The Promise of Therapeutic Psilocybin: An Evaluation of the 134 Clinical Trials, 54 Potential Indications, and 0 Marketing Approvals on ClinicalTrials.gov.

Introduction: Psilocybin, a tryptamine psychedelic, has been touted in the media both historically and recently as a potential game-changing mental health therapeutic. ClinicalTrials.gov has over one hundred and thirty psilocybin clinical trials listed covering the last twenty years. The single most important aspect of any therapeutic is to gain approval for marketing and thus enter the real-world phase of development. A typical new chemical entity progresses from inception to US Food and Drug Administration (FDA) approval in approximately 12 years and seeks approval for a single indication. Methods: An observational study was conducted with the available information on the ClinicalTrials.gov site to observe the extent of progress made demonstrating the clinical utility of psilocybin. Results: The results showed 134 psilocybin trials typically unblinded studies of 10-20 participants, recruited over years at a single site. Additionally, there have been only three advanced trials (1 Phase 2/3 and 2 Phase 3) submitted, and only in the last two years. Discussion: The hundreds of psilocybin clinical trials initiated over the past twenty years comprising a myriad of potential indications may actually be slowing this potential game-changing mental health therapeutic agent's approval and is costing excessive amounts of capital. To fully evaluate the actual potential of psilocybin, purposeful clinical trials need to be designed well, executed efficiently, and analyzed utilizing sequential and statistically valid processes for each potential indication. This will require a change from the current exploratory forays to defined, well-funded, sequential pharmaceutical development practices, including adequate and appropriate blinding of studies, statistical design to determine the number of participants and more importantly, professional expertise in conducting multicenter trials. Unfortunately, these results demonstrate little real progress towards FDA approval of psilocybin and a field with no clear direction forward.

Diagnostic performance of kSORT, a blood-based mRNA assay for noninvasive detection of rejection after kidney transplantation: A retrospective multicenter cohort study.

The Kidney Solid Organ Response Test (kSORT) blood gene expression assay was developed to noninvasively detect acute rejection (AR) after kidney transplantation. Its performance in a setting with natural disease prevalence has not been evaluated. A retrospective, multicenter cohort study was conducted across all single kidney transplant recipients, transplanted between 2011 and 2015, with samples within the first year after transplantation available in existing biobanks. The primary objective was to determine the diagnostic performance of the kSORT assay to detect AR (T cell-mediated and/or antibody-mediated rejection) as compared to a concomitant renal biopsy. AR was reported on the concomitant biopsy in 188 of 1763 (10.7%) blood samples and any rejection (including borderline changes) in 614 of 1763 (34.8%) blood samples. In 320 of 1763 samples (18.2%) the kSORT risk category was indeterminate. The kSORT assay had no diagnostic value for AR (area under the curve [AUC] 0.51, 95% confidence interval [CI] 0.50-0.56; P = .46) overall, or when considering indication biopsies (N = 487) and protocol-specified biopsies (N = 1276) separately (AUC of 0.53, 95% CI 0.50-0.59, P = .44 and 0.55, 95% CI 0.50-0.61, P = .09, respectively). This large retrospective study utilizing samples obtained under real-world clinical conditions, was unable to validate the kSORT assay for detection of AR in the first year after transplantation.

Statewide analysis of missed opportunities for human papillomavirus vaccination using vaccine registry data.

BACKGROUND: Human papillomavirus (HPV) vaccine 3-dose completion rates among adolescent females in the US are low. Missed opportunities impede HPV vaccination coverage. METHODS: A population-based secondary data analysis of de-identified vaccination and demographic data from the Utah Statewide Immunization Information System (USIIS) was conducted. Records were included from 25,866 females ages 11-26 years at any time during 2008-2012 who received at least one of the following adolescent vaccinations documented in the USIIS: Tdap (Tetanus, Diphtheria, Pertussis), meningococcal, and/or influenza. A missed opportunity for HPV vaccination was defined as a clinical encounter where the patient received at least one adolescent vaccination, but not a HPV vaccine. RESULTS: Of 47,665 eligible visits, there were 20,911 missed opportunities (43.87%). Age group, race/ethnicity, and rurality were significantly associated with missed opportunity (p<0.0001). In a multivariable mixed-effects logistic regression model that included ethnicity, location and age, as fixed effects and subject as a random effect, Hispanics were less likely to have a missed opportunity than whites OR 0.59 (95% CI: 0.52-0.66), small rural more likely to have a missed opportunity than urban youth OR 1.8 (95% CI: 1.5-2.2), and preteens more likely than teens OR 2.4 (95% CI: 2.2-2.7). CONCLUSION: Missed clinical opportunities are a significant barrier to HPV vaccination among female adolescents. Interventions targeted at providers who serve patient groups with the highest missed opportunities are needed to achieve adequate protection from HPV-associated illnesses. IMPACT: This is one of the first studies to utilize state immunization information system data to assess missed opportunities for HPV vaccination.

Use of Oxandrolone to Promote Growth in Neonates following Surgery for Complex Congenital Heart Disease: An Open-Label Pilot Trial.

OBJECTIVE: Malnutrition and poor weight gain, common in neonates following repair of complex congenital heart disease (CHD), are associated with increased morbidity and mortality. Oxandrolone, an anabolic steroid, improves weight gain in older children at high-risk for growth failure. We sought to determine feasibility, safety, and efficacy of oxandrolone therapy in neonates following surgery for complex CHD. DESIGN: Neonates with RACHS-1 score >3 were eligible to receive open-label oxandrolone for 28 days in this prospective pilot trial. There were 3 cohorts of 5 subjects receiving oxandrolone therapy under 3 specified dosage and preparation protocols: 0.1 mg/kg/day aqueous solution, 0.2 mg/kg/day aqueous solution, and 0.1 mg/kg/day preparation in medium chain triglyceride (MCT) oil. Age- and diagnosis-matched neonates who underwent surgery, but received no oxandrolone, served as a control cohort. Anthropometric measurements, physical examination for virilization, safety labs, and adverse events were monitored. RESULTS: Of 25 eligible patients, 15 consented (60%, 13/15 with Norwood procedure). There was no evidence of virilization, no changes in safety labs, and no serious adverse events related to oxandrolone among subjects receiving therapy. No subject met criteria for termination of study drug. There was a significant difference in change in weight-for-age z-score among the four cohorts, with subjects receiving 0.1 mg/kg/day in MCT oil having the lowest decline during the study period (-1.8 ± 0.5 for controls, -1.7 ± 0.4 for 0.1 mg/kg/day aqueous, -1.0 ± 0.4 for 0.2 mg/kg/day aqueous, and -0.6 ± 0.7 for 0.1 mg/kg/day MCT oil, P = .012). CONCLUSIONS: Oxandrolone therapy at the doses studied appears safe in neonates after surgery for complex CHD. The decline in weight-for-age z-score was lowest in those receiving the MCT oil preparation suggesting better bioavailability of this preparation and a potential growth benefit with oxandrolone therapy. Further investigation is needed to define optimal dosing and assess efficacy.

Renal Function Descriptors in Neonates: Which Creatinine-Based Formula Best Describes Vancomycin Clearance?

Growth and maturational changes have been identified as significant covariates in describing variability in clearance of renally excreted drugs such as vancomycin. Because of immaturity of clearance mechanisms, quantification of renal function in neonates is of importance. Several serum creatinine (SCr)-based renal function descriptors have been developed in adults and children, but none are selectively derived for neonates. This review summarizes development of the neonatal kidney and discusses assessment of the renal function regarding estimation of glomerular filtration rate using renal function descriptors. Furthermore, identification of the renal function descriptors that best describe the variability of vancomycin clearance was performed in a sample study of a septic neonatal cohort. Population pharmacokinetic models were developed applying a combination of age-weight, renal function descriptors, or SCr alone. In addition to age and weight, SCr or renal function descriptors significantly reduced variability of vancomycin clearance. The population pharmacokinetic models with Léger and modified Schwartz formulas were selected as the optimal final models, although the other renal function descriptors and SCr provided reasonably good fit to the data, suggesting further evaluation of the final models using external data sets and cross validation. The present study supports incorporation of renal function descriptors in the estimation of vancomycin clearance in neonates.

A propensity-matched cohort study of vancomycin-associated nephrotoxicity in neonates.

BACKGROUND: The incidence of nephrotoxicity among vancomycin-treated neonates has been reported to range from 2% to 20%. These widely varying estimates have led to confusion and controversy regarding the safety of vancomycin among neonates. OBJECTIVE: Evaluate the incidence of nephrotoxicity among neonates receiving vancomycin concomitantly with gentamicin. DESIGN: Retrospective observational cohort study using propensity score matching to provide covariate balance between neonates who did or did not receive vancomycin based on factors known to be related to the development of renal dysfunction. SETTING: Hospitals (n=22) throughout the Intermountain West, including a quaternary care children's hospital. PATIENTS: Neonates ≤44 postmenstrual weeks (median gestational age: 31 (IQR 28-36) weeks) receiving intravenous gentamicin with or without exposure to vancomycin from January 2006 to December 2012. MAIN OUTCOME MEASURES: Nephrotoxicity based on the modified Acute Kidney Injury Network criteria for acute kidney injury (AKI) or serum creatinine concentration ≥1.5 mg/dL persisting for ≥48 h. RESULTS: The final cohort was comprised of 1066 neonates (533 receiving vancomycin and gentamicin vs 533 receiving gentamicin). In a propensity score-matched cohort that was well balanced across 16 covariates, AKI was not associated with vancomycin use (16 neonates receiving vancomycin vs 7 controls experienced AKI; OR 1.5; 95% CI 0.6 to 4.0). However, the presence of a patent ductus arteriosus, concomitant non-steroidal anti-inflammatory drug use, ≥1 positive blood cultures, low birth weight and higher severity of illness and risk of mortality scores were associated with an increased risk of nephrotoxicity. CONCLUSIONS: These results corroborate several earlier reports and much anecdotal evidence describing the infrequent occurrence of nephrotoxicity in neonates receiving concomitant vancomycin and gentamicin.

Challenges Associated with Route of Administration in Neonatal Drug Delivery.

The administration of drugs to neonates poses significant challenges. The aim of this review was to provide insight into some of these challenges and resolutions that may be encountered with several of the most commonly used routes of administration and dosage forms in neonatal care, including oral, parenteral, transdermal, intrapulmonary, and rectal. Important considerations include fluctuations in stomach pH hours to years after birth, the logistics of setting up an intravenous infusion, the need for reduced particle size for aerosol delivery to the developing neonatal lung, and variation in perirectal venous drainage. Additionally, some of the recently developed technologies for use in neonatal care are described. While the understanding of neonatal drug delivery has advanced over the past several decades, there is still a deficiency of technologies and formulations developed specifically for this population.

Pregnancy-induced changes in the pharmacokinetics of caffeine and its metabolites.

This study sought to assess the pharmacokinetic (PK) changes of caffeine and its CYP1A2 metabolites across the 3 trimesters of pregnancy. A prospective, multicenter PK study was conducted among 59 pregnant women (93.2% white) who were studied once during a trimester. One beverage with 30-95 mg caffeine was consumed, and a blood/urine sample was collected within 1 hour postingestion. Concentrations of caffeine and its primary metabolites were quantified from serum and urine by LC-MS/MS. There was a significant increase in dose-normalized caffeine serum and urine concentrations between the first and third trimesters (P < .05 and P < .01, respectively). Normalized theophylline concentrations also increased significantly in the third trimester in serum (P < .001) and in urine (P < .05). The caffeine urine/serum concentration ratio also increased in the last trimester (P < .05). No significant difference was found in normalized paraxanthine or theobromine concentrations. This study identified decreased caffeine metabolism and an increase in the active metabolite theophylline concentrations during pregnancy, especially in the third trimester, revealing evidence of the large role that pregnancy plays in influencing caffeine metabolism.

Evaluation of Vancomycin Use in Late-Onset Neonatal Sepsis Using the Area Under the Concentration-Time Curve to the Minimum Inhibitory Concentration ≥400 Target.

AIM: To develop a vancomycin population pharmacokinetic model and assess the probability of attaining a pharmacodynamic target associated with clinical and microbiological success, a ratio of the 24-hour area under the concentration-time curve to the minimum inhibitory concentration (MIC) ≥ 400, in a 5-year clinical cohort of preterm and term neonatal patients with late-onset staphylococcal sepsis. METHODS: Therapeutic drug monitoring data were obtained from septic neonates with ≥1 vancomycin concentration(s) from January 2006 to September 2011. Only neonates with a postnatal age of >72 hours and a positive microbiological culture were included. Population pharmacokinetic model was developed using nonlinear mixed effects modeling (NONMEM 7.2). Eleven demographic characteristics were evaluated as covariates. Probabilities of achieving the pharmacodynamic target were evaluated. RESULTS: A 1-compartment model with first-order elimination was constructed from 528 vancomycin concentrations collected from 152 preterm and term neonates. Body weight, creatinine clearance (CL), and postmenstrual age were identified as significant covariates. Estimated vancomycin CL and volume of distribution for typical neonates were 0.068 ± 0.03 L·h·kg and 0.62 ± 0.13 L/kg, respectively. Coagulase-negative staphylococci (85.5%) and Staphylococcus aureus (14.5%) were the common pathogenic organisms. The distribution of vancomycin MIC breakpoints was composed of approximately 70% MIC breakpoint of ≤2 mcg/mL. Approximately 54% of neonates, with a median serum creatinine concentration of 0.44 mg/dL, achieved the target ratio of 24-hour area under the concentration-time curve to the MIC ≥ 400 with a median daily dose of 30 (interquartile range, 21-42) mg/kg. CONCLUSIONS: Body weight, creatinine CL, and postmenstrual age significantly influenced vancomycin CL. The current vancomycin doses are acceptable at MICs ≤1 mcg/mL because they are likely to achieve the pharmacodynamic target in the majority of neonatal patients, although higher doses may be considered for more resistant staphylococcal infections.

Comanagement of Pediatric Depression and Obesity: A Clear Need for Evidence.

PURPOSE: The purpose of this article is to provide a review of the existing literature for the comanagement of depression and obesity in the pediatric population. METHODS: A review of the current literature was conducted using EBSCOhost and EMBASE to identify evidence and recommendations for the comanagement of depression and obesity among children and adolescents (aged 2-18 years). Additional search criteria included peer-reviewed, English language-only full-text articles published before August 2015. FINDINGS: Multiple factors contribute to and influence the interplay of obesity and depression in the pediatric population. These 2 chronic conditions are affected by multiple factors, including the roles of the family, school, health care practitioners, and access to health care. In addition, there are no formal recommendations for the treatment of depression in the setting of obesity for pediatric or adult populations, and there is only medication approved by the Food and Drug Administration (orlistat) for the treatment of obesity in the adolescent population. Bariatric surgery may play a role in some adolescents, but larger and long-term clinical studies with the use of therapeutic agents in conjunction with lifestyle modification need to be conducted to support this. IMPLICATIONS: The interrelatedness of these 2 separate diseases is not well understood; the presence of 1 of the diseases clearly contributes to the manifestation of the other and likely to the ability to treat the other disease. Current focus is on modifying behavior to decrease weight. Weight loss is associated with improvement in depressive symptoms but may not be adequate to treat depression.

Special population considerations and regulatory affairs for clinical research.

Special populations, including women (non-pregnant and pregnant), pediatrics, and the elderly, require additional consideration with regard to clinical research. There are very specific regulatory laws, which protect these special populations, that need to be understood and adhered to in order to perform clinical research. This review provides a broad overview of some of the physiological differences in special populations and discusses how these differences may affect study design and regulatory considerations. These various special populations, with respect to regulatory affairs, are clearly defined within the Code of Federal Regulations. The definition of "special population" exists to provide enhanced awareness of their vulnerabilities, thereby allowing the creation of regulatory guidance aimed to decrease injury or outright harm. Currently, progress is being made to be more inclusive of special populations in clinical trials. This reflects changing attitudes towards drug information, with it being more representative of those patients that will ultimately be prescribed or exposed to the therapy. However, all research undertaken in these populations should be performed in a manner that ensures all protections of each participant are upheld.

Quantitative Assay Validation for Oxandrolone in Human Plasma Using LC-MS-MS.

A high-performance liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for the determination of oxandrolone concentration in human plasma (0.5 mL) was developed and validated according to the 2001 FDA Bioanalytical Guidelines. Oxandrolone is an anabolic steroid used to promote weight gain for cachectic patients with severe burn injuries, HIV/AIDS, hepatitis C and other wasting syndromes. The assay procedure involved a liquid-liquid extraction of oxandrolone and methyltestosterone (the internal standard, IS) from plasma with n-butyl chloride. The organic layer was clarified by centrifugation and evaporated to dryness under a stream of air. The residue was reconstituted in a solution containing 25% methanol and 75% Milli-Q water, and injected onto a Luna C18 reversed-phase HPLC column (30 mm × 2.0 mm, 2 µm). Separation of oxandrolone and methyltestosterone was achieved with a mobile phase starting composition of 55% methanol and 45% ammonium formate buffer at a flow rate of 0.1 mL/min. The total run time was 21 min per sample. Selected reaction monitoring mode was used for quantifying oxandrolone (m/z 307 → 271) and the IS, methyltestosterone (m/z 301 → 149). To the authors' knowledge, this is the first LC-MS-MS method validated for oxandrolone quantification in human plasma. This method can be used in future pharmacokinetic studies involving oxandrolone.

Darbepoetin administration to neonates undergoing cooling for encephalopathy: a safety and pharmacokinetic trial.

BACKGROUND: Despite therapeutic hypothermia, neonates with encephalopathy (NE) have high rates of death or disability. Darbepoetin alfa (Darbe) has comparable biological activity to erythropoietin, but has extended circulating half-life (t(1/2)). Our aim was to determine Darbe safety and pharmacokinetics as adjunctive therapy to hypothermia. STUDY DESIGN: Thirty infants (n = 10/arm) ≥36 wk gestation undergoing therapeutic hypothermia for NE were randomized to receive placebo, Darbe low dose (2 µg/kg), or high dose (10 µg/kg) given intravenously within 12 h of birth (first dose/hypothermia condition) and at 7 d (second dose/normothermia condition). Adverse events were documented for 1 mo. Serum samples were obtained to characterize Darbe pharmacokinetics. RESULTS: Adverse events (hypotension, altered liver and renal function, seizures, and death) were similar to placebo and historical controls. Following the first Darbe dose at 2 and 10 µg/kg, t(1/2) was 24 and 32 h, and the area under the curve (AUC(inf)) was 26,555 and 180,886 h*mU/ml*, respectively. In addition, clearance was not significantly different between the doses (0.05 and 0.04 l/h). At 7 d, t(1/2) was 26 and 35 h, and AUC(inf) was 10,790 and 56,233 h*mU/ml*, respectively (*P < 0.01). CONCLUSION: Darbe combined with hypothermia has similar safety profile to placebo with pharmacokinetics sufficient for weekly administration.

Population Pharmacokinetics of Darbepoetin Alfa in Conjunction with Hypothermia for the Treatment of Neonatal Hypoxic-Ischemic Encephalopathy.

AIM: The aim of this study was to determine the population pharmacokinetics of darbepoetin alfa in hypothermic neonates with hypoxic-ischemic encephalopathy treated with hypothermia. METHODS: Neonates ≥36 weeks gestation and <12 h postpartum with moderate to severe hypoxic-ischemic encephalopathy who were undergoing hypothermia treatment were recruited in this randomized, multicenter, investigational, new drug pharmacokinetic study. Two intravenous darbepoetin alfa treatment groups were evaluated: 2 and 10 µg/kg. Serum erythropoietin concentrations were measured using an enzyme-linked immunosorbent assay. Monolix 4.3.1 was used to estimate darbepoetin alfa clearance and volume of distribution. Covariates tested included: birthweight, gestational age, postnatal age, postmenstrual age, sex, Sarnat score, and study site. RESULTS: Darbepoetin alfa pharmacokinetics were well described by a one-compartment model with exponential error. Clearance and the volume of distribution were scaled by birthweight (centered on the mean) a priori. Additionally, gestational age (also centered on the mean) significantly affected darbepoetin alfa clearance. Clearance and volume of distribution were estimated as 0.0465 L/h (95% confidence interval 0.0392-0.0537) and 1.58 L (95% confidence interval 1.29-1.87), respectively. CONCLUSIONS: A one-compartment model successfully described the pharmacokinetics of darbepoetin alfa among hypothermic neonates treated for hypoxic-ischemic encephalopathy. Clearance decreased with increasing gestational age.

Predictive Performance of a Vancomycin Population Pharmacokinetic Model in Neonates.

INTRODUCTION: The pharmacokinetics of vancomycin are highly variable among neonates, which makes dosing challenging in this population. However, adequate drug exposure is critical, especially when treating methicillin-resistant Staphylococcus aureus (MRSA) infections. Utilization of population pharmacokinetic models and Bayesian methods offers the potential for developing individualized therapeutic approaches. To meet this need, a neonatal vancomycin population pharmacokinetic model was recently published. The current study sought to externally evaluate the predictive performance and generalizability of this model. METHODS: A retrospective chart review of neonates who received vancomycin and had ≥1 peak and ≥1 trough concentrations at five Intermountain Healthcare neonatal intensive care units from 2006 to 2013 was performed and served as the external validation cohort. The published population pharmacokinetic model was implemented in NONMEM 7.2 with the structural and variance parameter values set equal to the estimates reported previously. The model was then used to predict the first peak and trough concentration for each neonate in the validation cohort and the model prediction error and absolute prediction error were calculated. Normalized prediction distribution errors (NPDE) were also evaluated. RESULTS: A total of 243 neonates were studied with a median postmenstrual age of 33 (range: 23-54) weeks and a median weight of 1.6 (range: 0.4-6.8) kg. The model predicted the observed vancomycin concentrations with reasonable precision. For all vancomycin concentrations, the median prediction error was -0.8 (95% CI: -1.4 to -0.4) mg/L and the median absolute prediction error was 3.0 (95% CI: 2.7-3.5) mg/L. No trends in NPDE across weight, postmenstrual age, serum creatinine, or time after dose were observed. CONCLUSION: An evaluation of a recently published neonatal vancomycin population pharmacokinetic model in a large external dataset supported the predictive performance and generalizability of the model. This model may be useful in evaluating neonatal vancomycin dosing regimens and estimating the extent of drug exposure.

Application of a method used to deconstruct a single dose pharmacokinetic profile from multiple dose data.

With traditional non-compartmental methods, it is challenging to deconstruct plasma concentration versus time curves to assess the influence of individual doses. This study describes the application of a mathematical approach used to deconstruct a single dose curve using data derived from the second, third, fourth or nth dosing interval. Using data from a prospective clinical trial it is demonstrated that this approach reliably estimates pharmacokinetic parameters measured following two doses of zolpidem tartrate. Additionally, the study demonstrates the application of this approach using previously published data from a single- and multiple-dose pharmacokinetic study of the antibiotic gatifloxacin. Copyright © 2015 John Wiley & Sons, Ltd.

National trends in the incidence, outcomes and charges of pediatric osteoarticular infections, 1997-2012.

In the United States, the incidence of osteoarticular infections among hospitalized children increased 15% from 2.07 to 2.38 cases per 1000 admissions from 1997 through 2012. The incidence of methicillin-resistant Staphylococcus aureus-coded infections increased from 0.02 to 0.36 cases per 1000 admissions. Methicillin-resistant S. aureus-coded cases had a larger number of therapeutic procedures, longer hospital stays and higher hospital charges.