Age-Dependent Abundance of CYP450 Enzymes Involved in Metronidazole Metabolism: Application to Pediatric PBPK Modeling.

The expression of cytochrome P450 (CYP) enzymes is highly variable and associated with factors, such as age, genotype, sex, and disease states. In this study, quantification of metronidazole metabolizing CYP isoforms (CYP2A6, CYP2E1, CYP3A4, CYP3A5, and CYP3A7) in human liver microsomes from 115 children and 35 adults was performed using a quantitative proteomics method. The data confirmed age-dependent increase in CYP2A6, CYP2E1, and CYP3A4 abundance, whereas, as expected, CYP3A7 abundance showed postnatal decrease with age. In particular, the fold difference (neonatal to adulthood levels) in the protein abundance of CYP2A6, CYP2E1, and CYP3A4 was 14, 11, and 20, respectively. In contrast, protein abundance of CYP3A7 was > 125-fold higher in the liver microsomes of neonates than of adults. The abundance of CYP2A6 and CYP3A5 was associated with genotypes, rs4803381 and rs776746, respectively. A proteomics-informed physiologically based pharmacokinetic (PBPK) model was developed to describe the pharmacokinetics of metronidazole and its primary metabolite, 2-hydroxymethylmetronidazole. The model revealed an increase in the metabolite-to-parent ratio with age and showed a strong correlation between CYP2A6 abundance and metabolite formation (r2 = 0.75). Notably, the estimated contribution of CYP3A7 was ~ 75% in metronidazole clearance in neonates. These data suggest that variability in CYP2A6 and CYP3A7 in younger children poses the risk of variable pharmacokinetics of metronidazole and its active metabolite with a potential impact on drug efficacy and safety. No sex-dependent difference was observed in the protein abundance of the studied CYPs. The successful integration of hepatic CYP ontogeny data derived from a large liver bank into the pediatric PBPK model of metronidazole can be extended to other drugs metabolized by the studied CYPs.

Feasibility of adolescent contraceptive care in the pediatric emergency department: A pilot randomized controlled trial.

BACKGROUND: This study assessed feasibility constructs of adolescent contraceptive care in the pediatric emergency department (PED), including contraception initiation. METHODS: We conducted a randomized trial in two PEDs with pregnancy-capable adolescents aged 15-18 years who were assigned to enhanced usual care (usual) or same-day initiation (same day). All received counseling and clinic referral, but same-day participants could also receive contraception in the PED. We trained PED clinicians in counseling and prescribing. Adolescents and clinicians rated feasibility using five Likert-type items (1 = strongly disagree to 5 = strongly agree) after the session. We assessed PED medication initiation and appropriateness via medical record review and contraception use and side effects at 30 days via adolescent survey. To further explore feasibility, we conducted clinician interviews at study completion; these were audio-recorded, transcribed, and analyzed. We hypothesized contraceptive care would be feasible (defined as average score ≥ 4 across five survey items). RESULTS: We enrolled 37 adolescents (12 in usual and 25 in same-day), mean age was 16.6 years, 73% were Black, and 19% were Hispanic. We trained 27 clinicians. Average feasibility scores were 4.6 ± 0.4 (adolescents) and 4.1 ± 0.8 (clinicians). Eleven (44%) same-day participants initiated contraception in the PED. One adolescent with migraines initially received estrogen-containing pills; this was corrected after discharge. At 30 days, same-day participants were more likely to report contraception use (78% vs. 13%; p = 0.007). One adolescent reported bloating as a side effect. Clinicians enjoyed delivering contraceptive care, found study resource materials useful, and identified staffing shortages as a barrier to care delivery. CONCLUSIONS: We are among the first to report on PED-based adolescent contraception initiation to prevent unintended pregnancy. Adolescents and clinicians reported that contraceptive care was feasible. Initiation was common and medications were largely appropriate and tolerated. Future efforts should explore integrating contraceptive care into routine PED care.

Pharmacogenetics and Oxcarbazepine in Children and Adolescents: Beyond HLA-B*15:02.

Background: Oxcarbazepine is thought to be better-tolerated and less susceptible to drug-drug interactions than its predecessor, carbamazepine. Genetic testing for HLA-B*15:02 is recommended in specific populations to identify those at high risk of severe hypersensitivity reactions; however, other pharmacologic and pharmacogenetic factors that can impact drug disposition may be involved. Methods: We present a case of an 8-year-old boy treated with oxcarbazepine who developed drug reaction with eosinophilia and systemic symptoms (DRESS) with Stevens-Johnsons syndrome overlap and was negative for HLA-B*15:02. We review the extant literature related to oxcarbazepine disposition, and potential pharmacogenetic variants in aldoketoreductase 1C (AKR1C)2-4 that may contribute to this risk. Results: Genetic variability in oxcarbazepine disposition pathways may contribute to tolerability and toxicity, including the development of hypersensitivity reactions. Conclusions: While preemptive genetic testing for HLA-B*15:02 in individuals of Asian ancestry is recommended to prevent severe hypersensitivity reactions to oxcarbazepine, oxcarbazepine concentrations and AKR1C variation may contribute to the risk of severe adverse reactions. We provide recommendations for future study to elucidate whether these individual factors are important for reducing the risk of severe adverse events.

Ontogeny of Scaling Factors for Pediatric Physiologically Based Pharmacokinetic Modeling and Simulation: Cytosolic Protein Per Gram of Liver.

Scaling factors are necessary for translating in vitro drug biotransformation data to in vivo clearance values in physiologically-based pharmacokinetic modeling and simulation. Values for microsomal protein per gram of liver are available from several sources for use as a scaling factor to estimate hepatic clearance from microsomal drug biotransformation data. However, data regarding the distribution of cytosolic protein per gram of liver (CPPGL) values across the lifespan are limited, and sparse pediatric data have been published to date. Thus, CPPGL was determined in 160 liver samples from pediatric (n = 129) and adult (n = 31) donors obtained from multiple sources: the University of Maryland Brain and Tissue Bank, tissue retrieval services at the University of Minnesota and University of Pittsburgh, and Sekisui-XenoTech. Tissues were homogenized and subjected to differential centrifugation to isolate cytosolic fractions. Cytosolic protein content was determined by BCA assay. CPPGL varied from two- to sixfold within each age group/developmental stage. Tissue source and sex did not contribute substantially to variability in protein content. Regression analyses revealed minimal change in CPPGL over the first two decades of life (logCPPGL increases 0.1 mg/g per decade). A mean ± S.D. CPPGL value of 44.4 ± 17.4 mg/g or median 41.0 mg/g is representative of values observed between birth and early adulthood (0-18 years, n = 129). SIGNIFICANCE STATEMENT: Cytosolic protein per gram of liver (CPPGL) is a scaling factor required for physiologically based pharmacokinetic modeling and simulation of drug biotransformation by cytosolic enzymes, but pediatric data are limited. Although CPPGL varies from two- to sixfold within developmental stages, a value of 44.4 ± 17.4 mg/g (mean ± S.D.) is representative of the pediatric period (0-18 years, n = 129).

Potential biomarker of brain response to opioid antagonism in adolescents with eating disorders: a pilot study.

Background: Eating Disorders (ED) affect up to 5% of youth and are associated with reward system alterations and compulsive behaviors. Naltrexone, an opioid antagonist, is used to treat ED behaviors such as binge eating and/or purging. The presumed mechanism of action is blockade of reward activation; however, not all patients respond, and the optimal dose is unknown. Developing a tool to detect objective drug response in the brain will facilitate drug development and therapeutic optimization. This pilot study evaluated neuroimaging as a pharmacodynamic biomarker of opioid antagonism in adolescents with ED. Methods: Youth aged 13-21 with binge/purge ED completed functional magnetic resonance imaging (fMRI) pre- and post-oral naltrexone. fMRI detected blood oxygenation-level dependent (BOLD) signal at rest and during two reward probes (monetary incentive delay, MID, and passive food view, PFV) in predefined regions of interest associated with reward and inhibitory control. Effect sizes for Δ%BOLD (post-naltrexone vs. baseline) were estimated using linear mixed effects modeling. Results: In 12 youth (16-21 years, 92% female), BOLD signal changes were detected following naltrexone in the nucleus accumbens during PFV (Δ%BOLD -0.08 ± 0.03; Cohen's d -1.06, p = 0.048) and anterior cingulate cortex during MID (Δ%BOLD 0.06 ± 0.03; Cohen's d 1.25, p = 0.086). Conclusion: fMRI detected acute reward pathway modulation in this small sample of adolescents with binge/purge ED. If validated in future, larger trials, task-based Δ%BOLD detected by fMRI may serve as a pharmacodynamic biomarker of opioid antagonism to facilitate the development of novel therapeutics targeting the reward pathway, enable quantitative pharmacology trials, and inform drug dosing. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04935931, NCT#04935931.

Feasibility of a Contraception Intervention for Hospitalized Adolescents and Young Adults.

OBJECTIVES: Unintended pregnancy in adolescents and young adults (AYAs) is linked with negative outcomes. We sought to evaluate the feasibility, acceptability, and preliminary efficacy of a contraception intervention in the pediatric hospital. METHODS: We conducted a pilot study of hospitalized AYA females aged 14 to 21 years who reported past or anticipated sexual activity. A health educator offered a tablet-based intervention to provide contraception education and medications, if desired. We assessed feasibility (ie, intervention completion, duration, disruption to care), acceptability (ie, proportion rating as acceptable or satisfactory) among AYAs, parents or guardians, and healthcare providers, as well as preliminary efficacy (eg, contraception uptake) at enrollment and 3-month follow up. RESULTS: We enrolled 25 AYA participants; mean age was 16.4 ± 1.5 years. The intervention demonstrated high feasibility as all enrolled participants (n = 25, 100%) completed the intervention and median intervention duration was 32 (interquartile range 25-45) minutes. Among 11 nurses, 82% (n = 9) reported the intervention was not at all or minimally disruptive to their workflow. All AYAs were very or somewhat satisfied with the intervention and 88% (n = 7) of 8 parents and guardians surveyed felt it was acceptable for the educator to meet privately with their child. Eleven participants (44%) started hormonal contraception, most commonly the subdermal implant (n = 7, 64%), and 23 (92%) received condoms. CONCLUSIONS: Our findings support the feasibility and acceptability of our contraception intervention in the pediatric hospital resulting in contraception uptake among AYAs. Efforts to expand access to contraception are important to reduce unintended pregnancy, especially as restrictions to abortion are increasing in some states.

Effects of genotype and food on naltrexone exposure in adolescents.

Naltrexone (NTX), an opioid antagonist metabolized by aldo-keto reductase 1C4 (AKR1C4), is prescribed for psychiatric conditions like eating disorders with variable response. Systemic exposure is highly variable in adults, yet no data exist in children. The purpose of this study was to evaluate NTX exposure in adolescents with eating disorders. Adolescents aged 12-21 years with eating disorders underwent postdose blood sampling in the fasted and/or fed state. NTX and primary active metabolite, 6-ß-naltrexol, were determined by ultra-high performance liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartmental analysis. DNA was genotyped for AKR1C4 missense mutations associated with decreased activity (rs3829125 and rs17134592). Linear mixed effects modeling was performed. In 21 participants, aged 16.9 ± 1.9 years (15-21 years), 81% female participants, maximum concentration (Cmax ) was 90.4 ± 129 nM/mg/kg, area under the concentration-time curve from zero to infinity (AUC0-∞ ) was 166 ± 154 nM h/mg/kg, and varied 63-fold and 21-fold, respectively. Compared with wildtype, those with AKR1C4 allelic variations (n = 7) displayed 3.2-fold higher AUC0-∞ , four-fold higher Cmax and delayed time to Tmax . Linear mixed effects modeling demonstrated a large effect of genotype on AUC0-∞ (Cohen's d -2.3) and Cmax (Cohen's d -1.4). Food effect was large for AUC0-∞ (Cohen's d 2.6), but highly variable and failed to reach significance for Cmax. The respective model accounted for 82% of the variance in NTX AUC0-∞ and 46% of the variance in Cmax . NTX systemic exposure is highly variable in adolescents with eating disorders and modulated, in part, by AKR1C4 genotype and food intake. These findings may, in part, explain the large degree of interindividual variability observed response to NTX.

Target to treatment: A charge to develop biomarkers of response and tolerability in child and adolescent psychiatry.

The current pediatric mental health crisis is characterized by staggering rates of depression, anxiety, and suicide. Beyond this, first-line pharmacologic interventions for depressive and anxiety disorders in children and adolescents produce variable responses with two in five youths failing to respond. Given the heterogeneity of treatment response in pediatric depressive and anxiety disorders, pharmacodynamic biomarkers are necessary to develop precision therapeutics by identifying clear targets to guide treatment. This mini-review summarizes candidate biomarkers and their development in pediatric mental health conditions. A framework for how these biomarkers may relate to safety, efficacy (e.g., surrogates for clinical endpoints), tolerability or target engagement (i.e., drug action) in children and adolescents is also presented. Taken together, accumulating data suggest that, in children and adolescents with myriad psychiatric disorders, pharmacodynamic biomarkers could facilitate developing drugs with well-defined targets in specific populations, could inform treatment decisions, and hasten patients' recovery.

The Impact of Age and Genetics on Naltrexone Biotransformation.

Naltrexone, an opioid antagonist primarily metabolized by aldo-keto reductase 1C4 (AKR1C4), treats pediatric conditions involving compulsiveness (e.g., autism spectrum, Prader-Willi, eating disorders, non-suicidal self-injury). Pharmacokinetic variability is apparent in adults, yet no data are available for children. This study aimed to examine the impact of age and genetic variation on naltrexone biotransformation. Human liver cytosol (HLC) samples (n = 158) isolated from children and adult organ donors were incubated with therapeutically relevant concentrations of naltrexone (0.1, 1 µM). Naltrexone biotransformation was determined by ultraperformance mass spectrometry quantification of the primary metabolite, 6-beta-naltrexol (6ßN), and 6ßN formation rates (pmol/mg protein/min) were calculated. HLCs from organ donors, age range 0-79 y (mean 16.0 ± 18.2 y), 37% (n = 60) female, 20% (n = 33) heterozygous and 1.2% (n = 2) homozygous for co-occurring AKR1C4 variants (S145C/L311V) showed >200-fold range in 6ßN formation (0.37-76.5 pmol/mg protein/min). Source of donor samples was found to be a substantial contributor to variability. Model estimates for a trimmed data set of source-adjusted pediatric samples (aged 0-18 y) suggested that AKR1C4 genetic variation, age, and sex explained 36% of the variability in 6ßN formation. Although activity increased steadily from birth and peaked in middle childhood (2-5 years), genetic variation (S145C/L311V) demonstrated a greater effect on activity than did age. Naltrexone biotransformation is highly variable in pediatric and adult livers and can be partly accounted for by individual factors feasible to obtain (e.g., genetic variability, age, sex). These data may inform a precision therapeutics approach (e.g., exposure optimization) to further study Naltrexone responsiveness in children and adults. SIGNIFICANCE STATEMENT: Biotransformation of the commonly used opioid antagonist naltrexone is highly variable and may contribute to reduced therapeutic response. Age, sex, and genetic variation in the drug-metabolizing enzyme, AKR1C4, are potential factors contributing to this variability. In pediatric samples, genetic variation (S145C/L311V) demonstrates a greater impact on activity than age. Additionally, the source of donor samples was identified as an important contributor and must be accounted for to confidently elucidate the biological variables most impactful to drug biotransformation.

Developmental Considerations for the Use of Naltrexone in Children and Adolescents.

Naltrexone (NTX) is a well-tolerated drug with a wide safety margin and mechanism of action that affords use across a wide variety of indications in adults and children. By antagonizing the opioid reward system, NTX can modulate behaviors that involve compulsivity or impulsivity, such as substance use, obesity, and eating disorders. Evidence regarding the disposition and efficacy of NTX is mainly derived from adult studies of substance use disorders and considerable variability exists. Developmental changes, plausible disease-specific alterations and genetic polymorphisms in NTX disposition, and pharmacodynamic pathways should be taken into consideration when optimizing the use of NTX in the pediatric population. This review highlights the current state of the evidence and gaps in knowledge regarding NTX to facilitate evidence-based pharmacotherapy of mental health conditions, for which few pharmacologic options exist.

Long-acting reversible contraceptives (LARCs) as harm reduction: a qualitative study exploring views of women with histories of opioid misuse.

BACKGROUND: The sharp rise in opioid use disorder (OUD) among women coupled with disproportionally high rates of unintended pregnancy have led to a four-fold increase in the number of pregnant women with OUD in the United States over the past decade. Supporting intentional family planning can have multiple health benefits and reduce harms related to OUD but requires a comprehensive understanding of women's perspectives of preventing unintended pregnancies. The purpose of this study was to comprehensively evaluate the knowledge, attitudes and experiences as they relate to seeking contraception, particularly LARCs, among women with active or recovered opioid misuse. METHODS: In-depth interviews and focus group discussions with 36 women with current or past opioid misuse were recorded and transcribed. Transcripts were coded by ≥ 2 investigators. Themes related to contraceptive care seeking were identified and contextualized within the Health Belief Model. RESULTS: Our analysis revealed seven interwoven themes that describe individual level factors associated with contraceptive care seeking in women with current or past opioid misuse: relationship with drugs, reproductive experiences and self-perceptions, sexual partner dynamics, access, awareness of options, healthcare attitudes/experiences, and perceptions of contraception efficacy/ side effects. Overall, perceived susceptibility and severity to unintended pregnancy varied, but most women perceived high benefits of contraception, particularly LARC. However, perceived barriers were too high for most to obtain desired contraception to support family planning intentions. CONCLUSIONS: The individual-level factors identified should inform the design of integrated services to promote patient-centered contraceptive counseling as a form of harm reduction. Interventions should reduce barriers to contraceptive access, particularly LARCs, and establish counseling strategies that use open, non-judgmental communication, acknowledge the continuum of reproductive needs, explore perceived susceptibility to pregnancy, and utilize peer educators.

Profiling Pretomanid as a Therapeutic Option for TB Infection: Evidence to Date.

Tuberculosis (TB) is the most deadly infectious disease globally. Although most individuals achieve a cure, a substantial portion develop multi-drug resistant TB which is exceedingly difficult to treat, and the number of effective agents is dwindling. Development of new anti-tubercular medications is imperative to combat existing drug resistance and accelerate global eradication of TB. Pretomanid (PA-824) represents one of the newest drug classes (ie, nitroimidazooxazines) approved in 2019 by the United States Food and Drug Administration as part of a multi-drug regimen (with bedaquiline and linezolid, BPaL) and recommended by the World Health Organization (WHO) to treat extensively-resistant (XR-TB) and multi-drug resistant tuberculosis (MDR-TB). Approval was granted through the FDA's Limited Population Pathway for Antibacterial and Antifungal Drugs, which accelerates approval for antimicrobial drugs used to treat life-threatening or serious infections in a limited population with unmet need. This review details the pharmacology, efficacy, and safety of this new agent and describes evidence to date for its role in the treatment of drug resistant TB including published, ongoing, and planned studies.

Brief Motivational Intervention to Improve Adolescent Sexual Health Service Uptake: A Pilot Randomized Controlled Trial in the Emergency Department.

OBJECTIVE: To test the hypothesis that our motivational sexual health intervention (SexHealth) would increase health service uptake when compared with control. STUDY DESIGN: In a randomized controlled trial at a pediatric emergency department, sexually active adolescents received either the SexHealth intervention or printed materials (control). SexHealth, delivered by a health educator, was a tablet-based, interactive intervention that included motivational techniques to promote sexual health, condom skills training, and tailored service recommendations. We assessed feasibility (eg, intervention completion, recommendations discussed, intervention duration), acceptability (ie, proportion enrolled and rating intervention as satisfactory), and efficacy; secondary outcomes were sexual and care-seeking behaviors at 6 months. The efficacy outcome was completion of ≥1 service at the index visit (ie, counseling, condoms, emergency contraception for immediate or future use, pregnancy/sexually transmitted infection/HIV testing, sexually transmitted infection treatment, and clinic referral). RESULTS: We enrolled 91 participants (intervention = 44; control = 47). The intervention demonstrated high feasibility: 98% completed the intervention; 98% of recommendations were discussed; duration was 24.6 minutes, and acceptability: 87% of eligible adolescents enrolled and 93% rated the intervention as fairly to very satisfactory. Compared with controls, intervention participants were more likely to complete ≥1 service (98% vs 70%, P < .001) including HIV testing (33% vs 6%, P = .02) and emergency contraception (80% vs 0%, P = .01). There were no meaningful differences between arms in behaviors at follow-up. CONCLUSIONS: SexHealth was feasible to implement, acceptable to youth, and resulted in increased uptake of health services during the emergency department visit. Additional strategies may be needed to extend intervention effects over time. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT03341975.

Adolescent perceptions of pharmacogenetic testing.

Background: Despite the expansion of pharmacogenetics (PGx), the views of pediatric patients remain unknown. This study explores adolescents' understanding and perceptions of PGx testing. Methods: Adolescents who had PGx testing were interviewed and their electronic health records were reviewed. Results: Adolescents accurately described reason for testing and most felt the results impacted their current and future care. None perceived risks to securing future employment or insurance. All felt PGx would benefit their peers. Conclusion: Adolescents understand the reasons for PGx and perceive testing to be useful, low risk and applicable to peers. Findings from this study advocate for the inclusion of adolescents in shared decision-making regarding testing and for active engagement in the discussion of results.

Retrospective Review of Pharmacogenetic Testing at an Academic Children's Hospital.

There is limited evidence to support pharmacogenetic (PGx) testing in children. We conducted a retrospective review of PGx testing among 452 patients at an academic children's hospital to determine the potential utility of PGx in diseases of childhood and to identify targets for future pediatric pharmacogenetic research. An actionable gene-drug pair associated with the 28 genes tested (Clinical Pharmacogenetics Implementation Consortium (CPIC) level A or B, Pharmacogenomics Knowledge Base (PharmGKB) level 1A or B, or US Food and Drug Administration (FDA) recommendation and a PharmGKB level) was present in 98.7% of patients. We identified 203 actionable gene-drug-diagnosis groups based on the indications for each actionable drug listed in Lexicomp. Among patients with an actionable gene-drug-diagnosis group, 49.3% had a diagnosis where the drug was a therapeutic option and PGx could be used to guide treatment selection. Among patients with an associated diagnosis, 30.9% had a prescription for the actionable drug allowing PGx guided dosing. Three genes (CYP2C19, CYP2D6, and CYP3A5) accounted for all the gene-drug-diagnosis groups with matching diagnoses and prescriptions. The most common gene-drug-diagnosis groups with matching diagnoses and prescriptions were CYP2C19-citalopram-escitalopram-depression 3.3% of patients tested; CYP2C19-dexlansoprazole-gastritis-esophagitis 3.1%; CYP2C19-omeprazole-gastritis-esophagitis 2.4%; CYP2D6-atomoxetine-attention deficit hyperactivity disorder 2.2%; and CYP2C19-citalopram-escitalopram-obsessive-compulsive disorder 1.5%. PGx could be used to guide selection of current treatment options or medication dosing in almost half (48.7%) of pediatric patients tested. Mood disorders and gastritis/esophagitis are promising targets for future study of PGx testing because of the high prevalence of these diagnoses and associated actionable gene-drug pairs in the pediatric population.

Expanding Contraception Access for Women With Opioid-Use Disorder: A Qualitative Study of Opportunities and Challenges.

PURPOSE: As almost nine in ten pregnancies among women with opioid use disorder (OUD) are unintended, expanding access to contraception is an underutilized but potentially effective strategy in increasing reproductive agency and reducing the overall burden of neonatal abstinence syndrome. We aimed to identify where and how contraceptive services could be integrated into existing points-of-contact for women with OUD. APPROACH: In-depth qualitative interviews. SETTING: Three diverse catchment areas in Missouri. PARTICIPANTS: Women with OUD (n = 15) and professional stakeholders (n = 16) representing five types of existing OUD service points: syringe exchange programs, recovery support programs, substance use treatment programs, emergency departments, and Federally Qualified Health Centers. METHOD: Interviews were audio-recorded, transcribed, and thematically coded using Dedoose software. RESULTS: Six themes emerged as essential components for integrating contraceptive services into existing points-of-contact for women with OUD: (1) reach women with unmet need; (2) provide free or affordable contraception; (3) maximize service accessibility; (4) provide patient-centered care; (5) employ willing, qualified contraceptive providers; and (6) utilize peer educators. Participants affirmed the overall potential benefit of contraceptive service integration and illuminated various opportunities and challenges relevant to each type of existing service point. CONCLUSION: As health promotion initiatives look to increase access to contraception among women with OUD, these six' participant-identified components offer essential guidance in selecting advantageous points-of-contact and addressing remaining gaps in services.

Naltrexone Reduces Binge Eating and Purging in Adolescents in an Eating Disorder Program.

Objective: Little evidence exists for pharmacologic treatment of binge eating and purging in adolescents with eating disorders. Given the role of the opioid reward system in compulsive binge eating and purging, naltrexone, an opioid antagonist, may be effective in reducing these behaviors. Previous studies have demonstrated that naltrexone reduces binge eating and purging in adults, yet evidence for its use in adolescents is lacking. This case series describes naltrexone utilization, response, and safety in adolescents with eating disorders. Methods: A retrospective chart review of adolescent patients prescribed naltrexone at an academic eating disorder program was completed. Results: Thirty-three adolescents aged 15.3 ± 1.49 years, 94% female gender identity, were treated with naltrexone with the most common expected outcome "to reduce vomiting." Naltrexone was prescribed for 129 ± 125 days. Over half of patients (52%, n = 17) had liver function tests during follow-up, all of which were within normal limits. Three patients (9.1%) experienced nausea related to naltrexone. Just over half of adolescents (67%; n = 22) had documentation of positive naltrexone response (e.g., reduced purging or urge to purge). The mean Clinical Global Impressions-Improvement score was 2.7 ± 1.3 (2 = much improved; 3 = minimally improved). Conclusions: Naltrexone is safe, well tolerated, and effective for the treatment of adolescents with binge eating and/or purging as part of a comprehensive eating disorder treatment plan. Further study is necessary to confirm the effectiveness of naltrexone prospectively and evaluate factors contributing to naltrexone response vs. nonresponse to promote an individualized approach to treatment of binge eating and purging behavior.

Evaluating metronidazole as a novel, safe CYP2A6 phenotyping probe in healthy adults.

AIMS: CYP2A6 is a genetically polymorphic enzyme resulting in differential substrate metabolism and health behaviours. Current phenotyping probes for CYP2A6 exhibit limitations related to procurement (deuterated cotinine), toxicity (coumarin), specificity (caffeine) and age-appropriate administration (nicotine, NIC). In vitro, CYP2A6 selectively forms 2-hydroxymetronidazole (2HM) from metronidazole (MTZ). The purpose of this study was to evaluate MTZ as a CYP2A6 phenotyping probe drug in healthy adults against the well-established method of measuring trans-3-hydroxycotinine (3HC)/cotinine (COT). METHODS: A randomized, cross-over, pharmacokinetic study was completed in 16 healthy, nonsmoking adults. Separated by a washout period of at least 2 weeks, MTZ 500 mg and NIC gum 2 mg were administered and plasma was sampled over 48 hours and 8 hours, respectively. Correlations of plasma metabolite/parent ratios (2HM/MTZ; 3HC/COT) were assessed by Pearson coefficient. CYP2A6 genotyping was conducted and incorporated as a variable of plasma ratio response. RESULTS: Correlations between the plasma ratio 2HM/MTZ and 3HC/COT were ≥ 0.9 at multiple time points (P < 0.001), demonstrating a wide window during which 2HM/MTZ can be queried post-MTZ dose. CYP2A6 genotype had significant impacts on both MTZ and NIC phenotyping ratios with decreased activity predicted phenotypes demonstrating 2HM/MTZ ratios ≤58% and 3HC/COT ratios ≤56% compared with extensive activity predicted phenotypes at all time points examined in the study (P < 0.05). No adverse events were reported in the MTZ arm while 38% (n = 6) of participants reported mild adverse events in the NIC arm. CONCLUSIONS: Metronidazole via 2HM/MTZ performed well as a novel, safe phenotyping probe for CYP2A6 in healthy adults.

Adolescent Reproductive Health Care: Views and Practices of Pediatric Hospitalists.

BACKGROUND AND OBJECTIVES: Many hospitalized adolescents are at increased risk for pregnancy complications due to an underlying medical condition, however sexual risk assessment is not consistently performed in this setting. While adolescents and their parents are supportive of sexual health discussion in the inpatient setting, a thorough understanding of factors that influence provision of this care among pediatric hospital physicians is lacking. This formative information is needed to facilitate efforts to improve and standardize clinical care provision. Our objective is to assess the frequency and factors that influence the provision of adolescent sexual and reproductive care by pediatric hospitalists. METHODS: We performed a cross-sectional computerized survey of hospitalists at 5 pediatric hospitals who cared for ≥1 adolescent (14-21 years old) in the past year. Sexual and reproductive care practices were assessed by using a 76-item novel survey informed by the theory of planned behavior. We used descriptive statistics to summarize the data. RESULTS: Sixty-eight pediatric hospitalists participated (49% response rate): 78% were women and 65% were aged <40 years. Most (69%) reported treating >46 adolescents annually, including many who are at an increased risk for pregnancy complications due to teratogenic medication use or a comorbid condition. A majority felt that sexual and reproductive services are appropriate, although many endorsed barriers, including concern about follow-up after emergency contraception (63%) and time constraints (53%). Most reported insufficient knowledge regarding contraception (59%), desired contraception education (57%), and were likely to increase contraceptive provision if provided education (63%). Hospitalists rarely provided condoms or referral for an intrauterine device. CONCLUSIONS: Pediatric hospitalists frequently care for adolescents who are at risk for pregnancy complications and generally agree that reproductive care is appropriate in the inpatient setting. With these findings, we highlight the critical need for effective comprehensive reproductive health service interventions that are tailored to address the numerous actionable barriers identified in this study.