title: Pharmacokinetics and Pharmacodynamics of NPH Insulin in Type 1 Diabetes: The Importance of Appropriate Resuspension Before Subcutaneous Injection.
abstract: OBJECTIVE
  Crystalline NPH insulin comes in a two-phase solution with either a solvent or a rapid-acting insulin (in premixed formulations) and needs adequate mixing for complete resuspension before injection. The aim of this study was to establish pharmacokinetics (PK) and pharmacodynamics (PD) after injection of appropriately resuspended versus nonresuspended NPH insulin.
  
  
  METHODS
  PK and PD were assessed after subcutaneous injection of NPH insulin 0.35 units/kg at steady state by pen either resuspended (R+, tipping of insulin pen 20 times) or nonresuspended (pen maintained in fixed position either horizontally [R- horizontal] or vertically with tip up [R- up] or tip down [R- down]). Eleven subjects with type 1 diabetes (age 31.5 ± 12 years, diabetes duration 17.5 ± 7.7 years, BMI 22.9 ± 1.5 kg/m2, A1C 7.2 ± 0.4% [55.2 ± 4.4 mmol/mol]) were studied (euglycemic clamp) with a randomized crossover design.
  
  
  RESULTS
  Compared with resuspended NPH insulin (R+), nonresuspended NPH insulin resulted in profound PK/PD differences with either reduced (R- horizontal and R- up) or increased (R- down) plasma insulin concentrations [FIRI_AUC(0-end of study) (free immunoreactive insulin area under the concentration-time curve between 0 and end of study)] and PD activity [glucose infusion rate (GIR)_AUC(0-end of study)] (all P < 0.05). Duration of NPH insulin action was shorter in R- up (9.4 ± 1.7 h) but longer in R- down (15.4 ± 2.3 h) compared with R+ (11.8 ± 2.6 h) (P < 0.05). Within-subject variability (percent coefficient of variation) among studies was as high as 23% for PK [FIRI_AUC(0-end of study)] and 62% for PD [GIR_AUC(0-end of study)].
  
  
  CONCLUSIONS
  Compared with resuspended NPH insulin, lack of resuspension profoundly alters PK/PD and may importantly contribute to day-to-day glycemic variability of type 1 diabetes.
authors.affiliation: Department of Medicine, Section of Internal Medicine, Endocrinology and Metabolism, Perugia University School of Medicine, Perugia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Lucidi
authors.affiliation: Department of Medicine, Section of Internal Medicine, Endocrinology and Metabolism, Perugia University School of Medicine, Perugia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Porcellati
authors.affiliation: Department of Medicine, Section of Internal Medicine, Endocrinology and Metabolism, Perugia University School of Medicine, Perugia, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Marinelli Andreoli
authors.affiliation: Department of Medicine, Section of Internal Medicine, Endocrinology and Metabolism, Perugia University School of Medicine, Perugia, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Carriero
authors.affiliation: Department of Medicine, Section of Internal Medicine, Endocrinology and Metabolism, Perugia University School of Medicine, Perugia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Candeloro
authors.affiliation: Department of Medicine, Section of Internal Medicine, Endocrinology and Metabolism, Perugia University School of Medicine, Perugia, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Cioli
authors.affiliation: Department of Medicine, Section of Internal Medicine, Endocrinology and Metabolism, Perugia University School of Medicine, Perugia, Italy geremia.bolli@unipg.it.
authors.forename: Geremia B
authors.initials: GB
authors.lastname: Bolli
authors.affiliation: Department of Medicine, Section of Internal Medicine, Endocrinology and Metabolism, Perugia University School of Medicine, Perugia, Italy.
authors.forename: Carmine G
authors.initials: CG
authors.lastname: Fanelli
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D011232:Chemical Precipitation; D018592:Cross-Over Studies; D003460:Crystallization; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D004339:Drug Compounding; D016503:Drug Delivery Systems; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007279:Injections, Subcutaneous / Q000295:instrumentation; D007336:Insulin, Isophane / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D008297:Male; D019999:Pharmaceutical Solutions / Q000008:administration & dosage / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D019999:Pharmaceutical Solutions; D007336:Insulin, Isophane