Effectiveness of Upadacitinib for Patients With Acute Severe Ulcerative Colitis: A Multicenter Experience.

INTRODUCTION: A significant proportion of patients with acute severe ulcerative colitis (ASUC) require colectomy. METHODS: Patients with ASUC treated with upadacitinib and intravenous corticosteroids at 5 hospitals are presented. The primary outcome was 90-day colectomy rate. Secondary outcomes included frequency of steroid-free clinical remission, adverse events, and all-cause readmissions. RESULTS: Of the 25 patients with ASUC treated with upadacitinib, 6 (24%) patients underwent colectomy, 15 (83%) of the 18 patients with available data and who did not undergo colectomy experienced steroid-free clinical remission (1 patient did not have complete data), 1 (4%) patient experienced a venous thromboembolic event, while 5 (20%) patients were readmitted. DISCUSSION: Upadacitinib along with intravenous corticosteroids may be an effective treatment for ASUC.

Duration of Simultaneous Exposure to High-Risk and Lower-Risk Nephrotoxic Antimicrobials in the Neonatal Intensive Care Unit (NICU) and Future Adolescent Kidney Health.

OBJECTIVE: To determine whether greater duration of simultaneous exposure to antimicrobials with high nephrotoxicity risk combined with lower-risk antimicrobials (simultaneous exposure) in the neonatal intensive care unit (NICU) is associated with worse later kidney health in adolescents born preterm with very low birth weight (VLBW). STUDY DESIGN: Prospective cohort study of participants born preterm with VLBW (<1500 g) as singletons between January 1, 1992, and June 30, 1996. We defined simultaneous exposure as a high-risk antimicrobial, such as vancomycin, administered with a lower-risk antimicrobial on the same date in the NICU. Outcomes were serum creatinine, estimated glomerular filtration rate (eGFR), and first-morning urine albumin-creatinine ratio (ACR) at age 14 years. We fit multivariable linear regression models with days of simultaneous exposure and days of nonsimultaneous exposure as main effects, adjusting for gestational age, birth weight, and birth weight z-score. RESULTS: Of the 147 out of 177 participants who had exposure data, 97% received simultaneous antimicrobials for mean duration 7.2 days (SD 5.6). No participant had eGFR <90 ml/min/1.73 m2. The mean ACR was 15.2 mg/g (SD 38.7) and 7% had albuminuria (ACR >30 mg/g). Each day of simultaneous exposure was associated only with a 1.04-mg/g higher ACR (95% CI 1.01 to 1.06). CONCLUSIONS: Despite frequent simultaneous exposure to high-risk combined with lower-risk nephrotoxic antimicrobials in the NICU, there were no clinically relevant associations with worse kidney health identified in adolescence. Although future studies are needed, these findings may provide reassurance in a population thought to be at increased risk of chronic kidney disease.

Psychometric properties of two instruments measuring self-efficacy and outcome expectations of providing inhaler technique education to patients.

INTRODUCTION: Both the National Heart, Lung, and Blood Institute (NHLBI) and Global Initiative for Asthma (GINA) asthma practice guidelines recommend that providers routinely check inhaler technique and correct any mistakes that patients may make when using these devices. Providers, however, rarely check inhaler technique during asthma visits. The objectives of this study were to: (1) describe the development of an instrument to measure self-efficacy and outcome expectations regarding inhaler technique patient education, (2) evaluate the internal consistency reliability of the new scales, and (3) provide preliminary evidence of construct validity. Methods: First- and second-year physician assistant (PA) students at two institutions completed an anonymous and voluntary survey evaluating two new instruments, the Teaching Inhalers to Patients: Self-efficacy (TIP-SE) and the Teaching Inhalers to Patients: Outcome Expectations (TIP-OE) scales and sociodemographic characteristics. The data were analyzed using Principal Components Analysis (PCA), Cronbach's α, and multivariable logistic regression. Results: We had usable responses from 146 PA students (71.9% participation rate). The PCA identified one factor for the TIP-SE and TIP-OE, respectively. The internal consistency of the TIP-SE and TIP-OE was α = 0.96 and α = 0.92, respectively. The logistic regression found that second-year PA students who had higher mean TIP-SE scores were significantly more likely to report teaching patients to use inhalers during rotations (OR = 1.8, 95% CI = 1.1, 2.9). There was not a statistically significant relationship between reporting teaching patients to use inhalers during rotations and mean TIP-OE scores. Conclusion: The TIP-SE and TIP-OE show preliminary evidence of reliability and validity.Supplemental data for this article is available online at https://doi.org/10.1080/02770903.2021.2008428 .

Vedolizumab Dose Escalation Improves Therapeutic Response in a Subset of Patients with Ulcerative Colitis.

BACKGROUND: The Gemini trial failed to detect a significant difference in response rate for patients with ulcerative colitis (UC) randomized to standard (every 8 week) vedolizumab dosing vs escalated (every 4 week) dosing. Subsequent real-world data imply the Gemini trial design may have obscured a benefit of escalated dosing. AIMS: We investigated outcomes after vedolizumab dose escalation for patients with UC. We also explored potential clinical predictors of dose escalation requirement. METHODS: In this retrospective study, we included patients with UC who received vedolizumab between 1/2017-1/2019. We compared rates of clinical response (decrease in partial Mayo score by ≥ 2) and remission (partial Mayo < 2) for standard vs escalated dosing. RESULTS: Among the 90 patients reviewed, 52 achieved and maintained remission on standard dosing. The average time to remission with standard dosing was 33.3 ± 6.6 weeks. After an average of 56.3 ± 7.4 weeks standard dosing, 24 patients (22 "partial responders" and 2 "non-responders") were dose-escalated. Of the 22 "partial responders" dose-escalated, 10 (45%) achieved remission, 10 (45%) achieved further improvement. Neither "non-responder" demonstrated further clinical benefit. Prior anti-tumor necrosis factor (anti-TNF) biologic exposure predicted dose escalation requirement (p = 0.008). Patients requiring dose escalation had more severe disease at baseline as measured by both full Mayo (p = 0.009) and partial Mayo scores (p = 0.01). CONCLUSIONS: We show dose escalation benefited patients with UC who exhibit a "partial response" to standard dosing. Early vedolizumab dose escalation should be considered in both patients with severe disease and those with prior anti-TNF experience.

Inflammatory Bowel Disease in Appalachian Kentucky: An Investigation of Outcomes and Health Care Utilization.

BACKGROUND: Rural residence has been associated with a lower incidence of inflammatory bowel disease (IBD) but higher health care utilization and worse outcomes. Socioeconomic status is intrinsically tied to both IBD incidence and outcomes. Inflammatory bowel disease outcomes have not been investigated in Appalachia: a rural, economically distressed region rife with risk factors for both increased incidence and unfavorable outcomes. METHODS: Hospital inpatient discharge and outpatient services databases were utilized to assess outcomes in patients diagnosed with either Crohn's disease (CD) or ulcerative colitis (UC) in Kentucky. Encounters were classified by patient residence in Appalachian or non-Appalachian counties. Data were reported as crude and age-adjusted rates of visits per 100,000 population per year collected in 2016 to 2019. National inpatient discharge data from 2019, stratified by rural and urban classification codes, were utilized to compare Kentucky to national trends. RESULTS: Crude and age-adjusted rates of inpatient, emergency department and outpatient encounters were higher in the Appalachian cohort for all 4 years observed. Appalachian inpatient encounters are more frequently associated with a surgical procedure (Appalachian, 676, 24.7% vs non-Appalachian, 1408, 22.2%; P = .0091). In 2019, the Kentucky Appalachian cohort had significantly higher crude and age-adjusted rates of inpatient discharges for all IBD diagnoses compared with national rural and nonrural populations (crude 55.2; 95% CI, 50.9-59.5; age-adjusted 56.7; 95% CI, 52.1-61.3). CONCLUSIONS: There is disproportionately higher IBD health care utilization in Appalachian Kentucky compared with all cohorts, including the national rural population. There is a need for aggressive investigation into root causes of these disparate outcomes and identification of barriers to appropriate IBD care.

The Kentucky Appalachian IBD population experiences increased health care utilization, with increased rates of inpatient admissions, emergency department, and outpatient visits compared with non-Appalachian Kentuckians. Kentucky Appalachian rates of inpatient admissions are higher compared with national rates, controlling for rural residence.

Post stroke pain: Is there under-diagnosis in Black versus White patients?

Stroke incidence is higher and stroke outcomes are poorer in Black patients compared to White patients. Poststroke pain, however, is not a well understood stroke outcome. Using the National Institutes of Health All of Us Research Program database, we hypothesized that the dataset would demonstrate proportionately higher relative risk of poststroke pain in the Black poststroke patient population compared to the White poststroke patient population. However, our analysis showed that Black stroke patients were diagnosed with poststroke pain at a similar rate as White stroke patients. As our results are not consistent with other poststroke outcomes in the literature, this study identifies a potentially underdiagnosed patient population, highlighting the need for further research.

Working Memory Recovery in Adolescents with Concussion: Longitudinal fMRI Study.

Background: Understanding the behavioral and neural underpinnings of the post-concussion recovery of working memory function is critically important for improving clinical outcomes and adequately planning return-to-activity decisions. Previous studies provided inconsistent results due to small sample sizes and the use of a mixed population of participants who were at different post-injury time points. We aimed to examine working memory recovery during the first 6 months post-concussion in adolescents. Methods: We used functional magnetic resonance imaging (fMRI) to scan 45 concussed adolescents [CONCs] at baseline (<10 days post-concussion) and at 6 months post-concussion. Healthy control adolescents [HCs; n = 32] without a history of concussion were scanned once. During the scans, participants performed one-back and two-back working memory tasks with letters as the stimuli and angry, happy, neutral, and sad faces as distractors. Results: All affected adolescents were asymptomatic and cleared to return to activity 6 months after concussion. Working memory recovery was associated with faster and more accurate responses at 6 months vs. baseline (p-values < 0.05). It was also characterized by significant difficulty-related activation increases in the left inferior frontal gyrus (LIFG) and the left orbitofrontal cortex (LOFC) at 6 months vs. baseline. Although the activation differences between one-back and two-back were comparable between HCs and CONCs at 6 months, HCs had more pronounced activation in the LIFG than concussed adolescents. Conclusions: Post-concussion recovery is associated with significant performance improvements in speed and accuracy, as well as the normalization of brain responses in the LIFG and LOFC during the n-back task. The observed patterns of LOFC activation might reflect compensatory strategies to distribute neural processing and reduce neural fatigue post-concussion.

Which analgesics are appropriate in patients with liver dysfunction?

Dose and frequency adjustments to analgesics may be needed for patients with liver dysfunction to avoid toxicity and minimize adverse reactions.

Are Physician Assistants Able to Correctly Identify Prescribing Errors? A Cross-Sectional Study.

PURPOSE: (1) To describe how often physician assistant (PA) students correctly identify prescribing errors and (2) examine between-cohort differences on ability to correctly identify prescribing errors. METHODS: This was a cross-sectional study of 2 cohorts of PA students at one institution. Students were presented with 3 hypothetical prescriptions, 2 of which contained a prescribing error. For each prescription, students were asked to (1) identify whether an error occurred and (2) indicate the type of error. A simple Poisson regression model analyzed the data. RESULTS: We received responses from 130 students (72.6% response rate). Approximately 12% (12.3%, n = 16) correctly identified whether all 3 prescriptions were correct. The median number of correctly identified prescriptions was 1 (interquartile range = 1). There was not a statistically significant between-cohort difference identifying the correct number of prescriptions (ß = 0.27, P = .10). CONCLUSION: Physician assistant students' prescribing error identification was similar to previous research in medical and nursing students. Efforts to improve prescribing training are critical to ensure patient safety.

Adaptation and factor structure of three psychometric instruments measuring behavioral aspects of medication prescribing in physician assistants.

OBJECTIVES: (1) Present the factor structure of two psychometric instruments for self-efficacy and one for outcome expectations of medication prescribing; (2) evaluate the reliability of the scales, and (3) present preliminary evidence of validity. METHODS: Physician assistants (PA) and PA students completed a survey evaluating three psychometric instruments: (1) Self-Efficacy in Prescribing (SEP), (2) Self-Efficacy in Prescribing-Geriatric (SEPG), and (3) Outcomes Expectations of Prescribing Errors (OEP). Students also evaluated 3 hypothetical prescriptions, two of which contained a prescribing error. Students were instructed to identify (1) if an error occurred and (2) what type of error. The data were analyzed using parallel analysis with a varimax rotation, Cronbach's α, Pearson and Spearman correlations. RESULTS: One hundred eighty five (n = 185) respondents completed the survey (response rate = 63.8%). The parallel analysis found that the SEP had one 7-item factor with α = 0.94 (M = 5.7 (SD = 1.9) out of 10). The SEPG also had one 7-item factor with α = 0.95 (M = 5.5 (1.9). The OEP had one 6-item factor with α = 0.89 (M = 3.5 (SD = 0.8) out of 5). The SEP and SEPG, were correlated to the OEP each other (both p < 0.01). Actively practicing PAs had the highest composite mean SEP and SEPG scores. First-year PA students had the highest mean scores for the OEP. There was a weak association between the mean SEPG score and the number of correctly identified prescriptions (rs = 0.18, p = 0.04). CONCLUSION: The SEP, SEPG, and OEP show preliminary evidence of reliability and structural, construct, and known-group validities using simulated prescriptions. These tools may be able to be used by educators and implementation scientists as one method to show the effectiveness of future interventions to reduce incidence of prescribing errors.

Nimbolide Inhibits SOD2 to Control Pancreatic Ductal Adenocarcinoma Growth and Metastasis.

Reactive oxygen species are frequently associated with various cancers including pancreatic ductal adenocarcinomas (PDACs). Superoxide dismutase 2 (SOD2) is an enzyme that plays an important role in reactive oxygen species (ROS) signaling. Investigating the molecular function and biological functions of SOD2 can help us develop new therapeutic options and uncover new biomarkers for PDAC diagnosis and prognosis. Here, we show that nimbolide (NB), a triterpene limonoid, effectively blocks the growth and metastasis of PDACs by suppressing the expression and activity of SOD2. To identify the role of SOD2 in NB-induced anticancer activity, we used RNA interference to silence and plasmid transfection to overexpress it. Silencing SOD2 significantly reduced the growth and metastatic characteristics like epithelial-to-mesenchymal transition, invasion, migration, and colony-forming capabilities of PDACs, and NB treatment further reduced these characteristics. Conversely, the overexpression of SOD2 enhanced these metastatic characteristics. ROS signaling has a strong feedback mechanism with the PI3K/Akt signaling pathway, which could be mediated through SOD2. Finally, NB treatment to SOD2-overexpressing PDAC xenografts resulted in significant inhibition of tumor growth and metastasis. Overall, this work suggests that NB, a natural and safe phytochemical that silences SOD2 to induce high levels of ROS generation, results in increased apoptosis and reduced growth and progression of PDACs. The role of SOD2 in regulating NB-induced ROS generation presents itself as a therapeutic option for PDACs.

Time spent in home meal preparation affects energy and food group intakes among midlife women.

Time spent in meal preparation may be indicative of the healthfulness of meals and therefore with weight status. The purpose of this study was to examine the association between amount of time spent preparing meals and meal food group and nutrient content by meal occasion (breakfast, lunch, and dinner) among 1036 midlife women. Participants completed a 1-day food record and eating occasion questionnaires for each meal occasion. ANCOVA was used to identify possible associations. Approximately half of the participants reported spending <5 min preparing breakfast and lunch, and <20 min preparing dinner. Less time spent preparing breakfast was associated with lower energy and fat intakes (p<0.0001), while less time spent preparing lunch and dinner was associated with lower vegetable and sodium intakes (p<0.0001). There were no apparent differences in the association between time spent preparing meals and meal content by weight status. Nutrition education should encourage home meal preparation while stressing the selection of healthier options. The differing associations by meal occasion suggest that interventions should be tailored according to meal type.

Bezlotoxumab Therapy for Recurrent Clostridium difficile Infection in an Ulcerative Colitis Patient.

Background: Clostridium difficile infection (CDI) is the most common infectious cause of nosocomial diarrhea, comprising 10%-20% of all cases. CDI is a significant complication in patients with inflammatory bowel disease (IBD). New monoclonal antibody therapies have emerged as leading treatment options for recurrent CDI (rCDI). Bezlotoxumab, a novel monoclonal antibody, has shown success in decreasing the recurrence rates of patients with rCDI. However, data extrapolating diminished rCDI in patients with concomitant IBD is limited. Methods: A single infusion of bezlotoxumab @ 10mg/kg was given with fidaxomicin 200mg for 10 days in a patient with rCDI and ulcerative colitis. Results: The patient's symptoms improved, inflammatory markers normalized, and she has remained asymptomatic for twelve months. Conclusions: This case supports the findings in the MODIFY I/II trials that Bezlotoxumab is a viable treatment option of rCDI in IBD patients.

Impact of Patient-Specific Aminoglycoside Monitoring for Treatment of Pediatric Cystic Fibrosis Pulmonary Exacerbations.

OBJECTIVE: Aminoglycosides are frequently used for empiric and definitive treatment of cystic fibrosis (CF) pulmonary exacerbations. Various methods have been described for aminoglycoside therapeutic drug monitoring. The objective of this study is to evaluate the effect of patient-specific pharmacokinetic calculations for aminoglycosides used to treat CF pulmonary exacerbations. METHODS: Ambidirectional cohort study of patients admitted to a children's hospital from June 1, 2018, through February 28, 2019, and June 1, 2019, through February 8, 2021. The primary outcome was the occurrence of dosing changes after analysis of initial serum concentrations in either group. Secondary outcomes included occurrence of nephrotoxicity, duration of antibiotics, and length of stay. RESULTS: Twenty-four patients (75%) in the intervention group versus zero in the control group required dosing adjustments after initial analysis of serum concentrations were completed (p < 0.001). There was not a statistically significant between-group difference for duration of antibiotics in days (median, 14 vs 13.5; Z, 1.07; p = 0.29) or length of stay (median, 11 vs 11; Z, -0.31; p = 0.76). There was also not a statistically significant between-group difference in forced expiratory volume in one second (FEV1) change from admission to discharge (11.4% vs 13.9%; t, 0.61; Degrees of Freedom, 39; p = 0.55). Two patients (6.25%) in the intervention group experienced nephrotoxicity compared with zero patients in the control group (risk difference, 6.25%; 95% CI, -2.14 to 14.64; number needed to harm, 16). CONCLUSIONS: Patient-specific pharmacokinetic monitoring led to significantly more dosing changes and was associated with similar patient outcomes as trough-only monitoring. Further studies are needed to identify methods to optimize aminoglycoside dosing and monitoring for these patients with the goal of reducing toxicities while maximizing efficacy.

Chronic opioid use is associated with early biologic discontinuation in inflammatory bowel disease.

BACKGROUND: Chronic opioid use is associated with poorer clinical outcomes in inflammatory bowel disease. AIMS: To investigate an association between chronic opioid use and persistence with biologic agents in management of inflammatory bowel disease. METHODS: A total of 16 624 patients diagnosed with inflammatory bowel disease and receiving a first-time biologic prescription from 2011 to 2016 were identified retrospectively from the Truven MarketScan Database. A cohort of 1768 patients were identified as chronic opioid users utilising outpatient prescription claims. Utilisation patterns of biologic therapies were assessed from inpatient administration and outpatient claims data, including persistence calculations. Information on healthcare utilisation and common comorbidities was also collected. A Cox regression model was constructed to assess the hazard of chronic opioid use on early discontinuation of biologic therapy controlling for disease severity. RESULTS: A mean 1.5 different biologic agents were utilised by inflammatory bowel disease patients with chronic opioid use (vs 1.37 in the comparator group; P < 0.0001). A lower proportion of the chronic opioid use cohort persisted on biologic therapies to the end of the study period (16.2% vs 33.5% P < 0.0001). Inflammatory bowel disease patients with chronic opioid use utilised more healthcare resources and had a higher rate of comorbidities than the reference cohort. Patients with chronic opioid use were 23% more likely (hazard ratio 1.23; 95% CI [1.16-1.31]) to be non-persistent with biologic therapy while accounting for relevant markers of disease acuity. CONCLUSIONS: Chronic opioid use is associated with increased hazard of biologic discontinuation in inflammatory bowel disease. Symptoms of opioid withdrawal may mimic IBD flares thereby leading providers to inappropriately switch biologic therapies and compromise disease control.

Mixed Oil-Based Lipid Emulsions vs Soybean Oil-Based Lipid Emulsions on Incidence and Severity of Intestinal Failure-Associated Liver Disease in a Neonatal Intensive Care Unit.

BACKGROUND: Neonates requiring long-term parenteral nutrition (PN) are at risk for developing intestinal failure-associated liver disease (IFALD). The purpose of this study was to compare the incidence and severity of IFALD in a highly surgical neonatal population receiving mixed oil-based lipid emulsions (MOLEs) vs soybean oil-based lipid emulsions (SOLEs) for long-term PN. METHODS: This retrospective cohort study evaluated patients admitted to a neonatal intensive care nursery that received PN for ≥14 days. Patients were separated into 2 cohorts; those who received SOLE and those who received MOLE. The primary outcome of this study was the occurrence of IFALD. Secondary outcomes included time to IFALD, peak bilirubin level during therapy, incidence of hypertriglyceridemia, bronchopulmonary dysplasia, and retinopathy of prematurity. RESULTS: A total of 107 patients were included in the study, IFALD occurred in 44.8% of patients receiving SOLE compared with 30% of patients receiving MOLE (relative risk, 0.67; 95% CI, 0.39-1.15). In the multivariable analysis, adjusting for the known confounders (prematurity, necrotizing enterocolitis, presence of ostomy, and duration of PN and lipids), the type of lipids was not a significant predictor for development of IFALD. Duration of PN and duration of lipids were determined to be significant risk factors for IFALD, regardless of type of lipid emulsion (odds ratio, 1.03; 95% CI, 1.01-1.05). CONCLUSIONS: Use of MOLE resulted in no significant difference in the outcomes studied when compared with SOLE. Duration of PN and duration of lipids were significant risk factors for development of IFALD.

Dietary energy restriction, in part through glucocorticoid hormones, mediates the impact of 12-O-tetradecanoylphorbol-13-acetate on jun D and fra-1 in Sencar mouse epidermis.

Dietary energy restriction (DER, 40% calorie reduction from fat and carbohydrate) inhibited mouse skin carcinogenesis and decreased 12-O-tetradecanoyl-13-phorbol acetate (TPA)-induced activator protein-1 (AP-1):DNA binding previously. This study measured protein levels of c-jun, jun B, jun D, c-fos, fra-1, and fra-2 and examined their contribution to AP-1:DNA binding by electrophoretic mobility shift assay (EMSA) with supershift analysis in the epidermis of control and DER Sencar mice exposed to TPA. TPA significantly increased c-jun, jun B, c-fos, fra-1, and fra-2 and decreased jun D within 3-6 h after treatment. AP-1:DNA binding reached a maximum 2.5-fold induction over controls 4 h after TPA treatment and antibodies to jun B, jun D, and fra-2 in the EMSA binding reaction resulted in supershifts in both acetone- and TPA-treated mice 1-6 h after treatment. The effect of corticosterone (CCS) and DER on the AP-1 proteins and on the composition of the AP-1:DNA complex was measured in adrenalectomized (adx) mice. DER reduced the TPA impact on jun D and enhanced the induction of fra-1. In addition, CCS-supplemented groups had significantly lower jun D and higher fra-2 than adx groups and sham groups. While sham animals treated with either acetone or TPA contained jun B, jun D, and fra-2 proteins in the AP-1:DNA complex by supershift analysis, fra-2 was no longer seen in adx DER animals. In summary, our study supports potential roles for jun D, jun B, and fra-1 in the DER regulation of AP-1 function in the Sencar mouse skin carcinogenesis model.

Double Biologic Therapy for Refractory Stricturing Crohn's Disease: A Successful Case of Deep Remission with Ustekinumab and Vedolizumab.

Stricturing Crohn's disease (CD) is a severe phenotype that presents unique challenges to therapeutic management. Emerging literature suggests that anti-TNF monoclonal antibody (mAb) therapies are inadequate for preventing progression to stricture. We hereby present a case of a patient with refractory CD who required multiple surgical resections despite several anti-TNF treatment regimens. Subsequent surgical complications were avoided after changing to combination vedolizumab and ustekinumab therapies every 4 weeks. This case argues for a tailored approach to CD therapy based on disease phenotype and demonstrates that combination therapy with ustekinumab and vedolizumab is a viable option for patients with stricturing disease.

Utilization of Physiologically Based Pharmacokinetic Modeling in Clinical Pharmacology and Therapeutics: an Overview.

The purpose of this review was to assess the advancement of applications for physiologically based pharmacokinetic (PBPK) modeling in various therapeutic areas. We conducted a PubMed search, and 166 articles published between 2012 and 2018 on FDA-approved drug products were selected for further review. Qualifying publications were summarized according to therapeutic area, medication(s) studied, pharmacokinetic model type utilized, simulator program used, and the applications of that modeling. The results showed a 13-fold increase in the number of papers published from 2012 to 2018, with the largest proportion of articles dedicated to the areas of infectious diseases, oncology, and neurology, and application extensions including prediction of drug-drug interactions due to metabolism and/or transporter-mediated effects and understanding drug kinetics in special populations. In addition, we profiled several high-impact studies whose results were used to guide package insert information and formulate dose recommendations. These results show that while utilization of PBPK modeling has drastically increased over the past several years, regulatory support, lack of easy-to-use systems for clinicians, and challenges with model validation remain major challenges for the widespread adoption of this practice in institutional and ambulatory settings. However, PBPK modeling will continue to be a useful tool in the future to assess therapeutic drug monitoring and the growing field of personalized medicine.