Monday, June 26, 2017

Bioequivalence between generic and branded lamotrigine in people with epilepsy

Michel Berg, Timothy E. Welty, Barry E. Gidal, Francisco J. Diaz, Ron Krebill, Jerzy P. Szaflarski, Barbara A. Dworetzky,; John R. Pollard,; Edmund J. Elder Jr,; Wenlei Jiang, Xiaohui Jiang, Regina D. Switzer, Michael D. Privitera.  Bioequivalence Between Generic and Branded Lamotrigine in People With Epilepsy.  The EQUIGEN Randomized Clinical Trial. JAMA Neurol. Published online June 26, 2017.

Key Points

Question  Are branded-to-generic and generic-to-generic lamotrigine switches bioequivalent in people with epilepsy?

Findings  In this randomized clinical trial involving 50 adults with epilepsy, bioequivalence between branded and generic lamotrigine products was established for 2 key pharmacokinetic measures (area under the concentration–time curve and maximal concentration).

Meaning  Branded and generic lamotrigine products can be substituted with an expectation of bioequivalence.

Importance  Switching between generic antiepileptic drugs is a highly debated issue that affects both clinical care and overall health care costs.

Objective  To evaluate the single-dose pharmacokinetic bioequivalence of 3 (1 branded and 2 generic drugs) on-market, immediate-release lamotrigine drug products.

Design, Setting, and Participants  The Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy (EQUIGEN) single-dose study is a crossover, prospective, sequence-randomized, replicate pharmacokinetic study conducted at 5 US academic epilepsy centers. Fifty adults (≥18 years) with epilepsy who were taking concomitant antiepileptic drugs and not currently receiving lamotrigine were enrolled between July 18, 2013, and January 19, 2015. Every participant was randomly assigned to 1 of 3 equivalent sequences, each comprising 6 study periods, during which they had blood draws before and after medication administration. Forty-nine participants were included in intention-to-treat analyses.

Interventions  Participants received a single 25-mg dose of immediate-release lamotrigine at the start of each period, with the branded and the 2 most disparate generic products each studied twice. Lamotrigine was selected as the antiepileptic drug of interest because of its wide use, publications indicating problems with generic switches, and complaints to the US Food and Drug Administration regarding generic products. Both participants and study personnel were blinded to the specific generic products selected.

Main Outcomes and Measures  The primary outcome was bioequivalence between products. Maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) were compared, and average bioequivalence (ABE) was established if the 90% CIs of the ratios of the 2 products were within equivalence limits (80%-125%).

Results  Of the 50 randomized participants, 49 (98%) received all 3 lamotrigine products and completed at least 3 pharmacokinetic assessments and 46 (92%) completed all 6 pharmacokinetic assessments. Among the 49 participants, 28 (57%) were men and 21 (43%) were women, 42 (86%) self-identified as white, and 46 (16) years was the mean (SD) age. The 3 drug products were considered bioequivalent because the 90% CIs were within equivalence limits (lowest and highest CI limits for Cmax, 92.6% and 110.4%; for AUC0-96, 96.9% and 101.9%). Replicate testing demonstrated no significant differences in within-subject variability across the 3 products (likelihood ratios, χ22 for log-transformed variables: AUC0-96, 2.58; Cmax, 0.64; and AUC0-∞, 4.05; P ≥ .13) and that the 3 products were also bioequivalent according to scaled ABE and individual bioequivalence criteria with no subject × formulation interaction (Cmax, 0.00; AUC0-96, 0.54; and AUC0-∞, 0.36; P ≥ .76).

Conclusions and Relevance  This study provides evidence that the disparate lamotrigine products studied are bioequivalent when tested in people with epilepsy taking concomitant antiepileptic drugs.

Trial Registration Identifier: NCT01733394

From the article 

To inform the debate about generic AED equivalence, we performed a single-dose replicate study (among people with epilepsy taking concomitant AEDs) comparing bioequivalence between disparate generic lamotrigine products and bioequivalence of each generic product to branded lamotrigine. Confidence intervals comparing the extent (AUC) and rate (Cmax) of absorption of these tested products were all well within the FDA ABE range, thus establishing bioequivalence. This study provides further support to the bioequivalence found in 2 recently reported long-term–dose studies, especially because single-dose study designs are considered more sensitive to PK differences than are long-term–dose studies.

Most of the published literature concerning the therapeutic implications of branded-to-generic or generic-to-generic substitutions is uncontrolled or comprises retrospective studies that did not account for confounding factors (eg, adherence and participant bias). This study’s prospective replicate design enabled us to determine the within-subject variations over time in the PK profile for the 3 products and to explore subject × formulation interaction. Replicate testing demonstrated variability of approximately 8% (AUC) and 15% (Cmax) within each of the individual products. The finding that biological variation was similar for the branded and both generic products suggests that this variation may account for some of the differences reported when switching among branded and generic products.

Biological factors are presumed to have similar effects regardless of the product (branded or generic) taken by the participant. Establishing the amount of variation from these factors for the branded product is important for understanding how much variation among generic products is acceptable. That is, if there is a wide variation in the PK measures from a replicate study of the branded product, then similar wide variations among generic products should be acceptable. By contrast, if the differences in a replicate study of the branded product are small, then wider variations among generic products may be unacceptable.

Within-subject variability is one of the factors proposed to characterize narrow therapeutic index drugs, which are required to meet reference-scaled bioequivalence limits using the scaled ABE method. The PK results for the products tested in our study fell well within scaled ABE bounds. Individual bioequivalence was also established with this set of lamotrigine data given that individual bioequivalence analyses reduced to scaled ABE analyses because there was no subject × formulation interaction…

Despite the inclusion of participants with multiple clinically relevant variables, the 3 lamotrigine products tested demonstrated essentially identical PK profiles and were all well within the FDA bioequivalence standards. In fact, our results fell within the standards for narrow therapeutic index drugs and showed no evidence of differences in within-subject variability between the 3 products.

Courtesy of a colleague

1 comment:

  1. Roach ES. The cost of gullibility. Arch Neurol. 2009 Nov;66(11):

    In this, the last Controversies in Neurology series, Ng and Hamikwa debate whether brand name antiepileptic drugs provide enough of an advantage to outweigh their enormous additional cost. Is there convincing evidence that generic drugs are risky, or is this debate just a clever smoke screen designed by those with much to gain in order to promote the continued use of higher cost drugs? There are really two separate, although often confused, issues in this discussion. One is whether physicians should try to prevent the use of generic AEDs based on persuasive evidence that these drugs are less effective than their brand name counterpart. An entirely different issue is whether pharmacists or payors should be able to substitute a cheaper generic drug without the authorization of a patient’s physician.

    The second question seems to be the simpler one. A few individuals with epilepsy apparently do not tolerate even minor differences in antiepileptic bioavailability without developing either seizures or side effects. The existence of such case reports is perhaps reason enough to require physician approval prior to substituting a generic AED, because even a physician who generally favors the use of generic drugs might have a very good reason to insist on a specific AED brand in selected individuals. But concern about unauthorized substitution is not the same thing as opposing the use of generic medication for all individuals.

    Case studies can be heart-wrenching, but how often generic drugs lead to either side effects or an increased seizure frequency lies at the heart of the debate. Should the existence of a few individuals with a narrow therapeutic window necessitate all epilepsy patients having to pay more for AEDs?...

    It is important to recognize potential sources of bias and conflict of interest when analyzing the suitability of generic drugs. The cost of developing and marketing a new drug is huge, so it is easy to understand the desire to continue selling a high cost brand name drug after its patent has expired. The fact that many of the articles promoting brand name AEDs over generic drugs have been written by individuals who are employed by AED manufacturers or those receiving personal financial and research support from these companies does little to promote confidence. What is difficult to explain, however, is how normally questioning physicians could accept such weak arguments without even a trace of skepticism or a demand for more evidence. We argue every minor point about the optimal treatment for stroke, Parkinson disease, or multiple sclerosis, but when it comes to the use of generic drugs, many of us seem to accept without a whimper of protest that a brand name AED is somehow superior.

    To prospectively compare the frequency and severity of seizures when converting to generic medication seems to be a relatively straight-forward study, and from there one might be able to develop ways to identify any individuals with a narrow therapeutic window. With so many patients affected and so much money at stake, why has this debate about the use of generic AEDs simmered for a quarter of a century? A well-designed prospective study would likely show parity of generic and brand name AEDs in all but a few patients. The results of such a study might be inconvenient for those better served by smoke screens, but we should demand no less.