The effects of family support and smartphone-derived homestay on daily mood and depression among sexual and gender minority adolescents.

Sexual and gender minority (SGM) adolescents are at elevated risk for depression. This risk is especially pronounced among adolescents whose home environment is unsupportive or nonaffirming, as these adolescents may face familial rejection due to their identity. Therefore, it is critical to better understand the mechanisms underlying this risk by probing temporally sensitive associations between negative mood and time spent in potentially hostile home environments. The current study included adolescents (N = 141; 43% SGM; 13-18 years old), oversampled for depression history, who completed clinical interviews assessing lifetime psychiatric history and depression severity as well as self-report measures of social support. Participants also installed an app on their personal smartphones, which assessed their daily mood and geolocation-determined mobility patterns over a 6-month follow-up period. Over the 6-month follow-up period, SGM adolescents reported elevated depression severity and lower daily mood relative to non-SGM youth. Interestingly, SGM adolescents who reported low family support experienced lower daily mood than non-SGM adolescents, particularly on days when they spent more time at home. Current findings reinforce evidence for disparities in depression severity among SGM adolescents and highlight family support as a key factor. Specifically, more time spent in home environments with low family support was associated with worse mood among SGM adolescents. These results underscore the need for clinical interventions to support SGM youth, particularly interventions that focus on familial relationships and social support within the home environment. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Cognitive inflexibility and heightened error monitoring are related to lower sexual functioning.

Sexual functioning is an important predictor of well-being and relationship satisfaction. Previous research indicates that several aspects of cognitive function are related to sex-related behaviors and functioning among individuals with sex-related disorders, neurological disorders, and in older adults; however, this has been relatively underexamined in younger populations. To examine this, the present study assessed whether behavioral and/or neurophysiological measures of cognitive function are associated with sexual functioning in a community sample of young 489 adults (64 % female) ages 18-30. Cognitive flexibility (n = 460) and inhibition (n = 466) were measured using neuropsychological assessment (D-KEFS), and conflict monitoring and error monitoring were measured by event-related potentials (conflict N2: n = 394; error-related negativity: n = 389). After separately testing relations between the different measures of cognitive function and sexual functioning, we assessed whether results (1) remained after covarying for externalizing and internalizing dimensions (PID-5; n = 489) or (2) varied by gender. Finally, we tested whether any aspects of cognitive function were unique predictors of sexual functioning. Cognitive flexibility and error monitoring (i.e., error-related negativity) were both significantly related to sexual functioning among males and females, such that poorer cognitive flexibility and heightened error monitoring were related to lower sexual functioning. No significant effects emerged for inhibition or conflict monitoring. In a multiple regression model, cognitive flexibility and error monitoring each accounted for a unique portion of variance in sexual functioning beyond other aspects of cognitive function and psychopathology-related traits. Results suggest that cognitive function is a meaningful correlate of sexual functioning in young adulthood, which should be considered further in future research.

Detecting adolescent depression through passive monitoring of linguistic markers in smartphone communication.

BACKGROUND: Cross sectional studies have identified linguistic correlates of major depressive disorder (MDD) in smartphone communication. However, it is unclear whether monitoring these linguistic characteristics can detect when an individual is experiencing MDD, which would facilitate timely intervention. METHODS: Approximately 1.2 million messages typed into smartphone social communication apps (e.g. texting, social media) were passively collected from 90 adolescents with a range of depression severity over a 12-month period. Sentiment (i.e. positive vs. negative valence of text), proportions of first-person singular pronouns (e.g. 'I'), and proportions of absolutist words (e.g. 'all') were computed for each message and converted to weekly aggregates temporally aligned with weekly MDD statuses obtained from retrospective interviews. Idiographic, multilevel logistic regression models tested whether within-person deviations in these linguistic features were associated with the probability of concurrently meeting threshold for MDD. RESULTS: Using more first-person singular pronouns in smartphone communication relative to one's own average was associated with higher odds of meeting threshold for MDD in the concurrent week (OR = 1.29; p = .007). Sentiment (OR = 1.07; p = .54) and use of absolutist words (OR = 0.99; p = .90) were not related to weekly MDD. CONCLUSIONS: Passively monitoring use of first-person singular pronouns in adolescents' smartphone communication may help detect MDD, providing novel opportunities for early intervention.

Capturing mood dynamics through adolescent smartphone social communication.

Most adolescents with depression remain undiagnosed and untreated-missed opportunities that are costly from both personal and public health perspectives. A promising approach to detecting adolescent depression in real-time and at a large scale is through their social communication on the smartphone (e.g., text messages, social media posts). Past research has shown that language from online social communication reliably indicates interindividual differences in depression. To move toward detecting the emergence of depression symptoms intraindividually, the present study tested whether sentiment (i.e., words connoting positive and negative affect) from smartphone social communication prospectively predicted daily mood fluctuations in 83 adolescents (Mage = 16.49, 73.5% female) with a wide range of depression severity. Participants completed daily mood ratings across a 90-day period, during which 354,278 messages were passively collected from social communication apps. Greater positive sentiment (i.e., more positive weighted composite valence score and a greater proportion of words expressing positive sentiment) predicted more positive next-day mood, controlling for previous-day mood. Moreover, greater proportions of positive and negative sentiment were, respectively, associated with lower anhedonia and greater dysphoria symptoms measured at baseline. Exploratory analyses of nonaffective linguistic features showed that greater use of social engagement words (e.g., friends and affiliation) and emojis (primarily consisting of hearts) predicted more positive changes in mood. Collectively, findings suggest that language from smartphone social communication can detect mood fluctuations in adolescents, laying the foundation for language-based tools to identify periods of heightened depression risk. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A prospective study of the relative contribution of adolescent peer support quantity and quality to depressive symptoms.

BACKGROUND: During adolescence, peer support has an increasingly important role in identity formation and well-being. Prior research has identified that lack of social support from peers in adolescence is a potent risk factor for depression. Two ways that social support has been operationalized is by the number of one's friends (i.e., 'quantity') and perception of one's network (i.e., 'quality'). Typically, these aspects of peer support are assessed separately. METHODS: Using data from the National Longitudinal Study of Adolescent to Adult Health (N = 3,857), this study sought to test whether (1) adolescent depression relates to having fewer friends versus lower quality friendships, (2) these aspects of adolescent peer support prospectively predict depression in adulthood, (3) gender moderates the effects of peer support on depression, and (4) these aspects of peer support buffer the effects of stressful life events on depression. RESULTS: Peer support quality uniquely predicted depression in adolescence and adulthood among both males and females. The effect of peer support quality on depressive symptoms, however, was greater for females than males. By contrast, peer support quantity did not uniquely predict depression for males or females. CONCLUSIONS: Qualitative aspects of adolescent peer support uniquely contribute to mental health not only in adolescence, but in adulthood as well. Potential processes through which peer support relates to depression are discussed, as well as implications for treatment.

Preliminary evidence that individuals with remitted alcohol use disorder and major depressive disorder exhibit enhanced neural responses to reward: An EEG study.

INTRODUCTION: Disruptions in neural responses to reward are implicated in risk for Alcohol Use Disorder (AUD) and Major Depressive Disorder (MDD). It is not clear whether these findings extend to those in remission from AUD and MDD, a critical question as studies of remission can (a) rule out effects due to current symptoms, and (b) can reveal potential trait-like differences. METHODS: Individuals with and without remitted AUD (rAUD) and/or rMDD (rMDD) were drawn from a larger study to create four groups: rAUD (n = 54), rMDD (n = 66), rAUD + rMDD (n = 53), and a community control group (CCG; n = 81). Participants completed a validated monetary reward task during electroencephalogram (EEG). Multilevel models examined group differences in event-related potentials and time-frequency indices of reward and loss responsiveness, namely, reward positivity (RewP), feedback negativity (FN), reward-related delta power, and loss-related theta power. RESULTS: Analyses revealed that the rAUD + rMDD group had significantly higher reward-related delta activity than the three other groups (p-values < 0.01), which did not differ from each other. Sensitivity analyses revealed this relationship fell just above the threshold set for significance after controlling for residual current MDD and AUD symptoms (p =.05). There were no other group differences or significant interactions (p-values > 0.05). CONCLUSIONS: To our knowledge, this is the first study to show that individuals with remitted AUD and MDD demonstrate increased sensitivity to rewards compared to individuals with remitted AUD alone, MDD alone, and without AUD or MDD. These findings suggest heightened motivational salience to reward might be an important factor in comorbid AUD and MDD.

Electrophysiological evidence of mal-adaptation to error in remitted depression.

Identifying risk markers for major depressive disorder (MDD) that persist into remission is key to address MDD's high rate of recurrence. Central to MDD recurrence are the disorder's negative information processing biases, such as heightened responses to errors, which may subsequently impair abilities to monitor performance and adjust behaviors based on environmental demands. However, little is known regarding the neurophysiological correlates of post-error adaptation in depression. The current study investigated event-related potentials (ERPs) and behavioral performance following errors from a flanker task in 58 participants with remitted MDD (rMDD) and 118 healthy controls (HC). Specifically, using trial-level data, we tested: (a) the impact of errors on response-locked ERPs of the current and post-error trials (error-related negativity [ERN] and correct response negativity [CRN]) and (b) longer-term adaptation to errors (ERN/CRN) over the course of the task. Compared to HC, rMDD participants showed a larger ERN to the current trial and smaller habituation in ERN over time. On trials immediately following errors, rMDD participants showed slower reaction times that were predicted by the previous-trial ERN amplitude but comparable accuracy to HC, suggesting a deficient ability to disengage from errors and/or a compensatory effort to mitigate accuracy decrements. Critically, this pattern of responding: (a) was concurrently associated with greater levels of anhedonia symptoms, more severe MDD history, and interpersonal impairment (but lower impairment in life activities) and (b) predicted more anhedonia symptoms at one-year follow-up. Collectively, a hyperactive performance monitoring system may be a useful risk marker for future MDD recurrence.

Childhood trauma predicts blunted error monitoring in adulthood: An event-related potential study.

Abuse and neglect have detrimental consequences on emotional and cognitive functioning during childhood and adolescence, including error monitoring, which is a critical aspect of cognition that has been implicated in certain internalizing and externalizing psychopathologies. It is unclear, however, whether (a) childhood trauma has effects on error monitoring and, furthermore whether, (b) error monitoring mediates the relation between childhood trauma and psychopathology in adulthood. To this end, in a large sample of young adults (ages 18-30) who were oversampled for psychopathology (N = 390), the present study assessed relations between childhood trauma and error-related negativity (ERN), which is a widely used neurophysiological indicator of error monitoring. Cumulative childhood trauma predicted ERN blunting, as did two specific types of traumas: sexual abuse and emotional neglect. Furthermore, the ERN partially mediated the effects of cumulative childhood trauma and emotional neglect on externalizing-related symptoms. Future studies should further examine the relations between childhood trauma and error monitoring in adulthood, which can help to inform intervention approaches.

Event-related potentials to acoustic startle probes during unpredictable threat are associated with individual differences in intolerance of uncertainty.

Individual differences in sensitivity to unpredictable threat may be a critical mechanism for internalizing psychopathology phenotypes. The present study examined whether the startle probe-elicited N100 and P300 during unpredictable threat - two event-related potentials indexing early and elaborative attentional processing of unpredictable threat - may be endophenotypes for internalizing psychopathology, including fear and distress/misery disorders and intolerance of uncertainty (IU), a clinical trait that is transdiagnostically associated with internalizing disorders. A large sample of adult siblings (N = 375) completed the no, predictable, and unpredictable threat task, during which the N100 and P300 were recorded. Relative to the no threat condition, N100 was more strongly enhanced in anticipation of unpredictable than predictable threat while P300 was suppressed to both predictable and unpredictable threat. While neither N100 enhancement nor P300 suppression to unpredictable threat was associated with fear or distress/misery disorders, they were negatively linked to inhibitory IU (a facet of IU). Thus, individuals high in inhibitory IU showed reduced attentional engagement with the threatening context when it was unpredictable. Further, N100 enhancement and, to a lesser degree, P300 suppression to unpredictable threat showed familial aggregation - a key criterion for determining whether a biomarker is an endophenotype. In sum, N100 enhancement and P300 suppression to unpredictable threat may be endophenotypes for dimensional measures of internalizing psychopathology.

Exposure-response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma.

BACKGROUND: Exposure-response analyses were conducted to explore the relationship between selected efficacy and safety endpoints and serum phosphate (PO4) concentrations, a potential biomarker of efficacy and safety, in locally advanced or metastatic urothelial carcinoma patients with FGFR alterations treated with erdafitinib. METHODS: Data from two dosing regimens of erdafitinib in a phase 2 study (NCT02365597), 6 and 8-mg/day with provision for pharmacodynamically guided titration per serum PO4 levels, were analyzed using Cox proportional hazard or logistic regression models. Efficacy endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Safety endpoints were adverse events typical for FGFR inhibitors. RESULTS: Exposure-efficacy analyses on 156 patients (6-mg = 68; 8-mg = 88) showed that patients with higher serum PO4 levels within the first 6 weeks showed better OS (hazard ratio 0.57 [95% CI 0.46-0.72] per mg/dL of PO4; p = 0.01), PFS (hazard ratio 0.80 [0.67-0.94] per mg/dL of PO4; p = 0.01), and ORR (odds ratio 1.38 [1.02-1.86] per mg/dL of PO4; p = 0.04). Exposure-safety analyses on 177 patients (6-mg = 78; 8-mg = 99) showed that the incidence of selected adverse events associated with on-target off-tumor effects significantly rose with higher PO4. CONCLUSIONS: The exploratory relationship between serum PO4 levels and efficacy/safety outcomes supported the use of pharmacodynamically guided dose titration to optimize erdafitinib's therapeutic benefit/risk ratio. CLINICAL TRIAL REGISTRATION NUMBER: NCT02365597.

Erdafitinib's effect on serum phosphate justifies its pharmacodynamically guided dosing in patients with cancer.

A population pharmacokinetic (PK)-pharmacodynamic (PD) model was developed using data from 345 patients with cancer. The population PK-PD model evaluated the effect of erdafitinib total and free plasma concentrations on serum phosphate concentrations after once-daily oral continuous (0.5-12 mg) and intermittent (10-12 mg for 7 days on/7 days off) dosing, and investigated the potential covariates affecting erdafitinib-related changes in serum phosphate levels. Phosphate is used as a biomarker for erdafitinib's efficacy and safety: increases in serum phosphate were observed after dosing with erdafitinib, which were associated with fibroblast growth factor receptor target engagement via inhibition of renal fibroblast growth factor 23-mediated signaling. PK-PD model-based simulations were performed to assess the approved PD-guided dosing algorithm of erdafitinib (8 mg once-daily continuous dosing, with up-titration to 9 mg based on phosphate levels [<5.5 mg/dl] and tolerability at 14-21 days of treatment). The serum phosphate concentrations increased after the first dose and reached near maximal level after 14 days of continuous treatment. Serum phosphate increased with erdafitinib free drug concentrations: doubling the free concentration resulted in a 1.8-fold increase in drug-related phosphate changes. Dose adjustment after at least 14 days of dosing was supported by achievement of >95% maximal serum phosphate concentration. The peak-to-trough fluctuation within a dosing interval was limited for serum phosphate concentrations (5.68-5.65 mg/dl on Day 14), supporting phosphate monitoring at any time relative to dosing. Baseline phosphate was higher in women, otherwise, none of the investigated covariate-parameter relationships were considered clinically relevant. Simulations suggest that the starting dose of 8-mg with up-titration to 9-mg on Days 14-21 maximized the number of patients within the target serum phosphate concentrations (5.5-7 mg/dl) while limiting the number of treatment interruptions. The findings from the PK-PD model provided a detailed understanding of the erdafitinib concentration-related phosphate changes over time, which supports erdafitinib's dosing algorithm.

An Effortful Approach to Social Affiliation in Schizophrenia: Preliminary Evidence of Increased Theta and Alpha Connectivity during a Live Social Interaction.

People with schizophrenia often experience a profound lack of motivation for social affiliation-a facet of negative symptoms that detrimentally impairs functioning. However, the mechanisms underlying social affiliative deficits remain poorly understood, particularly under realistic social contexts. Here, we investigated subjective reports and electroencephalography (EEG) functional connectivity in schizophrenia during a live social interaction. Individuals with schizophrenia (n = 16) and healthy controls (n = 29) completed a face-to-face interaction with a confederate while having EEG recorded. Participants were randomly assigned to either a Closeness condition designed to elicit feelings of closeness through self-disclosure or a Small-Talk condition with minimal disclosure. Compared to controls, patients reported lower positive emotional experiences and feelings of closeness across conditions, but they showed comparably greater subjective affiliative responses for the Closeness (vs. Small-Talk) condition. Additionally, patients in the Closeness (vs. Small-Talk) condition displayed a global increase in connectivity in theta and alpha frequency bands that was not observed for controls. Importantly, greater theta and alpha connectivity was associated with greater subjective affiliative responding, greater negative symptoms, and lower disorganized symptoms in patients. Collectively, findings indicate that patients, because of pronounced negative symptoms, utilized a less efficient, top-down mediated strategy to process social affiliation.

Prediction of the drug-drug interaction potential of the α1-acid glycoprotein bound, CYP3A4/CYP2C9 metabolized oncology drug, erdafitinib.

Erdafitinib is a potent oral pan-fibroblast growth factor receptor inhibitor being developed as oncology drug for patients with alterations in the fibroblast growth factor receptor pathway. Erdafitinib binds preferentially to α1-acid glycoprotein (AGP) and is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. This article describes a physiologically based pharmacokinetic (PBPK) model for erdafitinib to assess the drug-drug interaction (DDI) potential of CYP3A4 and CYP2C9 inhibitors and CYP3A4/CYP2C9 inducers on erdafitinib pharmacokinetics (PK) in patients with cancer exhibiting higher AGP levels and in populations with different CYP2C9 genotypes. Erdafitinib's DDI potential as a perpetrator for transporter inhibition and for time-dependent inhibition and/or induction of CYP3A was also evaluated. The PBPK model incorporated input parameters from various in vitro and clinical PK studies, and the model was verified using a clinical DDI study with itraconazole and fluconazole. Erdafitinib clearance in the PBPK model consisted of multiple pathways (CYP2C9/3A4, renal, intestinal; additional hepatic clearance), making the compound less susceptible to DDIs. In poor-metabolizing CYP2C9 populations carrying the CYP2C9*3/*3 genotype, simulations shown clinically relevant increase in erdafitinib plasma concentrations. Simulated luminal and enterocyte concentration showed potential risk of P-glycoprotein inhibition with erdafitinib in the first 5 h after dosing, and simulations showed this interaction can be avoided by staggering erdafitinib and digoxin dosing. Other than a simulated ~ 60% exposure reduction with strong CYP3A/2C inducers such as rifampicin, other DDI liabilities were minimal and considered not clinically relevant.

Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19.

The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to SARS CoV-1 that caused severe acute respiratory syndrome (SARS) in 2002. Both SARS coronavirus genomes encode two overlapping large polyproteins, which are cleaved at specific sites by a 3C-like cysteine protease (3CLpro) in a post-translational processing step that is critical for coronavirus replication. The 3CLpro sequences for CoV-1 and CoV-2 viruses are 100% identical in the catalytic domain that carries out protein cleavage. A research effort that focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CLpro employing ligand-protease structures solved by X-ray crystallography led to the identification of 3 and 4. Preclinical experiments reveal 4 (PF-00835231) as a potent inhibitor of CoV-2 3CLpro with suitable pharmaceutical properties to warrant further development as an intravenous treatment for COVID-19.

Schizotypy dimensions are associated with altered resting state alpha connectivity.

The disconnection hypothesis of schizophrenia says that symptoms are explained by dysfunctional connections across a wide range of brain networks. Despite some support for this hypothesis, there have been mixed findings. One reason for these may be the multidimensional nature of schizophrenia symptoms. In order to clarify the relationship between symptoms and brain networks, the current study included individuals at risk for schizophrenia-spectrum disorders who either report extreme levels of positive schizotypy traits (perceptual aberrations and magical ideation, or "PerMag"; n = 23), or an extreme negative schizotypy trait (social anhedonia, or "SocAnh"; n = 19), as well as a control group (n = 18). Resting-state alpha electroencephalography was collected, and functional networks for each subject were measured using the phase-lag index to calculate the connectivity between channel pairs based on the symmetry of instantaneous phase differences over time. Furthermore, graph theory measures were introduced to identify network features exclusive to schizotypy groups. We found that the PerMag group exhibited a smaller difference in node strength and clustering coefficient in frontal/occipital and central/occipital regional comparisons compared to controls, suggesting a more widespread network. The SocAnh group exhibited a larger difference in degree in the central/occipital regional comparison relative to controls, suggesting a localized occipital focus in the connectivity network. Regional differences in functional connectivity suggest that different schizotypy dimensions are manifested at the network level by different forms of disconnections. Taken together, these findings lend further support to the disconnection hypothesis and suggest that altered connectivity networks may serve as a potential biomarker for schizophrenia risk.

Differential item functioning of the Multidimensional Schizotypy Scale and Multidimensional Scale-Brief across ethnicity.

Schizotypy refers to traits or symptoms similar to schizophrenia, but in a diminished form, and schizotypy is thought to reflect a liability for the future development of schizophrenia. The Multidimensional Schizotypy Scale (MSS) is a new measure of schizotypy that improves on existing measures. The MSS contains full and brief subscales for positive, negative, and disorganized schizotypy. Although MSS scores have been validated in a variety of populations, the scales have not been thoroughly examined for differential item functioning in East Asian, Southeast Asian, Hispanic, Multiracial, and White participants. The current study included 567 East Asian, 351 Southeast Asian, 360 Hispanic, 230 Multiracial, and 345 White undergraduate participants from the United States. Overall, few of the items in the full or brief versions of the scales displayed differential item functioning across groups. The full and brief versions of the scales also displayed similar and not-significantly different validity coefficients with the Detachment and Psychoticism scales of the Personality Inventory for DSM-5. These findings suggest that the MSS measures the same constructs across ethnic groups, and the scale scores represent the same latent level of schizotypy among groups. Future research may use the MSS in these diverse groups without concern that the psychometric properties differ significantly among groups. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Effect of Plasma Protein Binding on the Pharmacokinetics of Erdafitinib: Results of an Integrated Cross-Study Analysis.

Erdafitinib, a potent oral fibroblast growth factor receptor inhibitor, is a low extraction ratio drug highly bound to alpha-1-acid glycoprotein (AGP) with free fraction (fu ) varying across populations. This analysis aimed to characterize the impact of plasma protein binding on erdafitinib pharmacokinetics (PK). Plasma protein-binding data (fu , AGP, albumin) and PK parameters were pooled from 6 phase 1 studies in healthy participants and 1 first-in-human study in patients with cancer. Binding kinetics were characterized using a nonlinear mixed-effects model. Mean (coefficient of variation, CV%) fu was 0.510% (39.4%) for healthy participants and 0.316% (64.0%) for patients, with a 2.1-fold higher AGP and 10% lower albumin. Linear binding of erdafitinib to AGP and albumin was observed, with >1000-fold higher binding constant for AGP than albumin (17.6 vs 0.017 µM-1 ). The fu decreased with increasing AGP in a nonlinear relationship. Despite its abundance in plasma relative to AGP, albumin contributed to <4% of the overall binding of erdafitinib (1.8% in patients; 4.0% in healthy participants). The AGP-binding constant was 68.0% lower in predose (spiked) versus postdose (ex vivo) samples. Total oral clearance was generally proportional to the fu and higher in healthy participants than in patients, consistent with the differences in AGP. Correcting for fu accounted for the majority of the relationship between oral clearance and fu as expected with a low extraction ratio drug. Characterizing free erdafitinib concentrations is critical to accounting for differences in fu and to further investigating its clinical relevance.

Effect of Fluconazole and Itraconazole on the Pharmacokinetics of Erdafitinib in Healthy Adults: A Randomized, Open-Label, Drug-Drug Interaction Study.

BACKGROUND AND OBJECTIVES: Erdafitinib, an oral selective pan-fibroblast growth factor receptor (FGFR) kinase inhibitor, is primarily metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The aim of this phase 1 study was to assess the pharmacokinetics and safety of erdafitinib in healthy participants when coadministered with fluconazole (moderate CYP2C9 and CYP3A inhibitor), and itraconazole (a strong CYP3A4 and P-glycoprotein inhibitor). The effect of CYP2C9 genotype variants (*1/*1, *1/*2, *1/*3) on the pharmacokinetics of erdafitinib was also investigated. METHODS: In this open-label, parallel-group, single-center study, eligible healthy adults were randomized by CYP2C9 genotype to receive Treatment A (single oral dose of erdafitinib 4 mg) on day 1, Treatment B (fluconazole 400 mg/day orally) on days 1-11, or Treatment C (itraconazole 200 mg/day orally) on days 1-11. Healthy adults randomized to Treatment B and C received a single oral 4-mg dose of erdafitinib on day 5. The pharmacokinetic parameters, including mean maximum plasma concentration (Cmax), area under the curve (AUC) from time 0 to 168 h (AUC168h), AUC from time 0 to the last quantifiable concentration (AUClast), and AUC from time 0 to infinity (AUC∞) were calculated from individual plasma concentration-time data using standard non-compartmental methods. RESULTS: Coadministration of erdafitinib with fluconazole increased Cmax of erdafitinib by approximately 21%, AUC168h by 38%, AUClast by 49%, and AUC∞ by 48% while coadministration with itraconazole resulted in no change in erdafitinib Cmax and increased AUC168h by 20%, AUClast by 33% and AUC∞ by 34%. Erdafitinib exposure was comparable between participants with CYP2C9 *1/*2 or *1/*3 and with wild-type CYP2C9 genotype. The ratio of total amount of erdafitinib excreted in the urine (inhibited to non-inhibited) was 1.09, the ratio of total amount of excreted metabolite M6 was 1.21, and the ratio of the metabolite to parent ratio in the urine was 1.11, when coadministration of erdafitinib with itraconazole was compared with single-dose erdafitinib. Treatment-emergent adverse events (TEAEs) were generally Grade 1 or 2 in severity; the most commonly reported TEAE was headache. No safety concerns were identified with single-dose erdafitinib when administered alone and in combination with fluconazole or itraconazole in healthy adults. CONCLUSION: Coadministration of fluconazole or itraconazole or other moderate/strong CYP2C9 or CYP3A4 inhibitors may increase exposure to erdafitinib in healthy adults and thus may warrant erdafitinib dose reduction or use of alternative concomitant medications with no or minimal CYP2C9 or CYP3A4 inhibition potential. TRIAL REGISTRATION: ClinicalTrials.gov identifier number: NCT03135106.

Population Pharmacokinetics of Total and Free Erdafitinib in Adult Healthy Volunteers and Cancer Patients: Analysis of Phase 1 and Phase 2 Studies.

A population pharmacokinetic (PK) model was developed using data pooled from 6 clinical studies (3 in healthy volunteers and 3 in cancer patients) to characterize total and free plasma concentrations of erdafitinib following single- and multiple-dose administration, to understand clinically relevant covariates, and to quantify the inter- and intraindividual variability in erdafitinib PK. An open, linear, 3-compartment disposition model with first-order absorption and a lag time was used to describe the PK profile of total and free erdafitinib plasma concentrations. The PK of erdafitinib were linear and time independent. After oral administration, erdafitinib was rapidly absorbed, with a time to maximum concentration between 2 and 4 hours. In patients, erdafitinib total apparent oral clearance was 0.200 L/h (median free fraction = 0.24%), and the effective terminal half-life of total drug was 76.4 hours. Interindividual variability in PK parameters was moderate for oral clearance and central volume of distribution, and large for absorption rate and peripheral volume of distribution. Sex and renal function were significant covariates on free oral clearance, while weight, sex, and α1 -acid-glycoprotein were significant on oral central volume of distribution. Age, race, and mild hepatic impairment were not significant covariates of erdafitinib exposure. Given that the magnitude of the covariate effects were within 25% of reference values and that the recommended dosing regimen of erdafitinib comprises individual dose up-titrations and reductions based on presence or absence of toxicities, the clinical relevance of the investigated covariates is expected to be limited, and no dose adjustments are warranted.

Assessment of the effect of erdafitinib on cardiac safety: analysis of ECGs and exposure-QTc in patients with advanced or refractory solid tumors.

PURPOSE: To characterize the effect of erdafitinib on electrocardiogram (ECG) parameters and the relationship between erdafitinib plasma concentrations and QTc interval changes in patients with advanced or refractory solid tumors. METHODS: Triplicate ECGs and continuous 12-lead Holter data were collected in the dose escalation part (Part 1) of the first-in-human study, with doses ranging from 0.5 to 12 mg. Triplicate ECG monitoring continued in Parts 2-4 where 2 dose regimens selected from Part 1 were expanded in prespecified tumor types. Analyses of ECG data included central tendency analyses, identification of categorical outliers and morphological assessment. A concentration-QTc analysis was conducted using a linear mixed-effect model based on extracted time matching Holter data. RESULTS: Central tendency, categorical outlier, and ECG morphologic analyses from 187 patients revealed no clinically significant effect of erdafitinib on heart rate, atrioventricular conduction or cardiac depolarization (PR and QRS), and no effect on cardiac repolarization (QTc). Concentration-QTc analysis from 62 patients indicated that the slopes of relationship between total and free erdafitinib plasma concentrations and QTcI (mean exponent of 0.395) were estimated as - 0.00269 ms/(ng/mL) and - 1.138 ms/(ng/mL), respectively. The predicted change in QTcI at the observed geometric mean of total and free concentration at the highest therapeutic erdafitinib dose (9 mg daily) was < 10 ms at the upper bound of the two-sided 90% confidence interval. CONCLUSIONS: ECG data and the concentration-QTc relationships demonstrate that erdafitinib does not prolong QTc interval and has no effects on cardiac repolarization or other ECG parameters. Clinical trial registration numbers NCT01703481, EudraCT: 2012-000697-34.