Twice-daily Dosing Research Articles

SUN-303 Effects of Open-Label, Adjunctive Ganaxalone Treatment on Resistant Depression in Postmenopausal Women: A Pilot Study

Resistance to selective serotonin reuptake inhibitor and serotonin norepinephrine reuptake inhibitor treatment occurs in about 50% to 70% of patients with major depressive disorder (MDD), a condition associated with significant morbidity that affects women at higher rates than men. Few well-tolerated, effective augmentation therapies are available for such patients, and new therapeutic strategies for resistant depression are needed. The neuroactive steroid metabolite of progesterone, allopregnanolone, is a positive allosteric modulator of GABAA receptors and a putative treatment for mood disorders. We performed a pilot study to determine whether an oral allopregnanolone analog (ganaxolone) may be effective adjunctive therapy for resistant depression in postmenopausal women. Ten postmenopausal women (age 62.8±6.3 years, range 53–69) with resistant depression [current DSM-IV major depressive episode per the Structured Clinical Interview for DSM-IV, Montgomery-Asberg Depression Rating Scale (MADRS) ≥16 despite treatment with an adequately dosed antidepressant for ≥6 weeks] were studied. Open-label ganaxolone (225 mg BID, increased to 450 mg BID if tolerated) was administered for 8 weeks, followed by a 2-week taper. Mean total MADRS depression score (primary endpoint) decreased by 8 weeks [24.4±1.6 (SEM) to 12.8±2.9, p=0.015] and persisted over the two-week taper (p=0.019); 44% of subjects experienced response (score decrease ≥50%) and remission (final score <10), which persisted in 100% and 50% of subjects at 10 weeks, respectively. Secondary endpoints showed significant improvement, including the Inventory of Depressive Symptomatology-Self-Report (IDS-SR; p=0.003), MADRS Reduced Sleep subscale (p<0.001), Symptoms of Depression Questionnaire (SDQ) total score (p=0.012), and SDQ subscales for disruptions in sleep quality (p=0.003) and changes in appetite and weight (p=0.009) over 8 weeks. No significant effects were observed on quality of life or sexual function. All subjects experienced sleepiness and fatigue; 60% experienced dizziness. In conclusion, adjunctive ganaxolone in this open label pilot study appeared to exert antidepressant effects in postmenopausal women with resistant depression but produces sedation with twice-daily dosing. The observed positive effects on sleep and the potential for sustained treatment effects merit further study, as ganaxolone may be particularly beneficial to patients with depression and insomnia. Randomized, placebo-controlled studies are necessary to rule out placebo effects. Given the sedation experienced by most participants, nighttime dosing only should be considered for future studies. Finally, should rigorous studies confirm an antidepressant effect, it will be important to identify subsets of women who respond (e.g. women with neuroactive steroid dysregulation) and mechanisms of action.

Twice-daily intravenous bolus tacrolimus infusion: A safe and effective regimen for graft-versus-host disease prophylaxis

Objective/BackgroundAmong patients undergoing allogeneic hematopoietic cell transplant, continuous intravenous (IV) tacrolimus infusion is frequently used for graft-versus-host disease (GvHD) prophylaxis. Twice-daily intermittent IV tacrolimus dosing may confer safety and convenience benefits. MethodsWe performed a retrospective chart review of 66 patients who received twice-daily IV bolus tacrolimus for GvHD prophylaxis. The primary end point of the study was safety, as measured by renal toxicity. The secondary end points included mean tacrolimus serum concentrations, incidence of grades II–IV acute GvHD, electrolyte abnormalities, hyperglycemia, hypertension, and neurologic toxicity. ResultsThere was acceptable, possibly favorable, incidence of renal toxicity (42%) and no significant difference in grades II–IV GvHD (37%), compared with published data. Mean tacrolimus blood concentrations were not affected by occurrence of renal toxicity. ConclusionWe conclude that administration of IV tacrolimus twice daily over 4 h may be safe and effective in preventing GvHD in allogeneic hematopoietic cell transplant.

Comparison of Dabigatran Plus a P2Y12 Inhibitor With Warfarin-Based Triple Therapy Across Body Mass Index in RE-DUAL PCI

BackgroundBody mass index (BMI) affects drug levels of nonvitamin K antagonist oral anticoagulants. We sought to assess whether BMI affected outcomes in the RE-DUAL PCI trial. MethodsRE-DUAL PCI (NCT02164864) evaluated the safety and efficacy of a dual-antithrombotic-therapy regimen using dabigatran (110 mg or 150 mg twice daily and a P2Y12 platelet antagonist) in comparison with triple therapy of warfarin, aspirin, and a P2Y12 platelet inhibitor in 2725 patients with atrial fibrillation who had undergone percutaneous coronary intervention (PCI). We compared the risk of first International Society on Thrombosis and Haemostasis (ISTH)-defined major or clinically relevant nonmajor bleeding events (primary endpoint) and the composite of death, myocardial infarction, stroke, systemic embolism, or unplanned revascularization (main efficacy endpoint) in relation to baseline BMI. ResultsMedian (range) BMI was 28.1 (14-66) kg/m2. Dabigatran dual therapy versus warfarin triple therapy had relevantly and similarly lower rates of bleeding at both 110 mg and 150 mg twice-daily doses, irrespective of BMI. Thromboembolic event rates appeared consistent across categories of BMI, including those <25 and ≥35 kg/m2 (P for interaction: 0.806 and 0.279, respectively). ConclusionsThe reduction in bleeding with dabigatran dual therapy compared with warfarin triple therapy in patients here evaluated appears consistent across BMI categories.

Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in the treatment of venous thromboembolism

Anticoagulant plasma concentrations and patient characteristics might affect the benefit–risk balance of therapy. This study assessed the impact of model-predicted rivaroxaban exposure and patient characteristics on outcomes in patients receiving rivaroxaban for venous thromboembolism treatment (VTE-T) using data from the phase 3 EINSTEIN–DVT and EINSTEIN–PE studies. In the absence of measured rivaroxaban exposure, exposure estimates were predicted based on individual increases in prothrombin time (PT) and the known correlation between rivaroxaban plasma concentrations and PT dynamics. The composite efficacy outcomes evaluated were recurrent deep-vein thrombosis (DVT) and pulmonary embolism (PE) and recurrent DVT, PE and all-cause death; safety outcomes were major bleeding and the composite of major or non-major clinically relevant (NMCR) bleeding. Exposure–response relationships were evaluated using multivariate logistic and Cox regression for the twice-daily (BID) and once-daily (OD) dosing periods, respectively. Predicted rivaroxaban exposure and CrCl were significantly associated with both efficacy outcomes in the BID period. In the OD period, exposure was significantly associated with recurrent DVT and PE but not recurrent DVT, PE and all-cause death. The statistically significant exposure–efficacy relationships were shallow. Exposure–safety relationships were absent within the investigated exposure range. During both dosing periods, low baseline hemoglobin and prior bleeding were associated with the composite of major or NMCR bleeding. In conclusion, based on the underlying data and analysis, no reliable target window for exposure with improved benefit–risk could be identified within the investigated exposure range. Therefore, monitoring rivaroxaban levels is unlikely to be beneficial in VTE-T.

Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results

AbstractTherapeutic targeting of Bruton tyrosine kinase (BTK) has dramatically improved survival outcomes for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Acalabrutinib is an oral, highly selective BTK inhibitor that allows for twice-daily dosing due to its selectivity. In this phase 1b/2 study, 134 patients with relapsed/refractory CLL or SLL (median age, 66 years [range, 42-85 years]; median prior therapies, 2 [range, 1-13]) received acalabrutinib 100 mg twice daily for a median of 41 months (range, 0.2-58 months). Median trough BTK occupancy at steady state was 97%. Most adverse events (AEs) were mild or moderate, and were most commonly diarrhea (52%) and headache (51%). Grade ≥3 AEs (occurring in ≥5% of patients) were neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%). Atrial fibrillation and major bleeding AEs (all grades) occurred in 7% and 5% of patients, respectively. Most patients (56%) remain on treatment; the primary reasons for discontinuation were progressive disease (21%) and AEs (11%). The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%; responses were similar regardless of genomic features (presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or immunoglobulin variable region heavy chain mutation status). Median duration of response and progression-free survival (PFS) have not been reached; the estimated 45-month PFS was 62% (95% confidence interval, 51% to 71%). BTK mutation was detected in 6 of 9 patients (67%) at relapse. This updated and expanded study confirms the efficacy, durability of response, and long-term safety of acalabrutinib, justifying its further investigation in previously untreated and treated patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.

Pregnancy Alters CYP- and UGT-Mediated Metabolism of Buprenorphine.

In the United States, drug addiction has become a nationwide health crisis. Recently, buprenorphine (BUP), a maintenance therapy approved by the Food and Drug Administration, has been increasingly used in pregnant women for the treatment of opioid use disorder. Pregnancy is associated with various anatomic and physiological changes, which may result in altered drug pharmacokinetics (PKs). Previously, we reported that dose-adjusted plasma concentrations of BUP are lower during pregnancy than after pregnancy. The mechanism(s) responsible for this difference has not yet been defined. Our study aimed to evaluate alterations in cytochromes P450 (CYP)- and uridine diphosphate glucunosyltransferases (UGT)-mediated metabolism of BUP during pregnancy to determine the mechanism(s) responsible for this observation. Data from 2 clinical studies were included in the current analysis. Study 1 was a prospective, open-labeled, nonrandomized longitudinal BUP PK study in pregnant women with a singleton gestation, stabilized on twice-daily sublingual BUP opioid substitution therapy. Each subject participated in up to 3 studies during and after pregnancy (the second, third trimester, and postpartum). The design of study 2 was similar to study 1, with patients evaluated at different time points during the pregnancy (first, second-half of pregnancy), as well as during the postpartum period. In addition, the dosing frequency of BUP study 2 participants was not restricted to twice-daily dosing. At each study visit, blood samples were collected before a BUP dose, followed by multiple collection times (10-12) after the dose, for up to 12 hours or till the end of the dosing interval. Plasma concentrations of BUP and 3 metabolites were quantified using validated ultraperformance liquid chromatography-tandem mass spectrometric assays. In total, 19, 18, and 14 subjects completed the PK study during 1/2 trimester, third trimester, and postpartum, respectively. The AUC ratios of norbuprenorphine and norbuprenorphine glucuronide to buprenorphine, a measure of CYP3A mediated N-demethylation, were 1.89, 1.84, and 1.33 during the first and second, third trimesters, and postpartum, respectively. The AUC ratios of buprenorphine glucuronide to BUP, indicative of UGT activity, were 0.71, 2.07, and 0.3 at first/second trimesters, third trimester, and postpartum, respectively. Linear mixed-effect modeling analysis indicated that the AUC ratios of CYP- and UGT-mediated metabolism of BUP were significantly higher during pregnancy compared with postpartum. The CYP and UGT activities were significantly increased as determined by the metabolic ratios of BUP during pregnancy compared with the postpartum period. The increased UGT activity appeared to account for a substantial part of the observed change in metabolic activity during pregnancy. This is in agreement with the need for BUP dose increment in pregnant women to reach similar BUP exposure and therapeutic effect as in nonpregnant subjects.

Licogliflozin, a Novel SGLT1 and 2 Inhibitor: Body Weight Effects in a Randomized Trial in Adults with Overweight or Obesity.

ObjectiveThe aim of this study was to explore the dose response of licogliflozin, a dual inhibitor of sodium/glucose cotransporter 1 (SGLT1) and 2 (SGLT2), by evaluating change in body weight in adults with overweight or obesity.MethodsThis dose‐response analysis evaluated change in body weight following 24 weeks with four once‐daily and twice‐daily licogliflozin doses (2.5‐150 mg) versus placebo (primary end point). A further 24‐week analysis evaluated the efficacy and safety of two once‐daily licogliflozin doses in maintaining initial weight reduction.ResultsLicogliflozin once daily or twice daily produced a significant dose‐response signal for weight loss versus placebo (P < 0.0001). However, mean adjusted percent changes in body weight after 24 weeks were modest, ranging from −0.45% to −3.83% (in the 50 mg twice daily group [95% CI: −5.26% to −2.48%]; n = 75). Responder analysis of ≥ 5% weight loss at week 24 revealed significant differences versus placebo, which were most pronounced with highest doses of 50 mg twice daily (45.3%) and 150 mg once daily (42.9%) (both P < 0.01). While weight loss was greater at higher doses, gastrointestinal adverse events were also more frequent. The 50‐mg once‐daily dose had perhaps the best balance between efficacy and tolerability.ConclusionsLicogliflozin produced significant reductions in body weight versus placebo. However, the magnitude of weight reduction was modest.

The Efficacy and Safety of Modified Docetaxel, Cisplatin, and 5-Fluorouracil Vs. Epirubicin, Oxaliplatin, and Capecitabine Regimen in the Advanced Gastric Cancer: A Randomized Controlled Clinical Trial.

Introduction:One of the major challenges of advanced gastric cancer treatment is the lack of a standard regimen for patients. However, several clinical trials have shown that modified docetaxel, cisplatin, and 5-fluorouracil (m-DCF) and epirubicin, oxaliplatin, and capecitabine (EOX) regimens are superior to other regimens. Methods:This randomized, single-center clinical trial was performed on 40 patients with advanced gastric cancer. The first group received the m-DCF regimen as follows: docetaxel (40 mg/m2) on the first day; cisplatin (40 mg/m2) on the first and second days; and 5-fluorouracil (400 mg/m2) from the first to fourth day. The second group received the EOX regimen, including epirubicin (50 mg/m2) and oxaliplatin (130 mg/m2) i.v on the first day and capecitabine at a twice-daily dose of 625 mg/m2 p.o for 21 days. Treatment was applied every three weeks for a total of eight cycles in both groups. In each group, the overall and progression-free survival rates and toxicity were assessed. Results:A total of 40 patients were enrolled in this study (21 samples in the m-DCF group and 19 samples in the EOX group), 62.5% of whom were male. The median survival rate was 14.00 (95% CI: 11.82-16.18) months in the m-DCF group and 15.00 (95% CI: 9.56-20.43) months in the EOX group; however, differences between the groups were not significant. The progression-free survival rate was higher in the EOX group, although there was no significant difference between the two groups. Also, there was no significant difference regarding the side effects (e.g., toxicity) or need for supportive care between the groups. Conclusion:It seems that both m-DCF and EOX regimens are similar in terms of survival and toxicity and are recommended as first-line treatment for advanced gastric cancer with respect to the patient’s status.

Impact of 12-Month Smartphone Breathing Meditation Program upon Systolic Blood Pressure among Non-Medicated Stage 1 Hypertensive Adults.

(1) Background: Hypertension (HTN) affects ~50% of adults and is a major risk factor for stroke and cardiovascular disease. In 2017, the SPRINT trial outcomes led to lowering of HTN cutoffs by the American College of Cardiology (ACC) and American Heart Association (AHA). The Joint National Committee (JNC8) and National High BP Education Program recommend that lifestyle modifications be used as first-line HTN treatment. Chronic stress is a risk factor for HTN and cardiovascular disease. A recently completed 12 month randomized controlled trial (RCT) of a breathing meditation smart phone app (Tension Tamer, TT) involving JNC8 designated pre-HTN adults provided an opportunity to examine its impact upon individuals now classified as having stage 1 HTN. The TT app captures continuous real-time heart rate (HR) from a user’s fingertip placed over a video camera lens during sessions. Users receive immediate feedback graphs after each session, showing their HR changes. They also receive motivational and social reinforcement SMS text messages the following day based upon levels of adherence. We conducted ancillary analyses of a 2-arm, 12-month, small-scale efficacy RCT among a subgroup of our total sample of participants, who are now classified as having stage 1 non-medicated systolic HTN. Primary outcome was change in resting systolic blood pressure (SBP). Secondary outcomes were change in resting diastolic blood pressure, adherence to the TT protocol, and perceived stress levels. (2) Methods: 30 adults (mean age: 45.0 years; 15 males; 16 White; 14 Black) with ACC/AHA 2017 defined systolic HTN (130–139 mmHg) on 3 consecutive sessions (mean SBP: 132.6 mmHg) were randomly assigned to TT or lifestyle education program delivered via smartphone (SPCTL). Each group received a twice-daily dosage schedule of TT or walking (month 1: 15 min; months 2 and 3: 10 min; months 4–12: 5 min). (3) Results: Mixed modeling results revealed a significant group x time effect for SBP (p<.01). The TT group showed greater SBP reductions at months 3 (−8.0 vs. −1.9), 6 (−10.0 vs. −0.7), and 12: (−11.6 vs. −0.4 mmHg; all p-values <0.04). (4) Conclusion: The TT app was beneficial in reducing SBP levels among adults with stage 1 systolic HTN. The TT app may be a promising, scalable first-line tactic for stage 1 HTN. Preparations are underway for an efficacy RCT involving uncontrolled stage 1 HTN patients.

Mechanistic Population Pharmacokinetic Model of Oseltamivir and Oseltamivir Carboxylate Accounting for Physiological Changes to Predict Exposures in Neonates and Infants.

A mechanistic population‐pharmacokinetic model was developed to predict oseltamivir exposures in neonates and infants accounting for physiological changes during the first 2 years of life. The model included data from 13 studies, comprising 436 subjects with normal renal function (317 pediatric subjects (≥ 38 weeks postmenstrual age (PMA), ≥ 13 days old) and 119 adult subjects < 40 years). Concentration–time profiles of oseltamivir and its active metabolite, oseltamivir carboxylate (OC), were characterized by a four‐compartment model, with absorption described by three additional compartments. Renal maturational changes were implemented by description of OC clearance with allometric function of weight and Hill function of PMA. Clearance of OC increased with weight up to 43 kg (allometric coefficient 0.75). Half the adult OC clearance was reached at a PMA of 45.6 weeks (95% confidence interval (CI) 41.6–49.6) with a Hill coefficient of 2.35 (95% CI 1.67–3.04). The model supports the European Union/United States‐approved 3 mg/kg twice‐daily oseltamivir dose for infants < 1 year (PMA ≥ 38 weeks) and allows prediction of exposures in preterm neonates.

In vivo efficacy of the boron-pleuromutilin AN11251 against Wolbachia of the rodent filarial nematode Litomosoides sigmodontis.

The elimination of filarial diseases such as onchocerciasis and lymphatic filariasis is hampered by the lack of a macrofilaricidal–adult worm killing–drug. In the present study, we tested the in vivo efficacy of AN11251, a boron-pleuromutilin that targets endosymbiotic Wolbachia bacteria from filarial nematodes and compared its efficacy to doxycycline and rifampicin. Doxycycline and rifampicin were previously shown to deplete Wolbachia endosymbionts leading to a permanent sterilization of the female adult filariae and adult worm death in human clinical studies. Twice-daily oral treatment of Litomosoides sigmodontis-infected mice with 200 mg/kg AN11251 for 10 days achieved a Wolbachia depletion > 99.9% in the adult worms, exceeding the Wolbachia reduction by 10-day treatments with bioequivalent human doses of doxycycline and a similar reduction as high-dose rifampicin (35 mg/kg). Wolbachia reductions of > 99% were also accomplished by 14 days of oral AN11251 at a lower twice-daily dose (50 mg/kg) or once-per-day 200 mg/kg AN11251 treatments. The combinations tested of AN11251 with doxycycline had no clear beneficial impact on Wolbachia depletion, achieving a > 97% Wolbachia reduction with 7 days of treatment. These results indicate that AN11251 is superior to doxycycline and comparable to high-dose rifampicin in the L. sigmodontis mouse model, allowing treatment regimens as short as 10–14 days. Therefore, AN11251 represents a promising pre-clinical candidate that was identified in the L. sigmodontis model, and could be further evaluated and developed as potential clinical candidate for human lymphatic filariasis and onchocerciasis.

Efficacy and safety of a fixed dose combination tablet of asunaprevir + beclabuvir + daclatasvir for the treatment of Hepatitis C

ABSTRACTIntroduction: Hepatitis C virus (HCV) is estimated to infect approximately 70 million people worldwide. If left untreated, chronic infection can progress to cirrhosis, liver failure or hepatocellular carcinoma. The advent of new direct-acting antivirals (DAA) has revolutionized patients’ chances of treatment and viral elimination. Currently, several DAA options are available on the market.Areas covered: This review focuses on the pharmacokinetics, efficacy, tolerability and safety profile of DCV-TRIO, a twice-daily fixed-dose combination of daclatasvir, asunaprevir and beclabuvir approved in Japan for the treatment of genotype 1 HCV infection.Expert opinion: The DCV-TRIO combination achieved good response rates in genotype 1 patients (SVR12 ≥ 95% in naïve subtype 1b), independently from IL28B genotype, cirrhotic status and prior interferon exposure. On the other hand, unsatisfying response rates were reported in DAA-experienced patients and the risk of RAS selection should not be underestimated. Moreover, DCV-TRIO lacks differentiation from its earlier-launched DAA rivals, presents an inconvenient twice-daily dosing schedule and is not recommended in patients with advanced liver and kidney disease. All these drawbacks considerably limit its effective commercial potential. However, it can be a therapeutic option against HCV in tailored approaches according to the needs of different markets across the world.Abbreviations AE: adverse event; ALT: alanine aminotransferase; AST: aspartate aminotransferase; ASV: asunaprevir; AUC: area under the curve; BCRP: Breast Cancer Resistance Protein; BCV: boceprevir; BID: bis in die; CI: confidence intervals; CLcr: creatinine clearance; DAA: direct acting antivirals; DCV: daclatasvir; EC50: Half maximal effective concentration; GT: genotype; HCV: Hepatitis C virus; IFN: Interferon; NHL: non-Hodgkin lymphoma; OATP: Organic anion transporting polypeptides; OR: odds ratio; P-gp: P-glycoprotein; PK: pharmacokinetics; QD: quo die; RAS: resistance-associated substitutions; SVR: sustained virological response; USD: Unites States dollar

Effects of 0.02% netarsudil ophthalmic solution on intraocular pressure of normotensive dogs.

To evaluate the effect of QD or BID 0.02% netarsudil ophthalmic solution (Aerie Pharmaceuticals) on intraocular pressure (IOP) in normotensive dogs and to describe any adverse effects. Normotensive Labrador retriever dogs were included in this study: 10 received netarsudil in one eye and artificial tears in the contralateral eye QD, and 10 received netarsudil in one eye and artificial tears in the contralateral eye BID. Intraocular pressure curves were acquired over a 3-day acclimation period, 5-day dosing period (QD or BID-10 dogs/group), and 3-day recovery period. Toxicity was assessed daily using slit-lamp biomicroscopy and the semiquantitative preclinical ocular toxicology scoring system. Once-daily dosing did not lower IOP over the entire 5-day dosing period (95% CI 0.1 to -0.9mmHg, P=.20) or on the last day of dosing (95% CI 0.4 to -0.9mmHg, P=.65). Twice-daily dosing resulted in a statistically significant, but clinically unimportant, IOP reduction over the entire 5-day dosing period (-0.6mmHg; 95% CI 0.05 to -1.1mmHg, P=.02) and on the last day of dosing (-0.9mmHg; 95% CI 0.2 to -1.5mmHg, P=.003). Adverse events were limited to transient mild-to-moderate conjunctival hyperemia during the dosing phase in eyes receiving netarsudil vs control (P<.0001). Netarsudil 0.02% ophthalmic solution twice daily resulted in a small, statistically significant, but clinically unimportant, IOP reduction in normotensive dogs. Future studies should investigate efficacy in glaucomatous dogs.

Antipsychotic prescription and polypharmacy among outpatients with schizophrenia in a Nigerian hospital.

International guidelines recommend antipsychotic monotherapy as the ideal treatment option in pharmacotherapy for schizophrenia, though this yields modest outcomes in a third of patients. Antipsychotic polypharmacy (APP) has been tried in many patients with schizophrenia to improve outcomes in those with poor treatment response. This study examined the pattern of antipsychotic prescription and polypharmacy among outpatient attendees with schizophrenia in a Nigerian psychiatric hospital. A cross-sectional study of 320 attendees with schizophrenia at the consultant outpatient department was undertaken. We administered a socio-demographic questionnaire, antipsychotic medication and health questionnaire to record the general health indices and the prescribed antipsychotic medication of participants and the Mini-International Neuropsychiatric Interview (MINI) Version 6.0 (psychosis module). Oral second-generation antipsychotics (SGAs) monotherapy was most commonly prescribed. The prevalence of APP was 50.9%. Participants on simultaneous anticholinergic agents (P < 0.001), a twice-daily antipsychotic dosing interval (P < 0.001,) alcohol use (P = 0.02), antidepressant use (P = 0.02) and a current episode of schizophrenia on the MINI (P < 0.001) were more likely to be on an APP regimen. Although a preference for SGA monotherapy was observed, the prevalence of APP remained high. Clinicians, therefore, should be cautious regarding the clinical utility of APP and discourage its persistent use.

Plasmapheresis Reduces Mycophenolic Acid Concentration: A Study of Full AUC0-12 in Kidney Transplant Recipients.

Background: Mycophenolic acid (MPA), a crucial immunosuppressive drug, and plasmapheresis, an effective immunoreduction method, are simultaneously used for the management of various immune-related diseases, including kidney transplantation. While plasmapheresis has been proven efficient in removing many substances from the blood, its effect on MPA plasma levels remains unestablished. Objectives: To evaluate the full pharmacokinetics of MPA by measuring the area under the time–concentration curve (AUC0–12), which is the best indicator for MPA treatment monitoring after each plasmapheresis session, and to compare the AUC0–12 measurements on the day with and on the day without plasmapheresis. Methods: A cross-sectional study was conducted in kidney transplantation recipients who were taking a twice-daily oral dose of mycophenolate mofetil (MMF, Cellcept®) and undergoing plasmapheresis at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, during January 2018 and January 2019. The MPA levels were measured by an enzymatic method (Roche diagnostic®) 0, 1/2, 1, 2, 3, 4, 6, 8, and 12 h after MMF administration, for AUC0–12 calculation on the day with and on the day without plasmapheresis sessions. Plasmapheresis was started within 4 h after administering the oral morning dose of MMF. Our primary outcome was the difference of AUC0–12 between the day with and the day without plasmapheresis. Results: Forty complete AUC measurements included 20 measurements on the plasmapheresis day and other 20 measurements on the day without plasmapheresis in six kidney transplant patients. The mean age of the patients was 56.2 ± 20.7 years. All patients had received 1000 mg/day of MMF for at least 72 h before undergoing 3.5 ± 1.2 plasmapheresis sessions. The mean AUC on the day with plasmapheresis was lower than that on the day without plasmapheresis (28.22 ± 8.21 vs. 36.79 ± 10.29 mg × h/L, p = 0.001), and the percentage of AUC reduction was 19.49 ± 24.83%. This was mainly the result of a decrease in AUC0–4 of MPA (23.96 ± 28.12% reduction). Conclusions: Plasmapheresis significantly reduces the level of full AUC0–12 of MPA. The present study is the first to measure the full AUC0–12 in MPA-treated patients undergoing plasmapheresis. Our study suggests that a supplementary dose of MPA is necessary for patients undergoing plasmapheresis.

Randomized, double-blind, placebo-controlled phase I dose escalation study of Dan Qi Tong Mai tablet in healthy volunteers

BackgroundThis study aims to assess the tolerability and safety of DQTM tablet, which contains a complex mixture of Salvia miltiorrhiza salvianolic acids and Panax notoginseng saponins.MethodsA double-blind, randomized, placebo-controlled phase I dose escalation study was conducted in 84 healthy volunteers. In a single ascending dose study, active ingredients were administered in various doses (90, 270, 540, 1080, 1800, 2880, 4320 or 5760 mg) to 60 subjects in cohorts 1–8. In a multiple ascending dose study, active ingredients were administered at doses of 360, 720 or 2160 mg twice daily to 24 subjects in cohorts 9–11 for 14 consecutive days. Safety was evaluated based on clinical symptoms, vital signs, physical examinations, electrocardiography, laboratory tests and adverse events.ResultsNo serious adverse events or clinically significant changes in vital signs or electrocardiography were observed. One subject experienced mildly elevated levels of alanine aminotransferase and aspartate transaminase but recovered spontaneously. Five subjects experienced a small increase in the number of daily stools.ConclusionsDQTM tablet was well tolerated at single doses of up to 5760 mg and twice-daily doses of up to 2160 mg for 14 consecutive days. The most frequent adverse event was an increase in the number of daily stools.

An Evaluation of Risperidone Dosing for Pediatric Delirium in Children Less Than or Equal to 2 Years of Age

Background: Risperidone dosing and safety data are limited in patients ≤2 years of age. Objective: To describe the dosing strategies, safety, and tolerability of risperidone in infants ≤2 years of age. Methods: An institutional review board-approved retrospective study was conducted in a 24-bed pediatric intensive care unit at an academic medical center in patients ≤2 years of age receiving risperidone for the management of ICU delirium. The primary outcome was mean initial daily dose of risperidone. Secondary outcomes included mean daily dose, dosing frequency, treatment duration, and adverse effects. Results: Seventeen patients who received at least 1 dose of risperidone were included in the study. The initial daily dose ranged from 0.1 to 0.25 mg (0.01-0.04 mg/kg), with a mean of 0.17 mg (0.02 mg/kg). Most patients were initiated on once-daily dosing (76.5%) versus twice-daily dosing (17.6%). More than 80% of patients required a dose increase during therapy. Median daily doses of fentanyl, morphine, ketamine, and midazolam were decreased following initiation of risperidone. No adverse events that led to discontinuation of risperidone were reported. Conclusion and Relevance: Risperidone was found to be safe and well tolerated at daily doses of risperidone of 0.1 to 0.25 mg in 1 or 2 doses per day in patients ≤2 years old for the management of ICU delirium. To our knowledge, these results provide the largest cohort describing dosing recommendations specific for risperidone in this age group. Further investigation on the effect of antipsychotic administration on other sedation and analgesic regimens is necessary.

Mitapivat (AG-348) in Adults with Pyruvate Kinase Deficiency Who Are Not Regularly Transfused: A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled Study (ACTIVATE) in Progress

Background: Pyruvate kinase (PK) deficiency is an under-recognized hereditary disease that causes lifelong hemolytic anemia. Mutations in the PKLR gene lead to reduced red cell PK (PK-R) enzyme activity, resulting in defective glycolysis and decreased lifespan of red blood cells. Mitapivat (AG-348) is a novel, first-in-class, oral, small-molecule allosteric activator of PK-R under clinical testing as the first targeted, disease-altering therapy for PK deficiency. The DRIVE PK study (NCT02476916; a phase 2, open-label, dose-ranging trial in adults with PK deficiency who are not regularly transfused) demonstrated that twice-daily (BID) dosing with mitapivat for &gt;6 months was well tolerated and induced rapid, substantial, and durable responses (Grace et al. ASH 2017). Of 52 enrolled subjects, 26 (50%) had a maximum hemoglobin (Hb) increase of &gt;1 g/dL in the 6-month treatment period. Among these 26 subjects, the mean maximum Hb increase was 3.4 g/dL, and 25 (96%) had ≥1 missense PKLR mutation. Based on these findings, mitapivat has entered phase 3 development in PK deficiency. The design of the ongoing phase 3 ACTIVATE study and its extension study are reported here, with an update on country/site activation. Methods: ACTIVATE is a phase 3, multicenter, randomized, double-blind, placebo-controlled study (NCT03548220) evaluating the efficacy and safety of mitapivat. Adults with PK deficiency who are not regularly transfused (≤4 transfusion episodes in the previous year and no transfusions in the prior 3 months) will be randomized in a 1:1 ratio to mitapivat (administered orally, BID) or matched placebo. Additional criteria include baseline Hb ≤10.0 g/dL and adequate organ function. Subjects who are homozygous for the R479H mutation or have 2 non-missense mutations (without the presence of another missense mutation) in PKLR will be excluded. The study consists of a screening period of up to 42 days, a 12-week dose optimization period, and a 12-week fixed-dose period (Figure). During the dose optimization period, mitapivat or matched placebo are titrated up to each subject's individually optimized dose, with an initial dose of 5 mg BID for all subjects and potentially 2 sequential dose increases (from 5 to 20 mg BID and from 20 to 50 mg BID), depending on safety and Hb change. The primary endpoint is the Hb response, defined as the proportion of subjects who achieve an increase of ≥1.5 g/dL in Hb sustained over at least 2 of the last 3 visits in the fixed-dose period. The average change in Hb during the fixed-dose period is considered a key secondary endpoint to further evaluate the magnitude of the treatment effect. Other secondary efficacy endpoints, such as markers of hemolysis and hematopoietic activity, will be evaluated to support the efficacy evaluation and confirm the mechanism of action, and safety is included as a secondary objective and endpoint. Two questionnaires, one specifically designed to measure the signs and symptoms of PK deficiency and the other designed to evaluate their impact on patients' lives, are also included for their validation and to further evaluate the efficacy of the treatment. All subjects who complete the study have the opportunity to enroll in an open-label extension study (NCT03853798) in which all participants will receive mitapivat for up to 192 weeks. An independent data monitoring committee will review the study data periodically and provide safety oversight. The ACTIVATE study is currently ongoing. Disclosures van Beers: Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Judge:Agios: Employment, Equity Ownership. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Mix:Agios: Employment, Equity Ownership.

Mitapivat (AG-348) in Adults with Pyruvate Kinase Deficiency Who Are Regularly Transfused: A Phase 3, Open-Label, Multicenter, Study (ACTIVATE-T) in Progress

Background: Pyruvate kinase (PK) deficiency is an under-recognized hereditary disease that causes lifelong hemolytic anemia. Mutations in the PKLR gene lead to reduced red cell PK (PK-R) enzyme activity, resulting in defective glycolysis and decreased lifespan of red blood cells. Mitapivat (AG-348) is a novel, first-in-class, oral, small-molecule allosteric activator of PK-R under clinical testing as the first targeted, disease-altering therapy for PK deficiency. In the DRIVE PK study (NCT02476916; a phase 2, open-label, dose-ranging trial in adults with PK deficiency who are not regularly transfused), twice-daily (BID) dosing with mitapivat for &amp;gt;6 months was well tolerated and induced rapid, durable responses (Grace et al. ASH 2017). As of July 14, 2017, 26 (50%) of 52 enrolled subjects had a maximum hemoglobin (Hb) increase of &amp;gt;1 g/dL. Among these 26 subjects, the mean maximum Hb increase was 3.4 g/dL, and 25 (96%) had ≥1 missense PKLR mutation. Based on these findings, mitapivat has entered phase 3 clinical development. The design of the ongoing phase 3 ACTIVATE-T study and its extension study are reported here, with an update on country/site activation and key early learnings on trial logistics in PK deficiency. Methods: ACTIVATE-T is a global, multicenter, open-label study (NCT03559699) to evaluate the efficacy and safety of mitapivat in regularly transfused adults with PK deficiency. Regularly transfused is defined as ≥6 transfusion episodes in the previous year. Subjects who are homozygous for the R479H mutation or have 2 non-missense mutations (without the presence of another missense mutation) in PKLR will be excluded, as will subjects with an average transfusion frequency of more than once every 3 weeks in the previous year. The study comprises an 8-week screening period, during which each subject's complete transfusion history from the prior 52 weeks is documented, followed by a 16-week dose optimization period and a 24-week fixed-dose period (Figure). During the dose optimization period, each subject will undergo individualized mitapivat dose optimization. All subjects will start on a dose of 5 mg BID, which may be increased twice over the course of 16 weeks (from 5 to 20 mg BID and from 20 to 50 mg BID). In the fixed-dose period, each subject will receive mitapivat at their optimized dose for 24 weeks. During the study, subjects will be transfused when their Hb reaches or falls below their individual transfusion trigger calculated from their transfusion history. The primary endpoint is the proportion of subjects who achieve a reduction in transfusion burden, defined as a reduction of ≥33% in the number of red blood cell units transfused during the 24 weeks of the fixed-dose period compared with the historical transfusion burden standardized to 24 weeks. Secondary endpoints include safety. All subjects who complete the study will have the opportunity to enroll in an open-label extension study (NCT03853798) in which all participants will receive mitapivat for up to 192 weeks. The ACTIVATE-T trial is enrolling globally. Disclosures Lynch: Agios: Employment, Equity Ownership. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Mix:Agios: Employment, Equity Ownership. Porter:Bluebird bio: Consultancy, Honoraria; Silence therapeutics: Honoraria; Vifor: Honoraria; La Jolla: Honoraria; Protagonism: Honoraria; Celgene: Consultancy, Honoraria; Agios: Consultancy, Honoraria.

One-Year Outcomes with Once or Twice Daily Enoxaparin

Background: Enoxaparin given once daily (QD) for thrombotic disorders is less burdensome than twice-daily (BID) dosing. However, long-term outcomes when enoxaparin given as QD monotherapy are unknown. Methods: We did a population-based cohort study. New users of enoxaparin alone (2005-2014) were identified in the linked healthcare databases of Quebec, Canada, and followed up for up to one year. The number of dispensed syringes divided by prescription length determined QD or BID enoxaparin by intention to treat. Cumulative rates of major bleeding and re-treatment with anticoagulants at one year were compared between enoxaparin groups. Re-treatment was initiation of anticoagulation after at least 30 days of no dispensed anticoagulants. The duration of enoxaparin monotherapy was the sum of prescriptions until discontinuation. Results: The cohort included 504 patients; QD and BID enoxaparin users were 445 and 59, respectively. Mean (SD) age was 78.0 (6.6) years, 43.8% were males, and 61.9% had cancer. At 12 months, major bleeding occurred in 21 (4.7%) and 4 (6.8%) among QD and BID enoxaparin users, respectively (Figure 1A, P = 0.49). Re-treatment with anticoagulants occurred in 37 (9.6%) and 5 (9.4%) of QD and BID users, respectively (Figure 1B, P = 0.98). The duration of enoxaparin monotherapy was on average 13.9 (95% CI, 4.4-23.4, P = 0.005) days longer with QD vs BID use. Conclusions: Monotherapy with QD enoxaparin was common and longer than BID enoxaparin with no apparent differences in bleeding or re-treatment with anticoagulants. Figure 1 Disclosures Klil-Drori: Sanofi Canada: Research Funding. Nazha:Sanofi Canada: Employment. Gharib:Sanofi Canada: Employment. Perreault:Sanofi Canada: Research Funding. Tagalakis:Servier: Other: participated on ad boards; Bayer: Other: participated on ad boards; Pfizer: Other: participated on ad boards; Sanofi Aventis: Other: investigator initiated grant;participated on ad boards; BMS-Pfizer: Other: participated on ad boards.