Christelle Darstein

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

AIMS Pasireotide, a multireceptor-targeted somatostatin analogue with efficacy in Cushings 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 single‐center, phase I, randomized, four‐way 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 dose–effect relationship of pasireotide on ΔΔQTcI in healthy volunteers. No safety concerns for pasireotide were identified during the study.

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

In 2012 the FDAapproved pasireotide (a cyclohexapeptide analogue of endogenous somatostatin) for the treatment of adult patients with Cushing disease for whom pituitary surgery is not an option or has not been curative.1 The recommended initial dosage is either 600 μg twice a day (BID) or 900 μg BID by subcutaneous injection (the calculated effective halflife was approximately 12 hours).2 Cushing disease is a rare disease that is caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma and most commonly affects adult females. The elevated levels of ACTH secreted by pituitary tumors stimulate the adrenal glands to produce excess cortisol, thereby causing the subsequent development of the clinical signs and symptoms of hypercortisolism. It is estimated that currently there are about 40,000 patients with Cushing disease: United States ( 16,848), Japan ( 6,604), France, Germany, Italy, Spain, and the United Kingdom ( 16,120 in the EU).3 Adult patients (n = 162) with Cushing disease were randomized (1:1) to 2 treatment arms (2 doses: 600 μg BID and 900 μg BID) in the phase 3 pivotal study.4 There was no placebo arm included in the registration trial. The primary analysis was to compare each group’s response rate, defined as the proportion of patients with normalizedmean urinary free cortisol (mUFC) (ie, mUFC ULN [upper limit of normal, 145 nmol/day]) at the end of 6 months with a prespecified threshold of 15%. The magnitude of this threshold was primarily selected on the basis of clinical practice experience that a response rate >15% would represent a clinically meaningful improvement in Cushing disease.5 The 900-μg BID dose met the primary efficacy criterion with a response rate of 26% and a lower bound of the 2-sided 95% confidence interval (CI) of 17%, above the prespecified 15% threshold. The 600-μg BID dose did not meet the primary efficacy criterion with a response rate of 15% and a lower bound of the 2-sided 95%CI of 7%, below the prespecified 15% threshold. This would usually be particularly convincing evidence to recommend the approval of 900 μg BID only, despite the fact that the study was not designed to detect a statistical difference in efficacy between the 2 doses. However, despite randomization, the 2 dose groups were not balanced with respect to the baseline prognostic factor (ie, mUFC): the mean values of mUFC at baseline for the 600and 900-μg BID groups were 8.0 and 5.4 × ULN, respectively.4 More importantly, this phase 3 study documented a substantial elevation in glycated hemoglobin (HbA1c) levels (approximately 1.5% mean absolute increase on treatment from baseline) that occurred early and continued throughout the duration of the study.5 This finding is of particular concern because hyperglycemia is a known complication of hypercortisolism, and one of the goals of treating Cushing disease is to improve

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.

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 Fridericias 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).