Annals of Pharmacotherapy

The effect of COVID-19 on immunosuppressant drug levels in organ transplant recipients (OTRs) has not been adequately studied.

To study the effect of COVID-19 on tacrolimus trough levels (primary outcome) in OTRs and the association of the later with acute kidney injury, bacterial infection, and oxygen requirements.

We studied adult (>18-year-old) hospitalized OTRs with COVID-19, who were receiving tacrolimus between 3/1 and 12/16/2020.

Among 30 OTRs, 67% were men, 90% had a kidney transplant. Median age was 60.5 (interquartile range [IQR]: 45-68) years, median time from transplant 36 (IQR: 20-84) months. Tacrolimus troughs were higher on admission for COVID-19 than baseline (average over 6 months prior) (P = .001). Eighteen patients (60%) had admission tacrolimus trough >10, 5 (17%) >20 ng/mL. Patients with diarrhea had borderline higher tacrolimus troughs, compared to those without diarrhea (P = .09). Organ transplant recipients with a tacrolimus trough >10 ng/mL were more likely to have elevated aspartate aminotransferase on admission (P = .01) and require supplemental oxygen. (P = .026).

Tacrolimus trough levels were elevated in most OTRs with COVID-19 at the time of hospital admission, compared to baseline. Potential mechanisms are diarrhea and hepatic involvement in COVID-19. In OTRs with COVID-19, including outpatients, immunosuppressant drug levels should be closely followed; management of immunosuppression should be individualized.

Clinical pharmacists play pivotal roles in multidisciplinary heart failure (HF) teams through the management of HF pharmacotherapy, but no study has examined the economic impact of HF ambulatory clinical pharmacists in an advanced HF clinic.

The objective of the study was to evaluate the economic impact of HF ambulatory clinical pharmacist interventions in an advanced HF clinic using a cost-benefit analysis.

This prospective observational study detailed HF ambulatory clinical pharmacist interventions over 6 months in an advanced HF clinic in a single-center tertiary teaching hospital. The economic impact of the interventions was estimated based on the indirect cost savings with pharmacist interventions and direct cost savings recommendations. A cost-benefit analysis was performed to assess the cost of delivering the interventions compared with the benefits generated by clinical pharmacists. Results were reported as a benefit-cost ratio and net benefits.

HF ambulatory clinical pharmacists made a total of 2,361 provider-accepted interventions over 6 months. Overall, the 3 most common intervention types were medication reconciliation (28.7%), dose change (20.8%), and addition of medication (12.3%). Anticoagulation (21.2%) was the most common intervened class of medication, followed by sodium-glucose cotransporter-2 inhibitor (12.3%) and angiotensin receptor neprilysin inhibitor (9.2%). The total net benefits were $55,553.24 over 6 months and the benefit-cost ratio was 1.55.

The addition of cardiology clinical pharmacists to an advanced HF clinic may be financially justified and cost-beneficial.

Despite multiple guideline recommendations of a goal blood glucose of 140 to 180 mg/dL in critically ill patients, no insulin infusion protocols (IIPs) targeting this range have been validated and published in the literature.

The purpose of this study is to determine the safety and efficacy of an IIP targeting a blood glucose of 140 to 180 mg/dL in critically ill patients, with the ultimate goal of validating such a protocol.

This retrospective chart review uses data of critically ill patients admitted from August 2018 to December 2018. Patient data from August 2017 to December 2017 served as a historical comparator to further assess safety outcomes. Percent of blood glucose readings within goal was the primary outcome measurement. Relevant clinical variables, insulin requirements, hypoglycemic events, and protocol adherence were also recorded.

A total of 88 insulin infusions were included in analysis, 34 of which served as a historical comparator. In the IIP targeting a blood glucose 140 to 180 mg/dL, once blood glucose levels decreased below 180 mg/dL, 54% of blood glucose readings were within goal (140-180 mg/dL) and 73% of blood glucose readings were within a “clinically acceptable” range (110-180 mg/dL). The number of hypoglycemic events decreased from 70 in the historical comparator group to 4 in the current IIP (P < .0001).

This IIP is both safe and effective at targeting a blood glucose of 140 to 180 mg/dL and could be used at other institutions to achieve satisfactory glycemic control.

Recent guidelines suggest that, for venous thromboembolism (VTE), standard doses of apixaban are appropriate in patients with body mass index (BMI) >40 kg/m2 or >120 kg. Atrial fibrillation (AF) is excluded from this recommendation.

The goals of our study were to measure and describe anti-Xa levels of patients with a BMI ≥40 kg/m2 and/or a weight ≥120 kg with a clinical indication of AF or VTE who were treated with apixaban, and to determine whether BMI or weight are associated with anti-Xa levels in this population.

We conducted an observational cohort study at a single health care system in Oregon, USA. Patients meeting enrollment criteria were recruited and had peak and trough apixaban anti-Xa levels drawn.

Of 55 patients enrolled, 5 (9%) had peak anti-Xa levels below the reference range and 3 (6%) had trough anti-Xa levels below the reference range. BMI did not significantly correlate with peak or trough anti-Xa levels (r = −0.10, p = 0.45 and r = −0.14, p = 0.31). Weight had a moderate, negative correlation with peak anti-Xa levels (r = −0.42, p = 0.002) and a weak, negative correlation with trough anti-Xa levels (r = −0.32, p = 0.02).

This study provides evidence that anti-Xa levels among obese patients are not substantially different from patients with nomral BMI and weight. This supports recent ISTH guidance for standard dosing of apixaban for VTE patients with BMI >40 kg/m2 or weight >120 kg and provides additional evidence that the standard dosing may also be appropriate in patients with AF.

Intrapleural fibrinolytic instillation is second-line treatment for retained hemothorax. Dornase alfa (DNase) has demonstrated efficacy in parapneumonic effusion, but the lack of deoxyribonucleoproteins limits direct extrapolation to traumatic retained hemothorax treatment.

This study evaluated the effectiveness of intrapleural tissue plasminogen activator (tPA) with and without DNase in the treatment of retained traumatic hemothorax.

This retrospective cohort study included patients aged 16 years and older admitted to a level 1 trauma center from January 2013 through July 2019 with retained hemothorax and one or more intrapleural tPA instillations. Exclusion criteria were tPA for other indications or concomitant empyema. The primary endpoint was treatment failure defined as the need for operative intervention.

Fifty patients were included (tPA alone: 28; tPA with DNase: 22). Baseline characteristics were similar between groups, including time to diagnosis (6.5 [interquartile range (IQR), 4-15.5] days vs 6 [IQR, 6.3-10.8] days, P = 0.52). Median tPA dose per treatment (6 [IQR, 6-6.4] mg vs 10 [IQR, 8.4-10] mg, P < 0.001) and cumulative tPA (18 [IQR, 6.5-24] mg vs 30 [IQR, 29.5-40], P < 0.001) dose were significantly lower in the tPA alone group. Treatment failure was similar between groups. Chest tube output, retained hemothorax reduction, and bleeding incidences were similar between groups. Multivariate logistic regression demonstrated no significant risk factors for treatment failure.

Dornase alfa added to tPA may not reduce the need for operation to treat retained hemothorax. Further studies should be directed at optimal tPA dose determination and economic impact of inappropriate DNase use.

Contradictory studies reporting vast heterogeneity in the teicoplanin-induced thrombocytopenia (TIT) incidence exist.

To identify the incidence of TIT associated with teicoplanin dosing range (6–12 mg/kg/dose) and the risk factors of TIT.

This retrospective observational study included adult patients who received teicoplanin for ≥3 consecutive days over a period of 3.5 years. Thrombocytopenia was defined as a platelet count of <100 × 10³/µL coupled with at least a 25% drop from the baseline count. The TIT incidence was assessed using the adverse drug reaction probability scale (Naranjo scale).

Data from 482 patients who received teicoplanin and met the predefined inclusion criteria were included in the analyses. The cohort presented a mean age of 53.5 ± 19 years, where 72.4% were male, and 49.2% exhibited normal baseline renal function. Teicoplanin was most commonly used for bacteremia (n = 134), and the most common isolated pathogen being Staphylococcus aureus (n = 221). The TIT incidence was 4.6% (the possible and probable category using the Naranjo scale; 22/482). The median time to first platelet count dropped to <100 × 10³/µL after teicoplanin initiation was 5 (interquartile range [IQR], 3-10) days and 8 (IQR, 5-14) days till the maximum platelet count dropped. None of the tested patient variables were found to be independently associated with an increased risk of thrombocytopenia.

The overall TIT incidence was low across our study cohort, including critically ill patients. Our study results may aid in the optimal monitoring of such serious teicoplanin-induced adverse effects.

To describe weight changes with integrase strand transfer inhibitor (INSTI) therapy.

A literature search was performed (through December 15, 2021) using the PubMed and CINAHL databases using the search terms: “integrase inhibitors,” “integrase strand transfer inhibitors,” and “weight.”

Studies were included that provided relevant information on weight or body mass index (BMI) changes on INSTI therapy. Controlled or observational studies comparing different INSTI therapies or compared INSTI therapy to another class of antiretroviral therapy were included.

Forty-three articles met criteria for inclusion, and data are presented. Although some trials have observed similar weight gains between INSTI, protease inhibitor, and non-nucleoside inhibitor therapies, the increase appears to be greater with INSTI therapy, particularly during initiation of therapy. Risk factors for weight gain with INSTI therapy include female gender, lower CD4 count, and combined use of tenofovir alafenamide. Within the INSTI class, dolutegravir and bictegravir appear to have the greatest propensity for weight gain.

INSTI-based therapies are the preferred initial management of HIV infection. Discerning the factors contributing to weight changes on INSTI therapy and risks of associated health-related outcomes is important to both the management of weight gain and HIV medical management.

Within the INSTI class, dolutegravir and bictegravir may be associated with the greatest risk for weight gain particularly when combined with tenofovir alafenamide. Further research is needed to determine mechanisms for observed weight changes and any contributions to clinically significant metabolic and cardiovascular adverse outcomes associated with INSTI therapy.

Ibuprofen is a widely used nonsteroidal anti-inflammatory drug, which has been occasionally associated with hypokalemia and metabolic acidosis. The objective of this report is to analyze the literature on this issue and to address the underlying pathophysiology.

Excerpta Medica, the National Library of Medicine, and Web of Science were searched from inception to July 16, 2021.

Papers reporting individually documented humans on ibuprofen with hypokalemia, acidosis, or both were retained. Data were extracted using a checklist.

For the final analysis, we evaluated 41 reports describing 50 cases (26 males and 24 females; 36 adults and 14 children) with often profound hypokalemia, acidosis, or both after ingestion of ibuprofen. Twenty-six cases were acute and 24 long term. Hypokalemia and acidosis occurred not only after ingestion of very high doses but also after ingestion of moderately high or even normal doses of ibuprofen. Laboratory values consistent with an excessive urinary potassium excretion or an altered urinary acidification were often disclosed in most cases. Discontinuation of ibuprofen resulted in a resolution of hypokalemia and acidosis within days in 47 cases. The course was lethal in 3 cases.

This review highlights potentially fatal side effects of ibuprofen and can help doctors who are confronted with such a situation.

These data highlight the potential of ibuprofen to occasionally induce hypokalemia and acidosis of renal origin. Discontinuation of ibuprofen results in a resolution within days.

To review the new indication of cyclin-dependent kinase (CDK4/6) inhibitor abemaciclib for the adjuvant treatment of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−), axillary lymph node (LN) positive early breast cancer (EBC) at high risk of recurrence and a Ki-67 ≥20%.

A literature search was performed through PubMed, ClinicalTrials.gov, and Food and Drug Administration (FDA) website (February 1, 2018, to December 23, 2021) to identify relevant information.

Human and animal studies related to pharmacology, pharmacokinetics, efficacy, and safety of abemaciclib were identified.

Addition of abemaciclib to standard of care endocrine therapy (ET) for patients with high-risk clinicopathologic features and Ki-67 ≥20% demonstrated 30% reduction in the risk of developing invasive disease and distant recurrence. At 15.5 months, abemaciclib + ET demonstrated a significant improvement in invasive disease-free survival (IDFS) vs ET alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60-0.93, P = 0.01). At 27 months, IDFS benefit was maintained (HR, 0.70; 95% CI, 0.59-0.82, P < 0.0001). Diarrhea occurred in more than 80% of patients in the abemaciclib arm.

This review describes the clinical applicability of adjuvant abemaciclib for patients with HR+, HER2− EBC at high risk for recurrence.

Adjuvant abemaciclib significantly reduces the risk for early development of invasive disease and distant recurrence in patients with HR+, HER2− node positive EBC. Longer follow-up is needed to determine the impact of adjuvant abemaciclib on late disease recurrence and survival outcomes.

To describe the safety, efficacy, and potential role in therapy of voclosporin, an oral calcineurin inhibitor approved by the Food and Drug Administration (FDA) in January 2021 as an adjunct treatment for lupus nephritis.

A literature search was conducted using PubMed with the following terms: voclosporin, Lupkynis, and lupus nephritis (January 1, 2010, to December 1, 2021). FDA product labeling was also reviewed for pertinent data sources.

All articles were considered for inclusion. English-language articles selected included preclinical and clinical studies examining the pharmacokinetics, efficacy, and/or safety of voclosporin.

Voclosporin has been studied as an adjunct immunosuppressive agent in patients with lupus nephritis. Drug design allows for a more predictable pharmacokinetic profile than other calcineurin inhibitors. Data suggest that adding this newly approved calcineurin inhibitor to a regimen of mycophenolate mofetil and corticosteroids produces promising therapeutic results. As such, voclosporin has been approved for use in patients with active lupus nephritis who are maintained on immunosuppressive therapy with mycophenolate mofetil and a corticosteroid.

Voclosporin may be a favorable calcineurin inhibitor in patients with lupus nephritis, due to a predictable pharmacokinetic profile. This allows for decreased therapeutic drug monitoring and suggests a favorable adverse effect profile. However, cost remains a consideration with this new agent.

Current available data suggest that voclosporin is a promising adjunct treatment option for patients with active lupus nephritis who are maintained on mycophenolate mofetil and a corticosteroid.