The Burden of the "False-Negatives" in Clinical Development: Analyses of Current and Alternative Scenarios and Corrective Measures.

The "false-negatives" of clinical development are the effective treatments wrongly determined ineffective. Statistical errors leading to "false-negatives" are larger than those leading to "false-positives," especially in typically underpowered early-phase trials. In addition, "false-negatives" are usually eliminated from further testing, thereby limiting the information available on them. We simulated the impact of early-phase power on economic productivity in three developmental scenarios. Scenario 1, representing the current status quo, assumed 50% statistical power at phase II and 90% at phase III. Scenario 2 assumed increased power (80%), and Scenario 3, increased stringency of alpha (1%) at phase II. Scenario 2 led, on average, to a 60.4% increase in productivity and 52.4% increase in profit. Scenario 3 had no meaningful advantages. Our results suggest that additional costs incurred by increasing the power of phase II studies are offset by the increase in productivity. We discuss the implications of our results and propose corrective measures.

Intra-Target Microdosing - A Novel Drug Development Approach: Proof of Concept, Safety, and Feasibility Study in Humans.

Intra-Target Microdosing (ITM) is a novel drug development approach aimed at increasing the efficiency of first-in-human (FIH) testing of new molecular entities (NMEs). ITM combines intra-target drug delivery and "microdosing," the subpharmacological systemic exposure. We hypothesized that when the target tissue is small (about 1/100th of total body mass), ITM can lead to target therapeutic-level exposure with minimal (microdose) systemic exposure. Each of five healthy male volunteers received insulin microdose into the radial artery or full therapeutic dose intravenously in separate visits. Insulin and glucose levels were similar between systemic administration and ITM administration in the ipsilateral hand, and glucose levels demonstrated a reduction in the ipsilateral hand but not in the contralateral hand. Positron emission tomography (PET) imaging of 18 F-fluorodeoxyglucose (FDG) uptake demonstrated differences between the ipsilateral and contralateral arms. The procedures were safe and well-tolerated. Results are consistent with ITM proof-of-concept (POC) and demonstrate the ethical, regulatory, and logistical feasibility of the approach.

Human endotoxin administration as an experimental model in drug development.

Linking human physiology to inflammatory mechanisms discovered in vitro or in animal models is essential to determine their importance. Innate immunity underlies many of these inflammatory responses in health and disease. Bacterial endotoxin is the quintessential trigger of innate immune responses. When administered to humans, endotoxin has been an important means of demonstrating key inflammatory mechanisms in vivo. Furthermore, endotoxin challenges have provided opportunities to test the effects of novel inflammation-modifying agents in humans.

Pharmacokinetics of pantoprazole in patients with moderate and severe hepatic dysfunction.

BACKGROUND: Patients with impaired hepatic function usually require gastric acid-suppressant therapy but are at increased risk for drug interactions and may require dosage adjustments. The proton pump inhibitor pantoprazole is rapidly absorbed and eliminated, primarily by cytochrome P450 (CYP) 2C19 isozymes. OBJECTIVE: This study sought to determine whether dosage adjustment of pantoprazole is required in patients with moderate or severe hepatic impairment by comparing the pharmacokinetic profile of pantoprazole in such patients with that in healthy slow metabolizers of pantoprazole, in whom no dosage adjustment is required. METHODS: Patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment received oral pantoprazole 40 mg once daily on days 1 through 4 and then on alternate days (days 6 and 8). Serial blood samples were collected on days 4 and 8 for analyses of plasma pantoprazole concentrations. Pharmacokinetic data were compared between the 2 groups with hepatic impairment and against historical data from 17 healthy subjects who were genetically slow CYP2C19 metabolizers of pantoprazole. RESULTS: Twenty-two patients participated in the study, 13 in the Child-Pugh class B group and 9 in the Child-Pugh class C group. No clinically significant differences in pantoprazole pharmacokinetics were noted between the patients with hepatic impairment and the healthy slow metabolizers of pantoprazole on days 4 and 8. Pantoprazole was well tolerated. Four Child-Pugh class B patients and 3 Child-Pugh class C patients reported > or = 1 adverse event. Adverse events were generally mild or moderate, and were similar to those reported in healthy subjects. Two patients discontinued the study because of severe events related to their underlying disease. CONCLUSIONS: The pharmacokinetics and tolerability of pantoprazole were similar in patients with moderate hepatic impairment, patients with severe hepatic impairment, and healthy slow metabolizers of pantoprazole, in whom no dosage adjustment is required. Thus, no dosage adjustment of pantoprazole is required in patients with hepatic impairment, regardless of its severity. However, caution should be exercised when giving pantoprazole to patients with severe hepatic impairment.

Dose-proportional and stereospecific pharmacokinetics of methylphenidate delivered using an osmotic, controlled-release oral delivery system.

Methylphenidate hydrochloride (HCl) is frequently used for the treatment of attention deficit/hyperactivity disorder (ADHD). A study was conducted in healthy subjects to evaluate the dose-ranging pharmacokinetics of 18, 36, and 54 mg methylphenidate HCl delivered using an oral, osmotic, controlled-release formulation (OROS). Plasma concentrations of l-methylphenidate were 40-fold lower than those of d-methylphenidate, whereas plasma concentrations of d-alpha-phenyl-2-piperidine acetic acid (d-PPA) and l-PPA, the major metabolite of methylphenidate, were comparable. Mean AUCinf values for d-methylphenidate were 42.2, 80.9, and 120 ng.h/mL for the 18, 36, and 54 mg doses, respectively, increasing dose proportionally. AUCinf values for l-methylphenidate were only approximately 1% of d-methylphenidate (0.43, 0.96, and 1.82 ng.h/mL for the 18, 36, and 54 mg dose groups, respectively). In contrast, AUCinf values of d- and l-PPA were comparable. The dose-normalized d- and l-methylphenidate plasma concentration-time profiles for the three treatment groups were superimposable. Similarly, dose-normalized plasma concentrations of d- and l-PPA were superimposable. Methylphenidate metabolism, measured as the ratio of d-methylphenidate AUCinf to d-PPA AUCinf and as l-methylphenidate AUCinf to l-PPA AUCinf, was similar for the three dose groups, indicating that methylphenidate metabolism was not affected by increasing dose. OROS (methylphenidate HCl) exhibits dose-proportional and linear pharmacokinetics.

Randomized safety studies of intravenous perflubron emulsion. I. Effects on coagulation function in healthy volunteers.

Previous perfluorocarbon (PFC) emulsions have been associated with transient adverse events (i.e., platelet activation, decreased platelet count, febrile responses, changes in hemodynamic function). The Phase I studies described in this report were parallel, randomized, double-blinded, placebo-controlled studies conducted in 48 healthy volunteers (n = 24 per study) with perflubron emulsion (Oxygent; Alliance Pharmaceutical Corp., San Diego, CA). Because of the decreased platelet counts observed with previous PFC emulsions and the intended use of perflubron emulsion in surgical patients, these studies assessed postdosing coagulation responses and hemostasis. PFC pharmacokinetic variables were also evaluated. The primary endpoint for examination of coagulation effects was prospectively defined as bleeding time. Subjects received either saline (3 mL/kg) control, or perflubron emulsion at 1.2 g PFC/kg or 1.8 g PFC/kg, and were evaluated for a 14-day period. No postinfusion changes in bleeding time or differences in ex vivo agonist-induced platelet aggregation were observed. A 17% reduction in platelet count was observed 3 days after dosing in the 1.8-g PFC/kg group; levels recovered to baseline by Day 7. The intravascular half-life of perflubron for the first 24 h was dose dependent: 9.4+/-2.2 h and 6.1+/-1.9 h in the 1.8- and 1.2-g PFC/kg groups, respectively. Results indicate that this perflubron emulsion did not affect coagulation function in healthy volunteers.

Randomized safety studies of intravenous perflubron emulsion. II. Effects on immune function in healthy volunteers.

Particle size distribution is a major determinant of particle clearance by the mononuclear phagocytic system and the potential for concomitant activation of resident macrophages. To test the safety of a second-generation perflubron-based emulsion (60% perfluorocarbon [PFC] wt/vol; Oxygent [Alliance Pharmaceutical Corp., San Diego, CA]) with a small mean particle size, two parallel, randomized, double-blinded, placebo-controlled studies were conducted in 48 healthy volunteers (n = 24 per study). The study described herein focuses on safety concerning immune function. The primary endpoint was defined prospectively as delayed hypersensitivity skin test responses with lymphocyte proliferative responses to mitogenic stimulation providing a secondary measure for changes in cell-mediated immunity. Subjects received either perflubron emulsion IV (1.2 g PFC/kg or 1.8 g PFC/kg) or saline (3 mL/kg) control. Perflubron emulsion had no effect on delayed hypersensitivity skin reactions, lymphocyte proliferative potential, circulating immunoglobulins, complement activation, or plasma levels of the inflammatory cytokines, tumor necrosis factor-alpha, interleukin-1 alpha, and interleukin-1 beta. Perflubron emulsion was generally well tolerated, although there was a dose-dependent increase in minor flu-like symptoms in the perflubron treatment groups at 24 h after dosing. Increased serum levels of interleukin-6 were observed in those subjects exhibiting febrile responses. The clinical safety profile of perflubron emulsion supports its continued investigation as a temporary oxygen carrier in surgical patients to reduce exposure to allogeneic blood transfusion.

The efficacy, tolerability, and safety of 1200 mg/d of oxaprozin and 1500 mg/d of nabumetone in the treatment of patients with osteoarthritis of the knee.

This 6-week, multicenter, double-masked, placebo-controlled study compared the efficacy, tolerability, and safety of the recommended starting dose of oxaprozin (1200 mg/d) and a 1500-mg/d dose of nabumetone in the treatment of patients with moderate-to-severe osteoarthritis (OA) of the knee. A total of 347 patients with a mean age of 61.1 years were randomized to receive oxaprozin (116 patients), nabumetone (115 patients), or placebo (116 patients). Adults of either sex who were older than 18 years of age were eligible for entry into the study, if they had had OA of the knee for at least 6 months. Efficacy variables included knee pain on weight bearing, knee pain on motion, patients' and physicians' global assessments of OA, pain intensity as measured on a visual analog scale, and time to walk 50 feet as quickly as possible. Efficacy variables were assessed at baseline and at weeks 1, 2, 4, and 6. Between-group differences in efficacy variables were evident by week 1. Mean improvements were significantly greater with oxaprozin than with placebo for all efficacy variables at all time periods, except knee pain on motion at weeks 2 and 4 and time to walk 50 feet at weeks 1, 2, and 4. Mean improvements were significantly greater with nabumetone than with placebo for all efficacy variables at all time periods, except the following: knee pain on weight bearing at weeks 2, 4 and 6; knee pain on motion at weeks 2 and 4; patients' global assessment at week 4; and pain intensity as measured on a visual analog scale at weeks 2 and 4. There were, however, no significant differences between oxaprozin and nabumetone in any of these efficacy variables. Adverse events were reported by 83 (71.6%) patients who took oxaprozin, by 80 (69.6%) patients who took nabumetone, and by 57 (49.1%) patients who took placebo. Adverse events were reported for significantly more patients taking oxaprozin or nabumetone than placebo. However, adverse events tended to be mild or moderate and rarely resulted in patients withdrawing from the study. Combined with the results of an earlier study, the results of this study showed that a 1500-mg/d dose of nabumetone, which is higher than the recommended starting dose of 1000 mg/d, is required for efficacy equivalent to that of the recommended starting dose of oxaprozin, 1200 mg/d, in relieving the symptoms of OA. Thus nabumetone may require dosage titration from the recommended starting dose. Oxaprozin and nabumetone were found to have similar tolerability profiles, as shown by adverse-event monitoring and withdrawal rates, as well as clinically similar safety profiles, as demonstrated by physical examinations, hematologic and biochemical laboratory testing, hemoccult testing, and adverse-event monitoring and symptom assessment.

Inhibition of platelet production induced by an antiplatelet drug, anagrelide, in normal volunteers.

Administration of anagrelide, an antiplatelet agent, to ten normal male subjects was accompanied by an asymptomatic fall in platelet count. The drop was gradual and usually occurred within two weeks. Only a slight shortening of platelet survival was seen. Bone marrow morphology appeared normal. Measurement of platelet production rates showed a reduced response to thrombocytopenia. A substantial increase in the percentage of large platelets was observed in drug treated subjects. These observations are compatible with a selective inhibition of platelet production. Based upon these findings, the use of anagrelide will probably be best limited to short-term applications or to conditions where selective lowering of platelet count may be desired such as in polycythemia rubra vera or idiopathic thrombocytosis.

Extrarenal contributions to indapamide's antihypertensive mechanism of action.

Autonomic responses in heart rate and blood pressure to Valsalva maneuvers and changes in vascular reactivity to pressor doses of phenylephrine and angiotensin II were studied before and after treatment with indapamide, a new antihypertensive diuretic. Six healthy male volunteers, placed on a daily diet consisting of 100 mEq of sodium, 80 mEq of potassium, and a fluid intake of 2500 ml, participated in this single-blind, placebo-controlled study. During active treatment, 5 mg of indapamide was administered once daily for 14 days. On the mornings of hemodynamic testing, samples of blood, 24-hour urine, and plasma were obtained and analyzed for hematocrit, catecholamines and their metabolites, plasma renin activity, and aldosterone levels. Since each subject served as his own control, the results were analyzed by the paired t-test method. Plasma renin activity and 24-hour urinary aldosterone levels increased (p less than 0.05), and serum potassium and chloride levels decreased (p less than 0.05). No other significant laboratory changes were noted after treatment, including changes in the plasma and urinary catecholamine levels. Following treatment, responses in heart rate and blood pressure to Valsalva maneuvers were unaltered. During the control period the doses of phenylephrine and angiotensin II required to raise the systolic pressure 25 to 35 mm Hg and the diastolic pressure 20 to 30 mm Hg were 5.03 +/- 0.72 micrograms/kg and 16.7 +/- 2.1 ng/kg, respectively. After treatment, the doses of phenylephrine and angiotensin II were significantly (p less than 0.05) greater: 10.72 +/- 1.02 micrograms/kg and 31.7 +/- 4.8 ng/kg, respectively. Dose-response relationships to these pressor agents were shifted in parallel to the right after treatment. A small but significant decrease in body weight, which may have reflected a decrease in plasma volume, was observed. However, no orthostatic changes between the supine and erect mean arterial blood pressures or incremental increases in heart rates were noted between the two periods. An increase in hematocrit and blunting of the diastolic overshoot during the Valsalva maneuvers that were used as indexes of plasma volume contraction were also not observed. In summary, our results indicate that changes in vascular responsiveness occurred by mechanisms independent of changes in the autonomic nervous system, since plasma norepinephrine levels did not change and responsiveness to Valsalva maneuvers was unaltered. Furthermore, it appears that this effect on the vasculature was probably not related to changes in plasma volume.

Clonidine-chlorthalidone combination once and twice daily in essential hypertension.

The antihypertensive effects of a clonidine-chlorthalidone combination (Combipres) as a single daily dose at bedtime and the same amount in twice-daily doses were compared in an open-label, crossover study in 14 patients. An analysis of the blood pressure and pulse data in nine patients who completed the study revealed no statistically significant differences between the two regimens, and no difference in the incidence of side effects was noted.

Comparison of analgesia by intravenous butorphanol and meperidine in patients with post-operative pain.

Intravenous doses of butorphanol tartrate (0.5 mg, 1.0 mg and 2.0 mg) and meperidine hydrochloride (20 mg and 40 mg) were compared under controlled conditions employing a double blind study design. Informed consent was obtained from all post-operative patients suffering from moderate to severe pain who participated in this study. Approximately 25 patients were included in each group. The data from 125 patients were subjected to statistical analysis. The results indicated that butorphanol is approximately 40 to 50 times more potent than meperidine. In addition, at most of the time intervals, there were no statistically significant differences between the responses to butorphanol 0.5 mg and 1 mg and meperidine 20 mg and 40 mg; but the response to butorphanol 2 mg was significantly (p less than 0.05) better than the low dose of each agent. The low doses of butorphanol (0.5 mg) and meperidine (20 mg) appear to have an effective duration of action of less than two hours. The larger doses (butorphanol 1.0 mg and 2.0 mg and meperidine 40 mg) appeared to produce a two- to four-hour duration of action. The largest butorphanol dose (2.0 mg) appeared to produce the longest duration of action. A comparison of the test groups with respect to the incidence and type of side effects showed that butorphanol 2.0 mg produced a greater incidence of drowsiness (39 per cent). The overall incidence of drowsiness for patients receiving either the 0.5 mg or 1.0 mg dose of butorphanol was 12 per cent, as compared with an 8 per cent overall incidence in the meperidine group. The incidence of other side effects was relatively low in all test groups. No significant differences were noted among the groups with regard to the onset (usually less than or equal to 30 minutes post-therapy) or the duration (usually less than or equal to 2 hours) of side effects. Butorphanol appears to be a safe and effective analgesic for the relief of moderate to severe post-operative pain.