Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products: Workshop Summary Report

Abstract

Modified release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current industry practices and regulatory expectations for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.

APPENDIX

Case Studies

Bupropion Hydrochloride Extended Release Products

Bupropion is a commonly prescribed antidepressant although the neurochemical mechanism of its antidepressive effect is unknown. Bupropion is a relatively weak inhibitor of neuronal reuptake of norepinephrine, serotonin and dopamine, and does not inhibit monoamine oxidase. Clearance of the drug has been found to be influenced by genetic polymorphism of CYP2B6.

The marketing approval of innovator bupropion HCl products (Wellbutrin®) was first obtained for immediate release (IR) tablets, 100 mg, three times once-a-day dosing, followed by sustained release (SR) tablets, 150 mg, twice-a-day dosing, and subsequently extended release (XL) tablets, 300 mg, once-a-day dosing. While the SR formulation was approved based on pharmacokinetic equivalence to the IR formulation, the XL formulation was approved based on pharmacokinetic equivalence to the respective IR and SR formulation given at the same doses. Regulatory approval of the original IR formulation was on the basis of ascending dose trials with doses up to 900 mg/day. However, after approval but before marketing, a dose-dependent seizure risk was identified with bupropion. A re-analysis of the clinical trial data was judged to support its antidepressant efficacy at doses of 450 mg/day or less and thus marketing proceeded with a label modification to not exceed 450 mg/day. A clinical trial program was undertaken with the SR formulation but failed to provide convincing evidence of efficacy at dose of 400 mg/day or less. However, retrospective pooled analyses of four clinical trials revealed that remission rates for Wellbutrin SR®, selective serotonin reuptake inhibitors (including fluoxetine and sertraline), and placebo were 45% (N = 507), 45% (N = 504), and 36% (N = 512), respectively. The remission rates for Wellbutrin SR®, fluoxetine, and sertraline were statistically superior to placebo in the pooled analysis, but not in two of the individual trials (9). There are no independent trials demonstrating the efficacy of Wellbutrin XL® tablets.

Bupropion exhibits a dose-dependent risk of seizure when doses exceed 450 mg/day (10). There is evidence suggesting that seizure risk on bupropion may also be related to peak concentration of bupropion and/or one or more of its active metabolites (10,11). Peak plasma levels of hydroxybupropion, a major metabolite, occur 7 h after administration of bupropion and are about seven times the peak level of the parent drug at steady state. The elimination half-life of hydroxyl metabolite is approximately 20 h, and its AUC at steady-state is approximately 13 times that of bupropion. The other two minor metabolites have similar T _max values with hydroxybupropion. The relative contribution of bupropion and its metabolites to the efficacy or seizure risk is unknown. It is also unclear whether the efficacy of bupropion is dependent on the peak or steady-state concentrations of bupropion and/or its metabolites.

The efficacy of bupropion is often observed after dosing for 1–2 weeks. For extended release bupropion, maintenance of steady-state concentrations was the targeted therapeutic endpoint, which is due partly to the rapid and nearly complete metabolism of bupropion to three active metabolites. Modeling and simulation results indicated that subtle differences in the absorption rate of bupropion would yield negligible effects on the steady-state concentrations of its metabolites. Recently, there have been reports that some patients experience worsening of their depression following a switch from the branded to a generic extended release product. This may be due to the natural course of major depressive disorder under treatment rather than a consequence of small pharmacokinetic differences between the two products that have met the regulatory bioequivalence criteria.

Methylphenidate Hydrochloride Extended Release Products

Methylphenidate is commonly prescribed medication for treatment of ADHD in children. Both IR and SR formulations of methylphenidate are currently available on the market. The IR formulation has short half-life and short duration of therapeutic effect (3–4 h), thereby requiring in-school and after-school dosing for most children. This formulation has a rapid onset of effect, but also yields fluctuations in peak and trough plasma levels upon multiple daily dosing. The SR formulation has a waxy matrix and behaves more like a slow release than a sustained release product. Zero-order release of methylphenidate in plasma leads to the development of acute tolerance to the drug (12). There is no authoritative literature information on the correlation of dose or plasma concentration with clinical effects of methylphenidate. The development of tolerance indicates that drug effect at any point may not be a function of concentration alone. Additional parameters such as partial AUCs may be necessary to document bioequivalence in this case.

Several methylphenidate MR products have been approved for marketing, including Concerta® (OROS), Metadate CD®, Metadate ER®, Ritalin LA®, and Ritalin-SR®. All formulations are therapeutically effective based on clinical trials and their unique individual shapes of the respective plasma concentration–time profile. These MR products have been clinically effective because they possess the following three essential properties: (a) avoidance of tolerance, (b) rapid onset of action, and (c) longer duration of effect. Evaluation of early exposure from the plasma profile (partial AUC) will be important for multi-source products of these brand methylphenidate products. To set bioequivalence limits on partial AUC, there is a need to evaluate carefully the within-subject variance associated with this parameter.

Zolpidem Tartrate Extended Release Products

Zolpidem is a non-benzodiazepine sedative hypnotic. The IR formulation of zolpidem (Ambien®) was indicated for short-term treatment of insomnia characterized by difficulties with sleep initiation. The extended release formulation (Ambien CR®) offers additional advantages of treating difficulties associated with sleep maintenance and producing no residual effects after wake-up. The current formulation of Ambien CR® was selected based on the results of a double-blind, placebo-controlled, ten-way crossover study where eight zolpidem formulations comprising different proportions of IR and extended release were compared with zolpidem IR and placebo using pharmacodynamic endpoints (13). The study revealed differential effects among formulations on awakening as well as correlations between residual effects and plasma concentrations. An in vitro–in vivo correlation (level A) was established between in vitro dissolution and pharmacokinetic profile of the final formulation chosen for marketing. A clinical trial was also conducted to confirm the efficacy and safety of the final formulation (14). In view of the essential properties of Ambien CR®, FDA has recently suggested additional metrics (partial AUCs) to ensure bioequivalence of zolpidem extended release products (15). The cutoff points for these partial AUCs will be determined pending further review of available data.