardiology and Uppsala Clinical Research Center, University Hospital, 751 85 Uppsala, Sweden.

Aims: This study was designed to compare the degree of inhibition of platelet aggregation (IPA) of prasugrel with that of clopidogrel in stable aspirin-treated patients with coronary artery disease (CAD).

Methods And Results: Subjects (n=101) were randomly assigned to the following loading dose (LD) (day 1)/maintenance dose (MD) (days 2-28) combinations: prasugrel, 40 mg/5 mg; 40 mg/7.5 mg; 60 mg/10 mg; 60 mg/15 mg; or clopidogrel, 300 mg/75 mg. Turbidometric platelet aggregation was measured at multiple timepoints during the study. At 4 h after dosing, with 20 microM ADP, both prasugrel LDs achieved significantly higher mean IPA levels (60.6% and 68.4 vs. 30.0%, respectively; all P<0.0001) and lower percentage (3 vs. 52%, P<0.0001) of pharmacodynamic non-responders (defined as IPA <20%) than clopidogrel. Prasugrel 10 and 15 mg MDs achieved consistently higher mean IPA than clopidogrel 75 mg at day 28 (all P<0.0001). At pre-MD on day 28, there were no non-responders in the 10 and 15 mg prasugrel group, compared with 45% in the clopidogrel group (P=0.0007).

Conclusion: In this population, prasugrel (40-60 mg LD and 10-15 mg MD) achieves greater IPA and a lower proportion of pharmacodynamic non-responders compared with the approved clopidogrel dosing.
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http://dx.doi.org/10.1093/eurheartj/ehi877DOI Listing
May 2006

Obesity does not alter the pharmacokinetics of drotrecogin alfa (activated) in severe sepsis.

Ann Pharmacother 2005 Feb 4;39(2):262-7. Epub 2005 Jan 4.

Acute Care, US Medical Division, Eli Lilly and Company, Indianapolis, IN 46285, USA.

Background: Drotrecogin alfa (activated) [DrotAA] is approved for the reduction of mortality in adults with severe sepsis (sepsis with acute organ dysfunction) and high risk of death. Patients whose actual body weight was >135 kg were excluded from the Phase III PROWESS trial.

Objective: To compare exposure to DrotAA in patients with severe sepsis weighing >135 kg with those weighing < or =135 kg in an open-label, Phase IV trial, and quantify the elimination half-life (t1/2) of DrotAA in these patients.

Methods: PROWESS inclusion/exclusion criteria were used, except that patients >135 kg were enrolled. Blood samples were collected for steady-state plasma concentration (Css) analysis of activated protein C once each day and for t1/2 analysis after infusion. Weight-normalized clearance (Clp) and t1/2 estimates for DrotAA were calculated and compared between weight groups.

Results: Patient weight range was 59-227 kg. There were 32 patients < or =135 kg and 20 patients >135 kg enrolled. Median Clp was 0.45 L/h/kg (interquartile range [IQR] 0.37-0.54) for patients < or =135 kg and 0.42 L/h/kg (IQR 0.33-0.54) for patients >135 kg (p = 0.692). Median estimates of Css were 51.9 ng/mL (IQR 43.4-62.0) and 56.5 ng/mL (IQR 44.9-71.1; p = 0.570). In patients < or =135 kg, DrotAA had a median t1/2 of 16.7 minutes (IQR 13.9-20.0) compared with 16.0 minutes (IQR 12.9-19.8) in patients >135 kg (p = 0.767), for a composite median t1/2 of 16.3 minutes (IQR 14.2-18.8).

Conclusions: There is no statistically significant difference in Css concentrations or t1/2 of DrotAA between patients weighing < or =135 kg and >135 kg. DrotAA should be dosed by actual body weight.
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http://dx.doi.org/10.1345/aph.1E386DOI Listing
February 2005