Budget impact analysis of long-acting injectable aripiprazole once-monthly 400 mg in bipolar I disorder in the USA.

AIM: To estimate the budget impact (BI) of introducing aripiprazole once-monthly 400 mg/300 mg (AOM 400) in the maintenance monotherapy treatment of bipolar I disorder versus long-acting injectables, oral antipsychotics and best supportive care. METHODS: A BI model was developed from a US-payer perspective using treatment-related, hospitalization and adverse event management cost estimates for a hypothetical 1,000,000-member health plan over a 5-year period. RESULTS: Market share of AOM 400 was predicted to increase from 0.6% in Year 1 (current scenario) to 1.3% in Year 5 (predicted scenario), with predicted increases for paliperidone palmitate, asenapine and cariprazine. Treatment-related costs explained the BI increase, while adverse event and hospitalization costs were reduced. The per member per month incremental cost ranged from US$0.06 to US$0.26 in Years 1-5. The largest increases were predicted for paliperidone palmitate. CONCLUSION: As market shares of atypical antipsychotics are predicted to increase, payers may wish to re-evaluate their use.

Glycol chitosan functionalized asenapine nanostructured lipid carriers for targeted brain delivery: Pharmacokinetic and teratogenic assessment.

Blood brain barrier (BBB) is a complex, tight barrier between endothelial cells of cerebral blood vessels. It acts as a physical barrier and provides access to only those moieties which are necessary for proper brain functioning. However, this selective prudence also acts as a hindrance in therapeutic targeting of brain necessitating pharmaceutical intervention. Intranasal drug delivery is one such approach which we have exploited here for targeted brain delivery of asenapine by glycol chitosan coated nanostructured lipid carrier (GC-ANLC). The best formulation was characterized for particle size (184.2±5.59nm), zeta potential (18.83±1.18mV), entrapment efficiency (83.52±2.59%) and surface morphology (spherical and smooth). In-vitro drug-release study showed that Higuchi model (r2=0.9938, AIC=52.94) dictated asenapine release from GC-ANLC. Cell compatibility study suggested biocompatibility of GC-ANLC with A549 cell line as well as nasal epithelial cell membrane. After intranasal delivery, Charles-Foster rats demonstrated approximately 2.3 and 4 fold higher systemic and brain bioavailability of GC-ANLC compared to asenapine solution (ASM). Embryo fetal toxicity study was further conducted to investigate the teratogenic effect of GC-ANLC. In conclusion, prepared GC-ANLC could be used as a promising drug carrier for delivery of asenapine via intranasal route with better pharmacokinetic and safety profile.

Changes in Patterns of Utilization and Cost of Health Care Services Associated With Initiation of Asenapine for the Treatment of Schizophrenia in Adults.

PURPOSE: To examine changes in patterns of utilization and cost of health care services associated with initiation of asenapine for the treatment of schizophrenia in adults. DESIGN: Retrospective cohort study using 2 large US health care claims databases. METHODOLOGY: All adults who initiated therapy with asenapine between Aug. 1, 2009, and Dec. 31, 2012, were identified; the date of the earliest claim for asenapine during this period was deemed the index date. Patients without ≥1 claims with a schizophrenia diagnosis within 12 months prior to the index date were excluded. We compared patterns of utilization and cost of health care services between 6-month periods immediately before and after index date ("preindex"and "postindex" respectively). RESULTS: 366 patients were identified who initiated asenapine and who met all other selection criteria; mean (SD) age was 40.5 (16.3) years and 57.1% were women. Relative to preindex, patients were less likely during postindex to be hospitalized (41.8% vs 26.2%, P<.001) or to visit the emergency room (24.9% vs 18.9%, P=.03). Mean (SD) total health care costs decreased by $4776 in the postindex period ($16,811 [$26,176] vs $12,035 [$17,037] during preindex), primarily due to a decrease in inpatient costs ($10,616 [$24,977] vs $5286 [$15,846]); mean pharmacy costs increased by $828 ($3656 [$3309] vs $4482 [$3,073]) (all P<.001). CONCLUSION: Use of asenapine for the treatment of schizophrenia was associated with reduced levels of health care utilization and cost during the 6-month period immediately following therapy initiation, primarily due to reduced levels of inpatient care.

Impact of initiation of asenapine on patterns of utilization and cost of healthcare resources associated with the treatment of bipolar I disorder.

OBJECTIVE: To assess the impact of initiation of asenapine on "real-world" levels of utilization and cost of healthcare services for the treatment of bipolar I disorder (BPD) in the US. METHODS: Using two large US healthcare claims databases that collectively included commercially insured patients aged < 65 years and Medicare enrollees, this study identified all adults (≥ 18 years) with evidence of BPD who began therapy with asenapine between 2009-2012. The date of the earliest claim for asenapine during this period was deemed the 'index date', and patients without continuous enrollment for the 6-month periods before and after this date were excluded ('pre-index' and 'post-index', respectively). Healthcare claims with a BPD diagnosis, plus psychiatric medications and the costs thereof (2012 dollars) were deemed 'BPD-related'. Differences in BPD-related utilization and cost of healthcare services were compared between the pre- and post-index periods. RESULTS: A total of 1403 patients met all selection criteria; the mean age was 42.8 years and 70.6% were women. Relative to pre-index, significant decreases were noted in post-index use of BPD-related healthcare services, most notably admissions (from 24.0% to 12.3% during the post-index period) and emergency department visits (from 4.6% to 2.6%) (both p < 0.05). While pharmacy costs increased, mean total post-index BPD-related healthcare costs were $979 lower than pre-index ($5002 vs $5981; p < 0.05), primarily due to the decrease in BPD-related admissions. CONCLUSIONS: Relative to the 6-month period beforehand, levels of utilization of BPD-related healthcare services and costs decreased during the 6-month period immediately following initiation of asenapine therapy.

Cost-effectiveness of asenapine in the treatment of patients with bipolar I disorder with mixed episodes in an Italian context.

INTRODUCTION: Bipolar disorder is a chronic disease characterized by periods of mania or hypomania, depression, or a combination of both (mixed state). Because bipolar disorder is one of the leading causes of disability, it represents an important economic burden on society. Asenapine (ASE) is a new second-generation antipsychotic developed and approved for the treatment of manic or mixed episodes associated with bipolar disorder. The objective of the present study was to assess the cost-effectiveness of ASE compared to olanzapine (OLA) in the treatment of patients experiencing mixed episodes associated with bipolar I disorder in the context of the Italian National Health Service (NHS). METHODS: A pharmacoeconomic model was developed to simulate the management of Italian bipolar I patients with mixed episodes over a 5-year time horizon by combining clinical parameters with resource utilization. An expert panel of Italian psychiatrists and health economists was responsible for adapting a UK model to the Italian context. The primary outcome measure of the economic evaluation was the incremental cost effectiveness ratio, where effectiveness is measured in terms of quality adjusted life-years gained. Scenario analyses, sensitivity analyses, and a probabilistic sensitivity analysis were performed to test the robustness of the model. RESULTS: This pharmacoeconomic model showed that ASE resulted to be dominant over OLA; in fact, ASE was associated with lower direct costs (derived largely by the savings from hospitalizations avoided) and also generated a better quality of life. Results were robust to changes in key parameters; both scenario analyses and sensitivity analyses demonstrated model reliability. CONCLUSIONS: Results from this study suggest that the management of bipolar I patients with mixed episodes using ASE as alternative to OLA can lead to cost saving for the Italian NHS and improve patients quality of life.

Cost-effectiveness of asenapine in the treatment of bipolar I disorder patients with mixed episodes.

OBJECTIVE: Around one-third of patients with bipolar I disorder (BD-I) experience mixed episodes, characterized by both mania and depression, which tend to be more difficult and costly to treat. Atypical antipsychotics are recommended for the treatment of mixed episodes, although evidence of their efficacy, tolerability, and cost in these patients is limited. This study evaluates, from a UK National Health Service perspective, the cost-effectiveness of asenapine vs olanzapine in BD-I patients with mixed episodes. METHODS: Cost-effectiveness was assessed using a Markov model. Efficacy was informed by a post-hoc analysis of two short-term clinical trials, with response measured as a composite Young Mania Rating Score and Montgomery-Åsberg Depression Rating Scale end-point. Probabilities of discontinuation and relapse to manic, mixed, and depressive episodes were sourced from published meta-analyses. Direct costs (2012-2013 values) included drug acquisition, monitoring, and resource use related to bipolar disorder as well as selected adverse events. Benefits were measured as quality-adjusted life years (QALYs). RESULTS: For treating mixed episodes, asenapine generated 0.0187 more QALYs for an additional cost of £24 compared to olanzapine over a 5-year period, corresponding to a £1302 incremental cost-effectiveness ratio. The higher acquisition cost of asenapine was roughly offset by the healthcare savings conferred through its greater efficacy in treating these patients. The model shows that benefits were driven by earlier response to asenapine during acute treatment and were maintained during longer-term follow-up. RESULTS were sensitive to changes in key parameters including short and longer-term efficacy, unit cost, and utilities, but conclusions remained relatively robust. CONCLUSIONS: RESULTS suggest that asenapine is a cost-effective alternative to olanzapine in mixed episode BD-I patients, and may have specific advantages in this population, potentially leading to healthcare sector savings and improved outcomes. Limitations of the analysis stem from gaps in clinical and economic evidence for these patients and should be addressed by future clinical trials.

Cost-effectiveness of asenapine in the treatment of schizophrenia in Canada.

OBJECTIVE: Asenapine is the first tetracyclic antipsychotic approved in Canada for the treatment of schizophrenia (SCZ). Asenapine has shown a comparable efficacy profile to other atypical antipsychotics and it is associated with a favourable metabolic profile and less weight gain. This study aimed to assess the economic impact of asenapine compared to other atypical antipsychotics in the treatment of SCZ in Canada. METHODS: A decision tree combined with a Markov model was constructed to assess the cost-utility of asenapine compared with other atypical antipsychotics. The decision tree takes into account the occurrence of extrapyramidal symptoms, the probability of switching to a different antipsychotic, and the probability of gaining weight. The Markov model takes into account long-term metabolic complications including diabetes, hypertension, coronary heart diseases, and stroke. In the base-case analysis, asenapine was compared to olanzapine. Asenapine was also compared with other atypical antipsychotics commonly used in Canada in alternative scenarios. Analyses were conducted from both Canadian Ministry of Health (MoH) and societal perspectives over a 5-year time horizon. RESULTS: In the treatment of SCZ, asenapine is a dominant strategy over olanzapine from both MoH and societal perspectives. Compared to quetiapine, asenapine is also a dominant strategy. Furthermore, asenapine has a favorable economic impact compared to ziprasidone and aripiprazole, as these antipsychotics are not cost-effective compared to asenapine from both MoH and societal perspectives. CONCLUSION: Despite the short time horizon, the lack of compliance data and the assumptions made, this economic evaluation demonstrates that asenapine is a cost-effective strategy compared to olanzapine and to most of the atypical antipsychotics frequently used in Canada.

Cost-effectiveness of asenapine in the treatment of bipolar disorder in Canada.

BACKGROUND: Bipolar disorder (BPD) is prevalent and is associated with a significant economic burden. Asenapine, the first tetracyclic antipsychotic approved in Canada for the treatment of BPD, has shown a comparable efficacy profile to other atypical antipsychotics. In addition, it is associated with a favourable metabolic profile and minimal weight gain potential. This study aimed to assess the economic impact of asenapine compared to olanzapine in the treatment of BPD in Canada. METHODS: A decision tree combined with a Markov model was constructed to assess the cost-utility of asenapine compared with olanzapine. The decision tree takes into account the occurrence of extrapyramidal symptoms (EPS), the probability of switching to a different antipsychotic, and the probability of gaining weight. The Markov model takes into account long-term metabolic complications including diabetes, hypertension, coronary heart diseases (CHDs), and stroke. Analyses were conducted from both a Canadian Ministry of Health (MoH) and a societal perspective over a five-year time horizon with yearly cycles. RESULTS: In the treatment of BPD, asenapine is a dominant strategy over olanzapine from both a MoH and a societal perspective. In fact, asenapine is associated with lower costs and more quality-adjusted life years (QALYs). Results of the probabilistic sensitivity analysis indicated that asenapine remains a dominant strategy in 99.2% of the simulations, in both a MoH and a societal perspective, and this result is robust to the many deterministic sensitivity analyses performed. CONCLUSIONS: This economic evaluation demonstrates that asenapine is a cost-effective strategy compared to olanzapine in the treatment of BPD in Canada.

In vivo assessment of the impact of efflux transporter on oral drug absorption using portal vein-cannulated rats.

The purpose of this study was to evaluate the impact of intestinal efflux transporters on the in vivo oral absorption process. Three model drugs-fexofenadine (FEX), sulfasalazine (SASP), and topotecan (TPT)-were selected as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and P-gp and BCRP substrates, respectively. The drugs were orally administered to portal vein-cannulated rats after pretreatment with zosuquidar (ZSQ), P-gp inhibitor, and/or Ko143, BCRP inhibitor. Intestinal availability (Fa·Fg) of the drugs was calculated from the difference between portal and systemic plasma concentrations. When rats were orally pretreated with ZSQ, Fa·Fg of FEX increased 4-fold and systemic clearance decreased to 75% of the control. In contrast, intravenous pretreatment with ZSQ did not affect Fa·Fg of FEX, although systemic clearance decreased significantly. These data clearly show that the method presented herein using portal vein-cannulated rats can evaluate the effects of intestinal transporters on Fa·Fg of drugs independently of variable systemic clearance. In addition, it was revealed that 71% of FEX taken up into enterocytes underwent selective efflux via P-gp to the apical surface, while 79% of SASP was effluxed by Bcrp. In the case of TPT, both transporters were involved in its oral absorption. Quantitative analysis indicated a 3.5-fold higher contribution from Bcrp than P-gp. In conclusion, the use of portal vein-cannulated rats enabled the assessment of the impact of efflux transporters on intestinal absorption of model drugs. This experimental system is useful for clarifying the cause of low bioavailability of various drugs.

Home injuries in Italy: patterns of injury and the most exposed people.

Home injuries are a significant public health problem in developed and developing countries. To support future policies for reducing their occurrence and controlling their consequences, this study investigated the home injuries situation in Italy in 1999, using a nation-representative sample. The weighted correspondence analysis showed four different patterns of injury and seven profiles of the people most exposed to them. As results of this study falls were followed by bumps and cuts requiring specialist assistance then burns. Women were the most exposed to burn and fall risks and men to the risk of cuts and bumps. Among the elderly and children, falls and bumps leading to fractures, wounds or other consequences were frequent. The risks were highest for people with a lower level of education. Bumps and cuts were prevalent among unmarried and with the highest education level subjects. These injury risks were higher for young males. Cuts in adults doing do-it-yourself jobs had the worst consequences, while domestic work cuts generally did not need medical treatment. Burns occurred almost exclusively in the kitchen (90%) and did not need specialist assistance. Because home injuries are largely preventable, an efficient public health policy could promote and disseminate home safety culture.

Long-term assessment of Asenapine vs. Olanzapine in patients with schizophrenia or schizoaffective disorder.

INTRODUCTION: We conducted a double-blind 1-year trial of asenapine in patients with schizophrenia or schizoaffective disorder. METHODS: Patients were randomized to asenapine (5 or 10 mg BID; n=913) or olanzapine (10-20 mg QD; n=312), and monitored regularly. RESULTS: Trial completion rates were 38% with asenapine, 57% with olanzapine; main reasons for discontinuation were withdrawal of consent (22%, 16%) and insufficient response (25%, 14%); fewer discontinuations were due to adverse events (6%, 7%). Mean weight gain was 0.9 kg with asenapine, 4.2 kg with olanzapine. Extrapyramidal symptoms reported as adverse events were more common with asenapine. Mean reductions in PANSS total score with asenapine and olanzapine were -21.0 and -27.5 ( P<0.0001); the exclusion of patients who had previous poor experience with olanzapine may have biased the results in favor of olanzapine. Scores on the subjective well-being on neuroleptics scale and functionality measures were similar between groups. CONCLUSION: Asenapine was well tolerated over 1 year of treatment, causing less weight gain than olanzapine but more frequent extrapyramidal symptoms. PANSS total score improved with both agents; the improvement was greater with olanzapine than with asenapine using last observations carried forward but not in an observed-case analysis.

Characterization of substrates and inhibitors for the in vitro assessment of Bcrp mediated drug-drug interactions.

PURPOSE: In vitro assessment of drug candidates' affinity for multi-drug resistance proteins is of crucial importance for the prediction of in vivo pharmacokinetics and drug-drug interactions. To have well described experimental tools at hand, the objective of the study was to characterize substrates and inhibitors of Breast Cancer Resistance Protein (BCRP) and P-glycoprotein (P-gp). METHODS: Madin-Darbin canine kidney cells overexpressing mouse Bcrp (MDCKII-Bcrp) were incubated with various Bcrp substrates, or a mixture of substrate and inhibitor to either the apical (A) or basolateral (B) compartment of insert filter plates. Substrate concentrations in both compartments at time points t = 0 h and t = 2 h were determined by LC-MS/MS, and respective permeation coefficients (Papp) and efflux ratios were calculated. RESULTS: The Bcrp inhibitor Ko143 blocked topotecan and ABZSO transport in a concentration-dependent manner. P-gp inhibitors ivermectin, LY335979, PSC833, and the P-gp/Bcrp inhibitor ritonavir did not influence Bcrp mediated topotecan transport, however, blocked ABZSO transport. Additionally, neither was ABZSO transport influenced by topotecan, nor topotecan transport by ABZSO. CONCLUSIONS: Data suggest different modes of substrate and inhibitor binding to Bcrp. In order to not overlook potential drug-drug interactions when testing drug candidates for inhibitory potential towards Bcrp, distinct Bcrp probe substrates should be used.

Assessment of active transport of HIV protease inhibitors in various cell lines and the in vitro blood--brain barrier.

OBJECTIVE: To investigate the involvement of P-glycoprotein (Pgp) and the multidrug resistance-associated protein (MRP) on the active transport of the HIV protease inhibitors amprenavir, ritonavir and indinavir. METHODS: The transport behaviour of ritonavir, indinavir and amprenavir in the presence and absence of Pgp modulators and probenecid was investigated in an in vitro blood--brain barrier (BBB) co-culture model and in monolayers of LLC-PK1, LLC-PK1:MDR1, LLC-PK1:MRP1 and Caco-2 cells. RESULTS: All three HIV protease inhibitors showed polarized transport in the BBB model, LLC-PK1:MDR1 and Caco-2 cell line. The Pgp modulators SDZ-PSC 833, verapamil and LY 335979 inhibited polarized transport, although their potency was dependent on both the cell model and the HIV protease inhibitor used. Ritonavir and indinavir also showed polarized transport in the LLC-PK1 and LLC-PK1:MRP1 cell line, which could be inhibited by probenecid. HIV protease inhibitors were not able to inhibit competitively polarized transport of other HIV protease inhibitors in the LLC-PK1:MDR1 cell line. CONCLUSIONS: Amprenavir, ritonavir and indinavir are mainly actively transported by Pgp, while MRP also plays a role in the transport of ritonavir and indinavir. This indicates that inhibition of Pgp could be useful therapeutically to increase HIV protease inhibitor concentrations in the brain and in other tissues and cells expressing Pgp. The HIV protease inhibitors were not able to inhibit Pgp-mediated efflux when given simultaneously, suggesting that simultaneous administration of these drugs will not increase the concentration of antiretroviral drugs in the brain.

Quantitative assessment of neuroprotection against NMDA-induced brain injury.

In immature rodent brain, unilateral intrastriatal injections of selected excitatory amino acid (EAA) receptor agonists, such as N-methyl-D-aspartate (NMDA), produce prominent ipsilateral forebrain lesions. In Postnatal Day (PND) 7 rats that receive a right intrastriatal injection of NMDA (25 nmol) and are sacrificed 5 days later, there is a considerable and consistent reduction in the weight of the injected cerebral hemisphere relative to that of the contralateral side (-28.5 +/- 1.9%, n = 6). In animals treated with specific NMDA receptor antagonists, the severity of NMDA-induced damage is markedly reduced. We have previously reported that the efficacy of potential neuroprotective drugs in limiting NMDA-induced lesions can be assessed quantitatively by comparison of hemisphere weights after a unilateral NMDA injection. In this study, we compared three quantitative methods to evaluate the severity of NMDA-induced brain injury and the degree of neuroprotection provided by NMDA receptor antagonists. We characterized the severity of brain injury resulting from intrastriatal injections of 1-50 nmol NMDA in PND 7 rats sacrificed on PND 12 by (i) comparison of cerebral hemisphere weights; (ii) assay of the activity of the cholinergic neuronal marker, choline acetyltransferase (ChAT) activity; and (iii) measurement of regional brain cross-sectional areas. The severity of the resulting brain injury as assessed by comparison of hemisphere weights increased linearly with the amount of NMDA injected into the striatum up to 25 nmol NMDA. The magnitude of injury was highly correlated with the degree of reduction in ChAT activity (r2 = 0.97).(ABSTRACT TRUNCATED AT 250 WORDS)

Gas chromatographic-mass spectrometric assessment of the pharmacokinetics of amineptine and its main metabolite in volunteers with liver impairment.

A pharmacokinetic study of amineptine (Survector) and its C5 metabolite, resulting from a beta-oxidation of the heptanoic acid side-chain, was undertaken with ten human volunteers, who received a single 100-mg tablet of amineptine orally. They were affected with liver impairment in order to determine if this situation would alter greatly the pharmacokinetic parameters. The internal standard was the octanoic acid homologue. Analyses were carried out by gas chromatography (GC) and GC-mass spectrometry using TMS ester derivatives. Plasma samples were extracted using a C18 reversed-phase cartridge at pH 4.0. Mass fragmentographic measurements on the plasma samples were performed on the m/z ions (M + H)+ and (base peak)+ using ammonia chemical ionization. The global evaluation of precision was good and the coherence between the two modes of measurements, (base peak)+ and (M + H)+ ions, gave a regression factor r close to unity. For amineptine the total body clearance and mean residence time were accurate and precise with eight volunteers, but only four volunteers showed such coherent data for the slope of the elimination curve, beta, and half-life. However, the beta value, half-life and mean residence time of the C5 metabolite were accurate and precise with seven, eight and ten volunteers, respectively. It is concluded that the drug was still detoxified at normal levels.

Psychometric assessment of the therapeutic efficiency of antidepressant agents.

A clinical trial of four weeks duration was conducted involving a total of thirty depressed patients, of both sexes, aged between twenty and thirty-four years. The total number of patients was divided into three groups of ten patients each. One group received amitriptyline, the second group was administered noxiptyline and the third group was given dibenzepine. All drugs were administered orally. Patients were submitted to psychometric testing before and after drug administration. The tests used included the 'Hamilton Rating Scale for depression', the 'Hildreth Feeling Scale' and the 'D Scale' and the 'Trail Making Test' for the evaluation of psychomotor retardation. It was concluded that the Hamilton Rating Scale was the most relatively sensitive test utilized in assessing the depressive state and its improvement. Amitriptyline was found to be mostly anxiolytic; noxiptyline controlled both depression and anxiety to approximately the same extent; and dibenzepine was found to be a mood-elevating drug with an energizing action.

A multi-centre general practitioner assessment of butriptyline hydrochloride ('Evadyne').

A multi-centre open study in general practice was carried out to assess the efficacy of and incidence of side-effects with the tricyclic antidepressant, butriptyline. Of a series of 153 patients with non-psychotic depression, with or without anxiety, 105 (69%) were judged as having a good or fair response to treatment with 75 mg to 150 mg butriptyline daily. Side-effects of an anticholinergic nature were seen in 13.7% of patients, but the incidence decreased to less than 4% in the 101 patients receiving treatment for over 7 weeks.

Assessment of cyclobenzaprine in the treatment of spasticity.

The efficacy of cyclobenzaprine 60 mg/day in the treatment of spasticity was assessed in a double-blind crossover trial of two weeks' duration in 15 patients suffering from cerebral or spinal spasticity. Independent clinical and electromyographic methods were used. The effects of cyclobenzaprine did not differ significantly from those of placebo. The administration of a higher dosage, 150 mg/day, to one patient revealed a dose-related response, but the degree of improvement was clinically small. Apart from a skin rash there were no significant untoward effects of therapy.