Peer mentoring in pharmacy programs: Recommendations for implementation based on a review of available literature.

BACKGROUND: Stress experienced by pharmacy students is on the rise and is negatively impacting student success. Pharmacy accreditation standards encourage schools to promote student success and well-being. Peer to peer student support is a largely under-investigated strategy to address this. The objective of this manuscript is to conduct a literature review on the development of peer mentoring programs for pharmacy students and describe best practices for successful implementation into pharmacy programs. METHODS: This literature review identified studies using major databases, including PubMed, Embase, International Pharmaceutical Abstracts, and Education Resources Information Center. Search terms included [(peer mentor*) AND pharmacy]. Any study that involved peer assessment, peer tutoring, or peer learning within a course, faculty mentors only, non-pharmacy students, and/or did not implement a mentor-mentee relationship, was excluded. RESULTS: Three studies met the criteria for inclusion. Mentorship programs varied with regard to duration, mentor recruitment, participant incentives, and overall structure. Various methods of analyses were employed. Despite major differences between the included studies, three themes were identified regarding development of peer mentoring programs: participation, support, and pairing. Active engagement led to higher perceived benefit and both mentors and mentees found the programs beneficial, agreed to recommend the programs to others, and provided positive feedback. IMPLICATIONS: Successful mentoring programs should aim to incorporate the following characteristics to some degree: mandatory participation by mentor and mentee as well as support for mentors with training and faculty oversight. Peer mentoring programs have a positive impact on participants. More studies are needed to assess the effects of peer mentoring in pharmacy programs. This is the first known review of peer mentoring within pharmacy programs and identifies a gap in knowledge in this area. There is a paucity of data surrounding peer mentoring in pharmacy and its potential value as a tool to improve student well-being.

Renal function estimating equations performance during pregnancy and postpartum.

STUDY OBJECTIVES: The objectives of this study were to evaluate the performance of renal function estimating equations compared to measured creatinine clearance (CrCl) during pregnancy and postpartum and to evaluate which body weight (pre-pregnancy weight (PPW), actual body weight (ABW), and ideal body weight (IBW)) provides the best performance. DESIGN: A retrospective study. SETTING: Collections tookplace in the University of Washington clinical research unit. PATIENTS: Women (n = 166) who completed ≥1 pharmacokinetic (PK) study with a 6-24 h measured CrCl during pregnancy and/or ≥3 months postpartum were included. INTERVENTION: CrCl was estimated utilizing estimated glomerular filtration rate (eGFR) and CrCl equations with common weight descriptors. Analyses included Bland-Altman, relative accuracies within 10% and 25%, and root mean squared error (RMSE). Overall performance was determined by summation of rank for evaluation parameters. MEASUREMENTS AND MAIN RESULTS: During pregnancy, correlations between measured CrCl and estimated CrCl were between 0.5-0.8; equations with slopes closest to one were Modification of Diet in Renal Disease (MDRD2; PPW and ABW) and Cockcroft-Gault (CG) (PPW); and y-intercept closest to zero was Preeclampsia Glomerular Filtration Rate (PGFR). The lowest bias was seen with CG (ABW), and the highest accuracy within 25% was CG (ABW). CG (PPW) had the lowest RMSE. Postpartum, the best correlation was found with MDRD2 (PPW), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI (ABW)), and CKD-EPI 2021 (PPW). For slopes closest to one, MDRD2 (ABW) was best, whereas the equation with y-intercept closest to zero was CKD-EPI (ABW). CG (PPW) had the highest accuracy within 25%, and 100/serum creatinine (SCr) had the lowest bias. Based on overall performance, CG (PPW) was the best followed by CG (ABW) and PGFR during pregnancy and 100/SCr followed by CG (PPW) and CG (ABW) postpartum. CONCLUSION: The new CKD-EPI 2021 equation did not perform well during pregnancy. When 24-h CrCls are not available during pregnancy, CG (PPW or ABW) performed the best overall, whereas at 3 months postpartum, 100/SCr performed the best overall.

Potential Association of Holidays on Internationalized Normalized Ratio in Warfarin-Users at a Multidisciplinary Clinic.

Background: Warfarin is approved by the United States Food and Drug Administration for numerous clinical indications. The effectiveness of warfarin is highly dependent on the time-in-therapeutic range based on the international normalized ratio (INR) goal, which may be altered by changes in diet, alcohol intake, concomitant drugs, and travel, all of which are prevalent during the holidays. At this time, there are no published studies assessing the impact of holidays on INR in warfarin-users. Methods: A retrospective chart review was conducted on all adult patients taking warfarin and managed at a multidisciplinary clinic. Patients were included if they were taking warfarin at home regardless of indication for anticoagulation. The INR pre- and post-holiday was assessed. Results: Of a total of 92 patients, the mean age was 71.5 ± 14.3 years, and most patients were on warfarin with an INR goal of 2 - 3 (89%). There were significant differences in INR before and after Independence Day (2.55 vs. 2.81, P = 0.043) and Columbus Day (2.39 vs. 2.82, P < 0.001). The remaining holidays showed no significant differences in INR before and after each respective holiday. Conclusions: There may be factors related to Independence and Columbus Day that are increasing the level of anticoagulation in warfarin-users. Although the mean post-holiday INR values, in essence, maintained within the typical target of 2 - 3, our study underscores the specialized care that is warranted in higher risk patients to prevent a continued increase in INR and subsequent toxicities. We hope our results would be hypothesis-generating and aid in the development of larger, prospective evaluations to validate the findings of our present study.

The Usage of Concomitant Beta-Blockers with Vasopressors and Inotropes in Cardiogenic Shock.

Vasopressors and inotropes (Vs/Is) are widely used in the treatment of cardiogenic shock (CS). Despite improvements in hemodynamic variables and end-organ perfusion, these agents have been associated with an increase in mortality, potentially due to the increased risk of tachyarrhythmias-which we hypothesize may be mitigated by beta-blockers (BBs). We conducted a retrospective chart review of patients who received a V/I (dobutamine, milrinone, dopamine, and norepinephrine) for CS. The primary objective was to assess the effect of BB in patients receiving Vs/Is for CS. In our final analysis of 227 patients, those in the BB group were younger, were more likely to have acute coronary syndrome as the reason for admission, had more reduced left ventricular ejection fraction, were more likely to have coronary artery disease and atrial fibrillation as pre-existing co-morbidities, and had a lower rate of in-hospital mortality. Nevertheless, in our multivariable logistic regression analysis, concurrent BB usage with a V/I was not associated with a reduction in in-hospital mortality. Our present study sheds light on the importance and urgency of large, carefully designed clinical studies to optimize inpatient medical therapy, particularly evaluating the combination of V/I and BB, in this high-risk patient population.

DOACs in Mechanical and Bioprosthetic Heart Valves: A Narrative Review of Emerging Data and Future Directions.

In the recent years, there has been significant transformation in the management of valvular heart disease (VHD), as a result of new minimally invasive technologies, such as the transcatheter aortic valve implantation (TAVI). Conventionally, mechanical heart valves require anticoagulation with warfarin to prevent thrombogenic events. Lately, there has been an uptrend in the usage of direct-acting oral anticoagulants (DOACs) in both mechanical and bioprosthetic heart valves. In clinical practice, there has shown to be notable heterogeneity in the antithrombotic regimen for patients. Recommendations from clinical guidelines and emerging data on DOAC use in these settings will be critically reviewed here. Future large, randomized-controlled trials are warranted to delineate the role of DOACs in patients receiving a bioprosthetic valve/TAVI or mechanical heart valve, with and without a baseline indication for anticoagulation or antiplatelets. Until clinical trial data from well-designed studies are available, providers must remain vigilant about DOAC use in patients with VHD, especially in patients with a bioprosthetic or mechanical heart valve.

Predictors of In-hospital Mortality in Cardiogenic Shock Patients on Vasoactive or Inotropic Support.

BACKGROUND: Though controversial, the short-duration in-patient use of inotropes in cardiogenic shock (CS) remain an ACC/AHA Class IIa indication, and are frequently used in the initial treatment of CS. We evaluated in-patient mortality and effect on mortality risk of commonly used vasoactive inotropic medications for the medical management of SCAI stage B and C cardiogenic shock patients in a tertiary care cardiac care unit: dobutamine, dopamine, milrinone, and norepinephrine. METHODS: We retrospectively evaluated 342 patients who received dobutamine, milrinone, dopamine, norepinephrine or a combination of these medications for SCAI stage B and C cardiogenic shock. Cox proportional hazards were used to form longitudinal mortality predictions. RESULTS: Overall in-patient mortality was 18%. Each 1 µg/kg/minute increase in dobutamine independently corresponded to a 15% increase in risk of mortality. High dose dobutamine >3 µg/kg/minute is associated with 3-fold increased risk compared to ⩽3 µg/kg/minute (P < .001). Use of milrinone, norepinephrine, and dopamine were not independently associated with mortality. CONCLUSION: We demonstrate that the overall in-hospital mortality of SCAI stage B and C cardiogenic shock patients medically managed on inotropes was not in excess of prior studies. Dobutamine was independently associated with mortality, while other vasoactive inotropic medications were not. Inotropes remain a feasible method of managing SCAI stage B and C cardiogenic shock.

Critical Analysis of Apixaban Dose Adjustment Criteria.

Apixaban is indicated for the prevention of ischemic stroke in non-valvular atrial fibrillation (NVAF), as well as for the prevention and treatment of venous thromboembolism (VTE). Dose adjustment is based on age, weight, and serum creatinine in NVAF, while there are no recommended adjustment criteria for VTE. Such adjustment is unconventional compared to other commonly used medications. The objective of this manuscript is to critically analyze each apixaban dosing adjustment criterion and its associated outcomes. PubMed articles from March 2013 to March 2020 were selected with search terms "apixaban," and "dose adjustment," "adjustment," or "adjustment criteria." Pharmacokinetic studies demonstrated increased apixaban exposure in patients >65 years of age, those with extreme body weights, and those with advanced renal impairment, though post-hemodialysis dosing may off-set the elevated apixaban exposure. However, clinical data show that among patients >75 years, <60 kg, and with estimated glomerular filtration rate <50 mL/min, including those on dialysis, there is no reduction in apixaban safety or efficacy. Published literature describes variable dosing strategies utilized in clinical practice. Overall, apixaban dose adjustment criteria may need to be re-evaluated.

A Review of Inotropes and Inopressors for Effective Utilization in Patients With Acute Decompensated Heart Failure.

ABSTRACT: Inotropes and inopressors are often first-line treatment in patients with cardiogenic shock. We summarize the pharmacology, indications, and contraindications of dobutamine, milrinone, dopamine, norepinephrine, epinephrine, and levosimendan. We also review the data on the use of these medications for acute decompensated heart failure and cardiogenic shock in this article.

Association of Sacubitril/Valsartan with Metabolic Parameters in Patients with Reduced Ejection Fraction Heart Failure at a Multidisciplinary Clinic.

Background: Sacubitril/valsartan was approved for New York Heart Association (NYHA) class II-IV heart failure with reduced ejection fraction (HFrEF) in 2015, based on the results of the PARADIGM-HF trial, which showed a reduction in cardiovascular (CV) death and heart failure hospitalization, compared with enalapril. A subsequent subgroup analysis of the trial showed glycemic improvement for patients on sacubitril/valsartan compared with those on enalapril. Methods: This was a retrospective observational study at the Loma Linda University (LLU) International Heart Institute (IHI). The aim was to evaluate the association of sacubitril/valsartan with glycemic index and other metabolic parameters, including change in hemoglobin A1C (HbA1C), blood pressure (BP), ejection fraction (EF), body weight, and lipid profile from baseline and at 3, 6, and 12 months. The rates of CV-related hospitalizations and total hospitalizations were also assessed. Results: The change in mean HbA1C from baseline was not significantly different at 1 year (P = 0.993). The mean EF was significantly higher and the mean diastolic BP was significantly lowered. Body weight and lipid parameters remained unchanged. Both the rates of CV-related hospitalizations and total hospitalizations were significantly lowered. For the prespecified subgroup analysis of diabetic HFrEF patients, the mean HbA1C was nonsignificant at 12 months (mean difference -0.48, P = 0.993). Conclusion: A non-significant reduction in HbA1C was associated in HFrEF patients with diabetes mellitus. Large randomized trials are needed to confirm our findings regarding the potential metabolic benefits of sacubitril/valsartan.

Effect of N-Acetyltransferase 2 Genotype on the Pharmacokinetics of Hydralazine During Pregnancy.

Hydralazine, an antihypertensive agent used during pregnancy, undergoes N-acetylation primarily via N-acetyltransferase 2 (NAT2) to form 3-methyl-1,2,4-triazolo[3,4-a]phthalazine (MTP). To characterize the steady-state pharmacokinetics (PK) of hydralazine during pregnancy and evaluate the effects of NAT2 genotype on hydralazine and MTP PK during pregnancy, 12 pregnant subjects received oral hydralazine (5-25 mg every 6 hours) in mid- (n = 5) and/or late pregnancy (n = 8). Serial blood samples were collected over 1 dosing interval, and steady-state noncompartmental PK parameters were estimated. Subjects were classified as either (rapid acetylators, n = 6) or slow acetylators (SAs, n = 6) based on NAT2 genotype. During pregnancy, when compared with the SA group, the RA group had faster weight-adjusted hydralazine apparent oral clearance (70.0 ± 13.6 vs 20.1 ± 6.9 L/h, P < .05), lower dose-normalized area under the concentration-time curve (AUC; 1.5 ± 0.8 vs 5.9 ± 3.7 ng·h/mL, P < .05), lower dose-normalized peak concentrations (0.77 ± 0.51 vs 4.04 ± 3.18 ng/mL, P < .05), and larger weight-adjusted apparent oral volume of distribution (302 ± 112 vs 116 ± 45 L/kg, P < .05). Furthermore, the MTP/hydralazine AUC ratio was ∼10-fold higher in the RA group (78 ± 30 vs 8 ± 3, P < .05) than in the SA group. No gestational age or dose-dependent effects were observed, possibly because of the small sample size. This study describes for the first time, the PK of oral hydralazine and its metabolite, MTP, during pregnancy, and confirmed that the PK of oral hydralazine is NAT2 genotype dependent during pregnancy.

Physicochemical Properties, Biotransformation, and Transport Pathways of Established and Newly Approved Medications: A Systematic Review of the Top 200 Most Prescribed Drugs vs. the FDA-Approved Drugs Between 2005 and 2016.

BACKGROUND: Enzyme-mediated biotransformation of pharmacological agents is a crucial step in xenobiotic detoxification and drug disposition. Herein, we investigated the metabolism and physicochemical properties of the top 200 most prescribed drugs (established) as well as drugs approved by the US Food and Drug Administration (FDA) between 2005 and 2016 (newly approved). OBJECTIVE: Our objective was to capture the changing trends in the routes of administration, physicochemical properties, and prodrug medications, as well as the contributions of drug-metabolizing enzymes and transporters to drug clearance. METHODS: The University of Washington Drug Interaction Database (DIDB®) as well as other online resources (e.g., CenterWatch.com, Drugs.com, DrugBank.ca, and PubChem.ncbi.nlm.nih.gov) was used to collect and stratify the dataset required for exploring the above-mentioned trends. RESULTS: Analyses revealed that ~ 90% of all drugs in the established and newly approved drug lists were administered systemically (oral or intravenous). Meanwhile, the portion of biologics (molecular weight > 1 kDa) was 15 times greater in the newly approved list than established drugs. Additionally, there was a 4.5-fold increase in the number of compounds with a high calculated partition coefficient (cLogP > 3) and a high total polar surface area (> 75 Å2) in the newly approved drug vs. the established category. Further, prodrugs in established or newly approved lists were found to be converted to active compounds via hydrolysis, demethylases, and kinases. The contribution of cytochrome P450 (CYP) 3A4, as the major biotransformation pathway, has increased from 40% in the established drug list to 64% in the newly approved drug list. Moreover, the role of CYP1A2, CYP2C19, and CYP2D6 were decreased as major metabolizing enzymes among the newly approved medications. Among non-CYP major metabolizers, the contribution of alcohol dehydrogenases/aldehyde dehydrogenases (ADH/ALDH) and sulfotransferases decreased in the newly approved drugs compared with the established list. Furthermore, the highest contribution among uptake and efflux transporters was found for Organic Anion Transporting Polypeptide 1B1 (OATP1B1) and P-glycoprotein (P-gp), respectively. CONCLUSIONS: The higher portion of biologics in the newly approved drugs compared with the established list confirmed the growing demands for protein- and antibody-based therapies. Moreover, the larger number of hydrophilic drugs found in the newly approved list suggests that the probability of toxicity is likely to decrease. With regard to CYP-mediated major metabolism, CYP3A5 showed an increased involvement owing to the identification of unique probe substrates to differentiate CYP3As. Furthermore, the contribution of OATP1B1 and P-gp did not show a significant shift in the newly approved drugs as compared to the established list because of their broad substrate specificity.

Atezolizumab for the First-Line Treatment of Non-small Cell Lung Cancer (NSCLC): Current Status and Future Prospects.

Purpose: Atezolizumab is a programmed death ligand 1 (PDL-1) blocking antibody that was approved for metastatic non-small cell lung cancer (NSCLC) in patients with disease progression. Various studies have been initiated to explore the effectiveness of atezolizumab among different patient cohorts and disease statuses, including as first-line therapy. The purpose of this paper is to identify and summarize the trials that use atezolizumab as a first-line agent in chemotherapy-naïve patients with NSCLC. Methods: A database search was performed on Pubmed, Embase, and Wiley Cochrane Library-Central Register of Controlled Trials to identify clinical trials using atezolizumab as first-line therapy in NSCLC. Additionally, ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP) were searched to identify relevant clinical trials. Conference abstracts from the American Society of Clinical Oncology, the European Society for Medical Oncology, and the American Association for Cancer Research were hand-searched. Any trial in which atezolizumab was used as first-line therapy in chemotherapy-naive patients with NSCLC was included. Results: Fifteen studies were ultimately included, all of which are current and ongoing. Of the 15 studies, 5 have reported results. When given in the first-line setting, atezolizumab had higher rates of objective response, progression-free survival, and overall survival, compared to the second and third-line settings. Among the 15 studies, atezolizumab is used as monotherapy (n = 5), in combination with chemotherapy (n = 6), in combination with targeted therapy such as bevacizumab (n = 1), as neoadjuvant/adjuvant therapy (n = 3), in combination with stereotactic body radiation therapy (n = 1), and in combination with or following chemoradiation (n = 1). Conclusion: Available evidence shows promising safety and efficacy with the use of atezolizumab as first-line therapy in NSCLC. Atezolizumab is currently being studied in a variety of treatment settings. If clinical benefits are shown, atezolizumab may deem to be a useful first-line agent in NSCLC.

Prednisone Pharmacokinetics During Pregnancy and Lactation.

To evaluate the steady-state pharmacokinetics of prednisone and its metabolite prednisolone in pregnant and lactating female subjects, 19 subjects received prednisone (4-40 mg/day orally) in early (n = 3), mid (n = 9), and late (n = 13) pregnancy as well as postpartum with (n = 2) and without (n = 5) lactation. Serial blood and urine samples were collected over 1 dosing interval. Prednisone and its metabolite, prednisolone, steady-state noncompartmental pharmacokinetic parameters were estimated. During pregnancy, prednisone apparent oral clearance increased with dose (35.1 ± 11.4 L/h with 5 mg, 52.6 ± 5.2 L/h with 10 mg, and 64.3 ± 6.9 L/h with 20 mg, P = .001). Similarly, unbound prednisone apparent oral clearance increased with dose. In addition, prednisolone renal clearance increased with dose (0.3 ± 0.3 L/h with 5 mg, 0.5 ± 0.4 L/h with 10 mg, and 1.3 ± 1.1 L/h with 20 mg, P = .002). Higher prednisone (r = 0.57, P ≤ .05) and prednisolone (r = 0.75, P ≤ .05) concentrations led to a higher percentage of unbound drug. Breast-milk/plasma area under the concentration-time curve ratios were 0.5-0.6 for prednisone and 0.02-0.03 for prednisolone. Relative infant doses were 0.35% to 0.53% and 0.09% to 0.18%, for prednisone and prednisolone, respectively. Prednisone and prednisolone exhibit dose- and concentration-dependent pharmacokinetics during pregnancy, and infant exposure to these agents via breast milk is minimal.

Pharmacokinetics of metoprolol during pregnancy and lactation.

The objective of this study was to evaluate the steady-state pharmacokinetics of metoprolol during pregnancy and lactation. Serial plasma, urine, and breast milk concentrations of metoprolol and its metabolite, α-hydroxymetoprolol, were measured over 1 dosing interval in women treated with metoprolol (25-750 mg/day) during early pregnancy (n = 4), mid-pregnancy (n = 14), and late pregnancy (n = 15), as well as postpartum (n = 9) with (n = 4) and without (n = 5) lactation. Subjects were genotyped for CYP2D6 loss-of-function allelic variants. Using paired analysis, mean metoprolol apparent oral clearance was significantly higher in mid-pregnancy (361 ± 223 L/h, n = 5, P < .05) and late pregnancy (568 ± 273 L/h, n = 8, P < .05) compared with ≥3 months postpartum (200 ± 131 and 192 ± 98 L/h, respectively). When the comparison was limited to extensive metabolizers (EMs), metoprolol apparent oral clearance was significantly higher during both mid- and late pregnancy (P < .05). Relative infant exposure to metoprolol through breast milk was <1.0% of maternal weight-adjusted dose (n = 3). Because of the large, pregnancy-induced changes in metoprolol pharmacokinetics, if inadequate clinical responses are encountered, clinicians who prescribe metoprolol during pregnancy should be prepared to make aggressive changes in dosage (dose and frequency) or consider using an alternate beta-blocker.

Gestational diabetes mellitus management with oral hypoglycemic agents.

Oral hypoglycemic agents such as glyburide (second-generation sulfonylurea) and metformin (biguanide) are attractive alternatives to insulin due to lower cost, ease of administration, and better patient adherence. The majority of evidence from retrospective and prospective studies suggests comparable efficacy and safety of oral hypoglycemic agents such as glyburide and metformin as compared to insulin when used in the treatment of women with gestational diabetes mellitus (GDM). Glyburide and metformin have altered pharmacokinetics during pregnancy and both agents cross the placenta. In this article, we review the efficacy, safety, and dosage of oral hypoglycemic agents for the treatment of gestational diabetes mellitus. Additional research is needed to evaluate optimal dosage for glyburide and metformin during pregnancy. Comparative studies evaluating the effects of glyburide and metformin on long-term maternal and fetal outcomes are also needed.

Pharmacokinetics of doxorubicin in pregnant women.

PURPOSE: Our objective was to evaluate the pharmacokinetics (PK) of doxorubicin during pregnancy compared to previously published data from non-pregnant subjects. METHODS: During mid- to late-pregnancy, serial blood and urine samples were collected over 72 h from seven women treated with doxorubicin for malignancies. PK parameters were estimated using non-compartmental techniques. Pregnancy parameters were compared to those previously reported non-pregnant subjects. RESULTS: During pregnancy, mean (±SD) doxorubicin PK parameters utilizing 72 h sampling were: clearance (CL), 412 ± 80 mL/min/m(2); steady-state volume of distribution (Vss), 1,132 ± 476 L/m(2); and terminal half-life (T1/2), 40.3 ± 8.9 h. The BSA-adjusted CL was significantly decreased (p < 0.01) and T1/2 was not different compared to non-pregnant women. Truncating our data to 48 h, PK parameters were: CL, 499 ± 116 ml/min/m(2); Vss, 843 ± 391 L/m(2); and T1/2, 24.8 ± 5.9 h. The BSA-adjusted CL in pregnancy compared to non-pregnant data was significantly decreased in 2 of 3 non-pregnant studies (p < 0.05, < 0.05, NS). Vss and T1/2 were not significantly different. CONCLUSIONS: In pregnant subjects, we observed significantly lower doxorubicin CL in our 72 h and most of our 48 h sampling comparisons with previously reported non-pregnant subjects. However, the parameters were within the range previously reported in smaller studies. At this time, we cannot recommend alternate dosage strategies for pregnant women. Further research is needed to understand the mechanism of doxorubicin pharmacokinetic changes during pregnancy and optimize care for pregnant women.