Drug Administration-approved Dose Research Articles

Seizure Occurring During Baclofen Monotherapy for Phenibut Withdrawal.

Phenibut is a widely available gamma-aminobutyric acid B receptor agonist. When taken chronically, phenibut causes dependence and subsequent withdrawal if stopped. Baclofen, a gamma-aminobutyric acid B receptor agonist structurally related to phenibut, has been used to manage phenibut withdrawal (PW), although baclofen doses for PW are not well defined and may exceed Food and Drug Administration-approved doses. Little data described outcomes from baclofen use. This case details a patient who experienced a seizure while on baclofen 10 mg thrice daily as monotherapy for PW and highlights a potential risk of underdosing baclofen as monotherapy in the management of PW. A man in his early 30s with anxiety, depression, and substance use disorder presented to the emergency department by family for lethargy and confusion starting earlier that day. He had been using 25-30 g of phenibut daily for the past 6 months. On arrival, he was hypertensive, tachycardic, tachypneic, and lethargic. The patient received 1 mg of intravenous lorazepam and was admitted to the hospital for presumed PW. His symptoms improved overnight, and he was discharged on 10 mg of baclofen thrice daily. He returned 28 hours later after having a seizure and required intensive care admission in addition to multimodal drug therapy. Phenibut use is rising, and treatment options for PW, such as baclofen, warrant additional study. Potential risks of underdosing baclofen if used as monotherapy in PW may include seizures as withdrawal progresses. Baclofen's role in therapy may be more appropriate as an adjunct than a cornerstone of therapy. Treatment done in consultation with providers experienced in managing withdrawal such as a toxicologist may help reduce this risk.

Tumour, whole-blood, plasma and tissue concentrations of metformin in lung cancer patients.

Metformin is used for the management of type 2 diabetes mellitus (T2DM) and is being tested clinically as an anticancer agent. Metformin concentrations safely achievable in human solid tissues including tumours are unknown. This study was designed to determine metformin concentration in tissue compartments as a function of dose to inform rational dosing in preclinical models and interpretation of clinical results." Subjects with solid tumours to be treated by resection and either (A) willingness to take metformin for 7-10 days before surgery or (B) taking metformin for T2DM were eligible. Whole blood, plasma, tumour, tumour-adjacent uninvolved tissue and subcutaneous adipose tissue were obtained for liquid chromatography with tandem mass spectrometry to measure metformin concentrations. All subjects had primary lung tumours. Metformin dose was significantly correlated with drug concentrations in all tissues analysed. Intersubject metformin concentrations varied by over two orders of magnitude. Metformin concentrations were significantly higher in tumour tissues and lower in adipose tissues compared to other tissues. Concentrations in blood and plasma were significantly correlated with concentrations in solid tissues. Metformin accumulates in cellular compartments. Concentrations observed in plasma, blood, lung and tumour tissues in subjects treated with US Food and Drug Administration-approved doses for T2DM are lower than those typically used in tissue culture studies. However, such tissue concentrations are in line with those found within cultured cells treated with supra-pharmacological doses of metformin. Given the large intersubject variability in metformin concentrations, it is imperative to determine whether there is an association between tissue metformin concentration and anticancer activity in humans.

Exposure-response analysis of efficacy and safety for pexidartinib in patients with tenosynovial giant cell tumor.

This analysis was conducted to assess exposure–response relationships for efficacy and safety of pexidartinib in patients with tenosynovial giant cell tumor. Efficacy was assessed categorically by overall response rate (ORR) with Response Evaluation Criteria in Solid Tumors version 1.1 and longitudinally (changes in tumor size and volume). Safety included hepatic parameters (i.e., alanine aminotransferase [ALT], aspartate aminotransferase [AST], and total bilirubin). Average pexidartinib concentration (Cavg) was identified as the primary exposure parameter correlated with response. In categorical and longitudinal analyses, higher Cavg coincided with greater ORR and tumor size reduction, respectively, with smaller joint size having a greater impact. For safety, a significant relationship was observed between Cavg and incidence of ALT‐related and AST‐related adverse events (AEs). With increased exposure, an increase in efficacy was predicted with near maximum effect at 800 mg/day. Higher initial dose (1000 mg/day) during the first 2 weeks did not improve efficacy. Higher doses were associated with an increased risk of ALT‐related and AST‐related AEs. These results support the US Food and Drug Administration–approved dose (400 mg two times/day without initial loading dose).

Use and Toxicity of Checkpoint Inhibitors for Solid Tumor Treatment in a Veteran Population.

New immunotherapy agents have provided additional options for the treatment of a variety of malignancies, including the programmed death 1 (PD-1) protein inhibitors nivolumab and pembrolizumab. Initial dosing was based on patient weight, but subsequent studies supported fixed dosing, thereby prompting a change in US Food and Drug Administration-approved dosing. Depending on patient weight, one dosing strategy may be more cost-effective than another; thereby, a combination of dosing strategies may be beneficial for institutions. While these agents have been shown to be efficacious, they have been associated with immune-related adverse events (IrAEs). The purpose of this study was to determine the dosing strategy used and identify actual and potential cost savings, as well as to determine the incidence of hypothyroidism with PD-1 inhibitors in patients of the US Department of Veterans Affairs (VA). This was a retrospective chart review of VA patients who received a PD-1 inhibitor for the treatment of a solid tumor between January 2015 and July 2017. Data were collected from the VA Corporate Data Warehouse through the VA Informatics and Computing Infrastructure. The dosing strategy for a PD-1 inhibitor was categorized into weight-based vs fixed-dosing where possible and used to identify actual and potential cost-savings opportunities. Thyroid laboratory values and levothyroxine prescriptions were evaluated to determine the overall incidence of the prespecified IrAEs. Descriptive statistics were used for primary and secondary outcomes. Nivolumab was the primary PD-1 inhibitor used for solid tumor treatment. Both nivolumab and pembrolizumab were primarily dosed based on patient weight. Nivolumab orders resulted in $8,514,300 estimated actual cost savings with $5,591,250 estimated missed cost savings identified. Of the patients who received nivolumab, 3249 patients were evaluated for thyroid dysfunction; 514 (15.8%) developed primary hypothyroidism based on laboratory values and levothyroxine prescription data. Utilization of a combination of both weight-based and fixed-dosing strategies for nivolumab has the potential for cost savings, thereby benefiting the health care institution. The incidence of IrAEs identified among patients who received PD-1 inhibitor within the VA health care system was similar to the incidences reported in published literature. This further supports recommendations for close IrAE monitoring and treatment.

Response Rates, Non-Relapse Mortality, and Financial Implications of Transplant-Associated Thrombotic Microangiopathy Treated with Eculizumab

Background: Hematopoietic cell transplantation associated thrombotic microangiopathy (TA-TMA) shares common features with atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura. TA-TMA affects multiple organ systems resulting in multi-organ failure and non-relapse mortality (NRM). Recently, complement activation has been associated with TA-TMA leading to utilization of complement blockade in TMA. Eculizumab is a humanized monoclonal antibody that binds to C5 and prevents the formation of the membrane attack complex (C5b-9) or the terminal complement pathway. Eculizumab may be an effective treatment for pediatric TA-TMA patients; however, there are limited data regarding its use in adult TA-TMA patients. Furthermore, eculizumab is an expensive medication and there are no published data regarding the financial implications of TA-TMA treated with eculizumab. The purpose of this study was to examine the response rates, NRM, and financial implications of TA-TMA treated with eculizumab.Methods: We performed a retrospective cohort study of patients with TA-TMA who received eculizumab at our institution between January 1, 2012, and April 9, 2017. TA-TMA was defined according to the BMT-CTN criteria with evidence of hemolysis, elevated LDH, renal dysfunction and negative Coombs' test. Serum complement biomarkers (C5b-9) were used to support the diagnosis when platelet or red blood cell transfusion dependence occurred with organ dysfunction or tissue evidence of microangiopathy. Patients were vaccinated against Neisseria meningitides and received appropriate antibiotic prophylaxis. Eculizumab therapy was initiated at the Food and Drug Administration-approved dosing schedule for aHUS: 900 mg intravenously weekly for the first 4 weeks followed by 1200 mg intravenously every other week beginning on week 5 for a total of 8 weeks, with some patients requiring longer than an 8 week course. The primary outcome was complete response to eculizumab therapy and responders were defined by achievement of transfusion independence and improvement in creatinine. Secondary outcomes included non-relapse mortality (NRM), inpatient cost, number of comorbidities, number of infections, number of hospitalizations, and hospital length of stay (LOS). Comorbidities were defined as any documented medical problem other than the reason for transplant and TA-TMA.Results: Twenty patients were included in the study (Table 1). The median (range) time from transplant to diagnosis of TA-TMA was 139 (14-388) days. The median (range) time from diagnosis of TA-TMA to first dose of eculizumab was 2 (0-272) days. The complete response rate was 55%. The median (range) number of doses of eculizumab was 6.5 (2-17) for responders compared to 3 (1-7) for non-responders including both inpatient and outpatient doses (p= 0.01). There were no significant differences between the number of hospitalizations for responders and non-responders. However, responders had shorter LOS and lower inpatient costs than non-responders. The median (range) LOS was 9 days (0-92) for responders compared to 61 days (26-94) for non-responders (p= 0.03). The median (range) total inpatient cost was $259,734 (0-1,670,070) for responders compared to $1,525,758 (385,092-1,948,190) for non-responders (p= 0.003). The itemized inpatient costs are shown in Figure 1. Patients who responded to eculizumab tended to be younger with less comorbidities. In fact, patients were 33% less likely to respond to eculizumab for every additional documented comorbidity at the time of TA-TMA diagnosis (HR=0.67 [95% CI 0.49-0.92]). The NRM was 1/11 (9%) for responders and 9/9 (100%) for non-responders (HR=0.07 [95% CI: 0.007-0.66]).Conclusions: TA-TMA is an important complication of HCT that is associated with high NRM and financial toxicity. Our data suggests that patients who respond to eculizumab have lower NRM, LOS, and financial costs than non-responders. There was a statistically non-significant trend in incidence of steroid-refractory GVHD in the non-responder group; additionally non-responders received significantly fewer doses than responders, which may explain partly the lower response rates compared to the 80% response rates in aHUS. Patient age and the number of comorbidities at the time of diagnosis of TA-TMA may be important predictive factors for response to eculizumab. [Display omitted] DisclosuresMims:Novartis: Honoraria. Hofmeister:Janssen: Research Funding; Karyopharm: Research Funding; Celgene: Research Funding; Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Takeda: Research Funding. Walker:Gilead: Research Funding. Vasu:Stemline Therapeutics: Research Funding; Boehringer-Ingelheim: Research Funding.

Evaluation of Prescribing Practices and Outcomes Using Direct-acting Oral Anticoagulants After Cardiac Surgery

Cardiac surgery patients frequently require anticoagulation. Warfarin remains the preferred agent, and a few trials have reported negative outcomes with the use of direct-acting oral anticoagulants (DOACs) in these patients. Therefore, limited literature exists that supports the dosing, safety, and efficacy of DOACs within the cardiac surgery population. This single-center, retrospective analysis was conducted at a tertiary academic medical center. All data were extrapolated from electronic medical records of qualifying patients from August 2017 to August 2019. Adult patients were included if they received at least 1 of 4 DOACs (apixaban, rivaroxaban, edoxaban, or dabigatran) after undergoing one of the following cardiac surgeries: coronary artery bypass graft, bioprosthetic valve replacement, aortic surgery, or valve repair. The composite safety end point included major bleeding and clinically relevant nonmajor bleeding, as defined by the International Society on Thrombosis and Hemostasis. The composite efficacy outcome of thromboembolic events included deep vein thrombosis, pulmonary embolism, ischemic stroke, and intracardiac thrombus. A total of 305 patient charts were identified for analysis; 229 patients met the inclusion criteria. The composite safety outcome occurred in 12 patients (5.2%) within 90 days after cardiac surgery. One patient (0.4%) experienced a thromboembolic event within 90 days after cardiac surgery. The most commonly prescribed DOAC was apixaban (79.0%). US Food and Drug Administration-approved dosing was used in 91.3% of patients, and DOACs were primarily used for the indication of stroke prevention in atrial fibrillation or atrial flutter (88.2%). These data provide insight into the prescribing practices, efficacy, and safety of DOACs in cardiac surgery patients.

Administration of valproic acid in clinically approved dose improves neurologic recovery and decreases brain lesion size in swine subjected to hemorrhagic shock and traumatic brain injury.

Traumatic brain injury (TBI) and hemorrhage remain the leading causes of death after trauma. We have previously shown that a dose of valproic acid (VPA) at (150 mg/kg) can decrease brain lesion size and hasten neurologic recovery. The current Food and Drug Administration-approved dose of VPA is 60 mg/kg. We evaluate neurologic outcomes and brain lesion size of a single dose of VPA at a level currently within Food and Drug Administration-approved dose in swine subjected to TBI and hemorrhagic shock. Swine (n = 5/group) were subjected to TBI and 40% blood volume hemorrhage. Animals remained in shock for 2 hours before randomization to normal saline (NS) resuscitation alone (control), NS-VPA 150 mg/kg (VPA 150), or NS-VPA 50 mg/kg (VPA 50). Neurologic severity scores (range, 0-32) were assessed daily for 14 days, and brain lesion size was measured via magnetic resonance imaging on postinjury day (PID) 3. Shock severity and laboratory values were similar in all groups. Valproic acid-treated animals demonstrated significantly less neurologic impairment on PID 1 and returned to baseline faster (PID 1 mean neurologic severity score, control = 22 ± 3 vs. VPA 150 mg/kg = 8 ± 7 or VPA 50 mg/kg = 6 ± 6; p = 0.02 and 0.003). Valproic acid-treated animals had significantly smaller brain lesion sizes (mean volume in mm3, control = 1,268.0 ± 241.2 vs. VPA 150 mg/kg = 620.4 ± 328.0 or VPA 50 mg/kg = 438.6 ± 234.8; p = 0.007 and 0.001). In swine subjected to TBI and hemorrhagic shock, VPA treatment, in a dose that is approved for clinical use, decreases brain lesion size and reduces neurologic impairment compared with resuscitation alone.

Histone deacetylase 6 inhibition improves survival in a swine model of lethal hemorrhage, polytrauma, and bacteremia.

Trauma is the leading cause of death for young Americans. Nonspecific histone deacetylase inhibitors, such as valproic acid, have been shown to improve survival in preclinical models of lethal trauma, hemorrhage, and sepsis. The doses needed to achieve a survival benefit are higher than Food and Drug Administration-approved doses, and the nonspecificity raises concerns about unintended adverse effects. The isoform-specific histone deacetylase 6 inhibitor, ACY-1083, has been found to be as efficacious as valproic acid in a rodent model of hemorrhagic shock. We hypothesized that ACY-1083 treatment would improve survival in a swine model of lethal hemorrhage, polytrauma, and bacteremia. Swine were subjected to 45% blood volume hemorrhage, brain injury, femur fracture, rectus crush, splenic and liver lacerations, and colon injury. After 1 hour of shock (mean arterial pressure, 30-35 mm Hg), animals were randomized to normal saline resuscitation (control) or normal saline plus ACY-1083 30 mg/kg treatment (n = 5/group). After 3 hours (simulating delayed evacuation), packed red blood cells and antibiotics were administered, the colon injury was repaired, and the abdomen was closed. Animals were then monitored for another 4 hours. Survival was assessed using Kaplan-Meier and log-rank test. This combination of injuries was lethal. All animals became bacteremic, in addition to the severe hemorrhagic shock. Survival in the control group was 0%, and ACY-1083 treatment increased survival to 80% (p = 0.019). There was no difference in the brain lesion size between the groups. A single dose of ACY-1083 markedly improves survival in an otherwise lethal model of polytrauma, hemorrhagic shock, and bacteremia.

Gadolinium deposition-"gadolinium deposition disease"

Gadolinium (Gd)-based contrast agents have been routinely used worldwide in diagnostic MRI since 1988. All routinely applied contrast agents for clinical use were considered extremely safe with regard to tolerance, adverse effects and diagnostic efficacy and when used at Food and Drug Administration-approved doses. With the identification of Gd-associated disorders, namely nephrogenic systemic fibrosis and adverse reactions, and in the longer term Gd-retention in the brain, this view changed and led to the withdrawal or restriction of approval of linear Gd chelates in Europe. Even though Gd deposition in different human body areas was described very early, recently published literature of intracerebral accumulation of contrast agents as well as deposition in bone have created surprising attention. Not only was the fact of Gd deposition in the body well known for many years, but there is currently no clinical evidence of patient symptoms and no resulting health issues of patients have been observed yet. The expression "gadolinium deposition disease" has been termed by active patient advocacy groups with an online presence with reports of individual members stating abroad spectrum of disorders yielding alarge symptom complex after administration of Gd-based contrast agents without evidence of any pre-existing or otherwise underlying disease process which could explain the mentioned disorder.

Macrocyclic lactones inhibit nasopharyngeal carcinoma cells proliferation through PAK1 inhibition and reduce in vivo tumor growth.

PurposeThe Epstein–Barr virus (EBV)-associated cancer nasopharyngeal carcinoma (NPC) is rare in Europe and North America but is a real public health problem in some regions of the world, such as southern Asia, North Africa, and for Inuit populations. Due to the anatomy and location of the nasopharynx, surgery is rarely used to treat primary NPC cancers. Treatment by radiotherapy, combined or not with chemotherapy, are efficient for primary tumors but often do not protect against fatal relapses or metastases.MethodsSearch for new therapeutic molecules through high content screening lead to the identification of Ivermectin (IVM) as a promising drug. IVM is a US Food and Drug Administration-approved macrocyclic lactone widely used as anthelmintic and insecticidal agent that has also shown protective effects against cancers.ResultsWe show here that IVM has cytotoxic activity in vitro against NPC cells, in which it reduces MAPKs pathway activation through the inhibition PAK-1 activity. Moreover, all macrocyclic lactones tested and a PAK1 inhibitor are cytotoxic in vitro for EBV-positive and EBV-negative NPC tumor cells. We have also shown that IVM intraperitoneal repeated injections, at US Food and Drug Administration-approved doses, have no significant toxicity and decrease NPC subcutaneous tumors development in nude mice.ConclusionMacrocyclic lactones appear as promising molecules against NPC targeting PAK-1 with no detectable adverse effect.

A Phase I/II Trial of the Combination of Azacitidine and Gemtuzumab Ozogamicin for Treatment of Relapsed Acute Myeloid Leukemia

IntroductionTreatment with hypomethylating agent therapy might enhance anti-CD33 monoclonal antibody-mediated cytotoxicity against acute myeloid leukemia (AML) blasts through epigenetic effects on Syk and SHP-1 expression. Patients and MethodsIn the present phase I/II study, we treated patients with relapsed or refractory AML with azacitidine, followed by 2 doses of gemtuzumab ozogamicin (GO) at 6 mg/m2, the Food and Drug Administration-approved dose and schedule at study initiation. We sought to determine the maximum tolerated dose and clinical activity of this combination therapy. Secondarily, we aimed to determine whether baseline Syk and SHP-1 expression can be used as predictive biomarkers of treatment response. ResultsThe established maximum tolerated dose was azacitidine 75 mg/m2 daily for 6 consecutive days, followed by GO 6 mg/m2 on days 7 and 21. Of the 50 evaluable patients, 12 (24%) obtained complete remission (CR) or CR with incomplete peripheral blood recovery (CRp). No dose-limiting toxicities were observed in phase I, and no patient developed hepatic sinusoidal obstructive syndrome. Although no significant correlation was found between Syk and SHP-1 expression and the clinical response to combination therapy, in vitro studies repeatedly demonstrated that azacitidine-treated AML cells had an increased response to GO treatment. ConclusionOur study found that the combination of GO with azacitidine is relatively well tolerated, with response rates similar to those with GO monotherapy at higher doses. Differences in the GO drug schedule, dose level, and frequency might explain the discrepant response rates between our study and others, suggesting that the optimal GO dose remains unclear, especially when combined with hypomethylating agent therapy.

Safety and tolerability of cariprazine in patients with acute exacerbation of schizophrenia: a pooled analysis of four phase II/III randomized, double-blind, placebo-controlled studies.

Cariprazine, a potent dopamine D3 and D2 receptor partial agonist antipsychotic with preferential binding to D3 receptors, is Food and Drug Administration approved for treating schizophrenia and manic or mixed episodes of bipolar I disorder. A post-hoc safety/tolerability analysis of data from the four acute trials in the cariprazine schizophrenia clinical development program (NCT00404573; NCT00694707; NCT01104766; NCT01104779) was carried out using the overall safety population (all patients who received ≥1 dose of study drug) and modal daily dose subgroups (1.5-3, 4.5-6, and 9-12 mg/day). These exploratory findings were summarized using descriptive statistics. Cariprazine was generally well tolerated. The incidence of treatment-emergent adverse events versus placebo was similar for cariprazine 1.5-3 mg/day and higher for cariprazine 4.5-6 and 9-12 mg/day; a dose-response relationship was observed for akathisia, extrapyramidal symptoms, and diastolic blood pressure. The mean changes in metabolic parameters were generally similar in cariprazine-treated and placebo-treated patients. There was no prolactin level increase or QTc value greater than 500 ms; small increases in mean body weight (∼1to2 kg) versus placebo were observed. Within the Food and Drug Administration-approved dose range (1.5-6 mg/day), cariprazine was generally safe and well tolerated in patients with schizophrenia.

Brivaracetam: An Adjunctive Treatment for Partial-Onset Seizures.

Brivaracetam is an analogue of levetiracetam that is Food and Drug Administration-approved for adjunctive treatment of partial-onset seizures in patients 16 years and older. In placebo-controlled trials adjunct brivaracetam demonstrated efficacy in reducing the frequency of seizures. The most commonly reported adverse effects are somnolence, dizziness, and fatigue. Clinical trials have evaluated brivaracetam for safety and efficacy in adjunctive treatment of partial-onset seizures in patients 16 years and older for up to 16 weeks. Brivaracetam's mechanism is similar to that of levetiracetam but with greater receptor binding affinity on synaptic vesicle protein 2A and inhibitory effects on sodium channels. Clinically significant differences between these agents are undetermined. Brivaracetam is available as oral tablets, oral solution, and intravenous solution. The Food and Drug Administration-approved dose is 50 mg twice daily, and titration is not required. Brivaracetam does not need dose adjustment for renal impairment and has minimal drug-drug interactions. Current limitations of brivaracetam include lack of head-to-head trials, limited long-term safety and efficacy data, and cost. Overall, brivaracetam is a viable adjunct therapeutic option for refractory partial-onset seizures in those who have failed conventional therapies.

Characterisation and management of dermatologic adverse events to agents targeting the PD-1 receptor

BackgroundDermatologic adverse events (AEs) are some of the most frequently observed toxicities of immune-checkpoint inhibitor therapy, but they have received little attention. The drugs, pembrolizumab and nivolumab are recently approved inhibitors of the programmed death (PD)-1 receptor that have overlapping AE profiles however, the incidence, relative risk (RR), and clinico-morphological pattern of the associated dermatologic AEs are not known. MethodsWe conducted a systematic review of the literature, and performed a meta-analysis of dermatologic AEs observed with the use of pembrolizumab and nivolumab in cancer patients. An electronic search was conducted using the PubMed, and Web of Science, and on the American Society of Clinical Oncology and European Society for Medical Oncology meeting abstracts' libraries for potentially relevant oncology trials, that employed the drugs at Food and Drug Administration-approved doses and reported dermatologic AEs. The incidence, RR and 95% confidence intervals were calculated using either random- or fixed-effects models based on the heterogeneity of included studies. The clinical presentation, histology of affected skin areas, and management strategies (based on institutional experience), are also presented. ResultsRash, pruritus and vitiligo were found to be the most frequently reported dermatologic AEs. The calculated incidence of all-grade rash with pembrolizumab and nivolumab was 16.7% (RR = 2.6) and 14.3% (RR = 2.5), respectively. Other significant all-grade AEs included pruritus (pembrolizumab: incidence, 20.2% [RR = 49.9]; nivolumab: incidence, 13.2% [RR = 34.5]) and vitiligo (pembrolizumab: incidence, 8.3% [RR = 17.5]; nivolumab: 7.5% [RR = 14.6]). Interestingly, all the vitiligo events were reported in trials investigating melanoma. The RR for developing dermatologic AEs in general, was 2.95 with pembrolizumab, and 2.3 with nivolumab. ConclusionWe found that pembrolizumab and nivolumab are both associated with dermatologic AEs, primarily low-grade rash, pruritus, and vitiligo, which are reminiscent of those seen with ipilimumab. Knowledge of these findings is critical for optimal care, maintaining dose intensity, and health-related quality of life in cancer patients receiving PD-1 inhibitors.

Efavirenz Capsule Sprinkle and Liquid Formulations With Didanosine and Emtricitabine in HIV-1-infected Infants and Children 3 Months to 6 Years of Age

AI266-922 was an open-label, dose-ranging study that assessed the pharmacokinetics, safety and efficacy of efavirenz (EFV) in children (3 months to 6 years). Antiretroviral-naïve and antiretroviral-experienced HIV-1-infected children received once-daily EFV as oral solution or capsule sprinkle plus didanosine and emtricitabine (FTC). Pharmacokinetic analyses were undertaken at week 2 and repeated at weeks 10 and 18 after an EFV dose change or switch from oral solution to capsule sprinkle. Thirty-seven subjects were treated. EFV area under the plasma concentration-time curve over 1 dosing interval from time 0 to 24 hours postdose values were generally suboptimal (<110 μM × h) in subjects younger than 3 years treated with oral solution; these subjects switched to capsule sprinkle. Twenty of 21 subjects younger than 3 years treated with capsule sprinkle achieved an EFV area under the plasma concentration-time curve over 1 dosing interval from time 0 to 24 hours postdose value >110 μM × h, although higher initial doses were administered in this age group. Interpatient variability in EFV exposure was high. By week 48, 77.8% and 63.0% of subjects achieved HIV-RNA <400 and <50 copies/mL, respectively. Median changes in log10 HIV-RNA and CD4 percentage from baseline were -3.18 copies/mL and +6%, respectively. Two (5.4%) patients discontinued because of adverse events (AEs). Serious AEs occurred in 20 (54.1%) subjects. Common AEs were diarrhea (49%), nasopharyngitis (35%) and pneumonia (30%). Overall, 43% of subjects with suboptimal EFV exposure at week 2 developed resistance. Once-daily EFV, given as capsule sprinkle, achieved target exposures in this study although doses were 2-3 times higher than Food and Drug Administration-approved doses for children younger than 3 years. These data are useful for dose selection modeling and simulation; however, Food and Drug Administration-approved doses should be used clinically. EFV + didanosine + FTC was efficacious with no new pediatric safety findings reported.

Systematic Review and Adjusted Indirect Comparison Meta-Analysis of Oral Anticoagulants in Atrial Fibrillation

Oral anticoagulants such as apixaban, dabigatran, and rivaroxaban are alternatives to warfarin for preventing events in patients with atrial fibrillation. Direct comparative studies between agents are unavailable. Our objective was to conduct an adjusted indirect comparison meta-analysis between new oral agents in atrial fibrillation. We searched MEDLINE and Cochrane Central through February 2012 for randomized, controlled trials in patients with atrial fibrillation evaluating apixaban, dabigatran, or rivaroxaban versus warfarin. For dabigatran, only data from the Food and Drug Administration-approved dose were included. Outcomes included the composite of stroke or systemic embolism, any stroke, and major bleeding among, others. Outcomes were initially pooled using standard random-effects methods, producing risk ratio and 95% confidence intervals. Adjusted indirect comparisons using these pooled estimates were then performed. A total of 44 733 patients from 4 studies were analyzed. Most analyses yielded no differences between agents. Dabigatran lowered risk of composite outcome (risk ratio, 0.75; 95% confidence interval, 0.57-1.00), ischemic stroke (0.67; 0.48-0.93), and hemorrhagic stroke (0.45; 0.45-0.99) versus rivaroxaban. No differences in all strokes or mortality were seen. Apixaban lowered the risk of major bleeding (0.74; 0.60-0.91) and gastrointestinal bleeding (0.58; 0.41-0.82) versus dabigatran and major bleeding versus rivaroxaban (0.68; 0.55-0.83), but increased systemic emboli versus rivaroxaban (3.86; 1.17-12.75). Significant differences in efficacy and safety parameters may exist between oral anticoagulant agents in patients with atrial fibrillation. Apixaban lowers the risk of major and gastrointestinal bleeding versus dabigatran and rivaroxaban. Dabigatran lowers the composite of stroke or systemic emboli, and ischemic stroke versus rivaroxaban. Head-to-head clinical trials are required to confirm these findings.

Cost Per Responder Associated with Biologic Therapies for Crohn’s Disease, Psoriasis, and Rheumatoid Arthritis

Biologic therapies have demonstrated efficacy and safety in several chronic systemic disorders. The authors indirectly compared response rates and costs per responder associated with biologic treatments for moderate-to-severe Crohn's disease (CD), psoriasis (Ps), and/or rheumatoid arthritis (RA). A systematic literature search was performed to identify phase 3 randomized controlled trials of biologics for CD (adalimumab, infliximab), Ps (adalimumab, etanercept, infliximab, ustekinumab 45 mg, ustekinumab 90 mg), or methotrexate-refractory RA (abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, tocilizumab). Food and Drug Administration-approved dosing schedules were evaluated. Published response rates were extracted, with response defined in CD, Ps, and RA as: ≥70-point reduction in CD Activity Index at 12 months; ≥75% improvement in Psoriasis Area and Severity Index at 3 months; and ≥50% improvement in American College of Rheumatology component scores at 6 months. Within each indication, mixed-treatment comparison meta-analyses were conducted to derive pooled estimates and 95% CIs of response rate difference versus placebo for each biologic, adjusting for cross-trial variation in control-arm response rates. Cost per responder was estimated for each biologic as projected per patient drug costs (2011 US$) divided by response rate difference. Altogether, 23 publications were selected. In CD, 12-month cost per responder was estimated at $116,291 (95% CI $71,637-208,348) for adalimumab and $125,169 (95% CI $60,532-267,101) for infliximab. Among biologics approved in Ps, 3-month cost per responder was lowest for adalimumab ($9,756; 95% CI $8,668-11,131), infliximab ($12,828; 95% CI $11,772-13,922), and ustekinumab 45 mg ($13,821; 95% CI $12,599-15,167). In RA, biologics with the lowest 6-month cost per responder were adalimumab ($27,853; 95% CI $19,284-40,270), etanercept ($29,140; 95% CI $14,170-61,030), and tocilizumab ($31,363; 95% CI $14,713-64,232). Meta-analyses of clinical trials found considerable variation in cost-effectiveness of biologic therapies for CD, Ps, and RA. These results may help determine biologic utilization in these chronic diseases.

High Prevalence of White-Coat Hypertension in Spanish Resistant Hypertensive Patients

See related article, pp 898–902 Resistant hypertension is a major public health challenge both in the United States and worldwide. Although various authors use different definitions, a recent scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research1 defined resistant hypertension as blood pressure either controlled by ≥4 antihypertensive medications or ≥140/90 mm Hg, despite 3 antihypertensive medications of different classes, at near-maximal US Food and Drug Administration–approved doses, one of which is a diuretic. Some authors add a minimum duration of 3 months of such treatment; others insist that the medications must be “appropriately chosen,” the patient adherent, and/or the patient referred by a physician to a hypertension center. Patients with resistant hypertension are of great public health importance, because they have a higher risk of future cardiovascular and renal events, greater healthcare expenditures, a higher prevalence of secondary hypertension and target organ damage, and are, by definition, “difficult to control.”1,2 Most reports of the prevalence of resistant hypertension come from tertiary referral centers2,3 or from clinical trials that implemented a stepwise sequence of medications to control blood pressure4,5; ≈15% to 20% of all hypertensives in these reports would be classified as “resistant.” A major confounder in the office diagnosis …

Plerixafor Dosing and Administration in a Patient with Dialysis-Dependent Renal Failure

To report on the use of plerixafor in a patient with multiple myeloma and dialysis-dependent renal failure. A 38-year-old man with multiple myeloma and dialysis-dependent renal failure was evaluated for stem cell transplantation. Stem cell mobilization with 6 doses of granulocyte colony-stimulating factor (G-CSF) 10 μg/kg/day yielded an inadequate maximum pre-apheresis CD34+ count of 5.6 cells/μL. The patient was treated with a postdialysis subcutaneous dose of plerixafor 160 μg/kg after 4 days of G-CSF therapy. After a single dose of plerixafor, the patient's pre-apheresis CD34+ count was 125.6 cells/μL. After 1 apheresis session, the stem cell collection yield was 5.33 x 10⁶ CD34+ cells/kg. There were no observed plerixafor toxicities. The patient underwent successful autologous stem cell transplantation. Times to neutrophil and platelet engraftment were 12 and 15 days, respectively. At 100-day follow-up, the patient's myeloma was in remission and he met all criteria for durable engraftment. Renal impairment is a common comorbidity in patients with multiple myeloma. Plerixafor is a chemokine receptor 4 antagonist approved for use to mobilize stem cells for collection and subsequent autologous transplantation in patients with non-Hodgkin's lymphoma and multiple myeloma. To date, there is limited information on safe and effective dosing and administration of plerixafor in patients who are dialysis-dependent. This report describes the use of plerixafor in a patient with multiple myeloma and dialysis-dependent renal failure. Based on our experience, we are instituting a policy to administer plerixafor at Food and Drug Administration-approved renal adjustment doses in patients on hemodialysis, with dialysis sessions scheduled prior to plerixafor administration and repeated as necessary after apheresis and prior to subsequent plerixafor doses. If clinically feasible, dialysis should be held during the days required to collect stem cells.

Developing a Safe Intravenous Sotalol Dosing Regimen

Recently, an intravenous formulation of sotalol has been approved by the food and drug administration for substitution for oral therapy in patients who are unable to take oral sotalol. The purpose of this randomized, 2-treatment, 2-period, crossover study was to develop a safe dosing regimen for intravenous sotalol that provides similar blood levels and therefore similar efficacy and safety to orally administered sotalol. Fifteen healthy subjects received 75 mg intravenous sotalol infusion administered over 2.5 hours and 80 mg oral sotalol. Standard pharmacokinetic methods were used to obtain maximum serum concentrations (Cmax) and areas under the concentration-time curves (AUC). Individual pharmacokinetic parameters were used in simulation studies to determine the optimal intravenous administration regimen. Intravenous sotalol administered over 2.5 hours resulted in a significantly greater Cmax than oral administration (830 +/- 391 vs. 601 +/- 289 ng/mL, P < 0.001). With increasing the length of infusions to 3, 4, and 5 hours, simulation studies showed that the Cmax decreased to 128%, 113%, and 102% of the oral Cmax. The length of infusion did not affect AUC. Based on these studies, a safe intravenous regimen for the replacement of 80-mg oral therapy requires 75 mg intravenous sotalol administered as a 5-hour infusion. Because the pharmacokinetics of sotalol are linear and dose proportional, 150 mg intravenous sotalol administered over 5 hours will provide similar Cmax and AUC as 160 mg oral sotalol. The food and drug administration-approved dosing regimen is 75 mg intravenous sotalol to replace 80 mg oral sotalol and 150 mg intravenous sotalol to replace 160 mg oral sotalol, both administered over 5 hours.