Our results demonstrate that the duration of calcemic response after the subcutaneous injection of teriparatide 20 μg is brief. One reason for this is the rapid rates of absorption and elimination of teriparatide. After subcutaneous injection, maximum teriparatide concentrations are achieved within 30 min, followed by a rapid decline from the systemic circulation with a half-life of 1 h. Teriparatide transiently increases serum calcium, with the maximal effect observed at approximately 4.25 h (median increase, 0.4 mg/dl or 0.1 mM) followed by a decline to predose levels before the next teriparatide dose is administered 24 h later.
The results of studies in rats have also shown that the therapeutic interval for PTH(1–34) exposure is brief but that prolonged exposure results in severe hypercalcemia. Using a total daily dose of 80 μg/kg body weight of hPTH(1–34), Dobnig and Turner [17
] demonstrated that a single subcutaneous injection or continuous infusion for 1 or 2 h/day had no effect on serum calcium. In contrast, continuous infusion of hPTH(1–34) for 6 h/day resulted in hypercalcemia. Frolik et al. [18
] confirmed that sustained elevated serum calcium concentrations occurred following subcutaneous injections of teriparatide every hour for six injections but not following once-daily subcutaneous injection of teriparatide or six injections within 1 h.
The PK–PD profile of teriparatide 20 μg has practical clinical implications because the PK and calcium PD results show notable differences compared to those of the full human recombinant PTH (rhPTH[1–84]), which is also available for the treatment of osteoporosis in some countries at a daily dose of 100 μg.
The PK and PD of single-dose rhPTH(1–84) subcutaneous injection (dose range 0.02–5.0 μg/kg) were reported by Schwietert et al. [19
]. The serum concentration–time profile of rhPTH(1–84) exhibited a double-peak profile, with the first peak appearing approximately 5–10 min after dosing and the second peak occurring about 1.5–2 h after subcutaneous injection of this hormone [19
]. Interestingly, at all rhPTH(1–84) doses administered, there was a fixed equilibrium between elevated PTH(1–84) and PTH(1–34), a biologically active fragment of PTH(1–84) that was further accompanied by a double-peak profile in serum total calcium concentrations [19
]. The apparent terminal half-life of rhPTH(1–84) was reported to be 1.5–2.5 h [19
]. In contrast, the time to peak concentration of teriparatide is 30 min following injection, with a half-life of 1 h [13
Based on the PK concentration–time profile for each drug, we calculated the duration of time that PTH concentrations were >65 pg/ml, the upper limit of normal for endogenous PTH, and >28 pg/ml, the typical basal endogenous PTH concentration for postmenopausal women. Using the published PK profile [19
] for rhPTH(1–84), we calculated that the time above the upper limit exceeded 6 h and the time above basal concentrations exceeded 9 h for the marketed dose of 100 μg (1.66 μg/kg, assuming an average body weight of 60 kg). In contrast, teriparatide concentrations exceeded the upper limit of normal and remained above the basal concentrations for approximately 3 and 4 h, respectively. Such differences compared to the PK–PD relationship of teriparatide could translate into the formation of a longer “drug exposure time” for rhPTH(1–84) compared with teriparatide. Indeed, the resulting calcemic response elicited by 100 μg rhPTH(1–84) led to a peak serum calcium increase of 0.6 mg/dl (0.15 mmol/l) between 6 and 8 h postdose [20
]. These apparent differences in the duration of exposure may help to explain why hypercalcemia and hypercalciuria are relatively rare events following administration of teriparatide 20 μg [6
], although they have been more frequently reported in the rhPTH(1–84) 100 μg pivotal trial [23
]. Whether it is the slower rate of absorption and elimination of rhPTH(1–84) due to its larger size and/or the parallel generation of PTH(1–34) and possibly other biologically active amino-terminal PTH fragments whose biological half-lives are less well characterized that leads to a larger calcemic response than teriparatide has yet to be determined.
Another potential explanation for the differences in the calcemic responses is that the dose of rhPTH(1–84) used in the pivotal phase 3 trial (100 μg/day, 10.62 μmol/day) [23
] is approximately twofold greater on a molar basis than teriparatide 20 μg. However, it has been reported that the bioavailability of rhPTH(1–84) is 55% [24
] compared with the 95% bioavailability of teriparatide [25
]. Thus, when adjusting for molecular weight and bioavailability, the relative doses administered in the rhPTH(1–84) pivotal phase 3 trial [23
] and the teriparatide Fracture Prevention Trial [6
] were 5.84 and 4.61 μmol, respectively, a difference that is unlikely to explain the disparity in the rates of hypercalcemia or drug exposure time between the two studies.
In conclusion, the pharmacologic effect of teriparatide following once-daily subcutaneous administration produces a modest but transient increase in serum calcium, consistent with the known effects of endogenous PTH on mineral metabolism. The PK–PD indirect-response model illustrates that the excursion in serum calcium is brief due to the short length of time that teriparatide concentrations are elevated.