SAGE-217, A Novel GABAA Receptor Positive Allosteric Modulator: Clinical Pharmacology and Tolerability in Randomized Phase I Dose-Finding Studies.

BACKGROUND: SAGE-217, a novel γ-aminobutyric acid A (GABAA) receptor positive allosteric modulator, was evaluated in phase I, double-blind, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) studies to assess the safety and pharmacokinetics (PK) of SAGE-217 following administration as an oral solution. METHODS: In the SAD study, subjects were randomized 6:2 to a single dose of SAGE-217 or placebo. Doses ranged from 0.25 to 66 mg across nine cohorts. In the MAD study, subjects were randomized 9:3 and received SAGE-217 (15, 30, or 35 mg) or placebo once daily for 7 days. In both studies, PK, maximum tolerated dose (MTD; against predetermined criteria), safety, and tolerability were assessed. RESULTS: A total of 108 healthy volunteers enrolled in the studies-72 subjects in the SAD study and 36 subjects in the MAD study. SAGE-217 was orally bioavailable, with a terminal-phase half-life of 16-23 h and a tmax of approximately 1 h. The MTDs for the oral solution of SAGE-217 in the SAD and MAD studies were determined to be 55 and 30 mg daily, respectively. In both studies, SAGE-217 was generally well tolerated, and no serious adverse events (SAEs) were reported. Most AEs were mild, dose-dependent, transient, occurred around the tmax, and related to drug pharmacology. CONCLUSIONS: SAGE-217 was generally well tolerated, and its PK profile was well characterized. Based on this profile, SAGE-217 has been advanced into multiple phase II clinical programs and pivotal studies of major depressive disorder and postpartum depression.

Pharmacokinetics of oral recombinant human parathyroid hormone [rhPTH(1-31)NH2] in postmenopausal women with osteoporosis.

BACKGROUND AND OBJECTIVES: Teriparatide [rhPTH(1-34)OH] is a subcutaneously administered bone anabolic drug that increases bone mineral density (BMD) and reduces the risk of osteoporotic fracture. Because rhPTH(1-34)OH is administered by injection, oral delivery is a desirable alternative. However, the peroral delivery of peptides is challenging due to their susceptibility to protease digestion and low permeability through the intestinal layers. The objective of this study was to assess the pharmacokinetics of a PTH analog (rhPTH(1-31)NH2) in a novel oral tablet formulation and to compare them to subcutaneously administered teriparatide in postmenopausal osteoporotic women in a phase 2 proof-of-concept clinical study. METHODS: This was a 24-week repeat-dose, randomized, double blind, parallel group phase 2 study with three once-daily treatment arms: oral rhPTH(1-31)NH2 tablets (5 mg), matching placebo tablets, and open-label teriparatide (20 µg daily subcutaneous injection). The primary endpoint of this study was to assess the change in lumbar spine BMD of orally administered rhPTH(1-31)NH2 tablets compared to baseline. This study was conducted at three sites in Denmark and at one site in Estonia. The patients included were women diagnosed with postmenopausal osteoporosis as detected by lumbar spine dual-energy X-ray absorptiometry, with exclusion of those with prior treatment with bone-active agents. The study treatment consisted of orally formulated recombinant human PTH(1-31)NH2, placebo, or subcutaneous teriparatide as an active comparator. RESULTS: The pharmacokinetic profile at first and last dose was evaluated and correlated with the primary endpoint, which was to characterize the percent change from baseline in BMD of the lumbar spine after 24 weeks of once daily treatment with rhPTH(1-31)NH2. The pharmacokinetic profile for the tablets showed a pulsatile peak with durations of at least 1 h but less than 5 h, which is consistent with the requirement for bone anabolic activity. The mean maximum (peak) plasma drug concentration (C max) values for patients receiving tablets at week 0 (n = 32) and week 24 (n = 28) were 295 and 207 pg/mL, respectively. The mean time to reach maximum (peak) plasma concentration following drug administration (t max) for both week 0 and week 24 was 3.25 h. The mean area under the concentration-time curve (AUC) for week 0 and week 24 was 178 and 141 pg·h/mL, respectively. No significant differences were observed between weeks 0 and 24 in any pharmacokinetic parameters tested, demonstrating good reproducibility, no time-dependent changes, and little or no accumulation of the study drug. The systemic exposure as measured by C max values was higher for the oral tablets formulation than for subcutaneous teriparatide. CONCLUSIONS: The observed data demonstrate that the enteric-coated tablet formulation technology was able to generate consistently robust and pulsatile levels of exposure of rhPTH(1-31)NH2. There was no apparent correlation between higher exposures and adverse events, even though the pharmacokinetic variability was somewhat higher with the tablets. These positive results recommend this orally delivered drug candidate for further clinical development.

Pharmacokinetics and tolerability of SRT2104, a first-in-class small molecule activator of SIRT1, after single and repeated oral administration in man.

AIM: SRT2104 is a novel, first-in-class, highly selective small molecule activator of the NAD + dependent deacetylase SIRT1. SRT2104 was dosed to healthy male and female volunteers in a series of phase 1 clinical studies that were designed to elucidate tolerability and pharmacokinetics associated with oral dosing to aid in dose selection for subsequent clinical trials. METHODS: In the first-in-human study, there was both a single dose phase and 7 day repeat dose phase. Doses used ranged from 0.03 to 3.0 g. A radioactive microtracer study was subsequently conducted to determine systemic clearance, bioavailability and preliminary metabolism, and a crossover study was conducted to determine the effect of gender, formulation and feeding state on SRT2104 pharmacokinetics. RESULTS: SRT2104 was well tolerated in all of these studies, with no serious adverse reactions observed. SRT2104 displayed a dose-dependent, but sub-proportional increase in exposure following single dose and repeated dose administration. Accumulation of three-fold or less occurs after 7 days of repeat dosing. The mean bioavailability was circa 14% and the mean clearance was circa 400 ml min(-1). Although there were no substantial effects on exposure resulting from gender or formulation differences, a notable food effect was observed, manifested as up to four-fold increase in exposure parameters. CONCLUSIONS: In the absence of an optimized formulation of SRT2104, the food effect can be used to maximize exposure in future clinical studies. Combined with the good tolerability of all doses demonstrated in these studies, the favourable selectivity profile of SRT2104 allows for the use of this SIRT1 modulator for target validation in the clinic.

Population pharmacokinetics of netilmicin in short-term prophylactic treatment.

AIMS: To characterize the population pharmacokinetics of netilmicin, an aminoglycoside antibiotic, in adult urology patients and to develop a covariate model for improved dose titration. METHODS: Data from 62 adult patients (55 male, seven female), undergoing urological surgery and treated with netilmicin for short-term prophylaxis, were evaluated retrospectively. The group had (median, range) ages 68, 31-92 years, weights 72, 43-106 kg and heights 167, 148-182 cm. No patient showed renal impairment before netilmicin treatment (serum creatinine