Annals of Pharmacotherapy

The US Food and Drug Administration (FDA) recommends using only FDA-reviewed pharmacogenetic information to make prescribing decisions based on genetic test results. Such information is available in drug labeling and in the Table of Pharmacogenetic Associations (“Associations table”).

To compile a list of drug-gene pairs from drug labeling and the Associations table and categorize the pharmacogenetic information and clinical outcome associated with each drug-gene pair.

This was a cross-sectional analysis of pharmacogenetic information in the Associations table and individual drug labeling in March 2020. We used the Table of Pharmacogenomic Biomarkers in Drug Labeling to identify drug labels to review. We categorized the pharmacogenetic information for each drug-gene pair according to whether the purpose was to describe (1) polymorphisms affecting drug disposition (metabolism or transport), (2) polymorphisms affecting a direct drug target, (3) variants associated with adverse drug reaction (ADR) susceptibility, (4) variants associated with therapeutic failure, (5) a biomarker-defined indication, or (6) a biomarker-defined ADR. We also categorized the clinical outcome—efficacy, safety, or unknown—associated with each drug-gene pair. We reported counts and proportions of drug-gene pairs in each pharmacogenetic information and clinical outcome category.

We identified 308 drug-gene pairs, of which 36% were associated with a biomarker-defined drug indication, 33% with polymorphic drug metabolism, and 28% with ADR susceptibility. Most drug-gene pairs (n = 267, 87%) were associated with an efficacy or safety-related outcome.

FDA-reviewed pharmacogenetic information is available for more than 300 drug-gene pairs and can help guide prescribing decisions.

In high-dose methotrexate (HD-MTX) therapy, delayed elimination of MTX from plasma leads to severe adverse effects. However, the risk factors for the delayed elimination of plasma MTX are still unclear.

The purpose of this study was to investigate the factors related to the delayed MTX elimination in HD-MTX monotherapy.

This retrospective study was performed on patients who received HD-MTX monotherapy between April 2009 and March 2019 at the Hiroshima University Hospital. Patients were divided into a “Normal” and a “Delayed” group according to their MTX plasma concentration at 48 or 72 hours after administration. Patient characteristics, dose of HD-MTX, MTX plasma concentration, and adverse effects were analyzed and compared between the 2 groups.

A total of 74 patients were included in this study. Logistic analysis of patient baseline characteristics was performed to identify risk factors for delayed MTX elimination. Serum albumin (ALB) was detected as a risk factor. Univariate and multivariate analysis revealed that low ALB level (<3.7 g/dL) and type of cancer were associated with delayed MTX elimination (univariate analysis: odds ratio [OR] = 6.00, P = 0.004, and OR = 4.33, P = 0.039, respectively; multivariate analysis: adjusted OR [AOR] = 6.45, P = 0.006, and AOR = 8.11, P = 0.018, respectively). Adverse effects were not significantly different between the 2 groups, excluding renal impairment.

Our study showed that low ALB is a risk factor for delayed MTX elimination in HD-MTX monotherapy. Pharmacokinetic analysis is needed to establish the dose of HD-MTX in patients with a low ALB level.

Shoulder pain most commonly originates from the tendon structures of the rotator cuff.

We compared the clinical effects of high- versus low-molecular-weight (LMW) hyaluronic acid for the management of rotator cuff tendinopathy.

We carried out a parallel, triple-blind, randomized comparative trial at a teaching hospital. In total, 56 patients aged 16 to 70 years with rotator cuff tendinopathy were randomly allocated to 2 groups. We administered a single shoulder injection of either 1 mL of 1% high- (>2000 kDa) or 1 mL of 1% LMW hyaluronate (500-700 kDa) to the corresponding groups. The primary outcome was the intensity of shoulder pain. The secondary outcomes were range of motion and disability of the shoulder, and quality of life. We performed the measurements at baseline and at 1, 4, and 12 weeks postintervention. The pain measurements were repeated at the sixth month postintervention.

Comparisons of baseline versus 3 months showed that both interventions were beneficial in the management of the tendinopathy (all P values <0.05). However, between-group analyses did not indicate any clinically significant difference between the 2 medications. The pain, induration (P = 0.007), and inflammation at the site of the injection were less prominent for LMW hyaluronate.

Both medications are effective for the treatment of tendinopathy. The benefits last at least for 3 months, and pain alleviation lasts partially for 6 months. The shoulder injection of LMW hyaluronate is more tolerable to the patient. Therefore, we recommend LMW hyaluronate as the first choice for the management of rotator cuff tendinopathy.

Patients with cardiogenic shock after percutaneous coronary intervention (PCI) may require mechanical circulatory support (MCS). The combination of dual antiplatelet therapy with cangrelor and continuous anticoagulation required for MCS may increase the risk of bleeding.

The objective of the study is to describe the complications and outcomes of patients who received cangrelor during MCS following PCI.

This is a single-center, retrospective, observational case series of 17 patients who received cangrelor while on MCS from June 2017 to September 2019.

In a case series of 17 patients, 8 patients (47%) were supported with an Impella device and 4 patients (24%) with venoarterial (VA) extracorporeal membrane oxygenation (ECMO); 5 required (29%) concomitant VA ECMO and Impella support in the setting of cardiogenic shock. All patients received triple antithrombotic therapy with aspirin, heparin, and cangrelor. Cangrelor was commonly initiated at a median dose of 0.75 (range 0.5-4) µg/kg/min. Cangrelor dose adjustments included changes in increments up to 0.25 µg/kg/min with review of P2Y12 levels. A total of 10 patients (59%) experienced a bleeding event, most commonly located at the peripheral cannulation site (40%) and in the gastrointestinal tract (30%). Seven (70%) and 3 (30%) of the bleeding complications were classified as major and minor, respectively. No patient developed in-stent thrombosis during the hospitalization; 14 (82%) patients survived their MCS course.

This case series suggests that cangrelor doses less than 0.75 µg/kg/min may be beneficial. Larger studies should evaluate alternative dosing regimens.

Literature suggests that 2 mg of vitamin K intravenously (IV) provides a similar effect as 10 mg to reverse warfarin. Doses <5 mg haven’t been studied in depth.

The objective was to determine the international normalized ratio (INR) reduction effect of ultra low-dose (ULD) IV vitamin K.

This retrospective, observational cohort study compared IV vitamin K doses of 0.25-0.5 mg (ULD) versus 1-2 mg (standard low dose [SLD]). The primary outcome assessed ΔINR at 36 hours; secondary outcomes assessed ΔINR at 12 hours and 30-day venous thromboembolism (VTE) and mortality rates.

Of 88 patients identified (median baseline INR [IQR], 5.1 [3.1, 7.3] vs 4.5 [2.8, 8.2], ULD vs SLD, respectively), 59 had an INR at 12 hours. The ULD had fewer 12-hour INR values <2, with no statistical difference in the ΔINR at 12 hours between the ULD and SLD cohorts (median ΔINR, 2.2 [1.1, 3.4] vs 2.2 [1.1, 6.3]; P = 0.54; median INR, 2.3 vs 1.8). A total of 41 patients had both a 12- and 36-hour INR. No significant difference in the ΔINR between the 12- and 36-hour values occurred (median ΔINR, 0.52 [0.2, 0.91] vs ΔINR, 0.46 [0.18, 0.55]; P = 0.61), suggesting no rebound or excessive reversal and no difference in 30-day rates of VTE (P > 0.99) or death (P = 0.38).

ULD IV vitamin K reversed INR similarly to doses of 1-2 mg without rebound. A ULD strategy may be considered in patients requiring more cautious reversal.

Fixed-dose (FD) regimens of 4-factor prothrombin complex concentrate (4F-PCC) may be effective for the emergent reversal of warfarin; however, the optimal dosing is unknown. Our institution transitioned to a FD regimen of 1000 or 2000 units of 4F-PCC based on indication.

The purpose of this study is to report our experience with FD 4F-PCC compared with a historical weight-based dosing cohort for warfarin reversal.

A retrospective analysis was conducted for 3 groups: central nervous system (CNS) bleeds regardless of international normalized ratio (INR), non-CNS bleeds with an initial INR ≤6, and non-CNS bleeds with an initial INR ≥6.1. The primary outcome of the study was achievement of the target INR.

There were 54 patients with a CNS bleed, 153 with a non-CNS bleed and INR ≤6, and 19 with a non-CNS bleed and INR ≥6.1. In the CNS bleeding group, weight-based and FD achieved target INR 79.4% and 70% (P = 0.52). In the INR ≥6.1 non-CNS bleeding group, weight-based and FD achieved target INR 100% and 70% (P = 0.21). In the INR ≤6 non-CNS bleeding group, weight-based and FD achieved target INR 86.4% and 57.5% (P = 0.0002).

An FD strategy of 2000 units for warfarin reversal for CNS bleeds or INR ≥6.1 was comparable to weight-based dosing. The FD strategy of 1000 units for INR ≤6 achieved target INR less often than weight-based dosing. Application of findings suggest that higher doses may be needed to achieve target INR.

To assess the current literature for blinatumomab in the treatment of adult and pediatric B-cell acute lymphoblastic leukemia (ALL).

We conducted a PubMed (inception to December 11, 2020) and ClinicalTrials.gov systematic literature search using the following terms: blinatumomab, Blincyto, lymphoblastic leukemia, and bispecific T-cell engager.

All relevant published articles, package inserts, and meeting abstracts evaluating the use of blinatumomab in ALL were considered for inclusion.

Blinatumomab, a first-in-class bispecific T-cell engager monoclonal antibody, facilitates cytotoxic T-cell activation and subsequent eradication of CD19-positive B cells. The confirmatory phase III TOWER trial demonstrated superior overall survival (OS) with blinatumomab compared with standard chemotherapy (7.7 months vs 4.0 months) in relapsed and refractory (R/R) B-cell ALL. In the phase II BLAST trial, blinatumomab achieved a complete measurable residual disease (MRD) response in 78% of evaluable patients, with a median OS of 36.5 months. Potentially life-threatening cytokine release syndrome and neurotoxicity occurred in approximately 15% and 65% of patients, respectively.

Following initial Food and Drug Administration approval in 2014, blinatumomab gained expanded approval in pediatric patients and in Philadelphia chromosome-positive R/R ALL. In 2018, blinatumomab became the first and only drug approved for the treatment of persistent MRD in any hematologic malignancy. Emerging data demonstrate promising efficacy with blinatumomab in specific ALL settings, including frontline therapy, as a bridge to transplantation, and in “chemotherapy-free” combination regimens.

Blinatumomab provides a paradigm-shifting treatment option; however, many questions surrounding optimal patient selection, sequencing, and cost-effectiveness remain.

To describe the efficacy and safety of pharmacologic neurostimulants after neurological injuries such as ischemic or hemorrhagic stroke and traumatic brain injury (TBI), critically evaluate the available literature, and make recommendations regarding which neurostimulants should be considered for use in clinical practice.

A literature search of PubMed was performed (1953 to October 2020) to identify relevant articles. Search terms included the following: “neurostimulant, neurorehabilitation” AND “traumatic brain injury, cerebrovascular accident, or stroke.” This review is limited to prospective studies and observational trials.

Relevant English-language studies conducted in humans were considered.

Cognitive and motor deficits caused by stroke and TBI account for high rates of long-term disability. Although not well-established, pharmacologic agents, broadly characterized as neurostimulants, may be prescribed after brain injury to treat these deficits. When prescribing these medications, it is imperative to be aware of the supporting evidence in order to accurately gauge the risk-benefit profile of each agent.

The following presents a literature review critically evaluating clinical studies that investigate neurostimulant use after brain injury. The intent of this review is to serve as an evidence-based guide for clinicians.

The pharmacologic agent with the most supporting literature is amantadine used for cognitive improvement after TBI. Other neurostimulants with positive, despite more limited, evidence include methylphenidate, modafinil, levodopa, and citalopram. Caution is warranted with other neurostimulants given higher rates of adverse effects or lack of benefit observed in clinical trials.

To provide clinical guidance and an overview of the available data on the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with heart failure with reduced ejection fraction (HFrEF), regardless of the presence of type 2 diabetes mellitus (T2DM).

We searched the MEDLINE database via PubMed (from January 2015 to November 2020) for the following key terms: SGLT2 inhibitors, sodium-glucose co-transporter-2 inhibitors, SGLT2i, heart failure, and heart failure with reduced ejection fraction.

To be included in the review, the articles needed to assess the effects of SGLT2 inhibitors in the heart failure (HF) scenario.

There is consistent evidence that SGLT2 inhibitors reduce the risk of major adverse cardiovascular (CV) events and hospitalization in patients with HFrEF, even in the absence of T2DM. On May 5, 2020, the U.S. Food and Drug Administration approved dapagliflozin for adults with HFrEF, regardless of the presence of T2DM, even in those patients on standard therapy, including an angiotensin receptor/neprilysin inhibitor.

The SGLT2 inhibitors are well tolerated, and their once-daily dosing without the need for adjustments is convenient. These drugs can be considered a major breakthrough in pharmacotherapy for HF, providing physicians with a new treatment approach to reduce major clinical outcomes.

SGLT2 inhibitor therapy reduces CV death and hospitalizations in HFrEF patients regardless of T2DM. The decision to prescribe this class of drugs should not be determined by glycemic status.

To review the pharmacology, efficacy, and safety of amisulpride and determine its role in the management of postoperative nausea and vomiting (PONV).

A PubMed search (1946 to November 2020) using the terms amisulpride and APD421 was conducted.

Relevant reports on intravenous amisulpride were included.

Six clinical trials were evaluated. In 4 trials on the prevention of PONV, a greater percentage of patients who received amisulpride 5 mg compared with placebo experienced a complete response (44%-60% vs 31%-33%, respectively, when used as monotherapy; 58% vs 47%, respectively, when used in combination with another antiemetic). In 2 trials on the treatment of PONV, a significantly greater percentage of patients who received amisulpride 10 mg compared with placebo experienced a complete response (31.4% vs 21.5%, respectively, in patients who had not received prophylaxis; 41.7% vs 28.5%, respectively, in patients who had received prophylaxis). Adverse effects included infusion site pain, chills, hypokalemia, procedural hypotension, and abdominal distension.

Amisulpride is effective for the management of PONV and may be less likely to cause QT prolongation and extrapyramidal symptoms than other dopamine antagonists. Additional information is needed on its use for chemotherapy-induced nausea and vomiting and in children.

Amisulpride is an important new option for the multimodal management of PONV in adults, and it may be the preferred dopamine antagonist because of the more favorable safety profile that results from its unique pharmacological properties.

To review the pharmacological characteristics, clinical evidence, and place in the management of acute postoperative pain severe enough to require an intravenous opioid.

A comprehensive literature search was conducted in PubMed (January 2000 to December 1, 2020). Key search terms included oliceridine or acute postoperative pain. Other sources were derived from product labeling and ClinicalTrials.gov.

All English-language articles identified from the data sources were reviewed and evaluated. Phase I, II, and III clinical trials were included.

Oliceridine is a novel selective µ-receptor G-protein pathway modulator. It has the property of activating G-protein signaling while causing low β-arrestin recruitment to the µ-receptor. Intravenous oliceridine showed statistically superior analgesia than placebo in patients with moderate or severe pain after surgery, with a favorable safety and tolerability profile regarding respiratory and gastrointestinal adverse effects, compared with morphine.

The analgesic capacity of oliceridine is at least comparable to that of morphine at clinically relevant dosages, with a rapid onset of action. Also, it may be associated with a lower incidence of adverse events at dosing regimens associated with comparable analgesia. These data suggest that oliceridine may provide an important new treatment option for the management of moderate to severe postoperative pain where an intravenous opioid is warranted.

Oliceridine has obvious analgesic effects in patients with moderate or severe pain after surgery; additionally, it has a favorable safety and tolerability profile.

To review the efficacy and safety of clascoterone 1% cream for the treatment of acne vulgaris in patients 12 years of age and older.

A literature search through PubMed, MEDLINE, and ClinicalTrials.gov was conducted using the following keywords: clascoterone, cream, acne, and CB-03-01. Articles published between 2004 and 2020 were included in this review.

Preclinical and clinical studies describing the efficacy and safety of topical clascoterone cream were included.

Early preclinical studies demonstrated that clascoterone exhibits local antiandrogenic effects without any systemic effects. Phase 2 and 3 trials demonstrated a statistically significant reduction in inflammatory and noninflammatory lesions and mild erythema with clascoterone use. Long-term studies confirmed the favorable safety profile of the drug in subjects for up to 9 months of use, with erythema being the most common treatment-emergent local skin reaction.

Pharmacological treatment options for acne vulgaris include topical and systemic agents. Systemic antiandrogen medications are associated with adverse effects and should be avoided in pregnancy and male patients. Clascoterone is a novel topical antiandrogen drug with no systemic adverse effects. This drug provides prescribers with an appealing treatment option for male and female patients 12 years of age and older, who are not candidates for systemic drugs because of contraindications or adverse effects or who have failed other topical therapies.

Clascoterone, a novel topical androgen receptor inhibitor, is a safe and effective treatment option for patients with acne vulgaris.