Transthyretin Amyloid Cardiomyopathy-Current and Future Therapies.

OBJECTIVE: To describe the clinical presentation of transthyretin amyloid cardiomyopathy (ATTR-CM) and discuss current treatments and investigational products and their effect on patient outcomes. DATA SOURCES: A literature search was performed in PubMed (September 2018 to December 2020) using the following keywords: transthyretin amyloidosis, cardiomyopathy, polyneuropathy and transthyretin amyloid cardiomyopathy, monoclonal light-chain, tafamidis, cardiac amyloidosis, ATTR cardiomyopathy, green tea and inhibition of cardiac amyloidosis, AG10, tolcapone, tolcapone and leptomeningeal ATTR, PRX004, NI006, patisiran, inotersen, vutrisiran, AKCEA-TTR-LRx, and NTLA-2001. STUDY SELECTION AND DATA EXTRACTION: Clinical trials were evaluated for evidence supporting pharmacology, safety, efficacy, and measured outcomes. DATA SYNTHESIS: Until 2019, there were no approved treatments for ATTR-CM. Treatment consisted of symptom management and organ transplant. Nonpharmacological and pharmacological treatments focused on the symptoms of heart failure (HF) associated with ATTR-CM. However, there are several emerging therapies recently approved or in development to address the underlying pathophysiology. Treatment classes for ATTR-CM include transthyretin stabilizers, human monoclonal antibodies, gene silencers, and CRISPR/Cas9 gene editing. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: ATTR-CM is a complex disease in which amyloidosis causes cardiomyopathy. Underdiagnosis is attributed to the clinical presentation being heterogeneous, indistinguishable from HF caused by other etiologies, and the need for invasive testing modalities, including endomyocardial biopsy. Improved diagnostic approaches along with targeted therapies can slow disease progression and enhance patient quality of life. CONCLUSION: Diagnostic modalities along with biomarker and genetic testing could detect disease earlier and target therapy more accurately. Novel therapies demonstrate potential treatment benefits and can help shape the standard of care for these patients.

Incorporating the American Pharmacists Association's Delivering Medication Therapy Management services certificate program into an accelerated pharmacy curriculum.

BACKGROUND AND PURPOSE: To describe the incorporation of the American Pharmacists Association (APhA) Delivering Medication Therapy Management (MTM) Services program into a PharmD curriculum and to describe student perceptions of the program. EDUCATIONAL ACTIVITY AND SETTING: The program was delivered over 12 months to students on two campuses via two didactic courses in the second professional year and during the first two advanced pharmacy practice experiences in the third professional year of an accelerated school of pharmacy program. FINDINGS: Student perceptions were assessed by review of responses to the APhA MTM program evaluation survey. DISCUSSION AND SUMMARY: Incorporation of the APhA MTM program into an accelerated PharmD program required careful planning and coordination amongst faculty and course coordinators. Students perceived that the program was valuable, met their educational needs, and incorporated effective learning experiences and cases. These perceptions were reinforced by the high percentage of students who completed the program.

Use of daptomycin to treat infections with methicillin-resistant Staphylococcus aureus isolates having vancomycin minimum inhibitory concentrations of 1.5 to 2 µg/mL.

OBJECTIVE: To evaluate daptomycin use for the treatment of infections with methicillin-resistant Staphylococcus aureus (MRSA) isolates having vancomycin minimum inhibitory concentrations (MICs) of 1.5 to 2 µg/mL. DATA SOURCES: The literature was retrieved through PubMed and EMBASE (January 2006 to August 2013). STUDY SELECTION AND DATA EXTRACTION: English articles were reviewed. Studies that included separate daptomycin data (clinical outcome or in vitro surveillance) for MRSA isolates with vancomycin MICs of 1.5 to 2 µg/mL by any testing methodology were included. DATA SYNTHESIS: Clinical and microbiological outcomes associated with daptomycin used as first-line or subsequent therapy for MRSA infections with vancomycin MICs of 1.5 to 2 µg/mL were reported in 7 retrospective clinical studies; susceptibility information involving such isolates was reported from 12 surveillancestudies. Although not all studies demonstrated outcome differences between daptomycin and comparator treatments (usually vancomycin), when differences were reported, they were in favor of daptomycin. Individual studies found lower 60-day (8% vs 20%, P = .046) and 30-day mortality (3.5% vs 12.9%, P = .047) and increased treatment success with daptomycin (68.6% vs 43.1%, P = .008; 76.9% vs 53.8%, P = .048) in bacteremic patients. The median doses used for treatment of bacteremia were greater than that approved by the FDA for this indication (6 mg/kg/d). CONCLUSIONS: Current published evidence indicates daptomycin may be an acceptable alternative to vancomycin for MRSA infections, especially bacteremia, involving isolates with vancomycin MIC values of 1.5 to 2 µg/mL. Additional evidence is needed to fully elucidate daptomycin utility in this area.

Boceprevir: a protease inhibitor for the treatment of chronic hepatitis C.

OBJECTIVE: To review the pharmacology, pharmacokinetics, safety, and efficacy of boceprevir, a novel oral hepatitis C virus (HCV) nonstructural 3 (NS3) protease inhibitor for the treatment of chronic HCV infection, specifically, genotype 1. DATA SOURCES: A literature search was conducted through MEDLINE and EMBASE (1966-May 2011) using the terms boceprevir and SCH 503034. Data from the package insert, abstracts obtained from conferences, and unpublished Phase 2-3 clinical trials, obtained through clinicaltrials.gov, were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were evaluated. References from selected articles were used to identify other pertinent citations. Article selection focused on pharmacology, clinical trials, safety analyses, and resistance. Preference was given to human data. DATA SYNTHESIS: Boceprevir is an oral protease inhibitor that binds to the NS3 protein of HCV, ultimately inhibiting viral intracellular replication. Boceprevir displays linear pharmacokinetics and is rapidly absorbed upon oral administration. In clinical studies of treatment-naïve and treatment-experienced patients, boceprevir, in combination with standard of care (pegylated interferon [Peg-IFN]-α-2b with or without ribavirin) achieved greater sustained viral response (SVR) rates compared to standard of care. Safety analyses showed an increased incidence of adverse effects when boceprevir was used with Peg-IFN-α-2b and ribavirin. The most common adverse events reported include fatigue, headache, nausea, dysguesia, and anemia; the incidence of the latter 2 adverse effects may be increased if boceprevir is added to standard therapy. Additional Phase 2 and 3 studies are currently enrolling participants. CONCLUSIONS: Boceprevir should be used in combination with Peg-IFN-α-2b and ribavirin in the treatment of chronic HCV genotype 1 infection. The improved response rates achieved with that combination will make boceprevir a viable option compared with other developing and approved NS3 protease inhibitors for treatment-naïve and treatment-experienced nonresponders/relapsers. Additional data are needed to clarify the potential for resistance and drug interactions.

Tigecycline for the treatment of severe Clostridium difficile infection.

OBJECTIVE: To evaluate the evidence for the use of tigecycline in the treatment of Clostridium difficile infection (CDI). DATA SOURCES: Searches were performed (2004 to June 2011), using the EMBASE and MEDLINE databases, with the terms tigecycline, Tygacil, Clostridium difficile, C. difficile, Clostridium difficile infection, and CDI. STUDY SELECTION: Six case reports that described the use of tigecycline for treatment of CDI were included for review. No clinical trials were identified. DATA SYNTHESIS: In all case reports except 1, tigecycline (alone or in combination with other CDI therapies) was used for the treatment of CDI that was refractory to metronidazole and/or vancomycin. In 6 of the cases, treatment success was reported following initiation of tigecycline therapy; 1 patient died following a complicated hospitalization. The treatment duration with tigecycline was 2-4 weeks. In the cases with successful outcomes, symptoms began to improve within 1 week. None of these patients experienced recurrence during follow-up of various lengths. In vitro studies demonstrated a 90% minimum inhibitory concentration range for tigecycline of 0.016-0.25 mg/L for all C. difficile isolates. Tigecycline exhibited good fecal penetration because of primary biliary excretion of unchanged drug. Up to 59% of the dose is recovered in feces following administration over 4 days in healthy volunteers. CONCLUSIONS: Case reports have suggested that tigecycline may be successful for treatment of severe or severe complicated CDI, when prior therapy has failed. Data demonstrating tigecycline use as initial therapy for CDI are limited; therefore, this option should be reserved for patients in whom other therapeutic options, including metronidazole and vancomycin, have failed. A randomized controlled trial is needed to assess the safety and efficacy of tigecycline in this patient population and better define the drug's role in the treatment of CDI.

Apricitabine: a nucleoside reverse transcriptase inhibitor for HIV infection.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of apricitabine, a nucleoside reverse transcriptase inhibitor that is currently under investigation and has fast-track approval status with the Food and Drug Administration. DATA SOURCES: A literature search was conducted using PubMed (1966-June 2009) to retrieve relevant material using the search terms apricitabine, SPD754, and AVX754. References from selected articles were evaluated to identify other pertinent trials. Information was also obtained from the manufacturer. STUDY SELECTION AND DATA EXTRACTION: All English-language in vitro and in vivo studies and abstracts evaluating apricitabine were reviewed and considered for inclusion. Preference was given to human data. DATA SYNTHESIS: Apricitabine is a prodrug that is phosphorylated to its active triphosphate form intracellularly, which ultimately results in chain termination and inhibition of reverse transcription. Apricitabine is administered orally, displays linear pharmacokinetics, and is renally excreted with minimal to no hepatic metabolism. It has demonstrated antiretroviral activity against drug-resistant strains both in vitro and in vivo. In clinical studies, in both antiretroviral-naïve and treatment-experienced patients, apricitabine achieved the primary endpoint of significant reductions in plasma viral load versus comparator. Further Phase 2 and 3 studies are currently enrolling. Safety analysis indicates that apricitabine is well tolerated and has a low potential for causing mitochondrial damage. The most common adverse events reported include headache and rhinitis. Development of resistance or further gene mutations has not been shown in clinical studies to date. CONCLUSIONS: Although the role of apricitabine in the treatment of HIV-1 infection has yet to be established, its activity against resistant HIV-1 strains and its tolerability profile will likely make it a viable second-line treatment option in patients who have failed regimens containing lamivudine or emtricitabine.

Elevated creatine phosphokinase levels associated with linezolid therapy.

PURPOSE: A case of elevated creatine phosphokinase (CPK) levels associated with linezolid therapy in a patient on chronic antihyperlipidemic therapy is presented. SUMMARY: A 79-year-old Caucasian man with a primary diagnosis of acute hemoptysis secondary to pneumonia was admitted to the medical-surgical intensive care unit. A chest radiograph showed a large, right, lower-lobe infiltrate with alveolar consolidation. The patient's medical history included hyperlipidemia that was chronically treated with lovastatin and gemfibrozil. Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia was suspected and confirmed. Vancomycin 1 g i.v. every 12 hours was administered for approximately 10 days into the admission and switched to linezolid 600 mg i.v. every 12 hours after a lack of response to vancomycin. On hospital day 11, the patient's CPK concentration was 47 units/L. Seven days later, his CPK concentration was 2584 units/L and his lovastatin and gemfibrozil were discontinued on that day. The patient's CPK concentration peaked at 5369 units/L on the following day, and linezolid was discontinued at that point. One week later, his CPK concentration was 28 units/L. Approximately two weeks after the patient's CPK levels normalized, he developed numerous complications. The patient died as a result of respiratory failure 11 days after being extubated, which occurred about 38 days after his admission. Although concomitant use of statins and gemfibrozil is known to increase the risk for CPK elevations, the continued rise in CPK levels after discontinuation of antihyperlipidemic therapy and the rapid time course for normalization after linezolid discontinuation are more consistent with an event associated with linezolid initiation. CONCLUSION: A patient on chronic antihyperlipidemic therapy developed elevated CPK levels after receiving linezolid for the treatment of MRSA pneumonia.

Omalizumab: a monoclonal anti-IgE antibody.

OBJECTIVES: To describe allergic asthma and allergic rhinitis pathophysiology and review the pharmacologic, pharmacokinetic, pharmacodynamic, efficacy, and safety data for omalizumab. METHODS: MEDLINE, In-Process & Other Non-Indexed Citations, and EMBASE Drugs & Pharmacology were searched using olizumab, omalizumab, E25, rhuMAb-E25, and anti-IgE. Combinations of rhinitis, asthma, and IgE captured information on disease pathophysiology. RESULTS: Omalizumab is a monoclonal antibody targeting the high-affinity receptor binding site on human immunoglobulin (Ig)E. Bound IgE is not available for basophil binding, degranulation is attenuated, and allergic symptoms are reduced. In asthma trials, omalizumab reduced inhaled corticosteroid and rescue medication requirements and improved asthma control and asthma quality of life in moderate to severe allergic asthmatics with disease poorly controlled by inhaled corticosteroids. In trials of patients with poorly controlled moderate to severe seasonal allergic rhinitis (SAR), omalizumab reduced the severity of exacerbations and rescue medication use, and improved rhinitis-related quality of life. Benefits were also observed in trials utilizing combinations of immunotherapy and omalizumab for SAR and in trials of perennial allergic rhinitis (PAR). Omalizumab has been well tolerated. Although malignant neoplasms have been observed in treated patients, they were likely not related to omalizumab therapy. CONCLUSIONS: Omalizumab has demonstrated efficacy in children, adults, and adolescents with uncontrolled moderate to severe allergic asthma and allergic rhinitis. Long-term safety beyond 52 weeks needs continued evaluation.

Evaluation of omalizumab from a health plan perspective.

OBJECTIVE: To review the pathophysiology of allergic asthma and information on the pharmacology, clinical efficacy, safety profile, and direct drug costs for omalizumab to provide a basis for a defined role of this agent in allergic asthma therapy in managed care organizations. SUMMARY: Omalizumab is a monoclonal antibody targeting the high-affinity receptor binding site on human immunoglobulin E (IgE). When bound by omalizumab, IgE does not bind to basophils. As a result, degranulation is attenuated and allergic asthma symptoms are reduced. In asthma trials, omalizumab reduced inhaled corticosteroid and rescue medication requirements and improved asthma control and asthma quality of life in moderate-to-severe allergic asthmatics with disease poorly controlled by inhaled corticosteroids. Omalizumab has generally been well tolerated. However, injection site reactions occur in nearly 1 of every 2 patients, a problem that generally becomes less with continued dose administration. Severe injection site reactions are reported in 12% of patients. Other adverse events commonly reported in clinical trials include viral infections (23%), upper respiratory infections (20%), sinusitis (16%), headache (15%), and pharyngitis (11%). Because the acquisition cost of omalizumab is high (generally $15,000 to $44,000 per patient per year, before contractual discounts), its use is cost-prohibitive in all but the most severe, poorly controlled allergic asthmatic patients who are utilizing large amounts of emergency health care resources to manage exacerbations. Experience with use of this drug beyond 52 weeks is lacking. CONCLUSION: Although omalizumab has demonstrated efficacy and safety in adults and adolescents with uncontrolled moderate-to-severe allergic asthma, its use should be restricted to a narrowly defined population of allergic asthmatics who utilize large amounts of health care resources. If targeted only toward this population, cost-of-care studies suggest that the high cost of this product in these patients could be offset by savings resulting from the less frequent use of high-intensity medical services for asthma exacerbations. The use of omalizumab beyond 52 weeks needs evaluation.