"PTHrP(1-36) IV Dose Escalation Study"
"PTHrP(1-36) IV Dose Escalation Study"
This is a single-blinded, one-treatment, combination dose escalation and pharmacokinetic
 study done in healthy volunteers. The investigators want to determine whether Parathyroid
 Hormone related Protein (1-36) [PTHrP(1-36)] shares anabolic properties with the only
 currently approved anabolic agent, parathyroid hormone(1-34) [PTH(1-34)], which stimulates
 both osteoblastic bone resorption and formation. In a previous study done by the
 investigators, postmenopausal osteoporotic women on estrogen received 6.56 mcg/kg PTHrP(1-36)
 subcutaneously for three months daily. They experiences a 4.7% increase in bone mineral
 density (BMD) of the lumbar spine when compared with those taking placebo. They also
 displayed an increase in serum osteocalcin, a marker of bone formation, with no change in
 several markers of bone resorption. It is believed that the rapid absorption and clearance of
 PTHrP(1-36) likely plays a central role in its anabolic effect In order to further assess
 absorption, we are combining both pharmacokinetic and dose escalation methods for studying
 intravenous PTHrP given via a one-time bolus injection. The purpose is to define the maximum
 safe dose and measure the pharmacokinetic parameters of a single intravenous dose of
 Parathyroid Hormone-related Protein (1-36)[PTHrP(1-36)]. The results will be useful in
 determining future treatment options for osteoporosis.
Osteoporosis is a growing health problem. The most commonly used treatment options are
 anti-resorptive agents, which give a bone density increase of the lumbar spine in the 6-8%
 range over a 3-5 year period. A 100 % increase in bone mass would be needed to restore bone
 mass to peak, premenopausal levels. The ideal drug to treat osteoporosis would be a pure
 skeletal anabolic agent; however, the only currently approved anabolic agent, parathyroid
 hormone [PTH(1-34)] appears to only increase lumbar spine mass by 12-15% over a 2-3 year
 period when given alone.

 Parathyroid hormone-related protein, [PTHrP(1-36)], is a peptide secreted by almost all
 normal tissues and cells that shares significant homology with Parathyroid Hormone (PTH); and
 the investigators believe that it shares anabolic properties with PTH. In a previous study,
 PTHrP(1-36) administered subcutaneously to postmenopausal women for two weeks increased
 markers of bone formation (osteocalcin) while decreasing markers of osteoclastic bone
 resorption. In a subsequent study, postmenopausal osteoporotic women on estrogen received
 6.56 mcg/kg PTHrP(1-36) subcutaneously for 3 months daily. They experienced a 4.7% increase
 in bone mineral density (BMD) of the lumbar spine compared to those taking placebo. The also
 displayed an increase in serum osteocalcin, a marker of bone formation, with no change in
 several markers of bone resorption. As a result of both rat and human research studies, the
 investigators feel the rapid absorption and clearance of PTHrP(1-36) likely plays a central
 role in its anabolic effect in humans.

 In order to further assess the absorption of PTHrP, the investigators are doing this
 pharmacokinetic study using bolus intravenous PTHrP. It combines both pharmacokinetic and
 dose escalation methods for studying intravenous PTHrP given via a one-time bolus injection.
 Subcutaneous PTHrP has been shown to increase bone mass in previous studies done and would be
 the preferred route for administration of PTHrP in the treatment of osteoporosis. Comparing
 intravenous with subcutaneous PTHrP will yield much information about the bioavailability of
 PTHrP in vivo.

 This six hour study has been designed to achieve the goals of (1) determining what is the
 maximum safe dose of PTHrP(1-36) that can be given intravenously as a one time bolus dose;
 and (2) what is the pharmacokinetic profile of a one-time intravenous bolus dose of PTHrP. A
 placebo group of 5 subjects will initially serve as a control. The investigators feel it is
 important to begin with very small amounts of intravenous PTHrP and gradually increase the
 dose for safety reasons. The initial single bolus intravenous dose to be tested is
 intentionally low (4 micrograms). Subsequent doses of PTHrP will be gradually increased using
 a standard dose escalation scale in groups of three subjects until a maximal dose of 400 mcg
 is reached or a dose limiting toxicity occurs at a dose lower than 400 mcg. The maximum
 determined safely tolerated dose will then be administered to a total of 10 normal healthy
 volunteers.

 In all subjects at different dosing groups, frequent blood sampling within the first 20
 minutes after IV administration of PTHrP will yield pharmacokinetic data about peak PTHrP
 blood levels and time to peak level T(max). After research subjects receive an intravenous
 bolus of PTHrP; blood samples will be collected for pharmacokinetic analysis of PTHrP at
 intervals of 2 minutes for the first 20 minutes, than at 25, 30, 45 and 60 minutes, then
 hourly for the next five hours. Measurement of calcium, creatinine, phosphorus, PTH, 1,25
 Vitamin D and markers of bone metabolism will be obtained at baseline, and at hours one and
 three. After the baseline urine sample is obtained, urine will be collected at two hour
 intervals for calcium, creatinine, phosphorus, and markers of bone metabolism.

 All subjects will be assigned in a single-blinded manner to receive either placebo or study
 drug. Initial subjects will be assigned to receive placebo or the starting dose of PTHrP: 4
 micrograms. all groups of subjects will receive of PTHrP or placebo via intravenous bolus
 injection followed by a 3 ml normal saline solution flush over a 30-60 period. If subjects in
 the initial groups do not experience any adverse effects, doses of intravenous PTHrP will be
 increased in subsequent groups of three subjects each, and the doses for these groups will be
 10, 40, 75, 150, 250 and lastly, 400 micrograms. 400 micrograms is the highest possible dose
 that will be given in this study. The dose that causes no dose-limiting toxicities will be
 given to a total of 10 healthy subjects. Data from this dosing group will be used to compare
 data from the investigator's previous pharmacokinetic and dose escalation studies, including
 recently completed a double-blind, crossover pharmacokinetic study comparing peak serum
 levels of PTH(1-34) and PTHrP(1-36) after a single subcutaneous injection. Preliminary
 results from that study indicated that PTHrP peaks earlier than PTH (6-15 minutes verses 45
 minutes), despite the fact that the dose of PTHrP (~420 mcg) was 20 times greater than the
 dose of PTH (20 mcg).

 This study will be performed in healthy young adults, ages 24-35 years. It is anticipated
 that we will need to screen 100 subjects to achieve a maximum of 52 evaluable subjects, to
 answer the questions posed by this study.
Inclusion Criteria:

 Healthy Caucasian subjects of both sexes between the ages of 24-35 years -

 Exclusion Criteria:

 Pregnancy Subjects with cardiac, hypertension, vascular, renal, pulmonary, endocrine,
 musculoskeletal, hepatic hematologic or malignant or rheumatologic disease.

 Body Mass Index greater than 30 anemia (hematocrit less than 36% in women, less than 40% in
 men) significant alcohol or drug abuse, baseline hypotension (systolic blood pressure less
 than 90 mm/HG) baseline hypertension (systolic BP greater than 140 mmHg or diastolic BP
 greater than 90 mmHg Abnormal screening labs including: ionized and total serum calcium,
 phosphorus, creatinine, albumin, 25-hydroxyvitamin D, and PTH.

 Subjects taking any chronic medication except oral contraceptives Those who have received
 an investigational drug in the past 90 days Any subject who has previously received either
 PTH or PTHrP African Americans and other ethnic minorities will be excluded since it is
 well documented that osteoporosis is far more common in Caucasians than in
 African-Americans, and there are clear quantitative differences in bone density and
 sensitivity to parathyroid hormone between African-Americans and Caucasians. -