Use of Pharmacokinetic and Pharmacodynamic Data to Develop the CDK4/6 Inhibitor Ribociclib for Patients with Advanced Breast Cancer.

Ribociclib is an orally bioavailable, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor. CDK4/6 inhibition by ribociclib leads to retinoblastoma tumor suppressor protein (Rb) reactivation, thereby restoring Rb-mediated cell cycle arrest. Ribociclib is approved for the treatment of patients with hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2-) advanced breast cancer (ABC), at the dose of 600 mg once daily (QD) during cycles of 21 days on/7 days off, with optional dose reduction to 400 mg and 200 mg. Ribociclib is rapidly absorbed with a median time to reach maximum plasma concentration of 2.4 h, mean half-life of 32.0 h and oral bioavailability of 65.8% at 600 mg. It is eliminated mainly by hepatic metabolism (~ 84% of total elimination), mostly by cytochrome P450 (CYP) 3A4. Age, body weight, race, baseline Eastern Cooperative Oncology Group status, food, mild hepatic impairment, mild-to-moderate renal impairment, proton pump inhibitors, and combination partners (non-steroidal aromatase inhibitors or fulvestrant) have no clinically relevant impact on ribociclib exposure. Ribociclib inhibits CYP3A at 600 mg leading to increased exposure of CYP3A substrates. Strong CYP3A inhibitors or inducers increase or decrease, respectively, ribociclib exposure. Exposure-safety and exposure-efficacy analyses support the clinical benefit of the 600 mg QD starting dose, with potential individualized dose reductions to 400 mg and 200 mg for effective management of the adverse events neutropenia and QTcF interval prolongation, while maintaining efficacy, in patients with HR+/HER2- ABC. Overall, these clinical pharmacology data informed ribociclib dose justification and clinical development, as well as its prescribing information for clinical use in advanced breast cancer patients.

Quantitative Assessment of Ribociclib Exposure-Response Relationship to Justify Dose Regimen in Patients with Advanced Breast Cancer.

Ribociclib in combination with endocrine therapy (ET) is a globally approved treatment option for patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) and has demonstrated significantly improved overall survival (OS) in 3 phase 3 clinical trials. To justify the dose regimen and dose modification scheme for patients with ABC, the pharmacokinetic (PK), safety, and efficacy data of ribociclib were analyzed. The data of several phase 1-3 clinical studies were pooled and analyzed to characterize the relationship between exposure (dose or PK) and efficacy (progression-free survival (PFS), time to response, and OS) or safety (neutropenia and QT interval prolongation). The exposure-efficacy analysis showed no apparent relationship between ribociclib exposure and efficacy (PFS and OS), and efficacy analysis by dose reduction showed that patients with ABC continued to benefit from the treatment following dose reduction, supporting the starting dose of 600 mg as well as dose reductions to 400 and 200 mg. The exposure-safety analysis showed that neutropenia and QT prolongation are related to ribociclib exposure that can be effectively managed by individualized dose modification (dose reduction/interruption). Collective evidence from the exposure-response analyses for efficacy and safety support the use of ribociclib in combination with ET partners at the starting dose of 600 mg, and also the effectiveness of individualized dose reductions in managing safety, while maintaining efficacy, in patients with HR+/HER2- ABC. This analysis illustrates the utility of quantitative assessment in justifying dose selection and dose modification for oncology medicines.

Combination of pasireotide and octreotide: effects on GH and IGF-I secretion and glucose metabolism in healthy volunteers.

PURPOSE: To assess the pharmacokinetics, pharmacodynamics and tolerability of different doses of octreotide and pasireotide (subcutaneous [sc] and long-acting release [LAR]) when co-administered in healthy volunteers. METHODS: This was an exploratory, Phase I, single-centre study. Healthy adults were enrolled in a staggered approach into seven cohorts to receive octreotide and pasireotide (sc and LAR formulations), alone or in combination. Plasma drug concentrations, growth hormone (GH), insulin-like growth factor I (IGF-I), and plasma glucose were assessed at baseline, immediately after sc treatment, and 21 and 28 days after LAR treatment. RESULTS: Of 88 enrolled subjects, 52 and 82 participated in sc and LAR dosing phases, respectively. There were no relevant pharmacokinetic interactions between octreotide and pasireotide. In combination, pasireotide sc (150 µg) and octreotide sc (100/300 µg) resulted in numerically greater reductions in insulin levels and a higher incidence of AEs than either single agent; the rapid (within 1 h) increase in plasma glucose after pasireotide was delayed with combination treatment. Octreotide sc and pasireotide sc, alone or in combination, reduced IGF-I levels and led to undetectable GH levels in most subjects. During the LAR phase, addition of a low dose of pasireotide (5 mg) to a standard dose of octreotide (20 mg) resulted in an ~2-fold reduction in median IGF-I versus octreotide 20 mg 21 days post-dose; this effect was numerically greater than seen for pasireotide 20 mg alone. Peak plasma glucose was substantially lower after LAR than sc dosing. Interestingly, glucose levels were also numerically lower in the pasireotide 5 mg plus octreotide 20 mg group than for 20 mg of octreotide or pasireotide alone. AEs were less frequent after LAR than sc dosing. CONCLUSIONS: Combined low doses of pasireotide LAR (5 mg) and octreotide LAR (10-30 mg) provided greater suppression of IGF-I than either single agent and did not increase blood glucose or incidence of AEs versus either agent alone.

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

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.

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

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/m2. 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.

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

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).

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.

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.

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

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.

Effects of Subcutaneous Pasireotide on Cardiac Repolarization in Healthy Volunteers: a Single­Center, Phase I, Randomized, Four­Way Crossover Study.

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 dose­effect relationship of pasireotide on ΔΔQTcI in healthy volunteers. No safety concerns for pasireotide were identified during the study.

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.

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.

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

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.

Evaluation of biomarkers for pharmacological activity.

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.

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

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.

Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects.

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.

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

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.

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

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.

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

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.

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

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.

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.

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.