A single administration of recombinant human interleukin-12 is associated with increased expression levels of interferon-gamma and signal transducer and activator of transcription in healthy subjects.

The objectives of this study were to assess the safety and tolerability of single doses of 1, 4, and 8 mug of recombinant human interleukin-12 (rhIL-12) administered subcutaneously to healthy subjects. The pharmacokinetics, pharmacodynamics, and pharmacogenomics of rhIL-12 were evaluated. Recombinant human IL-12 was well tolerated in these healthy male and female subjects. The most frequently reported adverse events were flu-like symptoms, which exhibited a dose-response relationship. Pharmacokinetic analysis suggested that serum IL-12 levels increased with dose. Analysis of serum levels indicated that interferon-gamma increased with the dose of rhIL-12, whereas IL-6 levels showed no changes with rhIL-12 treatment. The messenger ribonucleic acid expression of signal transducer and activator of transcription was significantly increased 24 hours after the administration of rhIL-12 for all dose groups versus placebo, and results indicated that the magnitude of increase may be dose dependent. This study suggests that interferon-gamma and signal transducer and activator of transcription are biomarkers of rhIL-12 activity.

The antiparasitic moxidectin: safety, tolerability, and pharmacokinetics in humans.

A study in healthy male volunteers was completed to evaluate the safety, tolerability, and pharmacokinetics of a single oral dose of the antiparasitic moxidectin (MOX). This drug is registered worldwide as a veterinary antiparasitic agent for use in companion and farm animals. This is the first study of MOX in humans. All subjects were between the ages of 18 and 45 years, with normal cardiac, hematologic, hepatic, and renal function. Doses of MOX studied were 3, 9, 18, and 36 mg in cohorts of 6 subjects each (5:1, MOX:placebo). At the 9-mg and 36-mg doses, two separate cohorts were completed, one in the fasted state and one after the consumption of a high-fat breakfast. For all other cohorts, administration was in the fasted state. Safety and tolerability were assessed by physical examinations, ongoing evaluation of adverse events (AEs), and measurement of laboratory values. Pharmacokinetic (PK) samples were collected just prior to dosing and at various time points until 80 days postdose. Safety assessments from all dose groups studied suggested that MOX was generally safe and well tolerated, with a slightly higher incidence of transient, mild, and moderate central nervous system AEs as the dose increased as compared to placebo. The PKs of MOX were dose proportional within the dose range studied, and the elimination half-life (t1/2 elim) was long (mean: 20.2-35.1 days). At the 9-mg and 36-mg doses, a high-fat breakfast was shown to delay and increase the overall absorption but did not increase maximal concentrations when compared to administration in the fasted state. In summary, the results from this study indicate that MOX is safe and well tolerated in humans between the doses of 3 mg and 36 mg.

Multiple-dose, safety, pharmacokinetics, and pharmacodynamics of a new selective estrogen receptor modulator, ERA-923, in healthy postmenopausal women.

ERA-923 is a new selective estrogen receptor modulator under clinical investigation for use in tamoxifen refractory metastatic breast cancer. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of once-daily oral ERA-923 (10-200 mg) for 28 days in healthy postmenopausal females. ERA-923 was well tolerated, and adverse events were mild and reversible. No clinically significant changes in laboratory values were found with ERA-923 versus placebo. ERA-923 appeared to undergo extensive metabolism and enterohepatic recirculation. In addition, pharmacokinetic analysis showed that a high-fat breakfast increased the extent of absorption. ERA-923-dosed subjects had no uterine or ovarian changes when evaluated with transvaginal ultrasound and compared to placebo subjects. Overall, ERA-923 was safe and well tolerated in postmenopausal women dosed for 28 days.

Electrocardiographic and cardiovascular diagnostic characteristics of patients receiving long-term opioid therapy for pain.

OBJECTIVE: To examine cardiovascular and electrocardiogram (ECG) abnormalities seen in patients with chronic pain receiving long-term opioid therapy and to compare them with findings in normal subjects. SETTING: Clinical pharmaceutical drug trial in a phase I pharmacology unit (normal subjects) and multiple phase 2b study sites (pain patients). PATIENTS: Four hundred sixty-one pain patients with constipation due to long-term opioid therapy who were screened for a clinical trial of an investigational treatment for opioid-induced constipation. INTERVENTIONS: None; all data used in this study were obtained prior to drug treatment. MAIN OUTCOME MEASURES: This is a retrospective analysis of ECG abnormalities and clinical cardiovascular abnormalities in study participants compared with those in a normal reference group of 36,999 subjects. RESULTS: Numerical ECG values were modestly but not clinically significantly different in the pain patients requiring opioids (mean heart rate +1.5 BPM, PR +5.2 milliseconds, QRS -4.7 milliseconds, and QT corrected for heart rate using the Fridericia formula +7.2 milliseconds). The largest difference in ECG diagnoses between the two groups was a fivefold greater incidence of previous myocardial infarction in the pain patient group (4.1 percent vs 0.8 percent). In addition, 50 percent of the pain patient group had a clinical cardiovascular diagnosis. CONCLUSIONS: Patients with significant chronic pain requiring opioids have underlying clinical disorders that may be associated with abnormal cardiovascular physiology and ECGs. Clinicians who manage patients with chronic pain should be aware of the higher incidence of cardiovascular disease in this group.

A multiple-dose, safety, tolerability, pharmacokinetics and pharmacodynamic study of oral recombinant human interleukin-11 (oprelvekin).

A study in healthy men and women was performed to assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of orally administered recombinant human interleukin-11 (oprelvekin) (OAO). Four cohorts of 10 subjects each received 3, 5, 10 or 30 mg (8:2/OAO:placebo ratio), first as a single dose with a 7-day washout period, then 7 consecutive daily doses. Safety was assessed by ongoing evaluation of adverse events (AEs) and laboratory values. PK samples were collected on the first and last day of dose administration. The established effects of subcutaneous oprelvekin on C-reactive protein (CRP, upward arrow), platelet count (upward arrow), fibrinogen (upward arrow) and hemoglobin (downward arrow), were evaluated. PK analysis showed that most subjects (27/34, 79%) had undetectable serum levels of IL-11. PD measures showed no changes from baseline between any OAO group and the placebo group. Orally administered oprelvekin was safe and well tolerated at all doses. A total of five AEs (abdominal pain, diarrhea, headache, rhinitis, grade 3 alanine aminotransferase elevation) were reported across all groups. Evaluations of serum IL-11 levels indicate that OAO is not systemically absorbed at levels above the lower limit of the bioanalytic assay. These data in addition to the lack of effect on PD measures suggest that there is a decreased potential of systemic adverse events with OAO.