Drug release profile of a novel exenatide long-term drug delivery system (OKV-119) administered to cats.

Beneficial weight-loss properties of glucagon-like peptide-1 receptor agonists (GLP-1RA) in obese people, with corresponding improvements in cardiometabolic risk factors, are well established. OKV-119 is an investigational drug delivery system that is being developed for the long-term delivery of the GLP-1RA exenatide to feline patients. The purpose of this study was to evaluate the drug release characteristics of subcutaneous OKV-119 implants configured to release exenatide for 84 days. Following a 7-day acclimation period, five purpose-bred cats were implanted with OKV-119 protypes and observed for a 112-day study period. Food intake, weekly plasma exenatide concentrations and body weight were measured. Exenatide plasma concentrations were detected at the first measured timepoint (Day 7) and maintained above baseline for over 84 Days. Over the first 28 days, reduced caloric intake and a reduction in body weight were observed in four of five cats. In these cats, a body weight reduction of at least 5% was maintained throughout the 112-day study period. This study demonstrates that a single OKV-119 implant can deliver the GLP-1RA exenatide for a months long duration. Results suggest that exposure to exenatide plasma concentrations ranging from 1.5 ng/ml to 4 ng/ml are sufficient for inducing weight loss in cats.

Safety, Tolerability, and Proof-Of-Concept Study of OKV-119, a Novel Exenatide Long-Term Drug Delivery System, in Healthy Cats.

Background: Glucagon-like peptide-1 (GLP-1) is an incretin hormone that plays an important role in glucose homeostasis and food intake. In people, GLP-1 receptor agonists (GLP-1RAs) are commonly used for the treatment of type 2 diabetes mellitus (DM) and obesity; however, non-adherence to injectable medications is common. OKV-119 is an investigational drug delivery system intended for subdermal implantation and delivery of the GLP-1RA exenatide for up to 6 months. Hypothesis/Objectives: Develop protocols for the subcutaneous (SC) insertion and removal of OKV-119 and to evaluate its tolerability, in vivo drug-releasing characteristics, and weight-loss effects in cats. Animals: Two cadaveric and 19 purpose-bred cats. Methods: In cadavers, OKV-119 insertion protocol and imaging were performed at three SC locations. The safety and tolerability of OKV-119 implants were assessed in a small (n = 4 cats) 62-day study. Weekly plasma exenatide concentrations and body weight were measured in a 42-day proof-of-concept study designed to evaluate OKV-119 prototypes implanted in cats (n = 15). Results: In anesthetized cats, the duration of insertion and removal procedures was 1-2 min. OKV-119 was easily identified on radiographs, and well-tolerated without any apparent implant site reactions. Following implantation, exanatide plasma concentrations were observed for up to 35 days. Plasma exenatide concentrations were correlated to weight loss. Conclusion and clinical importance: Our findings suggest that OKV-119 could be easily inserted and removed during a routine clinic visit and can be used to safely and effectively deliver exenatide. Future studies of OKV-119, configured to release exenatide for a longer extended months-long duration, are warranted to determine whether the combination of metabolic improvements and beneficial weight-loss, coupled with minimal impact on pet-owner's lifestyle, lead to improved outcomes for obese cats and feline DM patients.

Single-dose pharmacokinetics of mycophenolic acid following administration of immediate-release mycophenolate mofetil in healthy Beagle dogs.

Mycophenolic acid (MPA) is an immunomodulating agent commonly used in human medicine for the treatment of immune-mediated diseases. There is growing evidence that the immunomodulating properties of mycophenolate mofetil (MMF), a prodrug of MPA, are therapeutically beneficial for the treatment of immune-mediated diseases in dogs. A narrow therapeutic index and high inter-and intra-patient pharmacokinetic (PK) variability complicate the use of MMF. A better characterization of MPA pharmacokinetics is needed to help establish dosing regimens and standardized treatment protocols for canine patients. The purpose of this study was to evaluate the pharmacokinetics of MPA in dogs. MMF oral suspension (10 mg/kg) was administered to five healthy beagle dogs. Serial blood samples were collected from 0 to 18 hours after administration. The simultaneous quantification of MPA, and its metabolites MPA-7-O-glucuronide (MPAG), and acyl glucuronide (AcMPAG) was determined by liquid chromatography (LC)-mass spectrometry (MS)/MS. MPA peak concentrations were achieved rapidly (median Tmax of 0.5 h). Concentrations fell through 3 hours post-dose and then plateaued around 20% of Cmax. The mean elimination half-life was rapid (5.8 hours) and notable variability was observed in all PK parameters. The PK profiles for the MPAG and AcMPAG metabolites followed a similar pattern as MPA concentration. Future repeat-dose studies will be needed to evaluate steady-state PK parameters and to define therapeutic MPA dose levels.

Pharmacokinetics and Pharmacodynamics of Immediate- and Modified-Release Mycophenolic Acid Preparations in Healthy Beagle Dogs.

Background: Mycophenolic acid (MPA) is a broad-acting immunomodulating agent that may be therapeutically beneficial for the treatment of immune-mediated diseases in canine patients. Objectives: To determine the suppressive effects of MPA on T-cell proliferation, and to assess the feasibility of a canine-specific q24 h modified-release MPA formulation (OKV-1001b). Animals: Fifteen healthy purpose-bred male beagle dogs. Methods: Two nearly identical open-label fifteen-day studies were conducted in which dogs were randomized to receive mycophenolate mofetil (MMF; 10 mg/kg q12h), or two doses of OKV-1001b (270 mg and 180 mg; q24h). Serial pharmacokinetic (PK) and pharmacodynamic (PD) samples were collected on Days 1, 8, and 15. MPA plasma concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), while an ex vivo T-cell proliferation assay assessed PD effects. Dogs were continuously monitored for evidence of side effects and gastrointestinal tolerability. Results: MPA induced inhibition of T-cell proliferation was observed following administration of all MPA preparations in a clear concentration-dependent manner. The PK/PD relationship was maintained across all days and time-points. Data generated herein suggest that MPA plasma concentrations above 600 ng/mL achieve at least 50% inhibition of T-cell proliferation. Conclusions and Clinical Importance: MPA holds therapeutic potential for treating dogs with immune-mediated disease, but clinical trials will be necessary to determine its safety and efficacy in naturally occurring disease. Likewise, q24h oral modified release MPA preparations that maintain MPA plasma concentrations between 600 and 1,000 ng/mL are warranted for further studies in client-owned dogs.

Mycophenolic acid in patients with immune-mediated inflammatory diseases: From humans to dogs.

Mycophenolic acid (MPA), a noncompetitive, selective and reversible inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH), is an immunosuppressive agent that has a long history in medicine. Mechanistically, the inhibition of IMPDH leads to the selective and eventual arrest of T- and B-lymphocyte proliferation. Mycophenolate mofetil (MMF), the first MPA-based product to receive marketing approval over two decades ago, was originally indicated for the prophylaxis of organ rejection in human transplant patients. Given its broad immunosuppressive properties and ability to selectively inhibit lymphocyte division and effector functions, the clinical utility of MPA was subsequently explored in a host of autoimmune diseases. Human clinical studies have shown MPA to be safe and effective and support its off-label administration for immune-mediated diseases such as lupus, myasthenia gravis and atopic dermatitis. MMF became generically available in the United States in 2008, and its clinical utility is increasingly being explored as a treatment option for dogs with immune-mediated diseases. This review summarizes the available literature for MPA pharmacokinetics and pharmacodynamics, and the current status of MPA as a treatment for client-owned dogs diagnosed with immune-mediated diseases.

Acute and chronic lung function responses to salmeterol and salmeterol plus fluticasone propionate in relation to Arg16Gly beta(2)-adrenergic polymorphisms.

OBJECTIVE: There is conflicting clinical evidence describing the response to long-acting beta-agonist (LABA) bronchodilators for patients with Arg16Gly beta(2)-adrenergic receptor (ADRB2 ) genotype differences. Furthermore, the role of inhaled corticosteroids (ICS) in modulating Arg16Gly clinical responses is not well understood. The objective of this study was to investigate the effects of Arg16Gly polymorphism on the 12 hour post-dose bronchodilator response to the LABA salmeterol (SAL) or SAL plus fluticasone propionate (FSC) on first administration and following 12 weeks of treatment. RESEARCH DESIGN AND METHODS: Genotyping was retrospectively performed in patients with persistent asthma randomized to SAL or FSC who were participating in three similar double-blind clinical trials of 12 week duration. The primary outcome was area under the curve (AUC) for 12 hour serial FEV(1) by treatment and Arg16Gly genotype, recorded on Day 1 and Week 12. In addition, other single nucleotide polymorphisms (SNPs) associated with asthma outcomes we assessed at positions -47, +79 and +491 as well as common ADRB2 haplotypes. RESULTS: No statistically significant associations between Arg16Gly genotypes and serial FEV(1) clinical responses to SAL and FSC were observed following acute assessment. In addition, the FEV(1) response was preserved following 12 weeks of treatment with SAL and FSC and was not altered by Arg16Gly genotypes analyzed. These results may not be generalizable to other ethnic groups since they are derived predominantly from Caucasians. CONCLUSIONS: In subjects with persistent asthma, the ADRB2 Arg16Gly polymorphism does not alter lung function responses to SAL or FSC over the 12 hour dosing interval following acute and chronic dosing.

Pharmacogenetics of the 5-lipoxygenase biosynthetic pathway and variable clinical response to montelukast.

OBJECTIVE: Interindividual clinical response to leukotriene modifiers is highly variable, and less efficacious than inhaled corticosteroids in treating asthma. Genetic variability in 5-lipoxygenase biosynthetic and receptor pathway gene loci may influence cysteinyl-leukotriene production and subsequent response to leukotriene modifiers. METHODS: Using data from two clinical trials of 12-week duration, post-hoc analyses were performed in 174 patients randomized to montelukast. Associations between polymorphisms in 10 candidate genes (ALOX5, ALOX5AP, LTC4S, CYSLTR1, CYSLTR2, PLA2G4A, CYP2C9, CYP3A4, ADRB2, and NR3C1) and response to montelukast were modeled using change in morning peak expiratory flow and forced expiratory volume in 1 s (FEV1) to define the response phenotype. RESULTS: In our sample, eight out of 25 markers in 10 candidate genes were statistically associated with response to montelukast, with an estimated proportion of false discoveries of 16%. The strongest statistical evidence of clinically relevant pharmacogenetic effects peak expiratory flow were identified in CYSLTR2 (rs91227 and rs912278; P=0.02 and P=0.02, respectively) and ALOX5 (rs4987105 and rs4986832; P=0.01 and P=0.01, respectively). Patients with these variant genotypes, found in roughly 10-13% of patients, had an 18-25% improvement in peak expiratory flow. In contrast, the majority of patients with the wild-type alleles had only a marginal (8-10%) improvement. CONCLUSIONS: The overall mean response to montelukast may be skewed towards a response phenotype by a small subset (<15%) of asthma patients. CYSLTR2 and ALOX5 polymorphisms may predispose a minority of individuals to excessive cysteinyl-leukotriene concentrations, yielding a distinct asthma phenotype most likely to respond to leukotriene modifier pharmacotherapy. These findings require replication to establish validity and clinical utility.

Salmeterol response is not affected by beta2-adrenergic receptor genotype in subjects with persistent asthma.

BACKGROUND: Recent studies suggest that there might be an association between albuterol use and worsening asthma in patients homozygous for arginine (Arg/Arg) at codon 16 of the beta-receptor. However, it is not known whether similar responses occur in Arg/Arg patients receiving long-acting beta2-agonists. OBJECTIVE: We sought to evaluate the effects of variation in the beta2-adrenergic receptor gene (ADRB2) on clinical response to salmeterol administered with fluticasone propionate. METHODS: Subjects (n = 183) currently receiving short-acting beta2-agonists were randomized to twice-daily therapy with salmeterol, 50 microg, administered with fluticasone propionate, 100 microg, in a single inhaler or daily therapy with montelukast for 12 weeks, followed by a 2- to 4-day run-out period. RESULTS: There was sustained and significant improvement (P < .001) over baseline in all measures of asthma control in subjects receiving salmeterol, regardless of Arg16Gly genotype. Morning peak expiratory flow in subjects with the Arg/Arg genotype showed 89.0 +/- 16.1 L/min improvement over baseline compared with 93.7 +/- 12.7 L/min for Gly/Gly subjects and 92.5 +/- 11.9 L/min for Arg/Gly subjects. Pairwise changes were similar for Arg/Arg compared with Gly/Gly or Arg/Gly genotypes (estimated differences, 4.7 L/min and 3.5 L/min, respectively). Responses did not appear to be modified by haplotype pairs. During the run-out period, all subjects had predictable and similar decreases in measures of asthma control, with no differences between genotypes. CONCLUSION: Response to salmeterol does not vary between ADRB2 genotypes after chronic dosing with an inhaled corticosteroid. CLINICAL IMPLICATIONS: Analyses from this study indicate that genetic polymorphisms leading to Arg16Gly sequence changes within the beta2-adrenergic receptor do not affect patients' responses to recommended asthma therapy with salmeterol and fluticasone propionate.