The single dose pharmacokinetic profile of a novel oral human parathyroid hormone formulation in healthy postmenopausal women

• Published in: Bone (New York, N.Y.) Vol. 50; no. 4; pp. 965 - 973
• Main Authors: Hämmerle, Sibylle P, Mindeholm, Linda, Launonen, Aino, Kiese, Beate, Loeffler, Rolf, Harfst, Evita, Azria, Moise, Arnold, Michel, John, Markus R
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 01.04.2012
• Subjects: Administration, Oral; Adult; Aged; Biological and medical sciences; Caprylates - administration & dosage; Caprylates - pharmacology; Chemistry, Pharmaceutical; Cohort Studies; Confidence Intervals; Diseases of the osteoarticular system; Dose-Response Relationship, Drug; Female; Fundamental and applied biological sciences. Psychology; Health; Humans; Medical sciences; Middle Aged; Orthopedics; Osteoporosis. Osteomalacia. Paget disease; Postmenopause - drug effects; Teriparatide - administration & dosage; Teriparatide - adverse effects; Teriparatide - pharmacokinetics; Teriparatide - pharmacology; Time Factors; Vertebrates: anatomy and physiology, studies on body, several organs or systems; PTH; AUClast; Calcium metabolism; PTH134; Postmenopausal women; AUC; sc; subcutaneous; SD; Osteoporosis; PTH1-34; the maximum (peak) observed plasma concentration after single dose administration; pharmacokinetics; 8-(N-2-hydroxy-5-chloro-benzoyl)-amino-caprylic acid; parathyroid hormone; Cmax; AE; T1/2; Oral formulation; adverse event; Area under concentration-time curve; half-life; teriparatide, i.e. the N-terminal 34 amino acids of parathyroid hormone; 5-CNAC; The AUC from time zero to the last measurable concentration sampling time (tlast); PK; investigational compound comprised of human PTH1-34 as active ingredient and 5-CNAC as absorption-enhancing functional excipient, different quantities as indicated in the text; single dose; Teriparatide; Human; Antiosteoporotic; Calcium; Diseases of the osteoarticular system; Single dose; Oral administration; Metabolism; Parathyroid hormone; Formulation; Morphology; Postmenopause; Woman; Pharmacokinetics
• ISSN: 8756-3282; 1873-2763
• DOI: 10.1016/j.bone.2012.01.009

Abstract Parathyroid hormone (PTH), currently the only marketed anabolic treatment for osteoporosis, is available as the full-length hormone, human PTH1-84, or as the human PTH1-34 fragment (teriparatide). Both must be administered as a daily subcutaneous (sc) injection. A new oral formulation of human PTH1-34 (PTH134) is being developed as a more convenient option for patients. In this single-center, 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 4 single doses out of 6 different treatments: placebo, teriparatide 20 μg sc, or 1, 2.5, 5 or 10 mg of oral PTH134 formulated with 200 mg 5-CNAC. Subsequently, another 16 subjects were randomized to receive 4 out of 6 different treatments: placebo, teriparatide 20 μg sc, or 2.5 or 5 mg of oral PTH134 formulated with either 100 or 200 mg 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, PTH1-34 disappeared from blood faster after oral than after sc administration. Specifically, 2.5 and 5 mg PTH134 (containing 200 mg 5-CNAC) demonstrated Cmax and AUC0-last values closest to those of sc teriparatide 20 μg (Forsteo®). Mean +/− SD hPTH134 Cmax values were, respectively, 74 +/− 59, 138 +/− 101, 717 +/− 496, and 1624 +/− 1579 pg/mL for 1, 2.5, 5, and 10 mg doses of this peptide administered with 200 mg 5-CNAC; while mean +/− SD AUC (0-last) values were, respectively, 30 +/− 40, 62 +/− 69, 320 +/− 269, and 627 +/− 633 h*pg/mL. The corresponding estimates for teriparatide 20 μg sc were 149 +/− 35 for Cmax and 236 +/− 58 for AUC (0-last) Ionized calcium remained within normal limits in all treatment groups except for 3 isolated events. Nine subjects withdrew due to treatment-related AEs. Of those, seven were taking PTH134 2.5 or 5 mg: three withdrew for symptomatic hypotension (two of whom were in the 200 mg 5-CNAC group), three because of delayed vomiting (two from the 200 mg 5-CNAC group), one was proactively withdrawn by the investigator for symptomatic hypercalcemia (receiving 2.5 mg/100 mg 5-CNAC) at slightly supra-normal total calcium but normal ionized serum calcium levels. One subject receiving teriparatide and one receiving placebo withdrew for symptomatic hypotension. No serious AEs were reported. In conclusion, the study demonstrated potential therapeutically relevant PTH1-34 systemic exposure levels after oral administration of PTH1-34 formulated with the absorption enhancer 5-CNAC. Doses of 2.5 and 5 mg of oral PTH134 achieved exposure levels closest to those of teriparatide 20 μg sc, with a comparable incidence of AEs in healthy postmenopausal women.