A Systematic Review of Economic Evaluations Assessing the Cost-Effectiveness of Licensed Drugs Used for Previously Treated Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) Negative Advanced/Metastatic Non-Small Cell Lung Cancer Abstract Background Non-small cell lung cancer (NSCLC) is one of the most commonly diagnosed cancers. There are many published studies of cost-effectiveness analyses of licensed treatments, but no study has compared these studies or their approaches simultaneously. Objective To investigate the methodology used in published economic analyses of licensed interventions for previously treated advanced/metastatic NSCLC in patients without anaplastic lymphoma kinase or epidermal growth factor receptor expression. Methods A systematic review was performed, including a systematic search of key databases (e.g. MEDLINE, EMBASE, Web of Knowledge, Cost-effectiveness Registry) limited to the period from 01 January 2001 to 26 July 2019. Two reviewers independently screened, extracted data and quality appraised identified studies. The reporting quality of the studies was assessed by using the Consolidated Health Economic Evaluation Reporting Standards and the Philips’ checklists. Results Thirty-one published records met the inclusion criteria, which corresponded to 30 individual cost-effectiveness analyses. Analytical approaches included partitioned survival models (n = 14), state-transition models (n = 7) and retrospective analyses of new or published data (n = 8). Model structure was generally consistent, with pre-progression, post-progression and death health states used most commonly. Other characteristics varied more widely, including the perspective of analysis, discounting, time horizon, usually to align with the country that the analysis was set in. Conclusions There are a wide range of approaches in the modelling of treatments for advanced NSCLC; however, the model structures are consistent. There is variation in the exploration of sensitivity analyses, with considerable uncertainty remaining in most evaluations. Improved reporting is necessary to ensure transparency in future analyses.

Fetal Safety of Dydrogesterone Exposure in the First Trimester of Pregnancy Abstract Background The progestin dydrogesterone (DYD) is widely used for threatened and recurrent miscarriages, as well as for dysfunctional bleeding, infertility and other obstetric and gynecological indications. While its apparent efficacy has been compared to other progestins, its fetal safety has been only sparsely investigated. Objectives To follow up fetal outcome after gestational exposure to DYD and compare it to a non-exposed comparison group. Objectives To follow up fetal outcome after gestational exposure to DYD and compare it to a non-exposed comparison group. Patients and methods Using the 2.5 million patient database of Maccabi Health Services, we compared rates of congenital malformations among babies exposed in utero during the first trimester of pregnancy to DYD between Jan 1999 and December 2016, to a comparison group not receiving this medication. From the DYD group we excluded all cases with concomitant exposure to in vitro fertilization (IVF) and other forms of assisted reproductive technology (ART). Results There were 8508 children exposed to DYD during the first trimester of pregnancy (4417 males, 4091 females) out of 777,422 cases in the database. After excluding from the DYD group cases with concomitant exposure to IVF and other ART, DYD exposure was associated with increased risk for hypospadias [OR 1.28 (95% confidence interval 1.06–1.55)], for overall cardiovascular malformations [OR 1.18 (91.06–1.33)], spina bifida [OR 2.29 (1.32–3.97)] and hydrocephalus [OR 2.04 (1.28–3.25)]. In a sensitivity analysis, including also cases exposed to IVF and ART in addition to DYD, there were also increased risks for cryptorchidism [1.37 (1.19–1.58)] and congenital dislocation of the hip [OR 1.58 (1.42–1.78)]. Conclusions DYD confers teratogenic effects after exposure to the recommended doses in pregnant women. The risks of hypospadias and cryptorchidism have biological plausibility by the known effects on male genitalia, as is the risk for spina bifida, by the proven decrease in folic acid levels. Some of these adverse fetal effects appear to be further augmented by concomitant use of IVF and ART.

Correction to: Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes: Their Use and Differential Features The article Glucagon-Like Peptide-1 Receptor Agonists in Type 2 Diabetes: Their Use and Differential Features, written by KA Lyseng-Williamson, was originally published Online First without open access. After publication in volume 39, issue 8, pages 805-819, Springer Healthcare IME requested that the article be Open Choice to make the article an open access publication. Post-publication open access was funded by an independent educational grant from Novo Nordisk A/S . The article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

Different Clopidogrel Response Elicited by Lansoprazole or Esomeprazole in Patients Undergoing Neurointervention with Dual Antiplatelet Therapy Abstract Background Aspirin–clopidogrel dual antiplatelet therapy and a proton-pump inhibitor are used worldwide to prevent thromboembolism and peptic ulceration in patients undergoing neurointervention. We performed VerifyNow assays (Accumetrics, San Diego, CA, USA) to retrospectively examine the relationship between the effectiveness of antiplatelet agents and different proton-pump inhibitor types. Methods Sixty-four patients with unruptured intracranial aneurysm scheduled for neurointervention received aspirin–clopidogrel dual antiplatelet therapy plus the proton-pump inhibitor lansoprazole (n = 34) or esomeprazole (n = 30). A low response to aspirin and clopidogrel was defined in terms of aspirin reaction units > 550 and P2Y12 reaction units ≥ 230, respectively, by VerifyNow assay. The characteristics, response to antiplatelet therapy, and clinical outcomes were compared in patients treated with lansoprazole or esomeprazole. Results The preoperative mean VerifyNow aspirin reaction units and P2Y12 reaction units were 466.0 ± 67.3 and 205.0 ± 67.6, respectively. The mean aspirin reaction unit value was 482.0 ± 64.1 in the lansoprazole group, and 461.5 ± 70.9 in the esomeprazole group (p = 0.77). The mean P2Y12 reaction unit was 220.0 ± 64.4 in the lansoprazole group, and 174.5 ± 65.0 in the esomeprazole group; there was a significant difference in the clopidogrel response of patient treated with lansoprazole or esomeprazole (p = 0.005). Conclusions Our VerifyNow assay results suggest that when on lansoprazole fewer patients achieved the therapeutic goal and required extra therapy before neurointervention.

Pharmacokinetic/Pharmacodynamic Evaluation of Dexlansoprazole Infusion Injection Compared with Lansoprazole in Healthy Chinese Adults Abstract Background and Objective This study was performed in healthy Chinese subjects to evaluate the safety and pharmacokinetic/pharmacodynamic characteristics of a novel injection formulation of dexlansoprazole in the context of single and multiple administration, compared with the original lansoprazole injection. Methods Helicobacter pylori-negative healthy volunteers were recruited, and 70 participants were enrolled into five dosing groups (seven males and seven females in each group), including 15 mg once daily (qd), 15 mg every 12 h (q12h), 30 mg qd and 30 mg q12h of dexlansoprazole treatment for 5 days, as well as 30 mg q12h of lansoprazole treatment for 5 days. Blood samples were collected at scheduled time spots postdose on day 1 (first dose) and day 5 (last dose). Twenty-four-hour intragastric pH was continuously monitored on day 0 (baseline) and days 1 and 5. Dexlansoprazole and S-lansoprazole in human plasma were determined by validated chiral liquid chromatography with tandem mass spectrometry, and the pharmacokinetic parameters were determined by a non-compartmental method using Phoenix WinNonlin software. Safety assessment included changes in vital signs and laboratory tests, physical examination findings, and incidence or reports of adverse events. Results The half-life (t½) and clearance (CL) of dexlansoprazole were 1.76–2.06 h and 4.52–5.40 L/h, respectively, while the t½ and CL of S-lansoprazole were 0.87–1.02 h and 34.66–35.98 L/h, respectively. No drug accumulation after repeated administration was noted. Administration of lansoprazole 30 mg resulted in higher area under the concentration-time curve from time zero to the last measurable concentration (AUCt) of dexlansoprazole than that of dexlansoprazole 15 mg (p = 0.026). Zero to 24 h after q12h multiple dosing, median and mean intragastric pH, percentage of time with the intragastric pH above 4.0 [TpH ≥ 4.0(%)] and percentage of time with the intragastric pH above 6.0 [TpH ≥ 6.0(%)] in the dexlansoprazole 15 mg q12h group were 6.07 ± 0.61, 5.70 ± 0.76, 83.58 ± 12.34, and 53.70 ± 17.06, respectively, which was similar to the lansoprazole 30 mg q12h group, i.e. 6.15 ± 0.62, 5.88 ± 0.67, 87.26 ± 12.08 and 57.00 ± 16.35, respectively. A weak positive correlation between dexlansoprazole AUCt and baseline-adjusted TpH ≥ 4.0(%) over 0–24 h was observed, with Pearson correlation coefficients of 0.437 (p = 0.029), while no correlation was observed between AUCt and baseline-adjusted TpH ≥ 6.0(%) over 0–24 h. Conclusion Every 12 h intravenous dosing of dexlansoprazole up to 30 mg for 5 days was safe and well-tolerated in healthy Chinese subjects. Every 12 h dosing of dexlansoprazole 15 mg has a comparable effect of gastric acid inhibition as lansoprazole 30 mg q12h. Trial Registration ClinicalTrials.gov ID NCT03120273.

Mecapegfilgrastim in Chemotherapy-Induced Neutropenia: A Profile of Its Use in China Abstract Mecapegfilgrastim (HHPG-19K) is a long-acting pegylated recombinant human granulocyte-colony stimulating factor (rhG-CSF) that is administered subcutaneously as prophylaxis once per chemotherapy cycle as a weight-adjusted dose of 100 µg/kg or as a 6 mg fixed dose. It is approved in China to reduce the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer therapy associated with a clinically significant incidence of febrile neutropenia. In phase III trials, once per cycle prophylaxis with mecapegfilgrastim was more effective than placebo in reducing the incidence of grade ≥ 3 neutropenia in cycle 1 in patients with advanced non-small cell lung cancer and was more effective than filgrastim at reducing the mean duration of grade ≥ 3 neutropenia in cycle 1 in patients with breast cancer. The tolerability and safety profiles of mecapegfilgrastim were similar to those of filgrastim, with no unexpected adverse events (AEs); most adverse reactions in cycle 1 were mild or moderate in severity. Thus, mecapegfilgrastim is an effective and generally well tolerated treatment option for patients with non-myeloid malignancies receiving myelosuppressive chemotherapy, and extends the options available for managing chemotherapy-induced neutropenia in China.

HR+/HER2− Metastatic Breast Cancer: Epidemiology, Prescription Patterns, Healthcare Resource Utilisation and Costs from a Large Italian Real-World Database Abstract Background and Objective Breast cancer is the second leading cause of cancer death worldwide. The economic burden of breast cancer is crucial for the sustainability of healthcare systems. The objective of this study was to estimate the burden of HR+/HER2− metastatic breast cancer (MBC) in Italy, in terms of incidence, prescription patterns, healthcare resource utilisation and costs for the National Health System (NHS). Methods A cohort study based on healthcare administrative data (ReS database), covering > 10 million Italians, was performed. Incident cases of HR+/HER2− MBC were identified among adult women in 2013. The cohort was followed-up for 2 years to describe healthcare utilisation and integrated costs (pharmaceuticals, hospitalisations and outpatient services) for NHS. Prescription patterns were described as first-line choice and therapeutic changes. Specific therapeutic changes were used as proxies of disease progression. A survival analysis was performed to estimate the time from diagnosis to first disease progression. Results Of 5174,723 women, 355 cases of de novo HR+/HER2− MBC were selected (incidence: 6.9 per 100,000). During the 1st follow-up year, they generated an average cost of €7543, whereas €4834 in the 2nd year. The 85.9% received a monotherapy, while the 14.1% received a combination therapy. The most used monotherapy was nonsteroidal-aromatase-inhibitors (45.9%), while the most prescribed combination was tamoxifen + luteinizing hormone releasing hormone (LHRH) analogues (6.2%). Therapeutic changes occurred in 45.4% of patients, especially from chemotherapy to nonsteroidal-aromatase-inhibitors, after an average of 276.8 days from the first treatment. Disease progression was identified in 22.5% of patients occurring after a mean 13 ± 6 months from diagnosis. Conclusions This detailed picture of HR+/HER2− MBC, based on real-world data, could be helpful in health technology assessment and expenditure forecasts of future therapeutic strategies for this condition in Italy.

Cost-Effectiveness Analysis of Erenumab Versus OnabotulinumtoxinA for Patients with Chronic Migraine Attacks in Greece Abstract Background Migraine is a common, chronic neurovascular brain disorder with non-negligible multifaceted economic costs. Existing preventive treatments involve the selective use of onabotulinumtoxinA, which aims at migraine morbidity reduction for patients who have failed initial preventive treatment with oral agents. Erenumab is a new preventive treatment for migraines. Objective To evaluate the differences in costs and outcomes of the preventive treatment with erenumab versus onabotulinumtoxinA in patients with chronic migraines (CM) in Greece to assess the economic value of this treatment. Methods We conducted a cost-effectiveness analysis from both the payer and the societal perspective using a decision-tree analytic model. Outcomes were expressed in migraines avoided and in quality-adjusted life-years (QALYs). We obtained model inputs from the existing literature. The decision path adjusted for variation in the probability of adherence and the resulting differential effectiveness between the two treatments. Direct costs included the cost of the two drugs and administration costs, the costs of acute drugs used under usual care, and the costs of hospitalization, physician, and emergency department visits. Indirect costs for the societal perspective analyses included wages lost on workdays. The time-horizon of the analysis was 1 year and all costs were calculated in 2019 euros (€). Sensitivity analyses were conducted to control for parameter uncertainty and to evaluate the robustness of the findings. Results Our results indicate that treatment of CM with erenumab compared to onabotulinumtoxinA resulted in incremental cost-effectiveness ratios (ICERs) of €218,870 and €231,554 per QALY gained and €620 and €656 per migraine avoided, from the societal and the payer’s perspective, respectively. Using a common cost-effectiveness threshold equal to three times the local gross domestic product (GDP) per capita (€49,000), for the erenumab ICERs to fall below this threshold, the erenumab price would have to be no more than €192 (societal perspective) or €173 (payer perspective). Conclusion The prophylactic treatment of CM with erenumab in Greece might be cost effective compared to the existing alternative of onabotulinumtoxinA from both the payer and the societal perspective, but only at a highly discounted price. Nevertheless, erenumab could be considered a therapeutic option for patients who fail treatment with onabotulinumtoxinA.

Oral Contraceptives and Neutropenia: A Population-Based Cohort Study Abstract Background Oral contraceptives (OCs) are one of the most commonly used classes of drugs worldwide. A case of neutropenia and associated infections in a young woman using OCs that settled after discontinuation and reappeared upon re-challenge, has led us to investigate a potential association between oral contraceptives and neutropenia. Objectives To compare rates of neutropenia among women receiving OCs to a matched control group of women not exposed to the “pill”. Patients and Methods In this population-based cohort study we used a large computerized database of a health fund, comparing women prescribed OCs and a control group not using the pill. We selected a cohort of 51,394 OC users aged 16–40 years who purchased their first monthly pack of OCs between 2010 and 2018. Controls included all non-pregnant women aged 16–40 years for whom OC was not dispensed (n = 140,932). Neutrophil count before and during OC were compared. Results Prior to OC exposure, 1.3% of the women were neutropenic, compared to 1.6% after exposure to OC (RR 1.22; 95% CI 1.1–1.35). Mean neutrophil count changed from 3.87 × 103 to 3.82 × 103 mm3 (p < 0.001). In the control group (n = 140,932) no difference was seen in the proportion of neutropenic women between the first complete blood count (1.7%) compared to the second (1.8%) count (p = 0.305). In all severity levels, neutropenia was significantly more common in the OC group. The relative risk was higher for severe (RR 1.63) than for mild neutropenia (RR 1.13) (p = 0.034 for trend). Conclusions There is a significant increase in the proportion of neutropenic women after initiating OCs. More research is needed in order to evaluate the effect of neutropenia in this group of women.

Effect of DS-8500a, a Novel G Protein-Coupled Receptor 119 Agonist, on the Pharmacokinetics of Rosuvastatin and Atorvastatin in Healthy Subjects Abstract Background Non-clinical study data suggest that DS-8500a, a G protein-coupled receptor 119 agonist, exhibits antidiabetic activity, inhibition of some transporters and induction of cytochrome P450 (CYP) 3A. Statins are substrates for some transporters and CYP3A that may be coadministered with DS-8500a in clinical practice. Objective To determine the potential effects of DS-8500a on the pharmacokinetics of statins, we evaluated the effects of repeated oral administration of DS-8500a 75 mg on the pharmacokinetics of rosuvastatin and atorvastatin in healthy adults. Methods We performed two single-center, open-label, single-sequence studies. In Study I, subjects received single-dose rosuvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose rosuvastatin 10 mg (Period B). In Study II, subjects received single-dose atorvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose atorvastatin 10 mg (Period B). Primary pharmacokinetic endpoints were maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) of rosuvastatin and atorvastatin. Safety was evaluated. Results In Study I, the Cmax and AUC of rosuvastatin increased by 66% and 33%, respectively, when coadministered with DS-8500a, versus rosuvastatin alone. In Study II, the Cmax of atorvastatin increased by 28%, but AUC remained unchanged following coadministration with DS-8500a, versus atorvastatin alone. Treatment-emergent adverse events were mild to moderate and mostly unrelated to the study drugs. Conclusions Multiple doses of DS-8500a increased exposure to rosuvastatin and atorvastatin. This short-term study suggests that the impact of DS-8500a coadministration on atorvastatin exposure is limited and may not be clinically relevant. Nevertheless, caution may be necessary when patients are coadministered rosuvastatin with DS-8500a. ClinicalTrials.gov identifier NCT03699774. Japan Pharmaceutical Information Center identifier JapicCTI-152878.