DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Absorption, Fate, and Excretion. Pharmacokinetics and systemic
actions of teriparatide on mineral metabolism are the same as for
PTH. Teriparatide is administered by once-daily subcutaneous injection
of 20 μg into the thigh or abdomen. With this regimen, serum
PTH concentrations peak at 30 minutes after the injection and
decline to undetectable concentrations within 3 hours, whereas the
serum calcium concentration peaks at 4-6 hours after administration.
Based on aggregate data from different dosing regimens, teriparatide
bioavailability averages 95%. Teriparatide clearance averages
62 L/hour in women and 94 L/hour in men, which exceeds normal
liver plasma flow, consistent with both hepatic and extrahepatic PTH
removal. The serum t 1/2
of teriparatide is ~1 hour when administered
subcutaneously versus 5 minutes when administered intravenously.
The longer t 1/2
following subcutaneous administration reflects the
time required for absorption from the injection site. The elimination
of PTH(1-34) and full-length PTH proceeds by nonspecific enzymatic
mechanisms in the liver, followed by renal excretion.
Clinical Effects. In postmenopausal women with osteoporosis, teriparatide
increases BMD and reduces the risk of vertebral and nonvertebral
fractures. Several laboratories have examined the effects of
intermittent PTH on BMD in patients with osteoporosis. In these studies,
teriparatide increased axial bone mineral, although initial reports
of effects on cortical bone were disappointing. Co-administration of
hPTH(1-34) with estrogen or synthetic androgen led to impressive
gains in vertebral bone mass or trabecular bone. However, in some
early studies there was only maintenance or even loss of cortical
bone. Vitamin D insufficiency in patients at baseline or pharmacokinetic
differences involving bioavailability or circulating half-life may
have contributed to observed differences on cortical bone. The most
comprehensive studies to date established the value of daily
hPTH(1–34) administration on total BMD, with significant elevations
of BMD in lumbar spine and femoral neck and with significant reductions
of vertebral and nonvertebral fracture risk in osteoporotic
women (Neer et al., 2001) and men (Finkelstein et al., 2003).
Candidates for teriparatide treatment include women who
have a history of osteoporotic fracture, who have multiple risk factors
for fracture, or who failed or are intolerant of previous osteoporosis
therapy. Men with primary or hypogonadal osteoporosis are
also candidates for treatment with teriparatide. However, the effect
on fracture incidence in this group has not been established.
Adverse Effects. In rats, teriparatide increased the incidence of
osteosarcoma (Vahle et al., 2004). Because of these findings, a black
box warning appears on the FORTEO package insert. The clinical relevance
of this finding is unclear, especially because patients with
primary hyperparathyroidism have marked elevation of serum PTH
without a greater incidence of osteosarcoma. Nonetheless, teriparatide
should not be used in patients who are at increased baseline
risk for osteosarcoma (including those with Paget’s disease of
bone, unexplained elevations of alkaline phosphatase, open epiphyses,
or prior radiation therapy involving the skeleton). The safety and
efficacy of FORTEO have not been evaluated for extended use beyond
2 years of treatment and therapy should be limited to no more than
2 years. A tumor registry-based analysis of the occurrence of
osteosarcoma in teriparatide-treated patients is ongoing; cases of
osteosarcoma associated with the drug should be reported to the FDA.
Increases in bone density acquired during therapy with teriparatide
can maintained or extended with subsequent use of bisphosphonates
(Black et al., 2005).
Full-length PTH(1-84) has been associated with osteosarcomas
in rats (Jolette et al., 2006) although not in humans. The significance
and interpretation of the toxicological findings has been questioned
(Tashjian and Goltzman, 2008). However, adverse effects include exacerbation
of nephrolithiasis and elevation of serum uric acid levels.
CALCIUM SENSOR MIMETICS:
CINACALCET
Calcimimetics are drugs that mimic the stimulatory effect
of calcium on the calcium-sensing receptor (CaSR) to
inhibit PTH secretion by the parathyroid glands. By
enhancing the sensitivity of the CaSR to extracellular
Ca 2+ , calcimimetics lower the concentration of Ca 2+ at
which PTH secretion is suppressed. Inorganic di- and
trivalent cations, along with polycations such as spermine,
aminoglycosides (e.g., streptomycin, gentamicin,
and neomycin) and polybasic amino acids (e.g., polylysine)
are full agonists and are referred to a type I calcimimetics.
Phenylalkylamine derivatives that are
allosteric CaSR modulators that require the presence of
Ca 2+ or other full agonists to enhance the sensitivity of
activation without altering the maximal response are designated
type II calcimimetics. Cinacalcet (SENSIPAR)
(Figure 44–12) is approved for the treatment of secondary
hyperparathyroidism owing to chronic renal disease
and for patients with hypercalcemia associated with
parathyroid carcinoma. Cinacalcet lowers serum PTH
levels in patients with normal or reduced renal function
(Padhi and Harris, 2009).
In clinical trials, cinacalcet at 20- to 100-mg doses lowered
PTH levels in a concentration-dependent manner by 15–50% and
the serum calcium × phosphate product by 7% compared with
placebo (Franceschini et al., 2003). Cinacalcet also effectively
reduced PTH levels in patients with primary hyperparathyroidism
and provided sustained normalization of serum calcium without
altering bone mineral density (Shoback et al., 2003). Long-term control
of PTH levels was achieved during a 3-year study of cinacalcet,
suggesting that resistance does not develop. There currently is insufficient
information to know whether reducing serum PTH levels with
H 3 C
NH
CF 3
Figure 44–12. Structure of cinacalcet. Cinacalcet exists as optical
isomers. The R-enantiomer, which is more active, is shown.
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CHAPTER 44
AGENTS AFFECTING MINERAL ION HOMEOSTASIS AND BONE TURNOVER