Pegunigalsidase alfa, a novel PEGylated enzyme replacement therapy for Fabry disease, provides sustained plasma concentrations and favorable pharmacodynamics: A 1-year Phase 1/2 clinical trial.

Pegunigalsidase alfa, a novel PEGylated, covalently crosslinked form of α-galactosidase A developed as enzyme replacement therapy (ERT) for Fabry disease (FD), was designed to increase plasma half-life and reduce immunogenicity, thereby enhancing efficacy compared with available products. Symptomatic adults with FD participated in this open-label, 3-month dose-ranging study, followed by a 9-month extension. Three cohorts were enrolled in a stepwise manner, each receiving increased doses of pegunigalsidase alfa: 0.2, 1.0, 2.0 mg/kg, via intravenous infusion every other week. Pharmacokinetic analysis occurred on Day 1 and Months 3, 6, and 12. Kidney biopsies at baseline and Month 6 assessed peritubular capillary globotriaosylceramide (Gb3) content. Renal function, cardiac parameters, and other clinical endpoints were assessed throughout. Treatment-emergent adverse events (AEs) and presence of immunoglobulin G (IgG) antidrug antibodies (ADAs) were assessed. Sixteen patients completed 1 year's treatment. Mean terminal plasma half-life (each cohort) ranged from 53 to 121 hours. All 11 male and 1 of 7 female patients presented with classic FD phenotype, in whom renal peritubular capillary Gb3 inclusions were reduced by 84%. Mean estimated glomerular filtration rate was 111 mL/min/1.73 m2 at baseline, remaining stable throughout treatment. Three patients developed treatment-induced IgG ADAs; following 1 year's treatment, all became ADA-negative. Nearly all treatment-emergent AEs were mild or moderate. One patient withdrew from the study following a serious related AE. Pegunigalsidase alfa may represent an advance in ERT for FD, based on its unique pharmacokinetics and apparent low immunogenicity.

Effects of application durations and heat on the pharmacokinetic properties of drug delivered by a lidocaine/tetracaine patch: a randomized, open-label, controlled study in healthy volunteers.

BACKGROUND: The lidocaine/tetracaine heated patch is typically applied to the skin for 20 to 30 minutes to provide local dermal analgesia prior to venous access or minor dermatologic procedures. The potential exists for the use of multiple heated patches for longer application times, but the pharmacokinetic properties and tolerability of these multiple and/or longer applications have not been assessed. OBJECTIVE: The aim of this study was to assess the effects of heat and application time on the pharmacokinetic properties and tolerability of the patch after the application of 4 lidocaine/tetracaine (70/70 mg) heated patches applied at the same time in healthy volunteers for up to 12 hours. METHODS: In this randomized, open-labeled, controlled study, healthy subjects underwent 4 treatment periods (2-, 4-, or 12-hour application of 4 heated patches, or 4-hour application of 4 unheated patches), each separated by a 1-week washout period. RESULTS: Twelve subjects were enrolled (8 women, 4 men; mean age, 31.8 years; mean body mass index, 24.1 kg/m(2)). No tetracaine was detected in the plasma of any subject. Plasma concentrations of lidocaine increased rapidly during the first 2 hours of application in each heated-patch group, and with mean (SD) C(max) values of 18.2 (5.1), 25.7 (5.9), and 30.3 (8.1) ng/mL in the 2-, 4-, and 12-hour groups, respectively. Estimates of application time-normalized AUC(0-t) were not significantly different between the 2- and 4-hour applications of the heated patches, but were 25% lower during the 12-hour application time, suggesting continued but diminished drug delivery between 4 and 12 hours. Compared with subjects who received the unheated patch, those who received the heated patch had plasma lidocaine concentrations 5- and 3-fold higher after 30 and 60 minutes, respectively. Fifteen mild to moderate adverse events (AEs) were reported in 7 subjects, and none of the subjects discontinued the study due to treatment-related AEs. CONCLUSION: The heated patch continuously delivered drug for up to 12 hours and was generally well tolerated in these healthy subjects. ClinicalTrials.gov identifier: NCT01602757.

Tolerability, gut effects, and pharmacokinetics of methylnaltrexone following repeated intravenous administration in humans.

Previous studies have shown that a single dose of methylnaltrexone, a unique peripheral opioid antagonist, reverses opioid-induced gut hypomotility in humans. Because repeated drug doses are likely to be needed to treat patients with opioid-induced or postsurgical bowel dysfunction, the authors have now examined the safety, pharmacological activity, and pharmacokinetics of a multiple-dose regimen of methylnaltrexone, administered as 12 consecutive intravenous doses (0.3 mg/kg every 6 hours) in 12 healthy subjects. Steady state was achieved rapidly, and after repeated dosing for 3 days, methylnaltrexone decreased oral-cecal transit time from a pretreatment baseline value of 101.3 +/- 29.4 min (mean +/- SD) to 82.5 +/- 20.7 min. Maximum observed plasma concentrations, measured 5 minutes postdose, were 538 +/- 237 and 675 +/- 180 ng/mL after doses 1 and 2, respectively. Based on 6-hour sampling periods, the plasma half-life, 2.5 +/- 0.5 and 2.9 +/- 0.9 hours following the 1st and 12th doses, respectively, was unchanged at steady state. There was essentially no accumulation of methylnaltrexone, based on the ratio of AUC values after doses 12 and 1. This study showed that repeated administration of intravenous methylnaltrexone is well tolerated in humans, with no significant adverse events or changes in opioid subjective ratings and no clinically noteworthy alterations in pharmacokinetics. The observation of a significant reduction in the gut transit time after repeated administration of methylnaltrexone to these opioid-naive volunteers suggests that endogenous opioids modulate human gut motility.