As described previously, current testing to establish bioequivalence is based upon single-dose crossover experiments in young, healthy volunteers. Although this approach is certainly pharmacokinetically valid, one must question whether this is always appropriate, given the unique biopharmaceutical properties of several of our commonly used AEDs. In other words, can we always extrapolate data generated from young, healthy adults to other patient populations (e.g., elderly and intellectually developmentally disabled children) that may have multiple comorbid medical conditions?
For example, phenytoin, still one of the most commonly prescribed AEDs in the USA, displays nonlinear pharmacokinetics, owing to saturation of the cytochrome P450 isozymes responsible for its metabolism. Practically speaking, this implies that modest changes in dose, or amount absorbed, may result in disproportionate changes in serum concentration. Although this phenomenon is well recognized, it is important to appreciate that the elderly patient may be more susceptible, presumably because of age-related declines in hepatic metabolic capacity. In addition, as discussed previously, phenytoin absorption may display variability because of physiologic factors.
Several well-documented reports have suggested that there may be problems with generic formulations of this agent. Rosenbaum et al. (1994) reported that mean phenytoin serum concentrations declined by about 30% when branded drug was replaced by an approved generic phenytoin preparation in 10 patients. More recently, in a retrospective review, Burkhardt et al. (2004) reported increased seizures in a group of 11 patients over a 5-month period. Ten of these patients had undergone substitution of a generic formulation of phenytoin. Following substitution with the generic, phenytoin serum concentrations were noted to decline by approximately 30%. Of note, once the agent was switched back to the brand product, serum concentrations returned to pre-switch values (Burkhardt et al., 2004).
How can these observations be explained? Well-conducted regulatory studies confirm that these products are essentially the same from a pharmacokinetic perspective. One possible explanation is that given the nonlinear, saturable elimination of phenytoin, extrapolating results from single-dose studies may not necessarily predict outcomes when the medication is given chronically. To illustrate this, in one study, a group of healthy subjects were given single doses of both an approved generic phenytoin formulation, and branded Dilantin, in a cross-over pharmacokinetic study (Wilder et al., 2001). In this study, bioequivalence was assessed using accepted FDA testing methodology, except that subjects were given both the generic formulation and branded product with a high-fat meal. Under these testing conditions, AUC was only about 13% lower for the generic product versus brand. Interestingly, however, the investigators used pharmacokinetic parameters derived from this experiment, and conducted simulations to assess the impact this otherwise modest reduction in bioavailability might have when given chronically. These simulations suggested that a 13% decrease in bioavailability could result in a 37% reduction in mean serum concentration if this formulation was given with food. Taken together, data from this study, as well as the report of Burkhardt and colleagues (2004) suggest that extrapolation of data from single-dose studies to chronic, multiple-dosing situations may be problematic for a nonlinear medication such as phenytoin. Although clearly the generic formulation is prescribable, one must question whether it is truly switchable under all clinical circumstances.
Clinical and economic consequence of generic substitution
Although the previous discussion has focused strictly on biopharmaceutical considerations, ultimately, one must question whether these theoretical concerns are of any “real-world” clinical importance. Several recent reports would suggest that they are.
In a retrospective claims database (Ingenix LabRx) analysis, Zachry et al. (2007) sought to determine if patients who received urgent, seizure-related care in an inpatient hospital or emergency/urgent care setting, were at greater risk of having had a substitution of their branded AED to an A-rated generic product during the previous 6 months when compared with epilepsy patients with no evidence of receiving seizure-related care in similar settings. In this analysis, cases (patients requiring urgent care) had an 81% greater odds of having a generic AED formulation switch in the previous 6 months as compared to controls (11.3% vs. 6.2%).
Other potential indicators of undesired clinical outcomes associated with generic substitution may be found in switchback rates from generic alternatives back to branded products. In one retrospective analysis from Canada, Andermann et al. (2007) evaluated switchback rates of several classes of drugs including AEDs (lamotrigine, clobazam, and valproic acid), as well as several antidepressants and cholesterol-lowering drugs. Strict Ontario rules favoring generic formulations require a physician letter of medical necessity before switchback from generic to the original brand product can be allowed. In this analysis, a high rate of switchback to branded AEDs (12.9% to 20.9%) compared with non-AED drug classes such as selective serotonin reuptake inhibitor (SSRI) antidepressants (1.5% to 2.9%) was found.
Similar findings were noted by LeLorier et al. (2008a), who found markedly higher switchback rates for AEDs as compared to antihypertensive or lipid-lowering drugs. In addition, for patients switching from generic to branded lamotrigine, significantly higher rates of medical service utilization and longer hospital stays were noted during the time when patients were receiving the generic product. Daily doses of generic lamotrigine were also about 5% higher as compared to the brand product.
Although the reasons for this apparently high switchback rate for AEDs as compared to non-AEDs is still uncertain, these data do clearly suggest that patients, physicians, or perhaps both, are feeling compelled to return to using higher-cost branded medications for epilepsy, as compared to other medical conditions. It must be acknowledged that retrospective analyses clearly have limitations, especially with respect to establishing a causal relationship with product substitution; however, collectively, these reports do raise concerns.
Finally, it is important that any discussion of generic drug substitution includes an economic perspective. In several recent analyses (Duh et al., 2007; Lelorier et al., 2008b), Canadian investigators have evaluated the potential cost implications of generic substitution. Using health claims data from Quebec’s provincial health plan, Lelorier and colleagues (2008b) identified 671 patients with epilepsy who were being treated with branded lamotrigine (Lamictal, GlaxoSmithKline, Philadelphia, PA, U.S.A.). Periods of branded and generic use of lamotrigine were compared for total health care costs, stratified into prescription drugs, and inpatient services and outpatient services. Interestingly, despite the lower cost of the generic product, using two different cost-estimation methods, these authors calculated significant increase in total projected health care costs during the time patients were receiving the generic product as compared to the brand (US$1750–2500 per person-year, p < 0.01). By way of these pharmacoeconomic analyses, it is reasonable to suggest that the potential savings associated with a switch to a generic product (at least for lamotrigine) may not be as great as one might anticipate, owing to higher costs likely associated with increased physician visits, hospitalizations, and utilization of medical/pharmacy services. Although these observations clearly require confirmation, they do suggest that whether because of anticipated or actual untoward clinical consequences, generic substitution may actually be increasing overall cost of patient care.