Long-term safety and outcomes in hereditary tyrosinaemia type 1 with nitisinone treatment: a 15-year non-interventional, multicentre study.

BACKGROUND: Since the EU approval of nitisinone in 2005, prognosis for patients with hereditary tyrosinaemia type 1 has changed dramatically, with patients living with the disease now reaching adulthood for the first time in history. This study aimed to assess the long-term safety and outcomes of nitisinone treatment in patients with hereditary tyrosinaemia type 1. METHODS: We did a non-interventional, non-comparative, multicentre study in 77 sites across 17 countries in Europe and collected retrospective and prospective longitudinal data in patients with hereditary tyrosinaemia type 1 who were treated with oral nitisinone during the study period (Feb 21, 2005, to Sept 30, 2019). There were no specific exclusion criteria. Patients were followed-up with an investigator at least annually for as long as they were treated, or until the end of the study. The primary endpoints, occurrence of adverse events related to hepatic, renal, ophthalmic, haematological, or cognitive or developmental function, were assessed in the complete set (all patients already receiving treatment at the index date [Feb 21, 2005] or starting treatment thereafter) and the index set (the subset of patients who had their first dose on the index date or later only). FINDINGS: 315 patients were enrolled during the study period (complete set). Additionally, data from 24 patients who had liver transplantation or died during the post-marketing surveillance programme were retrieved (extended analysis set; 339 patients). Median treatment duration was 11·2 years (range 0·7-28·4); cumulative nitisinone exposure was 3172·7 patient-years. Patients who were diagnosed by neonatal screening started nitisinone treatment at median age 0·8 months versus 8·5 months in those who presented clinically. Incidences of hepatic, renal, ophthalmic, haematological, or cognitive or developmental adverse events were low. Occurrence of liver transplantation or death was more frequent the later that treatment was initiated (none of 70 patients who started treatment at age <28 days vs 35 [13%] of 268 patients who started treatment at age ≥28 days). 279 (89%) of 315 patients were assessed as having either very good or good nitisinone treatment compliance. Treatment and diet compliance declined as patients aged. Suboptimal plasma phenylalanine and tyrosine levels were observed. The majority of patients were reported to have good overall clinical condition throughout treatment; 176 (87%) of 203 during the entire study, 98% following 1 year of treatment. INTERPRETATION: Long-term nitisinone treatment was well tolerated and no new safety signals were revealed. Life-limiting hepatic disease appears to have been prevented by early treatment start. Neonatal screening was the most effective way of ensuring early treatment. Standardised monitoring of blood tyrosine, phenylalanine, and nitisinone levels has potential to guide individualised therapy. FUNDING: Swedish Orphan Biovitrum (Sobi).

A Randomized, Phase II Study Evaluating the Efficacy and Safety of Anakinra in the Treatment of Gout Flares.

OBJECTIVE: To evaluate the efficacy and safety of anakinra compared to triamcinolone in the treatment of gout flares. METHODS: Patients for whom nonsteroidal antiinflammatory drugs and colchicine were not suitable treatments were enrolled in this multicenter, randomized, double-blind study with follow-up for up to 2 years. The study was designed to assess superiority of anakinra (100 or 200 mg/day for 5 days) over triamcinolone (40 mg in a single injection) for the primary end point of changed patient-assessed pain intensity in the most affected joint (scored on a visual analog scale of 0-100) from baseline to 24-72 hours. Secondary outcome measures included: safety, immunogenicity, and patient- and physician-assessed global response. RESULTS: One hundred sixty-five patients were randomized to receive anakinra (n = 110) or triamcinolone (n = 55). The median age was 55 years (range 25-83), 87% were men, the mean disease duration was 8.7 years, and the mean number of self-reported flares during the prior year was 4.5. A total of 301 flares were treated (214 with anakinra; 87 with triamcinolone). Anakinra in both doses and triamcinolone provided clinically meaningful reduction in patient-assessed pain intensity in the first and subsequent flares. For the first flare, the mean decline in pain intensity from baseline to 24-72 hours for total anakinra and triamcinolone was -41.2 and -39.4, respectively (P = 0.688). Anakinra performed better than triamcinolone for most secondary end points. There were no unexpected safety findings. The presence of antidrug antibodies was not associated with adverse events or altered pain reduction. CONCLUSION: Anakinra was not superior to triamcinolone for the primary end point, but had comparable efficacy in pain reduction and was favored for most secondary end points. Anakinra is an effective option for gout flares when conventional therapy is unsuitable.

Detection of Drugs in Oral Fluid Samples Using a Commercially Available Collection Device: Agreement with Urine Testing and Evaluation of A and B Samples Obtained from Employees at Different Workplace Settings with Uncontrolled Sampling Procedures.

The use of oral fluid tests to detect drugs is of growing interest in various areas, including treatment centers, roadside and workplace testing. In this study, we investigated drug detection in oral fluid samples collected using a commercially available device, Oral Eze. Drug detection in oral fluid was compared to paired urine samples, which were simultaneously collected. We also evaluated the collection device by comparing A and B oral fluid samples. Finally, we studied the stability of various drugs in samples stored for at least 1 year. The drug profile was investigated by comparing the drugs detected in oral fluid samples with paired urine samples collected in a treatment center. A total of 113 paired oral fluid and urine samples were investigated for the presence of drugs in the following groups: amphetamines, benzodiazepines, opiates and opioids, cocaine and cannabis. A and B samples were collected from different workplaces through an uncontrolled sampling procedure (n = 76). The stability of drugs in A samples was assessed after storage at -20°C for 1 year. Generally, there was a good correlation between drugs detected in oral fluid samples and urine samples. The heroin metabolite, 6-MAM, was more frequently detected in oral fluid samples than in urine samples, while cannabis was better detected in urine samples. Drugs in oral fluid samples were stable when stored at -20°C for at least 1 year. However, in many positive A and B oral fluid samples, there was significant variation in the concentrations obtained. Hence, the collection device may need to be further standardized and improved.

A simple validated multi-analyte method for detecting drugs in oral fluid by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).

A UPLC-MS/MS method was developed to identify and quantitate 37 commonly abused drugs in oral fluid. Drugs of interest included amphetamines, benzodiazepines, cocaine, opiates, opioids, phencyclidine and tetrahydrocannabinol. Sample preparation and extraction are simple, and analysis times short. Validation showed satisfactory performance at relevant concentrations. The possibility of contaminated samples as well as the interpretation in relation to well-knows matrices, such as urine, will demand further study.

Prediction and modeling of effects on the QTc interval for clinical safety margin assessment, based on single-ascending-dose study data with AZD3839.

Corrected QT interval (QTc) prolongation in humans is usually predictable based on results from preclinical findings. This study confirms the signal from preclinical cardiac repolarization models (human ether-a-go-go-related gene, guinea pig monophasic action potential, and dog telemetry) on the clinical effects on the QTc interval. A thorough QT/QTc study is generally required for bioavailable pharmaceutical compounds to determine whether or not a drug shows a QTc effect above a threshold of regulatory interest. However, as demonstrated in this AZD3839 [(S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate] single-ascending-dose (SAD) study, high-resolution digital electrocardiogram data, in combination with adequate efficacy biomarker and pharmacokinetic data and nonlinear mixed effects modeling, can provide the basis to safely explore the margins to allow for robust modeling of clinical effect versus the electrophysiological risk marker. We also conclude that a carefully conducted SAD study may provide reliable data for effective early strategic decision making ahead of the thorough QT/QTc study.

Population pharmacokinetic and pharmacodynamic analysis of plasma Aß40 and Aß42 following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers.

Modulating deposition of Aß-containing plaques in the brain may be beneficial in treating Alzheimer's disease. ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors have been shown to reduce Aß in plasma and CSF in healthy volunteers. In this study safety, pharmacokinetics and pharmacodynamics that is reduction of the plasma biomarkers Aß40 and Aß42 , of the BACE1 inhibitor AZD3839 were evaluated. Single oral ascending doses (1-300 mg) of AZD3839 were administered to 54 young healthy volunteers in a randomized, double-blind, placebo-controlled study. The data was analyzed using non-linear mixed effects modeling. AZD3839 reduced Aß40 and Aß42 in plasma with estimated potencies (EC50 ) of 46 and 59 nM, respectively, and a maximum effect of approximately 55%. This was in excellent agreement with the concentration-response relationships obtained in mouse and guinea pig. AZD3839 exposure displayed non-linear kinetics, described by a three-compartment model with a saturated binding compartment and an increase in bioavailability with dose. AZD3839 was safe, although, a dose-dependent QTcF prolongation was observed (mean 20 milliseconds at 300 mg). In conclusion, AZD3839 reduced plasma Aß40 and Aß42 , demonstrating clinical peripheral proof of mechanism. Pre-clinical models were predictive for the effect of AZD3839 on the human plasma biomarker in a strictly quantitative manner.

Human exposure to triclosan via toothpaste does not change CYP3A4 activity or plasma concentrations of thyroid hormones.

Triclosan is an antibacterial compound commonly used in cosmetics and personal care products for everyday use. As previously shown, triclosan is found in the plasma, urine and milk from large parts of different human populations. Recent studies have revealed that triclosan is able to activate the human pregnane X receptor in vitro and thus possibly affecting metabolism of drugs in humans via the induction of CYP3A4. Besides, triclosan has been shown to affect thyroid hormonal levels in rats in vivo. In the present study, we investigated if an everyday exposure to triclosan via triclosan-containing toothpaste for 14 days in 12 adult humans caused an increase in plasma 4beta-hydroxycholesterol, indicative of CYP3A4 induction, and/or alterations in thyroid hormonal status. The plasma triclosan concentrations increased from 0.009-0.81 ng/g to 26-296 ng/g (ranges) upon exposure. Despite this, there were no significant changes in plasma levels of either plasma 4beta-hydroxycholesterol or thyroid hormones during the exposure. This indicates that the normal use of triclosan-containing toothpaste is not likely to alter metabolism of drugs via CYP3A4 induction or cause adverse events because of thyroid disturbances in humans.