Prevention of bone loss in ovariectomized rats by pulsatile transdermal iontophoretic administration of human PTH(1-34).
Serum human parathyroid hormone (1-34)[hPTH(1-34)] levels and the anabolic effect of hPTH(1-34) were compared after administration using multiple pulses of iontophoresis or subcutaneous (sc) intermittent injections to ovariectomized (OVX) Sprague Dawley rats. Triple-pulse iontophoretic administration of hPTH(1-34) (doses: 40-400 microg/patch), achieved by repeated 30-min applications of a 0.1 mA/cm(2) current separated by 45-min rest intervals, produced three sharp peaks in the serum hPTH(1-34) level in response to application of the current. Each peak appeared at the end of the 30-min current application period and was proportional to the hPTH(1-34) dose. Compared with once-daily sc injections (7 pulses/week), triple-pulses iontophoretic administered 3 times/week (9 pulses/week) for 4 weeks produced dose-related increases in the bone mineral density (BMD) of the distal 1/3 femur. For the sc administration, the relative BMD values using the vehicle injection as a reference standard for 1, 5, and 25 microg/kg/day were 104, 114, and 121%, respectively. For iontophoretic administration, the relative BMD values using the placebo patch as a reference standard for 40, 120, and 400 microg/patch were 104, 110, and 116%, respectively. The increase in the BMD plotted against the area under the hPTH(1-34) serum level-time curve (AUC) over 1 week resulted in similar straight lines in the 9 pulses/week iontophoretic administration and the 7 pulses/week sc administration groups. The estimated iontophoretic dose giving an equivalent BMD to once-daily sc administration at 5 microg/kg/day was 120 microg/patch. These findings strongly suggest that three iontophoretic pulses administered on alternate days will exert an anabolic effect equivalent to that of daily sc administration at doses giving the same weekly AUC. Furthermore, this method of administering hPTH(1-34) might enable self-medication, a useful advance in the treatment of osteoporosis.
Suzuki
Yasuyuki
Y
Drug Analysis & Pharmacokinetics Research Laboratories, Takeda Chemical Industries, Ltd., 17-85, Jusohonmachi 2-chome Yodogawa-ku Osaka 532-8686, Japan. Suzuki_Yasuyuki@takeda.co.jp
Nagase
Yoshinori
Y
Iga
Katsumi
K
Kawase
Masahiro
M
Oka
Masahiro
M
Yanai
Shigeo
S
Matsumoto
Yukihiro
Y
Nakagawa
Shizue
S
Fukuda
Tsunehiko
T
Adachi
Hirotoshi
H
Higo
Naruhito
N
Ogawa
Yasuaki
Y
D000279:Administration, Cutaneous; D000818:Animals; D019540:Area Under Curve; D015519:Bone Density / Q000187:drug effects; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D007478:Iontophoresis / Q000295:instrumentation / Q000379:methods*; D015663:Osteoporosis, Postmenopausal / Q000097:blood / Q000517:prevention & control*; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D019379:Teriparatide / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics
D019379:Teriparatide