Ex vivo human placental transfer of the peptides pramlintide and exenatide (synthetic exendin-4).
Two peptides, pramlintide (37 amino acids), an analog of human amylin, and exenatide, synthetic exendin-4 (39 amino acids), are both in late-stage clinical development as potential new treatments for people with diabetes. Both are potential long-term treatments, and there is the likelihood that some women will become pregnant while using one of these peptide therapies. Therefore, it was important to evaluate the potential for each peptide to cross the placental barrier and thereby result in exposure to the fetus. This was examined using ex vivo perfusions of human placentas. The fetal and maternal side of a cotyledon were cannulated and perfused first with buffer, and then with radioactive antipyrine in order to establish the integrity of the system and the perfusion constants. Either pramlintide or exenatide was then added to each acceptable cotyledon perfusate on the maternal side. Each peptide was evaluated at an initial concentration near the therapeutic plasma concentration and at approximately 10-50 times that concentration in each of the three cotyledons. Maternal and fetal perfusate samples were assayed for peptide concentrations using an immunoassay. The ratio of fetal-to-maternal peptide concentrations during equilibrium perfusion were extremely low (pramlintide < or = 0.006, exenatide < or = 0.017). These data demonstrate negligible passage of either peptide across the placental barrier. It is, therefore, likely that maternal use of either peptide during gestation will result in negligible exposure to the fetus.
Amylin Pharmaceuticals, Inc., San Diego, CA, USA. rhiles@amylin.com
Richard A
RA
Hiles
Roger E
RE
Bawdon
Ezio M
EM
Petrella
D000682:Amyloid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002404:Catheterization; D004353:Drug Evaluation, Preclinical; D000077270:Exenatide; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D007328:Insulin / Q000378:metabolism; D058228:Islet Amyloid Polypeptide; D008431:Maternal-Fetal Exchange / Q000187:drug effects* / Q000502:physiology; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010477:Perfusion / Q000379:methods; D010920:Placenta / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D021041:Placental Circulation / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D014688:Venoms / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000682:Amyloid; D007004:Hypoglycemic Agents; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; C105254:pramlintide