Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
A Novel Oral Parathyroid Hormone Formulation, PTH134, Demonstrated a Potential Therapeutically Relevant Pharmacokinetic and Safety Profile Compared with Teriparatide s.c. in Healthy Postmenopausal Women After a Single Dose
John, Markus R., Haemmerle, Sibylle, Launonen, Aino, Harfst, Evita, Azria, Moise, Arnold, Michel, Mindeholm, Linda
Parathyroid hormone (PTH), currently the only anabolic treatment for osteoporosis, is available as the full-length hormone, PTH184, or as the PTH134 fragment (teriparatide). Both must be given subcutaneously (s.c.). A new oral formulation of PTH134 (PTH134) is being developed as a more convenient option for patients. In this single-centre, partially-blinded, incomplete cross-over study, the safety, tolerability, and exposure of oral PTH134 (teriparatide combined with 2 different quantities of the absorption enhancer 5-CNAC) were assessed in 32 healthy postmenopausal women.
16 subjects were randomized to receive single doses of up to six different treatments: placebo, teriparatide 20mg s.c., or 1, 2.5, 5 or 10mg of oral PTH134 formulated with 200mg 5-CNAC. Subsequently, another 16 subjects were randomized to receive up to six different treatments: placebo, teriparatide 20mg s.c, or 2.5 or 5mg of oral PTH134 formulated with either 100 or 200mg 5-CNAC. Doses were given >= 6 days apart.
All doses of PTH134 were rapidly absorbed, and showed robust blood concentrations in a dose-dependent manner. Interestingly, PTH134 was eliminated faster after oral versus s.c. administration. Specifically, 2.5 and 5 mg PTH134 (containing 200 mg 5-CNAC) demonstrated Cmax and AUC0-last values closest to those of s.c. teriparatide 20mg. The geometric mean estimate for PTH134 2.5mg/200mg 5-CNAC was 98.7 pg/ml (90% CI 67.3144.7) for Cmax and 28.3 hr*pg/ml (90% CI 16.449.0) for AUC(0-last), while for PTH134 5mg/200mg 5-CNAC the estimated geometric mean values were 502.7 pg/ml (90% CI 304.5829.6) for Cmax and 175.4 hr*pg/ml (90% CI 86.0358.0) for AUC(0-last). The corresponding estimates for teriparatide 20 mg s.c. were 143.6 pg/ml (90% CI 123.7166.7) for Cmax and 229.9 hr*pg/ml (90% CI 198.9263.7) for AUC(0-last).
Ionized calcium remained within normal limits in all treatment groups. Nine subjects withdrew due to treatment-related AEs. Of those, seven were taking PTH134 2.5 or 5mg: three withdrew for symptomatic hypotension (two of whom were in the 200mg 5-CNAC group), three because of delayed vomiting (two from the 200mg 5-CNAC group), one withdrew for symptomatic, but unconfirmed, hypercalcemia (receiving 2.5mg/100mg 5-CNAC). One subject receiving teriparatide and one receiving placebo withdrew for symptomatic hypotension. No serious AEs were reported.
The study demonstrated potential therapeutically relevant PTH134 systemic exposure levels after oral administration of PTH134 formulated with the absorption enhancer 5-CNAC. Doses of 2.5 and 5mg of oral PTH134 achieved exposure levels closest to those of teriparatide 20mg s.c., with a comparable incidence of AEs in healthy postmenopausal women. PTH134 warrants further investigation
To cite this abstract, please use the following information:
John, Markus R., Haemmerle, Sibylle, Launonen, Aino, Harfst, Evita, Azria, Moise, Arnold, Michel, et al; A Novel Oral Parathyroid Hormone Formulation, PTH134, Demonstrated a Potential Therapeutically Relevant Pharmacokinetic and Safety Profile Compared with Teriparatide s.c. in Healthy Postmenopausal Women After a Single Dose [abstract]. Arthritis Rheum 2009;60 Suppl 10 :887