Efficacy and safety of Mydriatic Microdrops for Retinopathy Of Prematurity Screening (MyMiROPS): study protocol for a non-inferiority crossover randomized controlled trial.

BACKGROUND: Retinopathy of prematurity (ROP) eye examination screening presupposes adequate mydriasis for an informative fundoscopy of preterm infants at risk, on a weekly basis. Systemic absorption of the instilled mydriatic regimens has been associated with various adverse events in this fragile population. This report aims to present the fully developed protocol of a full-scale trial for testing the hypothesis that the reduced mydriatic drop volume achieves adequate mydriasis while minimizing systemic adverse events. METHODS: A non-inferiority crossover randomized controlled trial will be performed to study the efficacy and safety of combined phenylephrine 1.67% and tropicamide 0.33% microdrops compared with standard drops in a total of 93 preterm infants requiring ROP screening. Primary outcome will be the pupil diameter at 45 (T45) min after instillation. Pupil diameter at T90 and T120 will constitute secondary efficacy endpoints. Mixed-effects linear regression models will be developed, and the 95% confidence interval approach will be used for assessing non-inferiority. Whole blood samples will be analyzed using hydrophilic liquid chromatography-tandem mass spectrometry method (HILIC-MS/MS), for gathering pharmacokinetic (PK) data on the instilled phenylephrine, at nine specific time points within 3 h from mydriasis. Pooled PK data will be used due to ethical restrictions on having a full PK profile per infant. Heart rate, oxygen saturation, blood pressure measurements, and 48-h adverse events will also be recorded. DISCUSSION: This protocol is designed for a study powered to assess non-inferiority of microdrops compared with standard dilating drops. If our hypothesis is confirmed, microdrops may become a useful tool in ROP screening. TRIAL REGISTRATION: ClinicalTrials.gov NCT05043077 . Registered on 2 September 2021.

Steady-state bioequivalence 2-way crossover study of two quetiapine prolonged-release 400 mg tablet formulations in normal male and female healthy subjects under fasting conditions
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OBJECTIVE: The purpose of this study was to assess bioequivalence between a generic and a brand quetiapine 400 mg prolonged-release (PR) formulation (Pharmathen S.A.; AstraZeneca Seroquel Prolong®<) in healthy volunteers under steady-state conditions. METHODS: Randomized, open-label, steady-state, 2-way crossover design in 48 subjects under fasting conditions. As a quetiapine dose of 400 mg was suspected to be high when administered to healthy subjects, we proceeded with an innovative design where subjects were titrated up using 150 mg, 200 mg, and 300 mg daily doses; first treatment (days 4 - 9) and second treatment (days 10 - 15), and then a tapering down phase (days 16 - 17). Blood samples were collected in EDTA K2< tubes prior to each dosing and over a 24-hour sampling schedule on days 9 and 15. Quetiapine was measured in plasma using LC-MS/MS assay (range 2.5 - 2,000 ng/mL). Pharmacokinetic analyses were performed using non-compartmental method to evaluate AUC>τ, C_max, and C_min. ANOVA was performed on the ln-transformed data and 90% confidence interval (90% CI) was determined. Bioequivalence was concluded if the 90% CI of AUC_τ, C_min, and C_max fell within 80.00 - 125.00%. RESULTS: 46 volunteers completed the study and were included in the analyses. Arithmetic mean (SD) for AUCτ were 7,161.18 (3,687.10) ng×h/mL and 7,184.27 (3,304.29) ng×h/mL, Cmax were 595.61 (345.98) ng/mL and 597.06 (253.67) ng/mL, and Cmin were 119.47 (84.24) ng/mL and 124.22 (137.68) ng/mL, respectively, for the test and reference. All pharmacokinetic parameters met the acceptance criteria as the 90% CI felt within 95.98 - 104.21%, 91.48 - 105.89%, and 86.32 - 104.49% for AUCτ, Cmax, and Cmin, respectively. Both formulations were well tolerated and no serious adverse events were reported. CONCLUSION: Our innovative design allowed safe administration of quetiapine 400 mg PR daily doses to healthy volunteers. Both Pharmathen and AstraZeneca formulations were well tolerated and bioequivalent under steady-state conditions.
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A phase II study of sunitinib in patients with recurrent and/or metastatic non-nasopharyngeal head and neck cancer.

PURPOSE: Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) bear a grave prognosis. There are unmet needs for the development of novel agents for this incurable disease. Angiogenesis is an important biological process in SCCHN. We, therefore, evaluated the activity and safety of sunitinib, an oral tyrosine kinase inhibitor that targets multiple receptors, in patients with RM-SCCHN. PATIENTS AND METHODS: Seventeen patients were treated with sunitinib 50 mg per day administrated in 4-week cycles followed by a rest period of 2 weeks. Sunitinib and SU012662 plasma levels were determined based on a validated liquid chromatography-tandem mass spectrometry method and pharmacokinetic data were fitted in a non-compartmental analysis. RESULTS: Totally, 28 6-week cycles of treatment with sunitinib were administered (median, 2 cycles). Only three patients demonstrated stabilization of the disease; therefore, the study had to be terminated prematurely due to futility. Grade 3 toxicities, apart from fatigue, were infrequent. Other frequently reported side effects were skin discoloration, neutropenia, and thrombocytopenia. Ten various bleeding complications were reported in seven patients. Mean maximum concentrations (C(max)) were reached during the first day of treatment for sunitinib at 38.98 (+ or - 22.66) ng/ml and for SU012662 at 11.12 (+ or - 24.57) ng/ml. Our results showed that SU012662 has a longer half-life and a larger volume of distribution than the parent drug sunitinib. None of the biological markers tested was of any prognostic value. CONCLUSIONS: According to our findings, sunitinib monotherapy was not proven active in RM-SCCHN, and no further development of the drug in this indication is warranted.

A dose escalation and pharmacokinetic study of the biweekly administration of paclitaxel, gemcitabine and oxaliplatin in patients with advanced solid tumors.

PURPOSE: To determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) of the paclitaxel, gemcitabine, oxaliplatin combination administered biweekly in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received escalated doses of paclitaxel (starting dose: 100 mg/m(2)), gemcitabine (starting dose: 800 mg/m(2)) and oxaliplatin (starting dose: 50 mg/m(2)) on days 1 and 15 in cycles of every 4 weeks. DLTs were evaluated during the first cycle. RESULTS: Twenty-seven patients (median age 65 years) with performance status 0-1 were treated on six dose escalation levels. Eleven patients (40.7%) were chemotherapy naïve, six (22.2%) had received 1 prior chemotherapy regimen and ten (37.1%) 2 or more. The DLT level was reached at the doses of paclitaxel 110 mg/m(2), gemcitabine 1,150 mg/m(2) and LOHP 70 mg/m(2). The dose-limiting events were grade 4 neutropenia and grade 3 febrile neutropenia. Neutropenia was the most common adverse event. A median of 3 cycles per patient was administered. One complete and five partial responses were observed in patients with ovarian carcinoma, NSCLC, urothelial cancer, mesothelioma and cancer of unknown primary. No pharmacokinetic drug interactions were detected. CONCLUSIONS: The recommended doses for future phase II studies of this combination are paclitaxel 110 mg/m(2), gemcitabine 1,000 mg/m(2) and oxaliplatin 70 mg/m(2) every 2 weeks. The regimen is generally well tolerated and merits further evaluation.

Phase 1 trial of lipoplatin and gemcitabine as a second-line chemotherapy in patients with nonsmall cell lung carcinoma.

BACKGROUND: : Lipoplatin is a new liposomal cisplatin that already has been tested in solid tumors, with encouraging results. The purpose of the current study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicity (DLT) of a 21-day regimen of lipoplatin plus a fixed dose of gemcitabine in patients with refractory or resistant nonsmall cell lung carcinoma (NSCLC) with an Eastern Cooperative Oncology Group (ECOG) performance status of

A dose escalation and pharmacokinetic study of biweekly pegylated liposomal doxorubicin, paclitaxel and oxaliplatin in patients with advanced solid tumors.

PURPOSE: To evaluate the maximum tolerated doses (MTD) and the dose-limiting toxicities (DLT) of the combination of pegylated liposomal doxorubicin (PEG-LD), paclitaxel and oxaliplatin (L-OHP) administered every 2 weeks in patients with advanced solid tumors. METHODS: Thirty-nine pretreated patients with advanced solid tumors received escalated doses of PEG-LD (10-16 mg/m(2)), paclitaxel (100-120 mg/m(2)) and L-OHP (50-70 mg/m(2)) every 2 weeks. As one cycle of treatment was considered the administration of both drugs on days 1 and 15 of a 4-week cycle. RESULTS: The MTDs were PEG-LD 14 mg/m(2), paclitaxel 120 mg/m(2) and L-OHP 70 mg/m(2). Neutropenia was the DLT in all but one case with only one episode of febrile neutropenia and no toxic deaths. Four (4%) and 13 (12%) cycles were complicated by grades 4 and 3 neutropenia, respectively. Grades 2-3 fatigue and neurotoxicity occurred in 13 and 12% of cycles, respectively. Responses were observed in patients with breast, endometrial and ovarian carcinomas. CONCLUSIONS: This is a quite well-tolerated regimen which merits further evaluation in phase II studies.

Coadministration of oxaliplatin does not influence the pharmacokinetics of gemcitabine.

We investigated the possible pharmacokinetic interactions of gemcitabine and oxaliplatin in patients with advanced solid tumors. Ten patients with advanced stage solid tumors were treated with gemcitabine (1500 mg/m) as a 30-min intravenous infusion on days 1 and 8, followed by oxaliplatin (130 mg/m) as a 4-h intravenous infusion, on day 8 every 21 days. Pharmacokinetic data for 24 h after dosing were obtained for both day 1 (gemcitabine without oxaliplatin coadministration) and day 8 (gemcitabine with oxaliplatin) during the first cycle of treatment. Gemcitabine levels in plasma were quantified using a reverse-phase high-performance liquid chromatography assay with ultraviolet detection, and total and ultrafiltrated platinum levels by flameless atomic absorption spectrophotometry with deuterium correction. All pharmacokinetic parameters of gemcitabine seemed to be unchanged when coadministered with oxaliplatin (day 8) compared with pharmacokinetic data of gemcitabine given as a single agent (day 1). The mean (maximum) concentration of gemcitabine on days 1 and 8 was 13.57 (+/-7.42) and 10.23 (+/-5.21) mg/l, respectively (P=0.28), and the mean half-life was 0.32 and 0.44 h, respectively (P=0.40). Similarly, the P-values for AUC0-24 and the observed clearance were 0.61 and 0.30, respectively. Plasma total and free platinum levels were in agreement with other published data. Gemcitabine disposition appeared to be unaffected by oxaliplatin coadministration because no significant changes in pharmacokinetics between day 1 (gemcitabine without oxaliplatin coadministration) and day 8 (gemcitabine with oxaliplatin) were observed.