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The article “Dextromethorphan/quinidine for pseudobulbar affect” (Out of the Pipeline, Current Psychiatry, February 2011, p. 60-67) was of great interest. For the past 5 years I have led the clinical development of NuedextaTM (dextromethorphan hydrobromide and quinidine sulfate; DMQ) and I found the review extraordinarily comprehensive and applaud the authors for their exhaustive research. I would, however, like to take the opportunity to provide some additional insight into a few areas covered by the article.
The authors, in describing the control groups in an earlier phase III study of DMQ for the treatment of patients with pseudobulbar affect (PBA), state, “However, the control conditions may not have been adequate. Quinidine alone would not be expected to have an effect on PBA, and the DM dose, which was the same in combination and monotherapy, may have been too low to be effective by itself. In support of this hypothesis, the DM plasma level was 18 times higher in patients taking DMQ 30-30 than those taking DM monotherapy.” Although their observations regarding the effectiveness of higher doses may be true, the study was designed to meet the FDA standards for combination products—that a combination product’s efficacy needs to exceed that which is appreciated by either of the components administered alone. As the authors correctly pointed out, even high doses of DM, when administered alone, are rapidly metabolized and cannot reach substantial bioavailability in order to exert a therapeutic effect.
Having been involved in clinical drug development for nearly 20 years, I cannot agree with the authors conclusions that: “Although DMQ is convenient, its advantage over starting with DM alone and adding a small dose of a nonserotonergic 2D6 inhibitor if DM is not effective remains to be demonstrated.” The statement implies that a reasonable approach is to consider testing DM combined with a series of arbitrary CYP2D6 inhibitors. These combinations have not been tested and there is no evidence on which to base the efficacy or safety of this approach. As clinical researchers, we have an obligation to make recommendations that are based on available data and that ensure patient safety. In our own exhaustive research, we believe there is no other CYP2D6 inhibitor, other than low-dose quinidine, 10 mg/d (1% to 3% of a typical antiarrhythmic dose), that can provide a safe and predictable pharmacologic profile when used in combination with DM. Lastly, I am disappointed with the assertion that “it would seem prudent to consider using an SSRI (selective serotonin reuptake inhibitor) or a TCA (tricyclic antidepressant) first.” These drugs have not been extensively studied for the treatment of PBA, and have their own (not benign) risks. Moreover, these antidepressants have not met the standard of substantial clinical evidence required by the FDA and thus, are not approved for treating patients with PBA.
Randall E. Kaye, MD, MPH
Chief Medical Officer
Avanir Pharmaceuticals
Aliso Viejo, CA
The authors respond
We appreciate Dr. Kaye’s letter, but would like to point out that registration trials designed to get FDA approval are designed to demonstrate superiority of the product to placebo and not to answer the question “under what circumstances and compared with what alternatives is this product more likely to be effective and safe?” We would not necessarily agree that this particular product is superior because it was approved by the FDA in placebo-controlled research designed to maximize the apparent benefit of the combination, when only clinical experience supports the use of alternatives. Perhaps the manufacturer would care to design head-to-head comparisons to support Dr. Kaye’s contention that his product should be the first choice in the treatment of PBA, which has been done with cancer and human immunodeficiency virus products, among others. Such comparison trials should include patients with complex and comorbid disorders to reflect real-life clinical practice rather than efficacy in patients selected for their likelihood to respond to the product. In the meantime, clinicians have the task of evaluating marketing of products and ideas, which is inherent in many clinical recommendations, not only those for which the only controlled data come from industry-sponsored trials.
Alfonso Tan III, MD
Assistant Professor of Psychiatry
University at Buffalo
Buffalo, NY
Steven L. Dubovsky, MD
Professor and Chair
Department of Psychiatry
University at Buffalo
Buffalo, NY
Adjoint Professor of Psychiatry
and Medicine
University of Colorado
Denver, CO
The article “Dextromethorphan/quinidine for pseudobulbar affect” (Out of the Pipeline, Current Psychiatry, February 2011, p. 60-67) was of great interest. For the past 5 years I have led the clinical development of NuedextaTM (dextromethorphan hydrobromide and quinidine sulfate; DMQ) and I found the review extraordinarily comprehensive and applaud the authors for their exhaustive research. I would, however, like to take the opportunity to provide some additional insight into a few areas covered by the article.
The authors, in describing the control groups in an earlier phase III study of DMQ for the treatment of patients with pseudobulbar affect (PBA), state, “However, the control conditions may not have been adequate. Quinidine alone would not be expected to have an effect on PBA, and the DM dose, which was the same in combination and monotherapy, may have been too low to be effective by itself. In support of this hypothesis, the DM plasma level was 18 times higher in patients taking DMQ 30-30 than those taking DM monotherapy.” Although their observations regarding the effectiveness of higher doses may be true, the study was designed to meet the FDA standards for combination products—that a combination product’s efficacy needs to exceed that which is appreciated by either of the components administered alone. As the authors correctly pointed out, even high doses of DM, when administered alone, are rapidly metabolized and cannot reach substantial bioavailability in order to exert a therapeutic effect.
Having been involved in clinical drug development for nearly 20 years, I cannot agree with the authors conclusions that: “Although DMQ is convenient, its advantage over starting with DM alone and adding a small dose of a nonserotonergic 2D6 inhibitor if DM is not effective remains to be demonstrated.” The statement implies that a reasonable approach is to consider testing DM combined with a series of arbitrary CYP2D6 inhibitors. These combinations have not been tested and there is no evidence on which to base the efficacy or safety of this approach. As clinical researchers, we have an obligation to make recommendations that are based on available data and that ensure patient safety. In our own exhaustive research, we believe there is no other CYP2D6 inhibitor, other than low-dose quinidine, 10 mg/d (1% to 3% of a typical antiarrhythmic dose), that can provide a safe and predictable pharmacologic profile when used in combination with DM. Lastly, I am disappointed with the assertion that “it would seem prudent to consider using an SSRI (selective serotonin reuptake inhibitor) or a TCA (tricyclic antidepressant) first.” These drugs have not been extensively studied for the treatment of PBA, and have their own (not benign) risks. Moreover, these antidepressants have not met the standard of substantial clinical evidence required by the FDA and thus, are not approved for treating patients with PBA.
Randall E. Kaye, MD, MPH
Chief Medical Officer
Avanir Pharmaceuticals
Aliso Viejo, CA
The authors respond
We appreciate Dr. Kaye’s letter, but would like to point out that registration trials designed to get FDA approval are designed to demonstrate superiority of the product to placebo and not to answer the question “under what circumstances and compared with what alternatives is this product more likely to be effective and safe?” We would not necessarily agree that this particular product is superior because it was approved by the FDA in placebo-controlled research designed to maximize the apparent benefit of the combination, when only clinical experience supports the use of alternatives. Perhaps the manufacturer would care to design head-to-head comparisons to support Dr. Kaye’s contention that his product should be the first choice in the treatment of PBA, which has been done with cancer and human immunodeficiency virus products, among others. Such comparison trials should include patients with complex and comorbid disorders to reflect real-life clinical practice rather than efficacy in patients selected for their likelihood to respond to the product. In the meantime, clinicians have the task of evaluating marketing of products and ideas, which is inherent in many clinical recommendations, not only those for which the only controlled data come from industry-sponsored trials.
Alfonso Tan III, MD
Assistant Professor of Psychiatry
University at Buffalo
Buffalo, NY
Steven L. Dubovsky, MD
Professor and Chair
Department of Psychiatry
University at Buffalo
Buffalo, NY
Adjoint Professor of Psychiatry
and Medicine
University of Colorado
Denver, CO
The article “Dextromethorphan/quinidine for pseudobulbar affect” (Out of the Pipeline, Current Psychiatry, February 2011, p. 60-67) was of great interest. For the past 5 years I have led the clinical development of NuedextaTM (dextromethorphan hydrobromide and quinidine sulfate; DMQ) and I found the review extraordinarily comprehensive and applaud the authors for their exhaustive research. I would, however, like to take the opportunity to provide some additional insight into a few areas covered by the article.
The authors, in describing the control groups in an earlier phase III study of DMQ for the treatment of patients with pseudobulbar affect (PBA), state, “However, the control conditions may not have been adequate. Quinidine alone would not be expected to have an effect on PBA, and the DM dose, which was the same in combination and monotherapy, may have been too low to be effective by itself. In support of this hypothesis, the DM plasma level was 18 times higher in patients taking DMQ 30-30 than those taking DM monotherapy.” Although their observations regarding the effectiveness of higher doses may be true, the study was designed to meet the FDA standards for combination products—that a combination product’s efficacy needs to exceed that which is appreciated by either of the components administered alone. As the authors correctly pointed out, even high doses of DM, when administered alone, are rapidly metabolized and cannot reach substantial bioavailability in order to exert a therapeutic effect.
Having been involved in clinical drug development for nearly 20 years, I cannot agree with the authors conclusions that: “Although DMQ is convenient, its advantage over starting with DM alone and adding a small dose of a nonserotonergic 2D6 inhibitor if DM is not effective remains to be demonstrated.” The statement implies that a reasonable approach is to consider testing DM combined with a series of arbitrary CYP2D6 inhibitors. These combinations have not been tested and there is no evidence on which to base the efficacy or safety of this approach. As clinical researchers, we have an obligation to make recommendations that are based on available data and that ensure patient safety. In our own exhaustive research, we believe there is no other CYP2D6 inhibitor, other than low-dose quinidine, 10 mg/d (1% to 3% of a typical antiarrhythmic dose), that can provide a safe and predictable pharmacologic profile when used in combination with DM. Lastly, I am disappointed with the assertion that “it would seem prudent to consider using an SSRI (selective serotonin reuptake inhibitor) or a TCA (tricyclic antidepressant) first.” These drugs have not been extensively studied for the treatment of PBA, and have their own (not benign) risks. Moreover, these antidepressants have not met the standard of substantial clinical evidence required by the FDA and thus, are not approved for treating patients with PBA.
Randall E. Kaye, MD, MPH
Chief Medical Officer
Avanir Pharmaceuticals
Aliso Viejo, CA
The authors respond
We appreciate Dr. Kaye’s letter, but would like to point out that registration trials designed to get FDA approval are designed to demonstrate superiority of the product to placebo and not to answer the question “under what circumstances and compared with what alternatives is this product more likely to be effective and safe?” We would not necessarily agree that this particular product is superior because it was approved by the FDA in placebo-controlled research designed to maximize the apparent benefit of the combination, when only clinical experience supports the use of alternatives. Perhaps the manufacturer would care to design head-to-head comparisons to support Dr. Kaye’s contention that his product should be the first choice in the treatment of PBA, which has been done with cancer and human immunodeficiency virus products, among others. Such comparison trials should include patients with complex and comorbid disorders to reflect real-life clinical practice rather than efficacy in patients selected for their likelihood to respond to the product. In the meantime, clinicians have the task of evaluating marketing of products and ideas, which is inherent in many clinical recommendations, not only those for which the only controlled data come from industry-sponsored trials.
Alfonso Tan III, MD
Assistant Professor of Psychiatry
University at Buffalo
Buffalo, NY
Steven L. Dubovsky, MD
Professor and Chair
Department of Psychiatry
University at Buffalo
Buffalo, NY
Adjoint Professor of Psychiatry
and Medicine
University of Colorado
Denver, CO