Streamlining nonclinical drug development using the FDA 505(b)(2) new drug application regulatory pathway.

In the USA, drugs are approved by the FDA by three main regulatory pathways: (i) 505(b)(1) new drug applications (NDAs); (ii) 505(b)(2) NDAs; and (iii) 505(j) abbreviated NDAs (ANDAs). The appropriate pathway depends on the active ingredient, already approved drug products, drug formulation, clinical indication, route of exposure, among other factors. The 505(b)(2) NDA pathway is a regulatory approval pathway that allows sponsors to use existing public data in lieu of conducting studies; thus, potentially offering significant drug development and marketing advantages. Nonclinical testing programs for 505(b)(2) submissions are often reduced and, in some cases, are not even required. This paper provides an overview of the 505(b)(2) regulatory pathway with a focus on how nonclinical programs can be streamlined and accelerated.

Scientific and regulatory standards for assessing product performance using the similarity factor, f2.

The similarity factor, f2, measures the sameness of dissolution profiles. The following commentary is an overview of discussions and presentations from a group of industry and US regulatory experts that have integrated the science and regulatory research and practice for assessing product performance, particularly for modified-release (MR) dosage forms, using f2. For a drug development sponsor or applicant with an orally complex dosage formulation, it is critical to understand dissolution methods and the similarity factor and how and/or when to apply it in their NDA, ANDA, or PMA submission. As part of any regulatory submission, it is critical to justify that the product performance has not been impacted by any change in the manufacturing process and/or the delayed and/or prolonged drug release characteristics compared to a similar conventional or another orally complex dosage form. The purposes of this document are (1) to provide a description of appropriate dissolution methods, how is the f2 calculated and how it can be used to justify product performance similarity, or not; (2) to provide an overview of alternative methods available for dissolution profile comparisons, and (3) to illustrate how applying these concepts in a focused way supports approval of submissions and regulatory dossiers and aligns them with on-going science and regulatory initiatives. A case study will be used as an example to demonstrate how dissolution testing and the f2 calculation results can impact regulatory outcomes from an NDA (505(b)(1)), NDA (505(b)(2)), ANDA (505(j)), supplemental NDAs/ANDAs, or PMA perspective.

Short-term effects of new synthetic conjugated estrogens on biochemical markers of bone turnover.

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.

Bioavailability study of a 1200 mg miconazole nitrate vaginal ovule in healthy female adults.

This study was undertaken to determine the bioavailabilityof a 1200 mg miconazole nitrate vaginal ovule in 20 healthy premenopausal females following a single application (Day 1, Group 1) and two applications, 48 hours apart (Day 1 and Day 3, Group 2). In Dose Group 1 (n = 10), the mean Cmax of 10.7 ng/ml occurred at 18.4 hours. The average plasma miconazole concentration was calculated to be 5.7 ng/ml during the 4- to 96-hour time interval. In Dose Group 2 (n = 10), mean Cmax values were 10.8 ng/ml and 12.0 ng/ml and occurred at 18.4 hours (Day 1) and 16.0 hours (Day 3), respectively. Comparing AUC0-48 on Days 1 and 3 (338 vs. 408 ng x h/ml) indicated small accumulation of plasma miconazole, while AUC0-48 obtained from Dose Group 2, Day 1 was similar to that of Dose Group 1 (338 vs. 329 ng x h/ml, respectively). Plasma miconazole profiles were best described by a monoexponential equation with zero-order input. Pharmacokinetic simulations performed on the pooled data from two dose groups (n = 20) suggest a steady-state accumulation after five doses administered daily or three doses taken once every other day. Drug exposure was similar to that of the marketed formulation (MONISTAT 7 vaginal cream), applied once daily for 7 days and more than 100-fold less than that reported when given intravenously or orally.

Reanalysis of carbamazepine and carbamazepine-epoxide pharmacokinetics after multiple dosing of extended release formulation.

PURPOSE: To model and re-evaluate the pharmacokinetics of carbamazepine (CBZ) and CBZ-10, 11-epoxide (CBZ-E) after 5 day b.i.d. dosing with either Carbatrol (extended-release beads) or Tegretol-XR (an osmotic pump tablet, an Oros tablet) using compartmental method. METHODS: Plasma concentration time profile data from 15 normal healthy adults received, in a randomized crossover fashion, Carbatrol (2 x 200 mg capsules), b.i.d. for 5 days and Tegretol-XR (400 mg), b.i.d. for 5 days were available for analysis from previous study. The compartmental kinetic parameters of CBZ and CBZ-E were simultaneously fitted by assuming: i) one compartment open model with zero order absorption with lag time, and first order elimination for CBZ and ii) one compartment open model with Michaelis-Menten formation with a sigmoidity factor, and first order elimination for CBZ-E. Time to 50% of CBZ plateau concentrations (TC50) was estimated and statistically compared between the two products. RESULTS: There was a good agreement between simulated and observed plasma concentrations. For CBZ, the fitted parameters were: the first order elimination rate constant (K(10)) 0.024 and 0.022 hr(-1), t(1/2) 27.3 and 30.3 hr, volume of central compartment (V(1) ) 1.119 and 1.160 L/kg, for Carbatrol and Tegretol-XR, respectively. For CBZ-E, the fitted parameters were: the first order elimination rate constant (K (30) ) 0.128 and 0.157 hr (-1), t (1/2) 6.1 and 5.1 hr, volume of central compartment (V (3) ) 0.728 and 0.644 L/kg, V (max) 0.085 and 0.076 mg/hr/kg, K (m) 28.639 and 33.138 mg/mL, for Carbatrol and Tegretol-XR, respectively. The fitted pharmacokinetic parameters of CBZ and CBZ-E were generally consistent with published values from previous studies. A minimal rise in CBZ-E concentrations was observed during the first 12 hours, the finding of which has not been reported before. Consequently, the CBZ-E plasma profiles appear as sigmoid curves and have a different shape compared to those of the CBZ profiles. The inclusion of the sigmoidity factor allowed flexibility in the fitting and optimized the simulation results. When compared to published literature of single dose data, the investigation of CBZ and CBZ-E pharmacokinetics from this study suggested that autoinduction might occur by the fifth day of dosing and might partly contribute to the sigmoidal shape of CBZ-E profiles. CONCLUSION: The fitted model well described the plasma profiles of both CBZ and CBZ-E. Carbatrol and Tegretol-XR were similar in their pharmacokinetics based on compartmental analysis.