Inhaled drugs offer advantages, such as rapid onset of action, but require formulations and delivery systems that reproducibly and conveniently administer the drug. CVT-301 is a powder formulation of levodopa delivered by a breath-actuated inhaler that has been developed for treating OFF episodes (motor fluctuations between doses of standard oral levodopa) in patients with Parkinson's disease (PD). We present preclinical, phase 1, and phase 2 results for CVT-301. In dogs insufflated with a levodopa powder, plasma levodopa peaked in all animals 2.5 min after administration; in contrast, in dogs dosed orally with levodopa plus carbidopa, plasma levodopa was not detected until 30 min after administration. In 18 healthy persons, comparisons between inhaled CVT-301 and oral carbidopa/levodopa showed analogous differences in pharmacokinetics. Among 24 PD patients inhaling CVT-301 as a single 50-mg dose during an OFF episode, 77% showed an increase in plasma levodopa (>400 ng/ml) within 10 min versus 27% for oral dosing with carbidopa/levodopa at a 25-mg/100-mg dose. Improvements in timed finger tapping and overall motor function (Part III of the Unified Parkinson's Disease Rating Scale) were seen 5 and 15 min after administration, the earliest assessment time points. For average and best change, the improvements were statistically significant compared to placebo. The most common adverse event was cough; all cough events were mild to moderate, occurred at the time of inhalation, resolved rapidly, and became less frequent after initial dosing. These results support further development of CVT-301 for better management of PD.

A novel recombinant human growth hormone (rhGH) fusion protein (VRS-317) was designed to minimize receptor-mediated clearance through a reduction in receptor binding without mutations to rhGH by genetically fusing with XTEN amino acid sequences to the N-terminus and the C-terminus of the native hGH sequence. Although in vitro potency of VRS-317 was reduced approximately 12-fold compared with rhGH, in vivo potency was increased because of the greatly prolonged exposure to the target tissues and organs. VRS-317 was threefold more potent than daily rhGH in hypophysectomized rats and fivefold more potent than daily rhGH in juvenile monkeys. In juvenile monkeys, a monthly dose of 1.4 mg/kg VRS-317 (equivalent to 0.26 mg/kg rhGH) caused a sustained pharmacodynamic response for 1 month equivalent to 0.05 mg/kg/day rhGH (1.4 mg/kg rhGH total over 28 days). In monkeys, VRS-317, having a terminal elimination half-life of approximately 110 h, was rapidly and near-completely absorbed, and was well tolerated with no observed adverse effects after every alternate week subcutaneous dosing for 14 weeks. VRS-317 also did not cause lipoatrophy in pig and monkey studies. VRS-317 is currently being studied in GH-deficient patients to confirm the observations in these animal studies. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:2744–2754, 2012

The clearance and volume of distribution of five human proteins (recombinant CD4, CD4 immunoglobulin G, growth hormone, tissue-plasminogen activator, and relaxin) in humans and laboratory animals were analyzed as a function of body weight using allometric scaling techniques. These proteins cover a 16-fold range of molecular weight (6 to 98 kD), are produced by recombinant or synthetic methods, and may be cleared by different mechanisms. The analyses revealed that the clearance and volume data for each protein were satisfactorily described by an allometric equation (Y = a Wb). The allometric exponent (b) for clearance (ml/min) ranged from 0.65 to 0.84, the allometric exponent for the initial volume of distribution (ml) ranged from 0.83 to 1.05, and the allometric exponent for the volume of distribution at steady state (ml) ranged from 0.84 to 1.02. Exponent values from 0.6 to 0.8 for clearance and 0.8 to 1.0 for volumes are frequently cited for small molecules and are expected based on empirical interspecies relationships. When the preclinical data were analyzed separately, the preclinical allometric relationships were usually predictive of the human results. These findings indicate that the clearance and volume of distribution of select biomacromolecules follow well-defined, size-related physiologic relationships, and preclinical pharmacokinetic studies provide reasonable estimates of human disposition. Employing this methodology during the early phases of drug development may provide a more rational basis for dose selection in the clinical environment.

The effect of chronic consumption of alcohol on the circadian variations of the plasma corticosterone investigated in DBA/2J male mice. After 15 weeks of alcohol consumption (3.8%w/v for the first week and 7.5% for subsequent weeks) the alcohol groups exhibited a flattened circadian corticosterone curve, the level being intermediate between the peak and trough values of the water control groups. The diurnal patterns of food and liquid consumption were still present at the 10th week of alcohol treatment in the alcohol groups, although the absolute amount of food and liquid consumed at each of the 6-h intervals was somewhat different between the alcohol and water groups. The blood alcohol showed a peak at early morning with the mean of 100 mg/100 ml, but the levels of alcohol during the remaining periods were remarkably stable, the means ranging from 30 to 46 mg/100 ml. Chronic consumption of alcohol, even relatively low concentrations, appears to affect the neural sites in the CNS controlling the circadian rhythm of ACTH release.

Background:Administration of daily recombinant human GH (rhGH) poses a considerable challenge to patient compliance. Reduced dosing frequency may improve treatment adherence and potentially overall treatment outcomes.Objectives:This study assessed the safety and tolerability and the potential for achieving IGF-I levels within the target range in adults with GH deficiency after a single dose of the long-acting rhGH analog, VRS-317.Design:This was a randomized, double-blind, placebo-controlled, single ascending dose study.Patients:Fifty adults with growth hormone deficiency (mean age, 45 years) were studied in 5 treatment groups of 10 subjects each (8 active drug and 2 placebo).Setting:The study was conducted in 17 adult endocrinology centers in North America and Europe.Main Outcome Measures:Adverse events, laboratory safety assessments, and VRS-317 pharmacokinetics and pharmacodynamics (IGF-I and IGF binding protein-3) were analyzed.Results:At 0.80 mg/kg, VRS-317 had a mean terminal elimination half-life of 131 hours. Single VRS-317 doses of 0.05, 0.10, 0.20, 0.40, and 0.80 mg/kg (approximately equivalent to daily rhGH doses of 0.3–5.0 μg/kg over 30 d) safely increased the amplitude and duration of IGF-I responses in a dose-dependent manner. After a single 0.80 mg/kg dose, serum IGF-I was maintained in the normal range between −1.5 and 1.5 SD values for a mean of 3 weeks. No unexpected or serious adverse events were observed.Conclusions:The elimination half-life for VRS-317 is 30- to 60-fold longer and stimulates more durable IGF-I responses than previously studied rhGH products. Prolonged IGF-I responses do not come at the expense of overexposure to high IGF-I levels. The pharmacokinetics and pharmacodynamics combined with the observed safety profile indicate the potential for safe and effective monthly dosing.