Ignorance is not bliss: Statistical power is not probability of trial success.

The purpose of this commentary is to place probability of trial success, or assurance, in the context of decision making in drug development, and to illustrate its properties in an intuitive manner for the readers of Clinical Pharmacology and Therapeutics. The hope is that this will stimulate a dialog on how assurance should be incorporated into a quantitative decision approach for clinical development and trial design that uses all available information.

Model-based assessment of dosing strategies in children for monoclonal antibodies exhibiting target-mediated drug disposition.

Body weight/body surface area-based and/or tiered fixed dosing strategies are widely utilized for monoclonal antibodies with linear clearance to scale adult clinical doses to children. However, there is limited knowledge on whether or not body weight-based dosing strategies also yield comparable dose-concentration-response relationships in adults and children for monoclonal antibodies that exhibit target-mediated drug disposition. Our findings indicate that it is important to interpret pharmacokinetics information in a pharmacokinetics/pharmacodynamics context as similar systemic drug exposure in adults and children may not be reflective of the corresponding target occupancy. They further indicate that BW-based dosing is superior to fixed dosing for the same target concentration, whereas the opposite holds true for the same target amount in adults and children. Michaelis-Menten approximations yielded similar profiles compared to the full target-mediated drug disposition model for all simulation scenarios and may be used to guide the selection of appropriate dosing regimens in children.

Greater seasonal cycling of 25-hydroxyvitamin D is associated with increased parathyroid hormone and bone resorption.

SUMMARY: This analysis assessed whether seasonal change in 25-hydroxyvitamin D concentration was associated with bone resorption, as evidenced by serum parathyroid hormone and C-terminal telopeptide concentrations. The main finding was that increased seasonal fluctuation in 25-hydroxyvitamin D was associated with increased levels of parathyroid hormone and C-terminal telopeptide. INTRODUCTION: It is established that adequate 25-hydroxyvitamin D (25(OH)D, vitamin D) concentration is required for healthy bone mineralisation. It is unknown whether seasonal fluctuations in 25(OH)D also impact on bone health. If large seasonal fluctuations in 25(OH)D were associated with increased bone resorption, this would suggest a detriment to bone health. Therefore, this analysis assessed whether there is an association between seasonal variation in 25(OH)D and bone resorption. METHODS: The participants were (n = 279) Caucasian and (n = 88) South Asian women (mean (±SD); age 48.2 years (14.4)) who participated in the longitudinal Diet, Food Intake, Nutrition and Exposure to the Sun in Southern England study (2006-2007). The main outcomes were serum 25(OH)D, serum parathyroid hormone (sPTH) and serum C-terminal telopeptide of collagen (sCTX), sampled once per season for each participant. RESULTS: Non-linear mixed modelling showed the (amplitude/mesor) ratio for seasonal change in log 25(OH)D to be predictive of log sPTH (estimate = 0.057, 95 % CI (0.051, 0.063), p < 0.0001). Therefore, individuals with a higher seasonal change in log 25(OH)D, adjusted for overall log 25(OH)D concentration, showed increased levels of log sPTH. There was a corresponding significant ability to predict the range of seasonal change in log 25(OH)D through the level of sCTX. Here, the corresponding parameter statistics were estimate = 0.528, 95 % CI (0.418, 0.638) and p ≤ 0.0001. CONCLUSIONS: These findings suggest a possible detriment to bone health via increased levels of sPTH and sCTX in individuals with a larger seasonal change in 25(OH)D concentration. Further larger cohort studies are required to further investigate these preliminary findings.

Clinical Trial Simulation to Inform Phase 2: Comparison of Concentrated vs. Distributed First-in-Patient Study Designs in Psoriasis.

Clinical trial simulation (CTS) and model-based meta-analysis (MBMA) can increase our understanding of small, first-in-patient (FIP) trial design performance to inform Phase 2 decision making. In this work, we compared dose-ranging designs vs. designs testing only placebo and the maximum dose for early decision making in psoriasis. Based on MBMA of monoclonal antibodies in the psoriasis space, a threshold of greater than a 50 percentage point improvement over placebo effect at the highest feasible drug dose was required for the advancement in psoriasis. Studies testing only placebo and the maximum dose made the correct advancement decision marginally more often than dose-ranging designs in the majority of the cases. However, dose-ranging studies in FIP trials offer important design advantages in the form of dose-response (D-R) information to inform Phase 2 dose selection. CTS can increase the efficiency and quality of drug development decision making by studying the limitations and benefits of study designs prospectively.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e58; doi:10.1038/psp.2013.32; published online 24 July 2013.

A dose-response meta-analysis for quantifying relative efficacy of biologics in rheumatoid arthritis.

We present a dose-response meta-analysis to quantify relative efficacy of biologic disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). There is a strong rationale for this analysis because, although multiple biologics are available, information on head-to-head comparisons is limited. Data on the percentage of patients attaining American College of Rheumatology (ACR) 20, 50, and 70 responses were extracted from 50 randomized controlled trials representing 21,500 patients, five mechanisms of action, and nine biologics. The analysis showed that all tumor necrosis factor inhibitors (anti-TNFs) share the same dose-response relationship for ACR 20, 50, and 70, differing only in potency. Yet there are significant differences in efficacy among the anti-TNFs due to differences in the clinical dose ranges available. At the suggested starting dose, golimumab was the least efficacious, followed by infliximab, adalimumab, etanercept, and certolizumab. Significant differences in the dose-response relationship were found between anti-TNFs and other biologics, resulting in differences in efficacy and differential impact of dose titration.

Emergency department management of patients with seizures: a multicenter study.

OBJECTIVES: Patients with seizure disorders are common in the emergency department (ED), yet little is known regarding the management of these patients. This study was performed to define the frequency of patients with seizure disorders in the ED patient population and to determine possible seizure etiologies, characteristics of diagnostic activities, treatments, and dispositions. METHODS: Twelve EDs monitored all patients with a chief complaint related to seizure disorders presenting over 18.25 days (5% of the calendar year) in late 1997. Retrospective chart review was used to gather specific data regarding these consecutive cases. RESULTS: Of the 31,508 patients who presented to these 12 EDs during the study period, 368 (1.2%) had complaints related to seizures. Three hundred sixty-two charts were available for analysis and make up the study population. Two hundred fifty-seven (71%) utilized emergency medical services (EMS) for transport and care. Advanced care, including intravenous access, laboratory work, cardiac monitoring, or oxygen administration, was utilized in 304 (84%) patients. Antiepileptic drugs were given in 199 (55%) patients. Ethanol withdrawal or low antiepileptic drug levels were implicated as contributing factors in 177 (49%) of patients. New-onset seizures were thought to be present in 94 (26%) patients. Status epilepticus occurred in only 21 (6%) patients. Ninety-eight (27%) of all patients were admitted to the hospital. CONCLUSIONS: Patients with presenting complaints related to seizures are frequent in the ED population and make considerable demands on EMS and ED resources. Six percent of patients with seizure-related presentations were in status epilepticus and more than a fourth of all patients required hospitalization.

State of the art: therapeutic controversies in severe acute asthma.

This is a transcript of the 1999 SAEM State-of-the-Art session on "Therapeutic Controversies in Severe Acute Asthma," presented at the 1999 SAEM annual meeting in Boston. The aim of this session was to address some of the current controversies in the management of acute asthma exacerbations, a major issue in emergency medicine. Despite many recent advances in asthma management, morbidity and mortality remain high. While many of us have strong feelings on how asthma patients should be treated, many of our assertions are not based on good science, and there are numerous areas of controversy. This discussion focuses on the controversy over beta agonist treatment for acute asthma, the physiology of corticosteroids in asthma, and the emergency use of leukotriene-modifying agents.

Value of point-of-care blood testing in emergent trauma management.

BACKGROUND: No prospective study demonstrates the value of point-of-care laboratory testing (POCT) in the management of major trauma. METHODS: In a prospective, noninterventional, study of 200 major trauma patients, we evaluated the influence of a blood POCT profile (hemoglobin, Na+, K+, Cl-, blood urea nitrogen, glucose, pH, PCO2, PO2, HCO3-, base deficit, and lactate) on emergent diagnostic and therapeutic interventions. Physicians responded to a standardized set of questions on their diagnostic and therapeutic plans before and after the availability of POCT results. Management plan changes were deemed emergently appropriate, if they were influenced by the POCT results and, within the ensuing 30 minutes, the change in management was likely to reduce morbidity or conserve resources. RESULTS: For emergently appropriate plan changes, Na+, Cl-, K+, and blood urea nitrogen were never influential, whereas in each of 6.0% of cases (95% confidence interval [CI], 3.5%-10.2%) at least one of the remaining POCT parameters was influential. An emergently appropriate change was based on hemoglobin in 3.5% of cases (95% CI, 1.0%-6.1%), blood gas parameters in 3.0% of cases (95% CI, 0.64%-5.7%), lactate in 2.5% of cases (95% CI, 1.1%-5.7%), and glucose in 0.5% of cases (95% CI, 0.1%-2.8%). All of these cases involved blunt injury. CONCLUSION: Na+, Cl-, K+, and blood urea nitrogen levels do not influence the initial management of major trauma patients. In patients with severe blunt injury, hemoglobin, glucose, blood gas, and lactate measurements occasionally result in morbidity-reducing or resource-conserving management changes.

Persistent inhibition of CYP3A4 by ketoconazole in modified Caco-2 cells.

PURPOSE: The intestinal metabolism of some CYP3A substrates can be altered profoundly by co-administration of the potent inhibitor, ketoconazole. The present research was conducted to test the hypothesis that, unlike the inhibition kinetics observed with isolated microsomes, inhibition of CYP3A4 by ketoconazole in an intestinal cell monolayer is time-dependent and slowly reversible. METHODS: Confluent, 1alpha,25-dihydroxy Vitamin D3-treated Caco-2 cells were exposed to 1 microM ketoconazole for two hours (Phase I) and then washed three times with culture medium containing no inhibitor. This was followed by a second incubation period (Phase II) that varied in the composition of the apical and basolateral culture medium: Condition 1. apical/basolateral differentiation medium (DM); Condition 2, apical/ basolateral DM + basolateral 2g/dL Human Serum Albumin (HSA); Condition 3, apical/basolateral DM + apical/basolateral 2 g/dL HSA. After various lengths of time for the second phase (0 to 4 hours), both apical and basolateral medium were exchanged with fresh DM. Midazolam (6 microM) was included in the apical medium for determination of CYP3A4 activity (Phase III). RESULTS: Two-way ANOVA of the data revealed persistent inhibition of CYP3A4 under Conditions 1 and 2 (p < 0.001). In contrast, cells treated under Condition 3 exhibited rapid reversal of CYP3A4 inhibition. The level of CYP3A4 activity observed was inversely correlated with the amount of ketoconazole remaining in the cell monolayer at the end of Phase II. CONCLUSIONS: These studies provide mechanistic evidence that ketoconazole can be sequestered into the intestinal mucosa after oral administration, producing a persistent inhibition of first-pass CYP3A4 activity.

Hydroxyurea in the treatment of HIV-1.

OBJECTIVE: To describe the role of hydroxyurea in the treatment of HIV-1. DATA SOURCES: Published clinical studies using hydroxyurea in HIV treatment were accessed through MEDLINE (January 1994-March 1999) and conference abstracts. All relevant studies were evaluated. DATA SYNTHESIS: Adherence, expense, and resistance limit the pharmacotherapeutic options in the management of patients with HIV. Hydroxyurea may be an alternative to conventional HIV treatments. CONCLUSIONS: Several potential advantages of adding hydroxyurea to antiretroviral treatment regimens include the drug's well-documented toxicity, convenient dosing, good tolerability and low cost, and its unique mechanism of action. Hydroxyurea may have synergistic effects that prove promising in initial and salvage therapy antiretroviral regimens. Larger, well-controlled clinical studies are needed to adequately define the role of hydroxyurea in the treatment of HIV.

Ascorbic acid use in hyporesponders to Epoetin alfa.

I.v. ascorbic acid has been used in an effort to mobilize ferritin stores in hyporesponsive HD patients receiving Epoetin alfa. However, not all patients who respond to i.v. ascorbic acid therapy will have subsequent decline in feritin stores (Gastaldello et al., 1995; Tarng & Huang, 1998). Additionally, predicting those patients who will overcome their Epoetin alfa hyporesponsiveness remains unclear. Ascorbic acid's effect on hemosiderin deposits may be another possible mechanism to the increased Epoetin alfa response observed in some HD patients (Hemosiderin is a pathologic deposition of iron in tissues including the spleen, small intestine, and bone marrow). Although there are no well-controlled studies evaluating hemosiderin and i.v. ascorbic acid, it should be noted that subjects with scurvy often present with excessive iron deposits in the tissues, indicating the possible effects of ascorbic acid on hemosiderin metabolism (Bothwell et al., 1964). Ascorbic acid deficiency is often present in many HD patients due to its removal during dialysis and lack of dietary intake (Ponka & Kuhlback, 1983). It remains controversial whether oral ascorbic acid supplementation is indicated in patients receiving HD. Therefore, the Recommended Daily Allowance (RDA) of 60 mg/day should be advised (Makoff, 1999). I.v. ascorbic acid should be considered as a possible adjuvant to therapy in patients who are "iron-overloaded" and hyporesponsive to Epoetin alfa. Although the long-term effects of i.v. ascorbic acid on HD patients is unknown, the potential risk of secondary oxalosis should be considered (Costello, 1991; Pru, Eaton, & Kjellstrand, 1985). It may be necessary to monitor plasma oxalate levels if long-term therapy with i.v. ascorbic acid is used. Clinical studies have examined i.v. ascorbic acid doses from 300 mg-500 mg given up to TIW for a maximum duration of 12 weeks without any significant deleterious effects (Gastaldello et al., 1995; Tarng & Huang, 1998; Tarng et al., 1999). However, large-scale, prospective, and controlled trails are needed to determine the long-term safety and efficacy of i.v. ascorbic acid therapy in iron overloaded HD patients receiving Epoetin alfa.

Lateral line morphology and cranial osteology of the rubynose brotula, Cataetyx rubrirostris.

Cranial osteology, canal neuromast distribution, superficial neuromast distribution and innervation, and cephalic pore structure were studied in cleared and stained specimens of the deep sea brotulid Cataetyx rubrirostris. The cranial bone structure of C. rubrirostris is similar to other brotulids (Dicrolene sp.) and zoarcids (Zoarces sp.), except for an unusual amount of overlapping of the bones surrounding the cranial vault. The superficial neuromasts are innervated by the anterodorsal, anteroventral, middle and posterior lateral line nerves and are organized similarly to those of the blind ophidioid cave fish Typhliasina pearsei. The cephalic pores open into a widened lateral line canal system. The canal is compartmentalized into a series of neuromast-containing chambers that probably amplify signals received by the system.

Prospective multicenter study of relapse following treatment for acute asthma among adults presenting to the emergency department. MARC investigators. Multicenter Asthma Research Collaboration.

STUDY OBJECTIVE: To identify factors associated with relapse following treatment for acute asthma among adults presenting to the emergency department (ED). DESIGN: Prospective inception cohort study performed during October 1996 to December 1996 and April 1997 to June 1997, as part of the Multicenter Asthma Research Collaboration. SETTING: Thirty-six EDs in 18 states. PATIENTS: ED patients, aged 18 to 54 years, with physician diagnosis of acute asthma. For the present analysis, we restricted the cohort to patients sent home from the ED (n = 971), then further excluded patients with comorbid respiratory conditions (n = 32). This left 939 eligible subjects to have follow-up data. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Two weeks after being sent home from the ED, patients were contacted by telephone. A relapse was defined as an urgent or unscheduled visit to any physician for worsening asthma symptoms during the 14-day follow-up period. Complete follow-up data were available for 641 patients, of whom 17% reported relapse (95% confidence interval, 14 to 20). There was no significant difference in peak expiratory flow rate (PEFR) between patients who suffered relapse and those who did not. In a multivariate logistic regression analysis (controlling for age, gender, race, and primary care provider status), patients who suffered relapse were more likely to have a history of numerous ED (odds ratio [OD] 1.3 per 5 visits) and urgent clinic visits (OR 1.4 per 5 visits) for asthma in the past year, use a home nebulizer (OR 2.2), report multiple triggers of their asthma (OR 1.1 per trigger), and report a longer duration of symptoms (OR 2.5 for 1 to 7 days). CONCLUSION: Among patients sent home from the ED following acute asthma therapy, 17% will have a relapse and PEFR does not predict who will develop this outcome. By contrast, several historical features were associated with increased risk. Further research should focus on ways to decrease the relapse rate among these high-risk patients. The clinician may wish to consider these historical factors when making ED decisions.

Effect of inhibitor depletion on inhibitory potency: tight binding inhibition of CYP3A by clotrimazole.

The purpose of this work was to evaluate the effect of mutual unbound inhibitor and unbound enzyme depletion on the potency of three antifungal cytochrome P-450 (CYP)3A inhibitors with over 1000-fold range in enzyme affinity. Incubations were performed with human liver microsomal protein concentrations that varied from 25 to 1000 microg/ml. The effect of each inhibitor was evaluated using midazolam as a CYP3A probe. Clotrimazole was found to be a tight binding inhibitor of CYP3A with a Ki of 250 pM. Analysis of percent inhibition data by stepwise linear regression for the matrix of inhibitor and enzyme concentrations used showed that protein concentrations predicted the percent inhibition by clotrimazole (r2 = 0.60, p <.001). When clotrimazole concentrations were added to the model, the r2 improved to 0.81, p =.003. Clotrimazole concentrations alone were not a significant predictor of percent inhibition (r2 = 0. 21, p =.08). For ketoconazole, protein concentrations provided a weak prediction of the percent inhibition (r2 = 0.39, p =.006). Conversely, ketoconazole concentrations alone were a good predictor of percent inhibition (r2 = 0.55, p <.001). In contrast to results with clotrimazole and ketoconazole, percent inhibition by fluconazole was not dependent on protein concentrations (r2 = 0.06, p =.39). We conclude that microsomal inhibitory potency can be affected by incubation conditions that deplete the unbound concentration of inhibitor available to the enzyme. This may introduce serious error into a quantitative prediction of an in vivo drug-drug interaction based on an in vitro derived Ki value.

Inhibition of cytochrome P-450 3A (CYP3A) in human intestinal and liver microsomes: comparison of Ki values and impact of CYP3A5 expression.

The purpose of this study was to compare the kinetics of intestinal and hepatic cytochrome P-450 3A (CYP3A) inhibition by using microsomal midazolam 1'-hydroxylation as a marker of enzyme activity. The effect of two antifungal agents commonly implicated in CYP3A drug-drug interactions was examined. Inhibition type and affinities were determined for human liver and intestinal microsomes screened for the presence or absence of CYP3A4 and CYP3A5, as well as for cDNA-expressed CYP3A4 and CYP3A5 microsomes. Ketoconazole and fluconazole were found to be noncompetitive inhibitors of both enzymes. Ketoconazole exhibited a Ki for cDNA-expressed CYP3A4 of 26. 7 +/- 1.71 nM, whereas the Ki for cDNA expressed CYP3A5 was 109 +/- 19.7 nM. Corresponding Ki values for fluconazole were 9.21 +/- 0.51 microM and 84.6 +/- 12.9 microM. For liver and intestinal microsomes that contained only CYP3A4, the average ketoconazole Ki was found to be 14.9 +/- 6.7 nM and 17.0 +/- 7.9 nM, respectively, whereas fluconazole yielded mean respective Ki values of 10.7 +/- 4.2 microM and 10.4 +/- 2.9 microM. Liver and intestinal microsomes that contained an equal or greater amount of CYP3A5, in addition to CYP3A4, were less susceptible to inhibition by both ketoconazole and fluconazole. These findings suggest that there can be significant differences in the affinity of these two enzymes for inhibitors. This may further broaden interindividual variability with respect to the magnitude of in vivo drug-drug interactions. We also conclude that there is no significant difference in inhibition type and affinity of ketoconazole and fluconazole for hepatic versus intestinal CYP3A4.

Spectral sensitivity of the goldfish Torus longitudinalis.

We measured the photopic spectral sensitivity of multiunit activity in the torus longitudinalis and optic tectum of goldfish. Since negative contrast stimuli are most effective for exciting torus longitudinalis, spiking activity was evoked by the shadow of a disc moving through a monochromatic light beam projected upon a screen. The amount of activity evoked in torus longitudinalis generally increased with the monochromatic stimulus radiance at the same rate for all wavelengths, indicating a univariant response. Spiking activity in tectum, however, increased at different rates across the spectrum, indicating color-dependent responses. The action spectra for torus longitudinalis were all similar and relatively flat as expected of a homogeneous, broad-band luminance processing system, and about 1 log unit more sensitive than the tectal action spectra. The latter generally displayed sharp peaks and dips in sensitivity indicative of opponent processing.

EMT defibrillation does not increase survival from sudden cardiac death in a two-tiered urban-suburban EMS system.

OBJECTIVE: The use of automatic external defibrillators (AEDs) by EMS initial responders is widely advocated. Evidence supporting the use of AEDs is based largely on the experience of one metropolitan area, with effect on survival in many systems not yet proved. We conducted this study to determine whether the addition of AEDs to an EMS system with a response time of 4 minutes for first-responder emergency medical technicians (FREMTs) and 10 minutes for paramedics would affect survival from cardiac arrest. METHODS: This prospective, controlled, crossover study (AED versus no AED) of consecutive cardiac arrests managed by 24 FREMT fire companies took place from 1992 to 1995 in Charlotte, North Carolina, a city of 455,000. Patients were stratified using the Utstein criteria. The primary endpoint was survival to hospital discharge among patients with bystander-witnessed arrests of cardiac origin. RESULTS: Of the 627 patients, 243 were bystander-witnessed arrests of cardiac origin. Survival to hospital discharge was accomplished in 5 of 110 patients (4.6%; 95% confidence interval [CI] 0.6% to 8.4%) with AED compared with 7 of 133 (5.3%, 95% CI 1.5% to 9.1%) without AED (P = .8). Both groups were comparable with regard to age, gender, history of myocardial infarction, congestive heart failure or diabetes, arrest at home, bystander CPR, and whether or not ventricular fibrillation (VF) was the initial rhythm. For arrests of any cause, witnessed by bystanders or EMS personnel, with an initial rhythm of VF or ventricular tachycardia (VT), 5 of 77 (6.5%, 95% CI 1.0% to 12.0%) with AED survived compared with 8 of 105 patients (7.6%, 95% CI 2.5% to 12.7%) without AED (P = .8). Statistically significant differences were noted in race and EMS response times between the two groups, which did not affect survival. CONCLUSION: Addition of AEDs to this EMS system did not improve survival from sudden cardiac death. The data do not support routinely equipping initial responders with AEDs as an isolated enhancement, and raise further doubt about such expenditures in similar EMS systems without first optimizing bystander CPR and EMS dispatching.

Air medical transport services in North Carolina.

Air medical transport is an important component of contemporary prehospital care for patients with time-sensitive conditions and those whose clinical needs exceed the expertise of local providers. Early contact with trained flight dispatchers facilitates air transport. Appropriate stabilization, effective communication, and transfer of medical documents ensure that transports are appropriate, timely, and safe.

The role of torus longitudinalis in equilibrium orientation measured with the dorsal light reflex.

The torus longitudinalis (TL) is a paired elongated structure reciprocally connected with the optic tectum in actinopterygian fishes. Electrophysiological recordings have revealed a sustained neural discharge in TL inversely related to luminance [Northmore, 1984]. This photometric response may play a role in the comparison of light levels between the two eyes, which must occur for the dorsal light reflex (DLR) to orient the body in the environment. Based on the luminance response of TL, it was hypothesized that TL ablation would result in a reduced DLR. Individual goldfish (Carassius auratus) were observed with variable and constant light sources on opposite sides of a test tank. The DLR was measured with respect to angle (degree) and duration (seconds) of body tilt about the longitudinal axis. After baseline readings were obtained, the intertectal commissure was cut and TL was removed bilaterally. Surgical control fish had only the intertectal commissure cut. Following surgery, TL ablatees showed a significantly reduced DLR compared to controls. The results are consistent with the suggestion by Northmore [1984] that TL may be involved in the processing of luminance information.