Drugs in Research & Development最新文献

Background: Clinical trials have established the efficacy of brodalumab in treatment of psoriasis and psoriatic arthritis. Real-world evidence is needed to fully evaluate the drug.

Objective: Here we investigate drug survival and clinical effectiveness of brodalumab in patients with psoriasis and psoriatic arthritis in a real-world setting.

Methods: This was a retrospective single-centre study enrolling patients receiving brodalumab for psoriasis at the Department of Dermatology, Aarhus University Hospital, Denmark. The primary endpoints were drug survival, reasons for discontinuation, percentage of patients achieving a Psoriasis Area and Severity Index (PASI) ≤ 2 and clinical effectiveness against psoriatic arthritis.

Results: Eighty-three patients were included (mean age 49.2 ± 17.4 years, 59.0% male, 9.6% bio-naïve, mean baseline PASI 10.9 ± 6.9). Twenty-seven patients discontinued treatment primarily due to ineffectiveness and adverse events (AEs). Kaplan-Meier-estimated 1-year drug survival was 65.7%. An absolute Psoriasis Area and Severity Index (PASI) ≤ 2 was achieved by 68.2% of patients at end of follow-up, by 70.0% at weeks 12-17 and by 76.2% after 40-60 weeks of treatment. Neither drug survival nor PASI ≤ 2 was associated with baseline PASI ≥ 10, body mass index ≥ 30, previous treatment with > 2 biologics or other IL-17 inhibitors in particular (P > 0.05). Psoriatic arthritis remission or partial remission was achieved by 10 out of 18 patients with psoriatic arthritis; treatment failure was reported in 5 patients.

Conclusions: Brodalumab was effective against psoriasis and psoriatic arthritis in a real-world setting. The drug survival was lower than reported in other real-world settings.

Background and objective: Cervical cancer is the fourth leading cause of cancer death in women, and is one of the most common malignant tumors of the reproductive system. However, more effective treatment for cervical cancer is needed. In this study, we aim to investigate whether N-acetyl-L-cysteine (NAC) could inhibit the proliferation of human papillomavirus (HPV)-positive cells, and reduce cervical carcinogenesis.

Methods: The cervical cancer cell lines SiHa, HeLa, HPV-negative cell line C33A, and the immortalized human cervical keratinocyte cells S12 were used. The protein expression was determined using Western blot assay. mRNA expression was determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell proliferation was determined by Cell Counting Kit-8 assay. Cell apoptosis was evaluated using Annexin V-FITC apoptosis kits. The numbers of colonies were measured using colony-forming assay. Xenograft tumor necrosis and HPV16 E7 expression were determined using hematoxylin and eosin (H&E) staining and immunohistochemistry.

Results: Our results showed that NAC treatment at the concentration of 1.5 mM significantly promoted cell apoptosis and reduced cell growth by inhibiting HPV16 E7 expression. NAC inhibited HPV16-oncoprotein-induced hypoxia-inducible factor (HIF)-1α protein expression and Akt activation in vitro. Additionally, NAC suppressed tumor growth, as evidenced by the smaller tumor size in the xenograft mouse model and decreased HPV16 E7 expression in tumor tissues.

Conclusion: Our findings demonstrate that NAC exhibits the potential to promote HPV-positive cell apoptosis, and suppress the proliferation of HPV-positive cells by inhibiting cell inhibitor of apoptosis protein 2 and HIF-1α.

Background and objective: Palovarotene, a selective retinoic acid receptor γ agonist, is under investigation for the treatment of dry eye disease. This study aimed to determine the ocular and systemic safety, tolerability and pharmacokinetics of palovarotene ophthalmic solution (PVO-OS) in healthy adults.

Methods: This was a randomised, vehicle-controlled phase I study (NCT04762355; retrospectively registered). Participants received either PVO-OS (at 0.025, 0.05 or 0.10 mg/mL) or a vehicle (placebo-to-match PVO-OS) once-daily or twice-daily for seven consecutive days. Safety was assessed by ocular and systemic assessments. Blood samples for pharmacokinetic assessments were collected before and after dose administration.

Results: Thirty-six participants were randomised to PVO-OS and 12 to the vehicle. Overall, 89 treatment-emergent ocular adverse events (TEOAEs) were reported by 22 participants (61.1%) receiving PVO-OS and ten TEOAEs were reported by five participants (41.7%) receiving the vehicle. Erythema, irritation and skin dryness of the eyelid were the most common TEOAEs in participants receiving PVO-OS. The incidence of TEOAEs and eyelid-related findings in the PVO-OS groups increased with ascending dose and frequency compared with participants treated with the vehicle. All TEOAEs were mild (96.6%) or moderate (3.4%) and resolved without sequelae. Plasma palovarotene concentrations were generally measurable for up to 3-4 h for 0.025 mg/mL and 0.05 mg/mL and up to 12 h for 0.10 mg/mL dose regimens, independent of the frequency of administration.

Conclusions: PVO-OS was generally well tolerated at doses up to and including 0.10 mg/mL twice daily. Similar pharmacokinetic profiles were observed for the once-daily and twice-daily regimens following multiple ascending doses of PVO-OS.

Background: Dopamine antagonists are the main pharmacological options to treat gastroparesis. The aim of this study was to conduct a systematic literature review (SLR) to evaluate the profile of adverse events (AEs) of dopamine antagonists used in the treatment of children and adults with gastroparesis.

Methods: We searched EMBASE and MEDLINE up to March 25, 2021, for relevant clinical trials and observational studies. We conducted a proportional meta-analysis to estimate the pooled occurrence of AEs (%), with 95% confidence interval (CI), from arm-level data across studies and the comparative occurrence of AEs from placebo-controlled clinical trials (odds ratio [OR] with 95% CI).

Results: We identified 28 studies assessing AEs experienced by patients treated for gastroparesis with domperidone and metoclopramide; 22 studies contributed data to the meta-analyses. Cardiovascular, neurological, and endocrine AEs were commonly observed, with point incidences varying from 1 to > 50%. Clinically important AEs, such as QTc prolongation, occurred in 5% of patients treated with domperidone (95% CI: 3.32-8.62). Restlessness, an extrapyramidal AE, occurred in 15% of patients (95% CI: 7.48-26.61) treated with metoclopramide, with a 7-fold increase compared with patients receiving placebo (OR: 7.72; 95% CI: 1.27-47.05). Variation in terminology to describe extrapyramidal events precluded further pooled analyses. Additional meta-analyses were not feasible due to discrepancies in the assessment and reporting of the AEs.

Conclusions: The evidence confirms concerns of cardiovascular, extrapyramidal, and endocrine AEs in patients with gastroparesis treated with domperidone and metoclopramide. Imprecise AE reporting limits firm interpretation and conclusions.

Registration: PROSPERO international prospective register of systematic reviews (registration number: CRD42021248888).

Introduction: In Germany, incidence rates of basal cell (BCC) and squamous cell carcinoma (SCC) rose significantly from 1998 to 2010. Ultraviolet (UV) light exposure, immunosuppressants and drugs with photosensitising potential are known to increase the risk to develop BCC and SCC. The aim of our study was to analyse the adverse drug reaction (ADR) reports from Germany referring to BCC and SCC and to compare them to BCC and SCC occurring in the general population.

Methods: We analysed all validated spontaneous ADR reports referring to BCC (n = 191) and SCC (n = 75) from Germany contained in the European ADR database EudraVigilance prior to 6 March 2019. These reports were compared to 1,267,210 BCC and 476,903 SCC cases from the German Centre for Cancer Registry Data recorded from 2006 to 2018.

Results: The number of BCC and SCC reports as well as the BCC and SCC incidences in the registry increased in the analysed time period. Patients with drug-associated BCC (60 years) and SCC (64 years) were younger than patients with BCC (72 years) and SCC (76 years) in the registry. In 57.1 and 60.0% of BCC and SCC reports immunosuppressants were reported as suspected. The reported suspected drug was assumed to possess a photosensitising potential in 41.9 and 44.0% of BCC and SCC reports.

Conclusions: In Germany, drug-associated BCC and SCC occurred at a younger age than in the general population. The results underline the necessity for skin cancer screening of patients treated with immunosuppressants or with drugs with photosensitising potential.

Background: PF-06439535 (bevacizumab-bvzr; Zirabev^®) is a biosimilar of bevacizumab reference product (RP; Avastin^®). This study describes the formulation development for PF-06439535.

Methods: PF-06439535 was formulated in several buffers and stored for 12 weeks at 40 °C to determine the optimal buffer and pH under stressed conditions. Subsequently, PF-06439535 at 100 and 25 mg/mL was formulated in a succinate buffer with sucrose, edetate disodium dihydrate (EDTA), and polysorbate 80, and in the RP formulation. Samples were stored at - 40 °C to 40 °C for ≤ 22 weeks. The physicochemical and biological properties relevant to the safety, efficacy, quality, or manufacturability were investigated.

Results: When stored at 40 °C for 13 days, PF-06439535 demonstrated optimal stability in histidine or succinate buffers and was more stable in the succinate formulation than the RP formulation, under both real-time and accelerated stability conditions. There were no significant changes in the quality attributes of 100 mg/mL PF-06439535 after storage at - 20 °C and - 40 °C for 22 weeks, and there were no changes in the quality attributes of 25 mg/mL PF-06439535 after storage at 5 °C (recommended storage temperature). Changes were observed at 25 °C for 22 weeks or at 40 °C for 8 weeks as expected. No new degraded species were observed in the biosimilar succinate formulation compared with the RP formulation.

Conclusions: Results demonstrated that 20 mM succinate buffer (pH 5.5) is the PF-06439535 preferred formulation, and that sucrose is an effective cryoprotectant for processing and frozen storage, and an effective stabilizing excipient for 5 °C liquid storage of PF-06439535.

Background: A thorough and systematic analysis of potential endotoxin-related safety issues from parenteral drugs and devices is important to ensure appropriate current Good Manufacturing Practices, compendial requirements, standards and regulatory guidance. Lately, the US Food and Drug Administration has been expecting pharmaceutical firms to apply an arbitrary safety factor to compendial compliant drug specifications for endotoxin, potentially causing manufacturing challenges, supply issues and additional unwarranted costs.

Objective: The aim of this study was to evaluate data from three disparate sources over an extended period of time, from 2008 to 2021, to determine if there exists an industry-wide risk to patients from parenteral drugs and devices, thereby evaluating if changes to current Good Manufacturing Practices or compendial requirements are indeed warranted. Food and Drug Administration data from current Good Manufacturing Practices non-compliance observations, product recalls and the FDA Adverse Event Reporting System were used as the three sources of data.

Methods: Parenteral products were separated into drugs and devices, potential endotoxin-related patient safety issues were characterised in terms of the available non-compliance information, the type and number of product recalls, and the type and number of potential adverse events. Descriptive statistics in Microsoft Excel 2019 and Pivot tables were used for the analysis and presentation of the data.

Results: From 2011 to 2021, a total of 188 endotoxin-related current Good Manufacturing Practices compliance observations were recorded, 70% and 30% were associated with laboratory and manufacturing origins, respectively. Finished drug product testing accounted for 56% of these. In contrast, 95% of all endotoxin-related product recalls were associated solely with medical devices. Over the years 2008-2021, approximately 1.4% of all adverse events (23,663,780) were recorded with some reference to pyrexia (fever); however, there are sparse data categorically attributing this to the administration of parenteral drugs or devices or combinations of these possessing high levels of endotoxin.

Conclusions: Analysis of data concerning drug- and device-borne endotoxin obtained from FDA data from current Good Manufacturing Practices non-compliance observations, product recalls and the FDA Adverse Event Reporting System demonstrated the absence of industry-wide issues with endotoxin contamination. Based upon these data, changes to current Good Manufacturing Practices and the compendial methodology of setting endotoxin specifications (and hence the compendial methodology of testing for endotoxins) are unwarranted.

Background and objective: Systemic lupus erythematosus (SLE) is an autoimmune disease, with hydroxychloroquine being the main therapeutic agent for the treatment of SLE. This research explored the effects of hydroxychloroquine combined with low-dose aspirin on maternal and infant outcomes and cytokines of pregnant women with SLE.

Methods: Ninety pregnant women with SLE were divided into the hydroxychloroquine (HCQ) group (45 cases) and the hydroxychloroquine combined with low-dose aspirin (HCQASP) group (45 cases) by random number table. Patients in the HCQ group were treated with oral administration of hydroxychloroquine, while patients in the HCQASP group were treated with low-dose aspirin based on oral administration of hydroxychloroquine. Pregnancy outcomes, fetal outcomes, and cytokine levels were statistically analyzed.

Results: The HCQASP group had a significantly higher proportion of full-term pregnancies and a significantly lower proportion of hypertension, prematurity, and pregnancy loss than the HCQ group. Neonates in the HCQASP group also had significantly higher birth weights and Apgar scores and a significantly lower proportion of neonatal asphyxia than the HCQ group. After treatment, the HCQASP group had significantly higher interleukin (IL-2) and interferon (IFN)-γ levels and significantly lower IL-4 and IL-10 levels than the HCQ group.

Conclusion: Hydroxychloroquine combined with low-dose aspirin can effectively improve the pregnancy outcomes of pregnant women with SLE by affecting the levels of T helper (Th) 2 and Th1 cytokines.

Background: Chromogenic anti-factor Xa activity (AXA) assay is used to measure the pharmacodynamics of factor Xa inhibitors, including edoxaban. Although AXA concentrations in patients with non-valvular atrial fibrillation using edoxaban have been reported, the impact of renal function on AXA concentrations with edoxaban use in patients with non-valvular atrial fibrillation has not been fully assessed.

Methods: Trough and peak AXA concentrations were measured in 93 patients with non-valvular atrial fibrillation taking edoxaban (73.6 ± 11.2 years, 48 were male). The patients were divided into three groups: patients with moderate renal dysfunction (creatinine clearance 15-49 mL/min), mild renal dysfunction (creatinine clearance 50-95 mL/min), and normal renal function (creatinine clearance > 95 mL/min). Both trough and peak AXA concentrations were assessed among the groups according to the edoxaban dose (30 or 60 mg).

Results: At a 30-mg dose, patients with moderate renal dysfunction showed significantly higher trough AXA concentrations than patients with mild renal dysfunction or normal renal function. At a 60-mg dose, patients with mild renal dysfunction showed significantly higher trough AXA concentrations than patients with normal renal function. Peak AXA concentrations were not significantly different between the groups. Creatinine clearance was significantly and negatively correlated with trough AXA concentrations at a 60-mg dose, whereas the correlation of creatinine clearance with AXA concentrations was borderline significant at a 30-mg dose. No correlation was found between creatinine clearance and peak AXA concentrations at either dose.

Conclusions: Creatinine clearance tends to be negatively correlated with trough AXA concentrations in patients with non-valvular atrial fibrillation taking edoxaban, while renal function is not correlated with peak AXA concentrations.

Background: Cloperastine is a pivotal antibechic widely prescribed to treat cough caused by respiratory diseases. The present trial evaluated the pharmacokinetics (PK), bioequivalence (BE) and safety effects of the generic test (T) tablet of cloperastine after single-dose administration of cloperastine, compared with the original reference (R) tablet of cloperastine.

Objective: The purpose of this trial was to compare the PK, BE and safety of a test 10 mg versus the reference 10 mg formulation of cloperastine under fasting and postprandial conditions in healthy Chinese volunteers.

Methods: A single-centre, randomised, open, double-cycle, self-crossover, single oral administration Phase I trial was performed in healthy Chinese volunteers. A total of 60 subjects were enrolled in either the fasting (28 subjects) or the postprandial condition (32 subjects). Subjects randomly received a single dose of the T or R preparation (10 mg dose). Plasma concentrations of cloperastine were analysed by a validated LC-MS/MS method. The primary endpoints of the PK parameters were the area under the plasma concentration-time curve from zero to 72 h (AUC_0-72h), under the plasma concentration-time curve from zero to infinity (AUC_0-∞) and the maximal plasma concentration (C_max). The equivalence standard range (80.0-125.0%) was used to evaluate the BE of the two preparations. The safety parameter as secondary endpoint was mainly evaluated by the occurrence of adverse events (AEs).

Results: A total of 25 and 30 subjects in the fasting and postprandial conditions completed this clinical trial, respectively. The geometric mean ratio (GMR) of the T/R for the C_max, AUC_0-72h and AUC_0-∞ were 102.1%, 103.8% and 104.0% in the fasting condition, respectively. In the postprandial condition, the GMR of the T/R for the C_max, AUC_0-72h and AUC_0-∞ were 94.2%, 98.8% and 99.0%, respectively. All the values fell within the range (80.0-125.0%). The C_max and AUC_0-72h values of the T and R preparations in fasting and postprandial conditions were not statistically significant (P > 0.05). Furthermore, no serious adverse events (SAEs) occurred during the whole trial.

Conclusions: The T and R preparations were bioequivalent under both conditions. Food has no significant effect on the absorption of cloperastine. Moreover, T and R preparations were well tolerated. The trial registration number (TRN) and date of registrations were CTR20212515, 13 October 2021.