title: Pharmacokinetics of oral recombinant human parathyroid hormone [rhPTH(1-31)NH₂] in postmenopausal women with osteoporosis.
abstract: OBJECTIVE
  Teriparatide [rhPTH(1-34)OH] is a subcutaneously administered bone anabolic drug that increases bone mineral density (BMD) and reduces the risk of osteoporotic fracture. Because rhPTH(1-34)OH is administered by injection, oral delivery is a desirable alternative. However, the peroral delivery of peptides is challenging due to their susceptibility to protease digestion and low permeability through the intestinal layers. The objective of this study was to assess the pharmacokinetics of a PTH analog (rhPTH(1-31)NH2) in a novel oral tablet formulation and to compare them to subcutaneously administered teriparatide in postmenopausal osteoporotic women in a phase 2 proof-of-concept clinical study.
  
  
  METHODS
  This was a 24-week repeat-dose, randomized, double blind, parallel group phase 2 study with three once-daily treatment arms: oral rhPTH(1-31)NH2 tablets (5 mg), matching placebo tablets, and open-label teriparatide (20 μg daily subcutaneous injection). The primary endpoint of this study was to assess the change in lumbar spine BMD of orally administered rhPTH(1-31)NH2 tablets compared to baseline. This study was conducted at three sites in Denmark and at one site in Estonia. The patients included were women diagnosed with postmenopausal osteoporosis as detected by lumbar spine dual-energy X-ray absorptiometry, with exclusion of those with prior treatment with bone-active agents. The study treatment consisted of orally formulated recombinant human PTH(1-31)NH2, placebo, or subcutaneous teriparatide as an active comparator.
  
  
  RESULTS
  The pharmacokinetic profile at first and last dose was evaluated and correlated with the primary endpoint, which was to characterize the percent change from baseline in BMD of the lumbar spine after 24 weeks of once daily treatment with rhPTH(1-31)NH2. The pharmacokinetic profile for the tablets showed a pulsatile peak with durations of at least 1 h but less than 5 h, which is consistent with the requirement for bone anabolic activity. The mean maximum (peak) plasma drug concentration (C max) values for patients receiving tablets at week 0 (n = 32) and week 24 (n = 28) were 295 and 207 pg/mL, respectively. The mean time to reach maximum (peak) plasma concentration following drug administration (t max) for both week 0 and week 24 was 3.25 h. The mean area under the concentration-time curve (AUC) for week 0 and week 24 was 178 and 141 pg·h/mL, respectively. No significant differences were observed between weeks 0 and 24 in any pharmacokinetic parameters tested, demonstrating good reproducibility, no time-dependent changes, and little or no accumulation of the study drug. The systemic exposure as measured by C max values was higher for the oral tablets formulation than for subcutaneous teriparatide.
  
  
  CONCLUSIONS
  The observed data demonstrate that the enteric-coated tablet formulation technology was able to generate consistently robust and pulsatile levels of exposure of rhPTH(1-31)NH2. There was no apparent correlation between higher exposures and adverse events, even though the pharmacokinetic variability was somewhat higher with the tablets. These positive results recommend this orally delivered drug candidate for further clinical development.
authors.affiliation: Unigene Laboratories, Inc., 110 Little Falls Road, Fairfield, NJ, 07004, USA, asturmer@unigene.com.
authors.forename: Amy
authors.initials: A
authors.lastname: Sturmer
authors.forename: Nozer
authors.initials: N
authors.lastname: Mehta
authors.forename: Jenna
authors.initials: J
authors.lastname: Giacchi
authors.forename: Tulin
authors.initials: T
authors.lastname: Cagatay
authors.forename: Roxanne
authors.initials: R
authors.lastname: Tavakkol
authors.forename: Sheela
authors.initials: S
authors.lastname: Mitta
authors.forename: Lorraine
authors.initials: L
authors.lastname: Fitzpatrick
authors.forename: Jeff
authors.initials: J
authors.lastname: Wald
authors.forename: John
authors.initials: J
authors.lastname: Trang
authors.forename: William
authors.initials: W
authors.lastname: Stern
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017698:Postmenopause; D011994:Recombinant Proteins / Q000493:pharmacokinetics; D019379:Teriparatide / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: C470125:PTH protein, human; D010281:Parathyroid Hormone; D011994:Recombinant Proteins; D019379:Teriparatide