Annals of Pharmacotherapy

Background: Cyclosporine (CsA), which is used for graft-versus-host disease prophylaxis in allogeneic hematopoietic stem cell transplant (allo-HSCT), has a narrow therapeutic range and large interindividual and intraindividual pharmacokinetic variability. Nevertheless, population pharmacokinetic (PopPK) studies of CsA in allo-HSCT are scarce. Objective: The goal of our study was to build a PopPK model of CsA in allo-HSCT in consideration of demographic, clinical, and genetic polymorphisms data. Methods: A total of 34 adult allo-HSCT patients who received CsA were enrolled prospectively. Demographic, clinical, and CYP3A5 *1/*3, CYP2C19 *1/*2/*3, ABCB1 3435C>T, 1236C>T, 2677G>T/A, ABCC2 -24C>T, 1249G>A, VDR Bsml, Apal polymorphisms data were collected. A PopPK modeling was conducted with NONMEM program. Results: A 1-compartment model with a 2-transit absorption compartment model was developed. After the stepwise covariate model building process, weight was incorporated into clearance (CL) as a power function model with the exponent value of 0.419. The final typical estimate of CL was 21.2 L/h; volume of distribution was 430 L; logit-transformed bioavailability was 1.49 (bioavailability: 81%); and transit compartment rate was 2.87/h. None of the genetic polymorphisms in CYP3A5, CYP2C19, ABCB1, ABCC2, and VDR were significant covariates in the pharmacokinetics of CsA. Conclusions: In our study, it was observed that weight had a significant effect on CL. Genetic polymorphisms did not affect CsA pharmacokinetics. Prospective studies with a larger number of participants is needed to validate the results of this study.

Background: Discharge anticoagulation counseling is important for ensuring patient comprehension and optimizing clinical outcomes. As pharmacy resources become increasingly limited, the impact of informational videos on the counseling process becomes more relevant. Objective: To evaluate differences in pharmacist time spent counseling and patient comprehension (measured by the Oral Anticoagulation Knowledge [OAK] test) between informational videos and traditional face-to-face (oral) counseling. Methods: This prospective, open, parallel-group study at an academic medical center randomized 40 individuals—17 warfarin-naïve (“New Start”) and 23 with prior warfarin use (“Restart”)—to receive warfarin discharge education by video or face-to-face counseling. “Teach-back” questions were used in both groups. Results: Although overall pharmacist time was reduced in the video counseling group (P < 0.001), an interaction between prior warfarin use and counseling method (P = 0.012) suggests the difference between counseling methods was smaller in New Start participants. Following adjustment, mean total time was reduced 8.71 (95% CI = 5.15-12.26) minutes (adjusted P < 0.001) in Restart participants and 2.31 (−2.19 to 6.81) minutes (adjusted P = 0.472) in New Start participants receiving video counseling. Postcounseling OAK test scores did not differ. Age, gender, socioeconomic status, and years of education were not predictive of total time or OAK test score. Conclusion: Use of informational videos coupled with teach-back questions significantly reduced pharmacist time spent on anticoagulation counseling without compromising short-term patient comprehension, primarily in patients with prior warfarin use. Study results demonstrate that video technology provides an efficient method of anticoagulation counseling while achieving similar comprehension.

Background: Correct technique and patient acceptance of inhalation devices for lung disease influence successful long-term management. Patient ability to use the proper technique may differ depending on the device as well as patient factors. Objectives: The objectives of our study are to measure self-reported level of acceptability of inhaler devices in community settings and compare correct use of inhaler devices using a novel scale for measuring appropriate inhaler technique. Methods: This prospective observational study enrolled patients from 3 different practice sites with asthma and/or chronic obstructive pulmonary disease (COPD) who were using an inhaler device. In addition to describing the samples’ overall acceptability and correct use scores for the different inhalers, acceptability and correct use scores were compared based on patient characteristics. Results: A total of 161 patients completed the study. The results show that acceptability was lowest for the pressurized metered dose inhaler (pMDI) with a spacer (S); effective use was best demonstrated with pMDI and poorest with pMDI-S. Older patients were found to be more accepting of the HandiHaler device than younger patients. Patients reporting taking more inhaled drugs were found to be more accepting of the pMDI-S than those taking fewer drugs. Finally, patients reporting taking more inhaled drugs demonstrated less-effective use of the HandiHaler device than patients taking fewer drugs. Conclusion: Pulmonary disease duration does not ensure improved use for all inhalers; patients taking more drugs demonstrate less-effective use for some devices. Assessment of patient acceptance and factors that predict the ability to use a device should be considered to individualize therapy.

Background: Identifying patients at high risk for multidrug-resistant urinary tract infections (UTIs) is important for guiding empirical antimicrobial therapy. Clinical risk factors associated with antimicrobial-resistant urinary pathogens and the derivation of a simple clinical decision rule could help define health care–associated UTI. Objective: To derive a simple clinical decision rule to identify clinical risk factors associated with antimicrobial-resistant urinary pathogens. Methods: This was a retrospective case-control study of all emergency department (ED) patients from July 1, 2011, to July 1, 2012, who presented to the ED with UTI and a positive urine culture. Candidate risk factors were collected retrospectively from medical record review. We compared differences in patient characteristics stratified by the presence of an antimicrobial-resistant urinary pathogen. Results: A total of 360 patients with UTI had a positive, noncontaminated urine culture during the study period. About 6.7% of patients (n = 24) had a multidrug-resistant (MDR) urinary infection. Logistic regression modeling identified 3 clinical factors associated with the identification of a MDR pathogen: male sex, chronic hemodialysis, and nursing home residence. A scoring system was created to identify patients with MDR pathogens. Test characteristics were calculated using bootstrapping for internal validation, with a sensitivity of 74.7% (95% CI = 55.1%-91.3%) and specificity of 85.1% (95% CI = 77.8%-86.2%), positive likelihood ratio of 4.3, and a negative likelihood ratio of 0.3. Conclusions: Clinical factors can be used to identify UTI patients at high risk of MDR urinary pathogens.

Background: Key performance indicators (KPIs) are quantifiable measures of quality. There are no published, systematically derived clinical pharmacy KPIs (cpKPIs). Objective: A group of hospital pharmacists aimed to develop national cpKPIs to advance clinical pharmacy practice and improve patient care. Methods: A cpKPI working group established a cpKPI definition, 8 evidence-derived cpKPI critical activity areas, 26 candidate cpKPIs, and 11 cpKPI ideal attributes in addition to 1 overall consensus criterion. Twenty-six clinical pharmacists and hospital pharmacy leaders participated in an internet-based 3-round modified Delphi survey. Panelists rated 26 candidate cpKPIs using 11 cpKPI ideal attributes and 1 overall consensus criterion on a 9-point Likert scale. A meeting was facilitated between rounds 2 and 3 to debate the merits and wording of candidate cpKPIs. Consensus was reached if 75% or more of panelists assigned a score of 7 to 9 on the consensus criterion during the third Delphi round. Results: All panelists completed the 3 Delphi rounds, and 25/26 (96%) attended the meeting. Eight candidate cpKPIs met the consensus definition: (1) performing admission medication reconciliation (including best-possible medication history), (2) participating in interprofessional patient care rounds, (3) completing pharmaceutical care plans, (4) resolving drug therapy problems, (5) providing in-person disease and medication education to patients, (6) providing discharge patient medication education, (7) performing discharge medication reconciliation, and (8) providing bundled, proactive direct patient care activities. Conclusions: A Delphi panel of hospital pharmacists was successful in determining 8 consensus cpKPIs. Measurement and assessment of these cpKPIs will serve to advance clinical pharmacy practice and improve patient care.

Background: Topiramate has been associated with metabolic acidosis secondary to decreased serum bicarbonate. Product labeling recommends serum bicarbonate monitoring at baseline and periodically thereafter. Objective: The study objective was to assess changes in serum bicarbonate within the first year of topiramate use in an outpatient veteran population. Methods: This was a single-center, retrospective study conducted at the Iowa City Veterans Affairs Health Care System. Inclusion criteria required a minimum of 1 topiramate outpatient prescription between October 1, 1999, and August 31, 2012, and at least 1 serum bicarbonate level within 12 months prior to topiramate initiation. Patients with topiramate nonadherence, concurrent use of sodium bicarbonate or oral carbonic anhydrase inhibitors, and individual serum bicarbonate values obtained during inpatient hospitalizations were excluded. Change in bicarbonate was evaluated using a paired t test. Decreases in bicarbonate of ≥5 mEq/L, values <20 mEq/L, days to lowest value, and correlation between adverse drug reactions (ADRs) and topiramate discontinuation were evaluated. Results: Of 546 patients reviewed, 350 were included in the analysis. There was a statistically significant decrease of 2.7 mEq/L in bicarbonate following initiation of topiramate. Only 1 patient had a bicarbonate value <17 mEq/L. There was no association between bicarbonate decrease ≥5 mEq/L and ADRs. Conclusions: A statistically significant reduction in bicarbonate levels occurred with topiramate, which was clinically insignificant. ADR occurrence did not correlate with bicarbonate levels <17 mEq/L or a decrease ≥5 mEq/L. Our results indicate that serum bicarbonate levels should only be monitored before topiramate initiation and in patients presenting with symptoms suggestive of acidosis.

Objective: Review pharmacokinetics of new direct-acting antivirals (DAAs) for hepatitis C (HCV) infection and interactions with concomitant immunosuppressant and antiretroviral therapies (ART). Data Sources: MEDLINE (1948-January 2015), EMBASE (1964-January 2015), International Pharmaceutical Abstracts (1970-January 2015), Google, and Google Scholar were searched combining the terms simeprevir, sofosbuvir, ledipasvir, daclatasvir, paritaprevir, ABT-450, ombitasvir, dasabuvir, pharmacokinetics, drug interaction, drug metabolism, HIV, antiretroviral, immunosuppressant, transplant. Articles, conference proceedings, abstracts, and product monographs were reviewed. Study Selection and Data Extraction: Literature on pharmacokinetic or pharmacodynamic interactions with DAAs and immunosuppressants or ART was considered for inclusion. Pertinent information was extracted and summarized in the review. In the absence of data, pharmacokinetic and pharmacodynamic principles were used to predict the likelihood of interactions. Data Synthesis: DAA pharmacokinetics are reviewed and drug interaction data are presented with provision of management strategies. Fixed-dose combination paritaprevir/ritonavir/ombitasvir plus dasabuvir is most susceptible to drug interactions with immunosuppressants and ART mainly due to the influence of ritonavir on multiple enzymes. Simeprevir is also prone to drug interactions because of cytochrome P450(CYP) 3A4, CYP1A2, P-glycoprotein, and OATP1 involvement and is not recommended for use in combination with several HIV antiretrovirals (ARVs). Close therapeutic drug monitoring of calcineurin inhibitors is required with concomitant simeprevir. Few clinically significant interactions are expected with sofosbuvir or ledipasvir. Limited data suggest that daclatasvir may be coadministered with immunosuppressants but requires dose adjustments with certain ARVs. Conclusions: None of the DAAs are completely free of drug interactions. Awareness and management of drug interactions is critical to optimize outcomes and minimize adverse effects in these patient populations.

Objective: Consensus on combination options for patients with type 2 diabetes mellitus (T2DM) unable to use metformin is lacking. This review summarizes data describing–non-metformin based combination therapy. Data Sources: PubMed searches (January 1990 to August 2014) were conducted with terms for newer drug therapies alone and with the term combination; filters were applied for Clinical Trial, Meta Analysis, and English language. Study Selection and Data Extraction: Results were reviewed for multicenter, randomized controlled trials of non-metformin–based combination therapy conducted in the past 5 years and specific to the US or multinational populations. Data Synthesis: Although multiple injectable and oral agents have been studied in combination with metformin for management of T2DM, data are more limited for combinations without metformin. Combinations of incretins (injectable glucagon-like peptide-1 receptor agonists or oral dipeptidyl peptidase-4 [DPP-4] inhibitors) with a sulfonylurea, thiazolidinedione, or insulin are well studied and provide greater glucose-lowering efficacy than monotherapy. Incretins are associated with a low risk of hypoglycemia when used as monotherapy; the dosage of sulfonylurea or insulin should be reduced when used in combination. Newer studies are investigating the combined use of an oral sodium-glucose cotransporter 2 inhibitor and a DPP-4 inhibitor. In a recent study, reductions in glycated hemoglobin (A1C) of 1.1% to 1.2% and reduced weight with no additive risk of hypoglycemia were observed. Conclusions: Selecting the most appropriate combination therapy for patients with T2DM requires balancing clinical benefits with the risks, such as weight gain and hypoglycemia. Treatment approaches should be individualized for vulnerable patient populations for whom metformin is not appropriate.

Objective: To review the oral and injectable pharmacologic treatment options for type 2 diabetes. Data Sources: A literature search was conducted using PubMed electronic database for studies published in English between 1993 and September 2014. Search terms included diabetes mellitus, type 2 diabetes, and the individual name for each antidiabetic medication reviewed. In addition, manual searches were performed for cross-references from publications. Package inserts, United States Food and Drug Administration (FDA) Web site, Institute for Safe Medication Practices Web site, American Diabetes Association Web site and scientific session poster presentations, and individual drug company Web pages were also reviewed. Study Selection and Data Extraction: This review focused on information elucidated over the past 10 years to assist prescribers in choosing optimal therapy based on individual patient characteristics. Studies leading to the approval of or raising safety concerns for the antidiabetic medications reviewed in this article were included. Data Synthesis: In the past 10 years, there have been 4 novel oral antidiabetic medication classes and 10 new injectable agents and insulin products approved by the FDA for the treatment of type 2 diabetes as well as new information regarding the safety and use of several older antidiabetic medication classes. The distinctions were reviewed for each individual agent, and a comparison was completed if there was more than one agent in a particular therapeutic class. Using current information available, select investigational agents in phase III trials or with a pending new drug application were highlighted. Conclusion: There are now 9 distinct oral pharmacologic classes and a variety of insulin and noninsulin injectable medications available for the treatment of type 2 diabetes. Metformin remains the first-line treatment option for most patients. When considering options for alternative or additional treatment, prescribers must weigh the benefits and risks using individual patient characteristics.

Objective: To review the literature evaluating pharmacotherapeutic and nonpharmacotherapeutic options available to reduce migraines or headaches associated with intravenous immunoglobulin (IVIG) treatment. Data Sources: A search of MEDLINE (1946 to February 2015) and other secondary resources was performed using the terms immunoglobulin, immune globulin, intravenous immunoglobulins, migraine, and headache. Other relevant articles referenced from the MEDLINE search were also utilized. Study Selection and Data Extraction: Data sources were limited to English language clinical trials and case studies. In all, 6 clinical studies and 2 case reports met the criteria. Data Synthesis: Headaches or migraines are common adverse effects associated with the administration of IVIG. We evaluated 6 clinical studies and 2 case reports discussing this adverse event in patients treated with IVIG. Strategies used were hydration, switching to an alternate IVIG product, decreased infusion rates, or treating with oral analgesics, opioids, propranolol, sumatriptan, or dihydroergotamines before, during, or after the IVIG infusion. Overall, the majority of patients experienced improvement in headache symptoms, suggesting benefit, after using the various strategies discussed. However, the evidence is limited to case reports and clinical studies with small sample sizes that do not directly measure cause and effect of headache resolution and therapy given in those treated with IVIG. Conclusions: An individualized treatment plan consisting of a pharmacotherapy or nonpharmacotherapy strategy used in the literature should be recommended after careful consideration of the patient’s condition, specific IVIG product used, history of migraine, and previously failed and successful therapies.

Objective: To review the commercially available ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs), identify opportunities for therapeutic substitutions within and outside of their Food and Drug Administration (FDA)-approved indications, and identify clinically superior drugs within the class for specific indications. Data Source: A PubMed search (1992 through January 2014) was performed on the terms diclofenac, ketorolac, flurbiprofen, bromfenac, and nepafenac. Study Selection and Data Extraction: Clinical trials, meta-analyses, and review articles were evaluated if they were written in English and pertained to human subjects. Studies were excluded if they were in vitro studies, solely evaluated pharmacokinetic or pharmacodynamic properties, did not relate to the topical ophthalmic route, did not evaluate the FDA-approved indications of any available ophthalmic NSAID, or compared a reviewed drug with a nonreviewed drug (without placebo comparison). Data Synthesis: A total of 67 articles met the criteria for evaluation. Article quality, study design, and dosing of the medications were assessed to determine the clinical applicability of the results. The quality of the article was determined using the Oxford Centre for Evidence-based Medicine Levels of Evidence 1. Conclusions: Many formulations of the 5 reviewed NSAIDs have been studied across the 4 primary indications. These indications are (1) pain and inflammation associated with cataract surgery, (2) pain associated with corneal refractive surgery, (3) inhibition of intraoperative miosis, and (4) seasonal allergic conjunctivitis. Several studies have directly compared drugs within this class and have identified instances in which certain selections are therapeutically superior or equivalent to another. This information provides practitioners with guidance in selecting an optimal medication.

Objective: To review the evidence for the use of the direct-acting oral anticoagulants (DOACs) in adult patients with heparin-induced thrombocytopenia (HIT). Data Source: A PubMed search (1950-February 2015) was collected using the terms heparin-induced thrombocytopenia, with dabigatran, rivaroxaban, or apixaban, or heparin-induced thrombocytopenia and target-specific anticoagulants, or heparin-induced thrombocytopenia and direct-acting oral anticoagulants, or heparin-induced thrombocytopenia and new oral anticoagulants. Study Selection and Data Extraction: All English-language articles were reviewed for inclusion. The references of included articles were reviewed for additional data. Data Synthesis: HIT is an immune-mediated, prothrombotic adverse reaction that requires not only discontinuation of heparin but also initiation of an alternative nonheparin anticoagulant to counter the effects of the autoimmune cascade. Pharmacotherapeutic management with argatroban is unpredictable and problematic. The DOACs display predictable pharmacokinetic and pharmacodynamic profiles and exhibit no interaction with platelet factor 4. Currently, the DOACs are approved by the Food and Drug Administration for venous thromboembolism, yet have limited evidence in both in vitro and clinical HIT studies. Conclusions: Though dabigatran, rivaroxaban, and apixaban have been used in case reports, currently data are not yet sufficient to recommend clinical use of these agents in the management of HIT. Future trial results may further substantiate management of HIT with use of the DOACs.