Lack of pharmacokinetic interaction for ISIS 113715, a 2'-0-methoxyethyl modified antisense oligonucleotide targeting protein tyrosine phosphatase 1B messenger RNA, with oral antidiabetic compounds metformin, glipizide or rosiglitazone.
BACKGROUND
ISIS 113715 is a 20-mer phosphorothioate antisense oligonucleotide (ASO) that is complementary to the protein tyrosine phosphatase 1B (PTP-1B) messenger RNA and subsequently reduces translation of the PTP-1B protein, a negative regulator of insulin receptor. ISIS 113715 is currently being studied in early phase II clinical studies to determine its ability to improve or restore insulin receptor sensitivity in patients with type 2 diabetes mellitus. Future work will investigate the combination of ISIS 113715 with antidiabetic compounds.


METHODS
In vitro ultrafiltration human plasma protein binding displacement studies and a phase I clinical study were used to characterise the potential for pharmacokinetic interaction of ISIS 113715 and three marketed oral antidiabetic agents. ISIS 113715 was co-incubated with glipizide and rosiglitazone in whole human plasma and tested for increased free drug concentrations. In a phase I clinical study, 23 healthy volunteers received a single oral dose of an antidiabetic compound (either metformin, glipizide or rosiglitazone) both alone and together with subcutaneous ISIS 113715 200 mg in a sequential crossover design. A comparative pharmacokinetic analysis was performed to determine if there were any effects that resulted from coadministration of ISIS 113715 with these antidiabetic compounds.


RESULTS
In vitro human plasma protein binding displacement studies showed only minor effects on rosiglitazone and no effect on glipizide when co-incubated with ISIS 113715. The results of the phase I clinical study further indicate that there were no measurable changes in glipizide (5 mg), metformin (500 mg) or rosiglitazone (2 mg) exposure parameters, maximum plasma concentration and the area under the concentration-time curve, or pharmacokinetic parameter, elimination half-life when coadministered with ISIS 113715. Furthermore, there was no effect of ISIS 113715, administered in combination with metformin, on the urinary excretion of metformin. Conversely, there were no observed alterations in ISIS 113715 pharmacokinetics when administered in combination with any of the oral antidiabetic compounds.


CONCLUSIONS
These data provide evidence that ISIS 113715 exhibits no clinically relevant pharmacokinetic interactions on the disposition and clearance of the oral antidiabetic drugs. The results of these studies support further study of ISIS 113715 in combination with antidiabetic compounds.
Geary
Richard S
RS
ISIS Pharmaceuticals, Inc., Carlsbad, California 92008, USA. rgeary@isisph.com
Bradley
JoAnn D
JD
Watanabe
Tanya
T
Kwon
Younggil
Y
Wedel
Mark
M
van Lier
Jan J
JJ
VanVliet
André A
AA
D000284:Administration, Oral; D000328:Adult; D001798:Blood Proteins / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D005913:Glipizide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008875:Middle Aged; D009843:Oligoribonucleotides / Q000235:genetics / Q000493:pharmacokinetics*; D011485:Protein Binding; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000493:pharmacokinetics*
D001798:Blood Proteins; D007004:Hypoglycemic Agents; D009843:Oligoribonucleotides; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C496122:ISIS-113715; D008687:Metformin; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; D005913:Glipizide