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Combination Drugs: Innovation in Pharmacotherapy | Pharmaceutical Drug | Statin

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Combination Drugs: Innovation in Pharmacotherapy Albert I. Wertheimer, PhD and Alan Morrison, PhD A lthough most pharmaceutical innovation is incremen- tal, small improvements in therapy often add up to substantial progress over time. 1 Incremental innova- tion in drug therapy can take various forms, includ- ing new agents, new indications for existing drugs, and new dosage forms with improved pharmacologic profiles. 1 Combi- nation therapy with two or mo
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  Combination Drugs: Innovation in Pharmacotherapy  Albert I. Wertheimer, PhD and Alan Morrison, PhD A lthough most pharmaceutical innovation is incremen-tal, small improvements in therapy often add up tosubstantial progress over time. 1 Incremental innova-tion in drug therapy can take various forms, includ-ing new agents, new indications for existing drugs, and new dosage forms with improved pharmacologic profiles. 1 Combi-nation therapy with two or more agents having complemen-tary mechanisms of action represents a type of incrementalinnovation that has extended the range of therapeutic optionsin the treatment of almost every human disease. Combinationproducts—also known as fixed-dose combinations—are com-binations of two or more active drugs produced in a singletablet (see Table 1). They provide the advantages of combina-tion therapy while reducing the number of prescriptions andthe attendant administrative costs. Unfortunately, the real con-tribution of combination products to therapeutics has beenblurred by perceptions of inherent disadvantages and, as a result, these products are often perceived only as second-linetherapy. In this article, we describe the advantages of combi-nation products and discuss the evidence in support of their role in pharmacotherapy. Rationale for Combination Therapy  All drugs have unwanted side effects in addition to thedesired therapeutic effect. The idea of combining two or more drugs with complementary modes of action is to pro-duce additivity of the desired therapeutic effect but not of theside effects. As an example, at least five classes of drugs arecommonly used to treat hypertension: diuretics, beta-block-ers, ACE-inhibitors, angiotensin receptor blockers, and calci-um-channel blockers. The antihypertensive effects of an ACE-inhibitor and a calcium channel blocker, for instance,are additive, but these drug classes have different spectra of side effects, none of which are additive (although the spec-trum can be broadened in a combination drug). Because thecombination produces the same antihypertensive effect ashigher doses of either constituent, the exposure to sideeffects is reduced and the therapeutic ratio is increased. Thetherapeutic ratio can be increased in certain instances by thephenomena of potentiation and cancellation. Potentiation isthe synergistic effect on drug A by adding a dose of drug B without a therapeutic effect. An example is the combinationof bisprolol 2 or enalapril 3  with a low dose of hydrochloroth-iazide itself without antihypertensive effect. Cancellation is a phenomenon in which the adverse effects of one drug arenullified by the addition of a second (e.g., the hypokalemiceffects of thiazide diuretics are counteracted by the slight hyperkalemic effect of an ACE-inhibitor). 4,5  The conceptual basis for combination treatment of infec-tious disease is somewhat different from conditions such ashypertension, in which the drug target is human tissue. Ininfectious disease, the drug target is an evolutionarily unrelat-ed microbe, and drug side effects are of less concern than theloss of efficacy caused by the emergence of drug-resistant strains. Consider a bacterium with a spontaneous rate of muta-tion to antibiotic resistance of 10 -9 , i.e., one in 10 9 bacteria (a titer that can be grown in a milliliter of culture) will grow in the presence of the antibiotic. Consider next a combina-tion of two different antibiotics: the spontaneous rate of appearance of a strain resistant to both antibiotics is 10 -18 , sothat a million liters of culture would have to be grown to iso-late a single resistant bacterium. With triple antibiotic thera-py, the number of bacteria needed to generate a resistant cellis an astronomical 10 27 . However, the spontaneous mutationrate is under genetic control, and in some microorganisms it is drastically increased as a survival strategy. Because virus-es are far smaller than bacteria and can reach much higher titers, triple-combination therapy is required to prevent theappearance of drug-resistant strains of HIV. 44 P&T ® ã January 2002 ã Vol. 27 No. 1  Dr. Wertheimer is Professor of Pharmacy and Director of the Center for  Pharmaceutical Health Services Research, and Dr. Morrison is Associate Director of the Center for Pharmaceutical Health Services Research, at Temple University School of Pharmacy in Philadelphia, Pennsylvania.  To describe the therapeutic benefit from combi-nation therapy for various disease states  To critique the rationale for formulary inclusionof selected combination drug therapies  To identify advantages and barriers to utilizing combination drug therapy in clinical practice Educational Objectives CE CREDIT   Although combination therapy is typically a matter of two(or more) different classes of drugs with a common therapeu-tic effect, there are many types of combinations. In the combi-nation of amoxicillin and clavulanate (see Table 1), the latter compound acts by inhibiting bacterial degradation of amoxi-cillin, rather than having any direct therapeutic activity itself. This renders amoxicillin effective against strains that havebecome resistant through acquisition of a plasmid-borne geneencoding beta-lactamase. Similarly, in the combination of car-bidopa and levodopa, carbidopa itself has no beneficial thera-peutic effect, but it inhibits the systemic decarboxylation andinactivation of levodopa before it crosses the blood–brain bar-rier and is converted to dopamine, the active metabolite that relieves the symptoms of Parkinson’s disease. The combina-tions of amoxicillin/clavulanate and carbidopa/levodopa arefurther examples of potentiation. Some combinations are made from drugs in the sameclass. For example, the protease inhibitors ritonavir andsaquinavir, or the nucleoside analogs zidovudine and lamivu-dine, are all anti-retroviral agents used to treat HIV infection(see Table 1). In these examples, the mechanism of the twocombined drugs is the same, but there is little or no cross-reactivity, so that their inhibitory effects on HIV replicationare additive, and HIV strains spontaneously resistant to oneconstituent drug are not cross-resistant to the second. Combi-nation therapy can also be used to treat two different infec-tious diseases: a combination vaccine for hepatitis A and B isavailable (although both viruses cause hepatitis, they areunrelated species). It is important to note that the distinction between a singledrug with a single pharmacological activity and a combinationdrug with combined pharmacological activities is not abso-lute. Clozapine, for example, is a single drug with a relatively high affinity for multiple receptor sites, including a widerange of monaminergic, cholinergic, and histaminergic recep-tors. 6  A combination product with a pharmacological activity equivalent to that of clozapine could, in principle, be producedfrom several different drugs each specific to a single receptor class. Such a combination product exactly mimicking thepharmacological effects of clozapine would not, however, beapproved by the FDA. The FDA requires that each con-stituent in a combination product contribute to the therapeu-tic effect, and it is not established that all the receptor-bindingactivities of clozapine contribute to its antipsychotic activity. Advantages of Combination Products Combination products have the advantages of combinationtherapy as well as advantages related to reducing the number of pills to be taken. Reduced administration costs stem fromsimplified packaging, fewer prescriptions, and fewer dispens-ing fees and co-pays. It has been known for many years that there is an inverse relationship between patient adherenceand the complexity of the drug regimen. 7 Reducing the num-ber of pills diminishes the complexity of the regimen, so that improved patient adherence is expected with combinationproducts. Combination products make particular sense in thetreatment of infectious disease, where partial adherence canlead to the development of drug-resistant strains and a threat to public health. The likelihood of a strain acquiring resis-tance to a constituent of combination therapy is zero if adher-ence is either zero or 100%, and reaches a maximum at intermediate levels of adherence. 8  With combination prod-ucts, patients take either all of the drugs or none of them, andthe possibility of the serial development of strains resistant toeach constituent drug taken individually is eliminated. Attitudes Toward Combination Products  The medical establishment has in the past been indisposed tothe use of combination products. This historical resistance isin part a reflection of the checkered history of fixed-dose com-bination drugs. In the post-World War II era, many drugs withdubious viability were made marketable by combining them with drugs of known effectiveness. 9 In the resulting backlash,a generation of medical students was taught that fixed-dosecombinations were an anathema. The American Medical Association opposed fixed-dose combinations because they denied physicians the discretion to decide both the compo-nents and the ratios in which they were used. 10,11  These objections would seem to hold little merit today, when many different combination products have beenapproved by the FDA. Combination products are typically available in a variety of dose ratios that cover the therapeuti-cally relevant range of possibilities and allow for control of thedose ratios in which combinations are prescribed. The use of antibiotic or antiviral drug combinations has received accep-tance, particularly since it was seen that this was the only way to control HIV/AIDS. Elsewhere, however, a dogmatic bias Vol. 27 No. 1ãJanuary 2002 ã P&T ® 45  The Office of Health Policy and Clinical Outcomes, Thomas Jefferson University Hospital, is approved by the American Council on Pharmaceutical Education(ACPE) as a provider of continuing pharmaceuticaleducation and complies with the Criteria for Quality for continuingpharmaceutical education programming. This program (079-999-02-13-H01) is acceptable for 1.0 hour of continuing education credit (0.1 CEUs) in states that recognize ACPE-approved providers.Statements of Credit indicating hours/CEUs will be mailed quarter-ly to participants who completed this activity and submitted a com-pleted evaluation with payment. ACPE  ®  Combination products make particular sense in the treatment of infectious disease,where partial adherence can lead to thedevelopment of drug-resistant strains and a threat to public health.  against the use of combination products seems to have per-sisted, based apparently on the principles of drug therapy (i.e., accepted conventions of drug treatment intended to min-imize exposure to adverse effects). These principles state that drug treatment should begin with monotherapy, followed by dose titration if the initial dose is insufficient. Only if this pro-cess fails is combination therapy considered as a potentialalternative to repetition of the process of monotherapy titra-tion with a different drug. Because of these principles, combination products havebeen allowed only a secondary role in the treatment guide-lines promulgated by some institutions and professional bod-ies. For example, the JNC VI guidelines for the treatment of hypertension, published in 1997, recommend monotherapy witheither a diuretic or a beta-blocker as initial treatment, andupward titration of the dose if the initial dose is inadequate. 12 If this procedure fails, the guidelines recommend either switchingto monotherapy with an agent of a different class or the additionof a second-line drug from another class (i.e., combination ther-apy). The 1999 guidelines from the World Health Organiza-tion–International Society of Hypertension are similar, 13 but donot stipulate initial therapy with a diuretic or beta-blocker, theuse of which is viewed by some as dated practice. 14  The JNC VIrecommendations for either a diuretic or a beta-blocker as first-line therapy were based on the results of long-term trials in which morbidity and mortality were reduced. 15,16 It is, then,ironic that many of these trials in fact tested drug algorithmsthat began with combination therapy. In the Medical ResearchCouncil (MRC), Swedish Trial in Old Patients with Hyperten-sion (STOP-Hypertension), and European Working Party onHigh Blood Presssure in the Elderly (EWPHE) trials, the first-line therapy was not diuretic monotherapy but a fixed-dose com- 46 P&T ® ã January 2002 ã Vol. 27 No. 1 CE: Combination Drugs Component DrugsDrug classesTherapeutic Action Cardiovascular Disease Aspirin/dipyridamoleCyclo-oxygenase inhibitor/cyclic-AMP—Platelet inhibition by two separate drug classes allows bettercyclic-GMP phosphodiesterase inhibitoranticoagulation for secondary prevention of strokeAtorvastatin/amlodipine*HMG-CoA reductase inhibitor (statin)/Combination cholesterol-lowering drug and antihypertensivecalcium-channel blockeragent treats two different major risk factors for coronary heart disease Captopril/hydrochlorothiazideACE-inhibitor/thiazide diureticCombination of two antihypertensive drug classes andis FDA-approved as initial therapy for hypertension Respiratory Disease Fluticasone/salmeterolCorticosteroid/long-acting beta-Combination anti-inflammatory agent and bronchodilatoradrenergic-receptor agonist addresses two physiological components of persistent asthmaIpratropium bromide/albuterolAnticholinergic agent/beta-Inhaled aerosol of two different bronchodilators foradrenergic-receptor agonist chronic obstructive pulmonary diseaseMontelukast/loratadine*Leukotriene receptor antagonist/Combination of an anti-inflammatory/bronchodilator antihistamineand an anti-allergen to treat different components of chronic asthma Infectious Disease Amoxicillin/clavulanatePenicillin derivative/Clavulanate increases the effectiveness of amoxicillin against beta-lactamase inhibitorresistant strains that carry the beta-lactamase geneRitonavir/lopinavirProtease inhibitorsUse of two different anti-retroviral agents for treatment of HIV infection delays the appearance of resistant HIV strainsZidovudine/lamivudinePyrimidine nucleoside analogsCombination of reverse transcriptase inhibitors has synergistic anti-retroviral activity and delays the appearanceof resistant HIV strains  Miscellaneous Dorzolamide/timolol maleateCarbonic anhydrase inhibitor/Topical combination decreases intraocular pressure beta-adrenergic receptor blocker(by reducing aqueous humor secretion) more than either component aloneFluoxetine/olanzapine*Selective serotonin reuptakeCombination anti-depressant and anti-psychotic forinhibitor/multi-receptor antagonist treatment of depression with psychotic featuresHydrocodone/ibuprofenOpiate agonist/non-steroidalCombination narcotic and anti-inflammatory effectiveanti-inflammatory agent against chronic pain *Combination product in development Table 1 Some New and Old Combination Products in Different Disease Classes  bination of a thiazide and a potassium-sparing diuretic. 17-19  A substantial proportion of the patients in these trials eventually received diuretic/beta-blocker or other combination therapy,reflecting the fact that monotherapy fails to control hyperten-sion in about half of patients. 20-22 The Role of Combination Products It might be instructive to contrast the principles of drug thera-py with empirical evidence from clinical trials, taking asexamples the treatment of asthma and hypertension. Severalclasses of drugs are used in the long-term control of chronicasthma—principally inhaled corticosteroids (as anti-inflammato-ry agents), but also long-acting beta-agonists (as bronchodila-tors), theophylline, and the newer leukotriene modifiers. Thealternatives of increasing the dose of monotherapy or combina-tion therapy (the addition of a different class of drug) in patientsfailing the previous dose of monotherapy have been testeddirectly in several randomized, double-blinded clinical trials. In one trial, patients who still had symptoms following treat-ment with a low-dose inhaled corticosteroid (beclomethasone) were randomly assigned either to a higher dose of the inhaledcorticosteroid or to combination therapy with a long-acting beta-agonist (salmeterol). 23 Control of asthma symptoms was better  with the combination therapy, while there was no difference inadverse effects between the two treatments. In two similar trials,combination therapy with fluticasoneand salmeterol (see Table 1) wassuperior to an increased dose of fluti-casone in patients still symptomaticafter treatment with a lower dose of the corticosteroid. 24,25 In another trial, a combination of a low-doseinhaled corticosteroid (budesonide)and doses of theophylline below therecommended therapeutic range pro-duced control of asthma similar tothat with high-dose budesonide but  without affecting serum cortisol. 26 Finally, the idea, embedded innational guidelines, 27 that initial ther-apy should be monotherapy rather than combination therapy was alsotested in a randomized, double-blind-ed trial. Initial therapy with a combi-nation of fluticasone and salmeterol was tested against both monothera-pies. 28 Initiation with the combinationtherapy provided greater improve-ments in lung function and symptomcontrol than either monotherapy withnodifferences in any safety measure. In hypertension, randomized clinical trial data supports a role, for some combination antihypertensives,that is distinct from that recommended in national guidelines.First, some combinations are superior to either of their compo-nent monotherapies as initial treatment. The beta-blocker/diuretic combination bisoprolol/hydrochlorothiazide has a better therapeutic ratio than that of either constituent monotherapy. 2 Similarly, ACE-inhibitor/calcium-channel blocker combina-tions as a class have a better therapeutic ratio than their con-stituent monotherapies. 29-32 Second, a combination product  ACE-inhibitor-diuretic (lisinopril-hydrochlorothiazide) wastested against ACE-inhibitor (lisinopril) dose titration inpatients failing the initial ACE-inhibitor dose. 33 Blood pressurecontrol was similar in the two patient groups, but there weresignificantly fewer adverse events among patients receivingthe combination product.Not all combinations have unequivocally better therapeuticratios than their constituent monotherapies. For example, ACE-inhibitor/hydrochlorothiazide combinations as a classare more effective than their constituent monotherapies but also cause more adverse effects (captopril-hydrochloroth-iazide is an exception, with a considerably better therapeuticratio than either constituent monotherapy). 34 Many drug com-binations, however, do have better therapeutic ratios thantheir constituent monotherapies and, as clinical trial data haveshown, have a role as initial therapy and, in particular, in placeof monotherapy dose escalation. The principles of drug thera- Vol. 27 No. 1ãJanuary 2002 ã P&T ® 47 CE: Combination Drugs ClassCombinationDose (mg)Price Ratio†  Antidiabetics Glyburide/metformin1.25 – 5000.992.5 – 5000.985 – 5001.23  Antihyptertensives Triamterene/HCTZ37.5 – 250.31Enalapril/HCTZ10 – 251.54Captopril/HCTZ25 – 251.2450 – 251.35Lisinopril/HCTZ20 – 251.40Benazepril/HCTZ20 – 250.88Losartan/HCTZ100 – 250.79Benazepril/amlodipine5 – 100.53  Antiretrovirals Zidovudine/lamivudine300 – 1501.01 Hormone Replacement Premarin/medroxyprogesterone0.625 – 2.51.240.625 – 51.15 NSAIDs Diclofenac/misoprostol50 – 2000.7975 – 2000.69 *Retail list prices for brand-name drugs. Source: www.Rxlist.com, July/August 2001. † Price of combination product/ Price of the same dosages of the separate constituents. HCTZ = hydrochlorothiazide; NSAIDs = non-steroidal anti-inflammatory drugs. Table 2 Price Ratios of Selected Combination Products and the Separate Constituents*
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