Safety, tolerability, and pharmacokinetics of a single orally inhaled dose of PUR3100, a dry powder formulation of dihydroergotamine versus intravenous dihydroergotamine: A Phase 1 randomized, double-blind study in healthy adults.

BACKGROUND: Intravenous dihydroergotamine (DHE) has well-established efficacy for the acute treatment of migraine, but its use is limited by the need for in-hospital administration and the nausea/vomiting associated with a high maximum plasma concentration (Cmax). Inhalation is an alternative to intravenous dosing. The surface area of the lung allows for rapid absorption of a self-administered dose. OBJECTIVE: This study evaluated the safety, tolerability, and systemic pharmacokinetics (PK) of a dry powder formulation (PUR3100) DHE when delivered via inhalation compared to intravenous delivery. METHODS: In this double-blind, double-dummy Phase 1 study, healthy volunteers (N = 26) were randomized (1:1:1:1) to one of four groups: orally inhaled placebo plus intravenous DHE 1.0 mg or orally inhaled PUR3100 (0.5, 1.0, or 1.5 mg) plus intravenous placebo. Blood samples were drawn pre-dose and at time points post-dose over 48 h. Standard PK and safety parameters were assessed and values for Cmax and area under plasma concentration time curve (AUC) were used to assess comparative exposures of PUR3100 versus intravenous DHE. RESULTS: All doses of PUR3100 were associated with a lower incidence of nausea (21% vs. 86%), vomiting (0% vs. 29%), and headache (16% vs. 57%) compared to intravenous DHE. The PK profile of PUR3100 versus intravenous DHE was characterized by a similar mean time to Cmax (5 vs. 5.5 min), with reduced AUC0-2h (1120-4320 vs. 6340), and a lower Cmax (3620-14,400 vs. 45,000). Compared to intravenous DHE 1.0 mg, the highest nominal PUR3100 dose (1.5 mg), which delivers a fine-particle dose of approximately 0.9 mg to the lungs, had a geometric mean ratio percentage (90% confidence interval [CI]) for Cmax of 32% [17.2, 59.6] and AUC0-inf of 93% (62.9, 138.5), the latter of which was not significantly different. CONCLUSIONS: Inhaled PUR3100 is associated with rapid systemic PK within the therapeutic window and an improved safety profile relative to intravenous DHE.

Safety of intrathecal delivery of recombinant human arylsulfatase A in children with metachromatic leukodystrophy: Results from a phase 1/2 clinical trial.

BACKGROUND: Metachromatic leukodystrophy (MLD) is an autosomal recessive disorder caused by deficient arylsulfatase A (ASA) activity and characterized by neurological involvement that results in severe disability and premature death. We examined the safety and tolerability of intrathecally delivered recombinant human ASA (rhASA; SHP611, now TAK-611) in children with MLD (NCT01510028). Secondary endpoints included change in cerebrospinal fluid (CSF) sulfatide and lysosulfatide levels, and motor function (assessed by Gross Motor Function Measure-88 total score). METHODS: Twenty-four children with MLD who experienced symptom onset aged ≤ 30 months were enrolled. Patients received rhASA every other week (EOW) for 38 weeks at 10, 30, or 100 mg (cohorts 1-3; n = 6 per cohort), or 100 mg manufactured using a revised process (cohort 4; n = 6). RESULTS: No rhASA-related serious adverse events (SAEs) were observed; 25% of patients experienced an SAE related to the intrathecal device or drug delivery method. Mean CSF sulfatide and lysosulfatide levels fell to within normal ranges in both 100 mg cohorts following treatment. Although there was a general decline in motor function over time, there was a tendency towards a less pronounced decline in patients receiving 100 mg. CONCLUSION: Intrathecal rhASA was generally well tolerated at doses up to 100 mg EOW. These preliminary data support further development of rhASA as a therapy for patients with MLD.

Comparison of the efficacy and safety of oritavancin front-loaded dosing regimens to daily dosing: an analysis of the SIMPLIFI trial.

Oritavancin is a novel lipoglycopeptide with demonstrated effectiveness against complicated skin and skin structure infections (cSSSI) caused by Gram-positive pathogens, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). The pharmacokinetic and pharmacodynamic profile of oritavancin is favorable for single or infrequent dosing. A phase 2, multicenter, randomized, double-blind, parallel, active-comparator study (ClinicalTrials.gov identifier, NCT00514527) of single and infrequent dosing of intravenous (i.v.) oritavancin for the treatment of cSSSI caused by Gram-positive pathogens (wound infections, major abscess, and cellulitis) was undertaken to evaluate the noninferiority of front-loaded dosing regimens compared to a daily-dosing regimen. A total of 302 patients ≥ 18 years of age were randomized equally to one of three oritavancin treatment groups, receiving either a daily dose (200 mg) administered for 3 to 7 days, a single dose (1,200 mg), or an infrequent dose (800-mg dose, with the option for an additional 400 mg on day 5). The primary efficacy was defined as a clinical response in clinically evaluable (CE) patients assessed at days 21 to 29 (test of cure [TOC]). The cure rates in the CE population were 72.4% (55/76) in the daily-dose group, 81.5% (66/81) in the 1,200-mg-single-dose group, and 77.5% (55/71) in the infrequent-dose group. In patients with MRSA at baseline, the cure rates were 78.3% (18/23), 73.0% (27/37), and 87.0% (20/23) in the daily-, 1,200-mg-single-, and infrequent-dose groups, respectively; however, the study was not powered to assess outcomes in the MRSA subpopulation, and given the heterogeneity of the types of infection and the small sample size, these do not suggest any true differences in efficacy rates for these pathogens. The frequencies of adverse events were similar among treatment groups. The results of this study show that single- and infrequent-dosing schedules of oritavancin were as efficacious as daily administration and had a similar safety profile in treating cSSSI caused by Gram-positive pathogens, including MRSA.

Intravenous arylsulfatase A in metachromatic leukodystrophy: a phase 1/2 study.

OBJECTIVE: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by deficient activity of arylsulfatase A (ASA), resulting in severe motor and cognitive dysfunction. This phase 1/2 study evaluated the safety and efficacy of intravenous (IV) recombinant human ASA (rhASA; HGT-1111, previously known as Metazym) in children with MLD. METHODS: Thirteen children with MLD (symptom onset < 4 years of age) were enrolled in an open-label, nonrandomized, dose-escalation trial and received IV rhASA at 50, 100, or 200 U/kg body weight every 14 (± 4) days for 52 weeks (NCT00418561; NCT00633139). Eleven children continued to receive rhASA at 100 or 200 U/kg during a 24-month extension period (NCT00681811). Outcome measures included safety observations, changes in motor and cognitive function, and changes in nerve conduction and morphometry. RESULTS: There were no serious adverse events considered related to IV rhASA. Motor function and developmental testing scores declined during the study in all dose groups; no significant differences were observed between groups. Nerve conduction studies and morphometric analysis indicated that peripheral nerve pathology did not worsen during the study in any dose group. INTERPRETATION: IV rhASA was generally well tolerated. There was no evidence of efficacy in preventing motor and cognitive deterioration, suggesting that IV rhASA may not cross the blood-brain barrier in therapeutic quantities. The relative stability of peripheral nerve function during the study indicates that rhASA may be beneficial if delivered to the appropriate target site and supports the development of rhASA for intrathecal administration in MLD.

Pharmacokinetic Modeling of Intrathecally Administered Recombinant Human Arylsulfatase A (TAK-611) in Children With Metachromatic Leukodystrophy.

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by deficient arylsulfatase A (ASA) activity, which leads to neuronal sulfatide accumulation and motor and cognitive deterioration. Intrathecal delivery of a recombinant human ASA (TAK-611, formerly SHP611) is under development as a potential therapy for MLD. We used serum and cerebrospinal fluid (CSF) TAK-611 concentrations measured during the phase I/II trial of intrathecal TAK-611 to develop a pharmacokinetic (PK) model describing drug disposition. CSF data were well characterized by a two-compartment model in the central nervous system (CNS); a single central compartment described the serum data. Estimated parameters suggested rapid distribution of TAK-611 from CSF into the putative brain tissue compartment, with persistence in the brain between doses (median distributive and terminal half-lives in the CNS: 1.02 and 477 hours, respectively). This model provides a valuable basis for understanding the PK distribution of TAK-611 and for PK/pharmacodynamic analyses of functional outcomes.