- Email: [email protected]
Consultation-Liaison Psychiatry Drug–Drug Interactions Update
Consultation-Liaison Psychiatry Drug–Drug Interactions Update SCOTT C. ARMSTRONG, M.D. KELLY L. COZZA, M.D.
In this version of the DDI update, we review the Cytochrome P450 (P450)-inducing drugs carbamazepine(CBZ) and oxcarbazepine (OCBZ) through three recent papers. CBZ is a drug frequently used in psychiatric patients, and we predict that OCBZ, a newer drug available in the United States, will follow suit. We follow these antiepileptic drug (AED) reports with a review of an excellent primer on pharmacogenetics. Although not precisely an issue in regards to DDI, pharmacogenetics could dramatically change the way we prescribe medications.
Drug Interactions with Antiepileptic Drugs Carbamazepine and Oxcarbazepine
1. Hesslinger B, Normann C, Langosch JM, et al: Effects of carbamazepine and valproate on haloperidol plasma levels and on psychopathologic outcome in schizophrenic patients. J Clin Psychopharm 19:310–315, 1999. Twenty-seven patients with diagnoses of schizophrenia or schizoaffective disorder were randomized to receive haloperidol alone, with CBZ, or with valproate (VPA). All patients were brought to a steady haloperidol dose (mean⳱15.5Ⳳ5.6 mg/day) for 3 days, then the study groups had CBZ and VPA added. The additional drugs were titrated to therapeutic serum levels within 1 week when possible. Addi-
tional drugs allowed were chlorprothixine for insomnia and agitation as well as biperiden for extrapyramidal symptoms. Importantly, this study not only recorded pharmacokinetic information on the drugs delivered but also studied clinical effect using the Positive subscale of the Positive and Negative Syndrome Scale (pPANSS) and the Inpatient Multidimensional Psychiatric Scale (IMPS). The addition of CBZ resulted in significantly lower haloperidol plasma levels, associated with a worsened clinical picture compared with monotherapy with haloperidol. There were no differences in any plasma levels with the addition of VPA. The CBZ group also had a sixfold greater requirement for chlorprothixine for insomnia and agitation. The authors suggest that the combination of haloperidol and CBZ may lead to treatment failure because of a P450 interaction. The decline in haloperidol levels in the haloperidol-CBZ group is expected to be because of an induction of P450 enzymes 3A4 and 2D6, the enzymes responsible for the metabolism of haloperidol. Induction generally takes several weeks to occur, as new and increased enzyme synthesis takes 2–3 weeks to reach a new steady state, at a lower plasma level. In comparison, enzyme inhibition (or competitive binding) is immediate. This study found that the differences in haloperidol levels between the haloperidolCBZ group and the others were greatest between Days 0–14, supporting P450 induction as the etiology. There are two “take home” mes-
Psychosomatics 41:6, November-December 2000
sages from this report that are very important. First, this study used relatively low haloperidol dosages (proposed therapeutic window of 2–12 ng/mL) as compared with previous studies. Hesslinger et al. suspect that the CBZ-haloperidol P450 enzyme induction was previously not appreciated, because the addition of an inducer in light of excessive haloperidol may have been beneficial (i.e., lowering the haloperidol levels via induction brought it into therapeutic range alleviating adverse side effects). In Hesslinger et al.’s study and as in current practice, lower haloperidol dosages are at risk of becoming subtherapeutic if coadministered with CBZ. Secondly, this study is notable for “going the extra mile” by studying not just plasma levels to determine drug interactions but looking for clinical significance and relevance in a sick population by seeing if the interaction in question affected patient performance and lives. -KLC
2. Tecoma ES: Oxcarbazepine. Epilepsia 40(supp 5):S37–46, 1999. This is an excellent, digestible review of this new-to-the-U.S.-market antiepileptic drug (AED). Oxcarbazepine (OCBZ) was designed to overcome the significant limitations of carbamazepine (CBZ) to include autoinduction and hepatic drug interactions. CBZ’s metabolite, CBZ-10–11 epoxide, is responsible for clinical effect as well as toxicity. OCBZ is almost immediately converted to its active metabolite, 10,11, dihydro-10-hydroxy-5H-di541
Drug-Drug Interaction benzo(b,f)azepine-5-carboxamide (MHD) and has no epoxide metabolite. Antiseizure efficacy of OCBZ is similar to CBZ. Much of the metabolism of OCBZ is not dependent on microsomes. The conversion to MHD is by the reduction of the keto group by cytosol arylketone reductase. MHD is inactivated by glucuronide conjugation followed by renal excretion. OCBZ is considered a prodrug, MHD being the active metabolite. Tecoma describes the formation of 10,11-dihydro-10,11-trans-hydroxycarbamazepine (DHD) from MHD as a minor pathway, which does require P450 enzymes. DHD is common to both CBZ and OCBZ metabolism. The major advantage of OCBZ is supposed to be the low level of hepatic induction. Care is suggested when converting from CBZ to OCBZ because deinduction can take several weeks, and drugs that were induced (i.e., plasma levels lowered) by CBZ may become toxic 2– 3 weeks after the transition to OCBZ. Tecoma reviewed a study where phenytoin and valproic acid levels significantly increased when study patients were treated with OCBZ as compared to CBZ. Although OCBZ is not considered a potent P450 inducer, its effect on oral contraceptives may be similar to CBZ (see next review below). There is a suggestion that potent inhibitors of P450 enzymes may have some effect on the metabolism of MHD to DHD, with verapamil being specifically cited; however, the clinical significance is not yet known. Other potent inhibitors that have shown no effect on OCBZ include erythromycin and cimetidine. When administered with potent inducers of P450 enzymes like phenobarbital and CBZ, OCBZ dosage may need to be increased. Tecoma references several studies that examined hepatic induction and the positive changes in serum lipids, 542
sex hormones, and thyroid functioning after converting patients from CBZ to OCBZ. The hematological changes expected from CBZ (lowered white and red blood cell counts) were also reversed with conversion to OCBZ. There are still adverse effects with OCBZ, to include sedation, headache, rash, vertigo, double vision, dizziness, and ataxia, but tolerability is superior to CBZ. There are reports of hyponatremia. -KLC
3. Fattore C, Cipolla G, Gatti G, et al: Induction of ethinylestradiol and levonorgestrel metabolism by oxcarbazepine in healthy women. Epilepsia 40:783–787, 1999. This report nimbly goes into more detail about the induction of sex hormones by OCBZ than could be mentioned within the above review by Tecoma, and adds to the above review, being in press as the above review was printed. Sixteen healthy women completed the randomized, double-blind crossover study that spanned two different menstrual cycles. Placebo or OCBZ was given in a randomized sequence for 26 days with a one-cycle washout between. An oral contraceptive containing 50 micrograms ethinylestradiol (EE) and 250 micrograms levonorgestrel (LN) was taken for the first 21 days of each cycle, and plasma concentrations were measured of EE and LN on Days 21–23 of each cycle. Area under the concentration curve (AUC), peak plasma concentrations and half-lives all decreased during OCBZ treatment. Steroid hormone metabolism occurs at P450 3A4 in the liver and gut wall. Although OCBZ at 600 mgs/day did not affect the conversion of cortisol to 6-beta-hydroxycortisol in previous studies, this report in-
dicates that EE is induced at the 3A4-mediated 2-hydroxylation of the steroid. The reduced peak plasma concentration indicates that a great portion of the steroid is induced during first pass metabolism at the gut wall enzymes. LN does not undergo extensive first pass metabolism, and its peak plasma level was less effected by OCBZ. The induction of the metabolism of oral contraceptives is clinically important. OCBZ may have a better sideeffect, autoinduction, and toxicity profile than CBZ, but the reduction in EE and LN is similar to that found with the potent inducers CBZ, phenytoin, and the barbiturates. Although this study did not find a surge in the plasma progesterone levels (a sign of ovulation), breakthrough bleeding has occurred with this drug. Reduced effectiveness of oral contraceptives, especially of low potency preparations, should be expected with OCBZ. Fattore et al. suggest higher dosage contraceptives as well as counseling that additional or alternative contraceptives may be needed. -KLC
Pharmacogenetics Review
1. Linder MW, Valdes R: Pharmacogenetics in the Practice of Laboratory Medicine. Molecular Diagnosis 4(4):365– 379, 1999. In June of 2000, the sequencing of the human genome was completed. This article gives us some insight into one way that our understanding of the human genome may become practical for clinicians in the foreseeable future. Although we are all one species, we are all very different genetically.
Psychosomatics 41:6, November-December 2000
Drug-Drug Interaction Our genes demonstrate variability or polymorphisms. Intuitively we know this simply from variability of eye or skin color. In regard to drug metabolism and utilization, the human genome’s polymorphic variability often makes the practice of prescribing medications an adventure. If this were not so, all our patients when taking a particular drug—given similar external environments—would have identical drug levels (from identical pharmacokinetic [PK] processes) and clinical effects (from identical pharmacodynamic [PD] processes). We know from practical clinical experiences that this never occurs. For example, two identical doses of phenytoin can be prescribed to two similar sized and aged White males and end up with vastly dissimilar blood levels (from different PK processes) and/or variable clinical efficacy (from different PD processes). We discover early in our careers that each patient is unique in how they metabolize drugs and/or how they clinically respond to drugs. Linder and Valdes give the reader a glimpse into the future of pharmacology and pharmacogenetics (PG). PG may allow clinicians in the future to predict both dosages and effects of drugs before they are prescribed. This would certainly be an improvement from the current practice. This review article is detailed but not overdone. The
article gives examples of the current knowledge of genetic variability of some drug metabolizing enzymes [such as P450 2D6, 2C9, 2C19, Thiopurine S-methyltransferase (TMPT) and Nacetyltransferase 2] and one drug receptor (Beta-2 adrenergic). Linder and Valdes point out the abundant genetic variability—for example, P450 2D6 has 16 different known alleles! This variability creates enzyme function that can be “normal,” increased, decreased, or even nonexistent. Some of the drugs partly dependent on clearance by 2D6 include tricyclic antidepressants, antiarrhythmics and codeine. Clearly genetic variability of 2D6 in the metabolism of these drugs could have significant clinical consequences. For example, in those patients who lack 2D6 activity, codeine provides a poor analgesic response because it requires the enzyme to metabolize the codeine to a more active analgesic compound. Although genetic variability is often just a nuisance, sometimes it can have dire consequences. An example of the latter is when cancer chemotherapy patients lack TMPT. TMPT is necessary for metabolism of some chemotherapy agents. Having poor TMPT activity can lead to hematopoietic toxicity at standard doses. Standard protocols now exist to determine a chemotherapy patient’s genetic variability for TMPT before prescribing the dosage of chemotherapy drugs.
Psychosomatics 41:6, November-December 2000
The PG screening of TMPT is one of the very few current examples of determining polymorphisms to help predict drug metabolism and efficacy. Linder and Valdes state that the cost-benefit ratio for routine PG screening is currently poor. The techniques are available now, and costs will most likely go down as the tools for PG screening are improved, simplified, and automated. They believe that with more study and refinement it is likely that PG screening will become more readily available. Despite living and working in a very “modern” era of medicine, drug ineffectiveness and/or untoward outcomes are normally still discovered by happenstance. The potential for PG screening in the future will be a vast improvement to reduce the current inefficiencies of prescribing. I look forward to the day when routine PG screening of my patients can advise me what drugs to use or avoid. -SCA Dr. Armstrong is Medical Director, Willmar Regional Treatment Center, Willmar, Minnesota; Dr. Cozza is an HIV Psychiatrist at the Department of Medicine, Walter Reed Army Medical Center, Washington, DC. Address correspondence to Dr. Armstrong, Willmar Regional Treatment Center, 1550 Hwy 71 N, Willmar, MN 56201; e-mail Dr. Armstrong at [email protected]
543
In this version of the DDI update, we review the Cytochrome P450 (P450)-inducing drugs carbamazepine(CBZ) and oxcarbazepine (OCBZ) through three recent papers. CBZ is a drug frequently used in psychiatric patients, and we predict that OCBZ, a newer drug available in the United States, will follow suit. We follow these antiepileptic drug (AED) reports with a review of an excellent primer on pharmacogenetics. Although not precisely an issue in regards to DDI, pharmacogenetics could dramatically change the way we prescribe medications.
Drug Interactions with Antiepileptic Drugs Carbamazepine and Oxcarbazepine
1. Hesslinger B, Normann C, Langosch JM, et al: Effects of carbamazepine and valproate on haloperidol plasma levels and on psychopathologic outcome in schizophrenic patients. J Clin Psychopharm 19:310–315, 1999. Twenty-seven patients with diagnoses of schizophrenia or schizoaffective disorder were randomized to receive haloperidol alone, with CBZ, or with valproate (VPA). All patients were brought to a steady haloperidol dose (mean⳱15.5Ⳳ5.6 mg/day) for 3 days, then the study groups had CBZ and VPA added. The additional drugs were titrated to therapeutic serum levels within 1 week when possible. Addi-
tional drugs allowed were chlorprothixine for insomnia and agitation as well as biperiden for extrapyramidal symptoms. Importantly, this study not only recorded pharmacokinetic information on the drugs delivered but also studied clinical effect using the Positive subscale of the Positive and Negative Syndrome Scale (pPANSS) and the Inpatient Multidimensional Psychiatric Scale (IMPS). The addition of CBZ resulted in significantly lower haloperidol plasma levels, associated with a worsened clinical picture compared with monotherapy with haloperidol. There were no differences in any plasma levels with the addition of VPA. The CBZ group also had a sixfold greater requirement for chlorprothixine for insomnia and agitation. The authors suggest that the combination of haloperidol and CBZ may lead to treatment failure because of a P450 interaction. The decline in haloperidol levels in the haloperidol-CBZ group is expected to be because of an induction of P450 enzymes 3A4 and 2D6, the enzymes responsible for the metabolism of haloperidol. Induction generally takes several weeks to occur, as new and increased enzyme synthesis takes 2–3 weeks to reach a new steady state, at a lower plasma level. In comparison, enzyme inhibition (or competitive binding) is immediate. This study found that the differences in haloperidol levels between the haloperidolCBZ group and the others were greatest between Days 0–14, supporting P450 induction as the etiology. There are two “take home” mes-
Psychosomatics 41:6, November-December 2000
sages from this report that are very important. First, this study used relatively low haloperidol dosages (proposed therapeutic window of 2–12 ng/mL) as compared with previous studies. Hesslinger et al. suspect that the CBZ-haloperidol P450 enzyme induction was previously not appreciated, because the addition of an inducer in light of excessive haloperidol may have been beneficial (i.e., lowering the haloperidol levels via induction brought it into therapeutic range alleviating adverse side effects). In Hesslinger et al.’s study and as in current practice, lower haloperidol dosages are at risk of becoming subtherapeutic if coadministered with CBZ. Secondly, this study is notable for “going the extra mile” by studying not just plasma levels to determine drug interactions but looking for clinical significance and relevance in a sick population by seeing if the interaction in question affected patient performance and lives. -KLC
2. Tecoma ES: Oxcarbazepine. Epilepsia 40(supp 5):S37–46, 1999. This is an excellent, digestible review of this new-to-the-U.S.-market antiepileptic drug (AED). Oxcarbazepine (OCBZ) was designed to overcome the significant limitations of carbamazepine (CBZ) to include autoinduction and hepatic drug interactions. CBZ’s metabolite, CBZ-10–11 epoxide, is responsible for clinical effect as well as toxicity. OCBZ is almost immediately converted to its active metabolite, 10,11, dihydro-10-hydroxy-5H-di541
Drug-Drug Interaction benzo(b,f)azepine-5-carboxamide (MHD) and has no epoxide metabolite. Antiseizure efficacy of OCBZ is similar to CBZ. Much of the metabolism of OCBZ is not dependent on microsomes. The conversion to MHD is by the reduction of the keto group by cytosol arylketone reductase. MHD is inactivated by glucuronide conjugation followed by renal excretion. OCBZ is considered a prodrug, MHD being the active metabolite. Tecoma describes the formation of 10,11-dihydro-10,11-trans-hydroxycarbamazepine (DHD) from MHD as a minor pathway, which does require P450 enzymes. DHD is common to both CBZ and OCBZ metabolism. The major advantage of OCBZ is supposed to be the low level of hepatic induction. Care is suggested when converting from CBZ to OCBZ because deinduction can take several weeks, and drugs that were induced (i.e., plasma levels lowered) by CBZ may become toxic 2– 3 weeks after the transition to OCBZ. Tecoma reviewed a study where phenytoin and valproic acid levels significantly increased when study patients were treated with OCBZ as compared to CBZ. Although OCBZ is not considered a potent P450 inducer, its effect on oral contraceptives may be similar to CBZ (see next review below). There is a suggestion that potent inhibitors of P450 enzymes may have some effect on the metabolism of MHD to DHD, with verapamil being specifically cited; however, the clinical significance is not yet known. Other potent inhibitors that have shown no effect on OCBZ include erythromycin and cimetidine. When administered with potent inducers of P450 enzymes like phenobarbital and CBZ, OCBZ dosage may need to be increased. Tecoma references several studies that examined hepatic induction and the positive changes in serum lipids, 542
sex hormones, and thyroid functioning after converting patients from CBZ to OCBZ. The hematological changes expected from CBZ (lowered white and red blood cell counts) were also reversed with conversion to OCBZ. There are still adverse effects with OCBZ, to include sedation, headache, rash, vertigo, double vision, dizziness, and ataxia, but tolerability is superior to CBZ. There are reports of hyponatremia. -KLC
3. Fattore C, Cipolla G, Gatti G, et al: Induction of ethinylestradiol and levonorgestrel metabolism by oxcarbazepine in healthy women. Epilepsia 40:783–787, 1999. This report nimbly goes into more detail about the induction of sex hormones by OCBZ than could be mentioned within the above review by Tecoma, and adds to the above review, being in press as the above review was printed. Sixteen healthy women completed the randomized, double-blind crossover study that spanned two different menstrual cycles. Placebo or OCBZ was given in a randomized sequence for 26 days with a one-cycle washout between. An oral contraceptive containing 50 micrograms ethinylestradiol (EE) and 250 micrograms levonorgestrel (LN) was taken for the first 21 days of each cycle, and plasma concentrations were measured of EE and LN on Days 21–23 of each cycle. Area under the concentration curve (AUC), peak plasma concentrations and half-lives all decreased during OCBZ treatment. Steroid hormone metabolism occurs at P450 3A4 in the liver and gut wall. Although OCBZ at 600 mgs/day did not affect the conversion of cortisol to 6-beta-hydroxycortisol in previous studies, this report in-
dicates that EE is induced at the 3A4-mediated 2-hydroxylation of the steroid. The reduced peak plasma concentration indicates that a great portion of the steroid is induced during first pass metabolism at the gut wall enzymes. LN does not undergo extensive first pass metabolism, and its peak plasma level was less effected by OCBZ. The induction of the metabolism of oral contraceptives is clinically important. OCBZ may have a better sideeffect, autoinduction, and toxicity profile than CBZ, but the reduction in EE and LN is similar to that found with the potent inducers CBZ, phenytoin, and the barbiturates. Although this study did not find a surge in the plasma progesterone levels (a sign of ovulation), breakthrough bleeding has occurred with this drug. Reduced effectiveness of oral contraceptives, especially of low potency preparations, should be expected with OCBZ. Fattore et al. suggest higher dosage contraceptives as well as counseling that additional or alternative contraceptives may be needed. -KLC
Pharmacogenetics Review
1. Linder MW, Valdes R: Pharmacogenetics in the Practice of Laboratory Medicine. Molecular Diagnosis 4(4):365– 379, 1999. In June of 2000, the sequencing of the human genome was completed. This article gives us some insight into one way that our understanding of the human genome may become practical for clinicians in the foreseeable future. Although we are all one species, we are all very different genetically.
Psychosomatics 41:6, November-December 2000
Drug-Drug Interaction Our genes demonstrate variability or polymorphisms. Intuitively we know this simply from variability of eye or skin color. In regard to drug metabolism and utilization, the human genome’s polymorphic variability often makes the practice of prescribing medications an adventure. If this were not so, all our patients when taking a particular drug—given similar external environments—would have identical drug levels (from identical pharmacokinetic [PK] processes) and clinical effects (from identical pharmacodynamic [PD] processes). We know from practical clinical experiences that this never occurs. For example, two identical doses of phenytoin can be prescribed to two similar sized and aged White males and end up with vastly dissimilar blood levels (from different PK processes) and/or variable clinical efficacy (from different PD processes). We discover early in our careers that each patient is unique in how they metabolize drugs and/or how they clinically respond to drugs. Linder and Valdes give the reader a glimpse into the future of pharmacology and pharmacogenetics (PG). PG may allow clinicians in the future to predict both dosages and effects of drugs before they are prescribed. This would certainly be an improvement from the current practice. This review article is detailed but not overdone. The
article gives examples of the current knowledge of genetic variability of some drug metabolizing enzymes [such as P450 2D6, 2C9, 2C19, Thiopurine S-methyltransferase (TMPT) and Nacetyltransferase 2] and one drug receptor (Beta-2 adrenergic). Linder and Valdes point out the abundant genetic variability—for example, P450 2D6 has 16 different known alleles! This variability creates enzyme function that can be “normal,” increased, decreased, or even nonexistent. Some of the drugs partly dependent on clearance by 2D6 include tricyclic antidepressants, antiarrhythmics and codeine. Clearly genetic variability of 2D6 in the metabolism of these drugs could have significant clinical consequences. For example, in those patients who lack 2D6 activity, codeine provides a poor analgesic response because it requires the enzyme to metabolize the codeine to a more active analgesic compound. Although genetic variability is often just a nuisance, sometimes it can have dire consequences. An example of the latter is when cancer chemotherapy patients lack TMPT. TMPT is necessary for metabolism of some chemotherapy agents. Having poor TMPT activity can lead to hematopoietic toxicity at standard doses. Standard protocols now exist to determine a chemotherapy patient’s genetic variability for TMPT before prescribing the dosage of chemotherapy drugs.
Psychosomatics 41:6, November-December 2000
The PG screening of TMPT is one of the very few current examples of determining polymorphisms to help predict drug metabolism and efficacy. Linder and Valdes state that the cost-benefit ratio for routine PG screening is currently poor. The techniques are available now, and costs will most likely go down as the tools for PG screening are improved, simplified, and automated. They believe that with more study and refinement it is likely that PG screening will become more readily available. Despite living and working in a very “modern” era of medicine, drug ineffectiveness and/or untoward outcomes are normally still discovered by happenstance. The potential for PG screening in the future will be a vast improvement to reduce the current inefficiencies of prescribing. I look forward to the day when routine PG screening of my patients can advise me what drugs to use or avoid. -SCA Dr. Armstrong is Medical Director, Willmar Regional Treatment Center, Willmar, Minnesota; Dr. Cozza is an HIV Psychiatrist at the Department of Medicine, Walter Reed Army Medical Center, Washington, DC. Address correspondence to Dr. Armstrong, Willmar Regional Treatment Center, 1550 Hwy 71 N, Willmar, MN 56201; e-mail Dr. Armstrong at [email protected]
543