This study evaluated the effect of Cenestin, a synthetic conjugated estrogens product, on the maintenance of trabecular bone microarchitecture, bone strength, and of bone turnover in the ovariectomized (ovx) rat model. Two doses of Cenestin were chosen in an attempt to approximate the equivalent human oral doses of 0.3 mg and 0.625 mg. Forty-nine 6-month-old retired female breeder Sprague-Dawley rats were randomly assigned to one of four groups: (1) sham-operated + vehicle; (2) ovx + vehicle; (3) ovx + day 1 post-ovariectomy Cenestin (8.12 mg/kg); (4) ovx + day 1 post-ovariectomy Cenestin (16.24 mg/kg) for 8 weeks. Trabecular structure of the right proximal tibia of each rat was imaged noninvasively by microCT. A compression test to induce a tibial plateau fracture was performed to determine the mechanical properties of the proximal tibia. Urine was collected on days 0, 14, 28, 42 and 56 and serum on days 0, 28 and 56 to assess biochemical markers of bone turnover including deoxypyridinoline crosslinks and osteocalcin. Both biochemical markers of bone turnover were analyzed by ELISA. Trabecular bone mass, structure, and connectivity density in the Cenestin-treated groups did not differ statistically ( p>0.05) from those of the sham-operated + vehicle-treated rats, but all were significantly higher ( p<0.05) than in the ovx + vehicle-treated rats. Structure Model Index, a measure of trabecular plate morphometry, in Cenestin-treated rats maintained a more equal mix of plate- and rod-like structures similar to the sham group, whereas the ovx group had predominantly rod-like trabeculae. Fracture load in the Cenestin (16.24 mg/kg) treated group was 31% ( p<0.01) higher than in the sham + vehicle-treated group and 61% ( p<0.05) higher than in the ovx + vehicle-treated group. Both the sham-operated + vehicle-treated and Cenestin-treated groups showed significantly lower urinary deoxypyridinoline crosslink excretion at all timepoints and serum osteocalcin at day 56 compared with the ovx + vehicle-treated group. In summary, Cenestin maintained trabecular bone microarchitecture and strength in an ovariectomized rat model of estrogen deficiency.

Fifty early postmenopausal women completed a double-blind, placebo-controlled study evaluating the short-term effect of a new synthetic conjugated estrogens formulation (Cenestin) on bone turnover. Subjects were randomized to either 0.625 mg/day synthetic conjugated estrogens (n = 35) or placebo (n = 15) for 3 months. Biochemical markers were evaluated at baseline (three measurements at Days -2, -1, and 0) and Days 30, 60, and 90. Bone resorption assessed by urinary NTX (-31.4%) and serum CTX (-34.2%) was significantly (p < 0.01) decreased in the estrogen-treated group compared to the placebo group within 1 month of treatment. The mean percent decreases for urinary NTX from baseline during estrogen treatment were -58.0% (p < 0.01 vs. placebo) and -34.1% (ns) after 2 and 3 months, respectively. For serum CTX, the percent changes from baseline were -17.6% (p < 0.01) and -16.9% (p < 0.01) at 2 and 3 months, respectively. As expected, the decrease of both bone formation markers (bone ALP and PINP) was delayed compared to that of bone resorption and significant (p < 0.05-0.01) only after 2 months of treatment in the estrogen-treated group compared to the placebo group. Synthetic conjugated estrogens significantly decreased bone resorption and bone formation comparable to that previously reported for estrogen treatments proven efficacious in preventing postmenopausal bone loss.

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A multiple-dose, placebo-controlled, randomized pharmacokinetic study was performed in 15 early (i.e., 1-3 years) postmenopausal women to evaluate the single and steady-state pharmacokinetics of 0.625 mg Cenestin (Synthetic Conjugated Estrogens, A) tablets, administered once daily for 90 days. Plasma concentration-time profiles for both total (conjugated and unconjugated) estrone and equilin, two major estrogens in Cenestin, were nearly superimposable between Day 1 (single dose) and Day 90 (multiple dose), indicating equivalent drug exposure from one dose to the next. For total estrone, the mean estimates of Cmax and AUC0-24 were 2.5 ng/ml and 35.0 ng x h/ml for Day 1 and 3.0 ng/ml and 39.8 ng x h/ml for Day 90, respectively. Similarly, Cmax and AUC0-24 mean values for total equilin were 1.4 ng/ml and 17.4 ng x h/ml after Day 1 and 1.5 ng/ml and 17.3 ng x h/ml after Day 90, respectively. The mean tmax value for total estrone was 8.3 hours on Day 1 and 8.6 hours on Day 90, indicating a slower rate of absorption. The average estimate for observed drug accumulation index for the 24-hour dosing interval was calculated to be 1.1 for total estrone and 1.0 for total equilin. These data, taken together, indicate a slow and steady rate of absorption, minimal drug accumulation at steady state, and consistent drug exposure between Cenestin doses.

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The 505(b)(2) pathway is used to obtain U.S. Food and Drug Administration approval of changes to existing drugs based in whole or in part on public data. This chapter identifies sources of public data and how it can be used in lieu of sponsor-conducted studies. Examples are presented to illustrate a broad range of improvements that can be made to an existing drug under 505(b)(2) as well as the scope of development requirements that can range from simple bioequivalence studies to more complete Phase 2/Phase 3 clinical programs. Patents and market exclusivity are discussed as a means to improve the return on investment needed to encourage the development of these important drug products.

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