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.

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.

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.

Development of an optimal sampling schedule for children receiving ketamine for short-term procedural sedation and analgesia.

BACKGROUND: Intravenous racemic ketamine is commonly administered for procedural sedation, although few pharmacokinetic studies have been conducted among children. Moreover, an optimal sampling schedule has not been derived to enable the conduct of pharmacokinetic studies that minimally inconvenience study participants. METHODS: Concentration-time data were obtained from 57 children who received 1-1.5 mg·kg(-1) of racemic ketamine as an intravenous bolus. A population pharmacokinetic analysis was conducted using nonlinear mixed effects models, and the results were used as inputs to develop a D-optimal sampling schedule. RESULTS: The pharmacokinetics of ketamine were described using a two-compartment model. The volume of distribution in the central and peripheral compartments were 20.5 l∙70 kg(-1) and 220 l∙70 kg(-1), respectively. The intercompartmental clearance and total body clearance were 87.3 and 87.9 l·h(-1) ∙70 kg(-1), respectively. Population parameter variability ranged from 34% to 98%. Initially, blood samples were drawn on 3-6 occasions spanning a range of 14-152 min after dosing. Using these data, we determined that four optimal sampling windows occur at 1-5, 5.5-7.5, 10-20, and 90-180 min after dosing. Monte Carlo simulations indicated that these sampling windows produced precise and unbiased ketamine pharmacokinetic parameter estimates. CONCLUSION: An optimal sampling schedule was developed that allowed assessment of the pharmacokinetic parameters of ketamine among children requiring short-term procedural sedation.

Optimal design in pediatric pharmacokinetic and pharmacodynamic clinical studies.

It is not trivial to conduct clinical trials with pediatric participants. Ethical, logistical, and financial considerations add to the complexity of pediatric studies. Optimal design theory allows investigators the opportunity to apply mathematical optimization algorithms to define how to structure their data collection to answer focused research questions. These techniques can be used to determine an optimal sample size, optimal sample times, and the number of samples required for pharmacokinetic and pharmacodynamic studies. The aim of this review is to demonstrate how to determine optimal sample size, optimal sample times, and the number of samples required from each patient by presenting specific examples using optimal design tools. Additionally, this review aims to discuss the relative usefulness of sparse vs rich data. This review is intended to educate the clinician, as well as the basic research scientist, whom plan on conducting a pharmacokinetic/pharmacodynamic clinical trial in pediatric patients.

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.

Preliminary assessment of zolpidem pharmacokinetics in pediatric burn patients.

PURPOSE: Severely burned patients frequently experience sleep fragmentation and insomnia. This study evaluated the population pharmacokinetics of the sleep-enhancing agent zolpidem among burned children. METHODS: Zolpidem was administered according to the following age-based dosing schedule: 2.5 mg per dose for 2-4 year olds, 5.0 mg per dose for 5-10 year olds, and 10 mg per dose for older than 10 years. Serum samples were collected before and 1, 2, 4, 5, 6, and 8 hours after dosing. The population pharmacokinetic analysis modeled zolpidem concentrations using nonlinear mixed effects models. RESULTS: Eleven patients with a mean (±SD) age of 8.3 ± 4.0 years and a mean total burn surface area of 56% ± 22% were recruited. Seventy-three zolpidem concentrations were measured with a mean Cmax of 291 ± 140 ng/mL. A 2-compartment model with first-order absorption best described the data. Zolpidem clearance was estimated at 0.03 L·h(-1)·kg(-1) (relative standard error, 55%) and increased with body weight (P < 0.05). The central compartment volume of distribution was estimated at 0.05 L/kg (relative standard error, 25%), which was inversely related to the proportion of the body surface with third-degree burns (P < 0.001). CONCLUSIONS: A population pharmacokinetic model has been developed that reliably characterized the pharmacokinetic parameters of zolpidem when used as a sleep-enhancing agent among pediatric burn patients. Additional studies are needed to link this pharmacokinetic model with pharmacodynamic data, which may include an assessment of the effects of higher zolpidem doses and/or more frequent administration upon sleep architecture.

Intrapartum magnesium sulfate and the potential for cardiopulmonary drug-drug interactions.

BACKGROUND: This study sought to determine the frequency of possible cardiopulmonary drug-drug interactions among pregnant women who received intrapartum magnesium sulfate (MgSO4). METHODS: Pregnant women admitted to an Intermountain Healthcare facility between January 2009 and October 2011 were studied, if they received 1 or more doses of MgSO4. Concomitant medications were electronically queried from an electronic health records system. Adverse events were identified using administrative discharge codes. The frequency of cardiopulmonary drug-drug interactions was compared among women who did, and did not, receive aminoglycoside antibiotics, antacids/laxatives, calcium channel blockers, corticosteroids, diuretics, neuromuscular blocking agents, and vitamin D analogs, all of which were contraindicated for patients receiving MgSO4. RESULTS: Overall, 683 women received intrapartum MgSO4 during the study period. A total of 219 MgSO4 potentially interacting drugs were identified among 155 (23%) unique patients. The most commonly identified potentially interacting agents included calcium channel blockers (26%), diuretics (25%), and antacids/laxatives (19%). Longer hospital stays were significantly associated with increasing numbers of MgSO4 interacting drugs (P < 0.001). Three of 53 (6%) women who received furosemide experienced a cardiac arrest, compared with 0 of 618 (0%) women who did not receive furosemide (Fisher exact test, P < 0.001). CONCLUSIONS: Intrapartum administration of drugs that interact with MgSO4 is common and associated with prolonged hospital stays and potentially cardiopulmonary drug-drug interactions. Caution is warranted when prescribing MgSO4 in combination with known interacting medications.

Pharmacokinetic and pharmacodynamic optimisation of intravenous tobramycin dosing among children with cystic fibrosis.

This study aimed to characterize the pharmacokinetics of tobramycin administered one, two, or three times daily and to develop an optimal dosing scheme for children with cystic fibrosis. Therapeutic drug monitoring data were obtained from children hospitalized at three academic medical centres from 2006 to 2012. Population pharmacokinetic models were constructed using NONMEM 7.2. Model-based simulations were performed in Matlab R2012b to identify optimal dosing regimens using pharmacodynamic targets. The pharmacokinetic analysis involved 257 patients with a median age of 8.1 years (range 0.1-18.8). Clearance was estimated as 5.59 L/h and the volume of distribution was 18.90 L. Mean (±SD) maximum serum concentrations were highest among patients dosed once per day (24.1 ± 8.9 µg/mL) and were lower among patients dosed two and three times per day (11.2 ± 1.4 and 8.1 ± 2.4 µg/mL, respectively). Simulations revealed that once daily dosing was the only effective regimen for a Pseudomonas aeruginosa MIC of 1.5 µg/mL and none of the tested regimens reliably achieved the pharmacodynamic target for MICs ≥2 µg/mL. Once daily dosing resulted in higher maximum serum concentrations when compared to multiple-daily dosing. In simulations, once daily dosing was the only regimen to achieve the pharmacodynamic target for all subjects with MICs <2 µg/mL.

Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza.

BACKGROUND: Children <2 years of age are at high risk of influenza-related mortality and morbidity. However, the appropriate dose of oseltamivir for children <2 years of age is unknown. METHODS: The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group evaluated oseltamivir in infants aged <2 years in an age-de-escalation, adaptive design with a targeted systemic exposure. RESULTS: From 2006 to 2010, 87 subjects enrolled. An oseltamivir dose of 3.0 mg/kg produced drug exposures within the target range in subjects 0-8 months of age, although there was a greater degree of variability in infants <3 months of age. In subjects 9-11 months of age, a dose of 3.5 mg/kg produced drug exposures within the target range. Six of 10 subjects aged 12-23 months receiving the Food and Drug Administration-approved unit dose for this age group (ie, 30 mg) had oseltamivir carboxylate exposures below the target range. Virus from 3 subjects developed oseltamivir resistance during antiviral treatment. CONCLUSIONS: The appropriate twice-daily oral oseltamivir dose for infants ≤8 months of age is 3.0 mg/kg, while the dose for infants 9-11 months old is 3.5 mg/kg.

Epidemiological Evaluation of Blood Culture Patterns among Neonates Receiving Vancomycin.

The objective of this study was to assess the frequency of blood culture (BC) collection among neonates who received vancomycin. Demographic, clinical, microbiologic, and pharmacy data were collected for 1275 neonates (postnatal age 0-27 days) who received vancomycin at an Intermountain Healthcare facility between 1/2006 and 9/2011. Neonates treated with vancomycin had a BC collected 94 % (n = 1198) of the time, of which 37 % (n = 448) grew one or more bacterial organisms (BC positive). Of these, 1 % (n = 5) grew methicillin-resistant Staphylococcus aureus (MRSA), 71 % (n = 320) grew coagulase-negative Staphylococci (CoNS), 9 % (n = 40) grew methicillin-sensitive Staphylococcus aureus (MSSA), and 22 % (n = 97) grew other bacterial species (total exceeds 100 % due to co-detection). In patients with negative BC or no BC, vancomycin therapy was extended beyond 72 h 52 % of the time. The median duration of vancomycin therapy for patients with a negative BC was 4 (IQR: 2-10) days. BCs were frequently obtained among neonates who received vancomycin. Vancomycin therapy beyond the conventional 'empiric' treatment window of 48-72 h was common without isolation of resistant gram-positive bacteria.

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.

Pharmacology and pharmacogenomics of neurological medications used in pregnancy.

Pregnancy increases the pharmacological management challenge of numerous neurological diseases as a result of complex physiological changes. Understanding pregnancy-induced changes in pharmacokinetic and pharmacodynamic parameters can lead to better outcomes for both the mother and baby. Although the application of pharmacogenomics in maternal-fetal medicine is in its infancy, further research and developments will provide important new developments for managing the efficacy of drug treatments during pregnancy and improving maternal-fetal safety. Although a wide variety of neurological medications are used during pregnancy, this article will focus on the drugs with currently known pharmacogenomic implications.

Optimal study design for pioglitazone in septic pediatric patients.

The objective was to demonstrate the methodology and process of optimal sparse sampling pharmacokinetics (PK). This utilized a single daily dose of pioglitazone for pediatric patients with severe sepsis and septic shock based upon adult and minimal adolescent data. Pioglitazone pharmacokinetics were modeled using non-compartment analysis WinNonlin Pro (version 5.1) and population kinetics using NONMEM (version 7.1) with first order conditional estimation method (FOCE) with interaction. The initial model was generated from single- and multiple-dose pioglitazone PK data (15 mg, 30 mg, and 45 mg) in 36 adolescents with diabetes. PK models were simulated and overlaid upon original data to provide a comparison best described by a single compartment, first order model. The optimal design was based on the simulated oral administration of pioglitazone to three groups of pediatric patients, age 3.8 (2-6 years), weight 14.4 (7-28 kg); age 9.6 (6.1-11.9 years), weight 36.5 (28.1-48 kg) and age 15.5 (12-17 years,) weight 61.6 (48.1-80 kg). PFIM (version 3.2) was used to evaluate sample study size. Datasets were compiled using simulation for each dose (15, 30 and 45 mg) for the potential age/weight groups. A target dose of 15 mg daily in the youngest and middle groups was considered appropriate with area under the curve exposure levels (AUC) comparable to studies in adolescents. The final optimal design suggested time points of 0.5, 2, 6 and 21 h for 24 h dosing. This methodology provides a robust method of utilizing adult and limited adolescent data to simulate allometrically scaled, pediatric data sets that allow the optimal design of a pediatric trial. The pharmacokinetics of pioglitazone were described adequately and simulated data estimates were comparable to literature values. The optimal design provided clinically attainable sample times and windows.

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.

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.