1. INTRODUCTION:

Commercially available combination drug preparations contain several remedies. Therapeutics contains many examples of combinations of antibiotics. These preparations contain their drugs in fixed combinations and therefore have some advantages and some disadvantages. The advantages are that a broad spectrum of antibiotic activity can be achieved, an important feature in veterinary work because so many infections are mixed ones, and the possibility of resistant bacteria populations emerging is reduced. One disadvantage is that the drugs in the combination may be antagonistic.¹

When developing a fixed combination the non-clinical program will vary depending on the characteristics of the single components, on the existing non-clinical and clinical experience of their individual and concomitant use as well as the intended clinical use. When there is no experience from use of the combination, even if the individual components are known, bridging studies addressing expected and potential unexpected pharmacodynamic, pharmacokinetic and toxicological interactions are in principle needed.

For any non-clinical combination study, the dose selection should be based on considerations of interspecies differences in pharmacokinetics as well as pharmacodynamics in order to, as close as possible, encompass the clinical situation, both in terms of systemic exposure of animals to the individual components as well as in relation to pharmacodynamic effects while avoiding high dose non-clinical effects that may be irrelevant to human safety assessment.²

1.1. Rational Drug therapy:-

Rational drug therapy means the use of the right medicine in the right manner (dose, route, frequency of administration, duration of therapy etc) in the right patient at the right cost and at the right time. In an effort to initiate rational drug therapy, the World Health Organization (WHO) introduced the concept of an essential drugs list in 1977 and it updates the model list every two years³. The 15th list of essential medicines by WHO has only about 25 FDCs.⁴

Drug discovery is an uncertain process at best. Although the therapy of infective pathogens has been a great success story, emergence of resistance threatens our success. Consequently, it makes sense to prescribe doses of currently available therapeutic agents, alone and in combination, that will maximize the probability that the therapy will not only produce a high likelihood of success with a low likelihood of toxicity but will also diminish the probability that a resistant clone will become the dominant part of the population while under the pressure of the therapeutic agent or agents.⁵

1.1.1. The rationality of FDCs should be based on certain aspects such as:

· The drugs in the combination should act by different mechanisms.

· The pharmacokinetics must not be widely different.

· The combination should not have supra-additive toxicity of the ingredients.⁶

1.1.2. Rationale for combination medicines:

Research with combination products has provided therapeutic advances in a number of different ways and the following examples may be cited where such products have proved to be more advantageous than single-drug therapy.

Protection of active drug: A decarboxylase inhibitor together with L-dopa prevents its destructive metabolism. Amoxycillin can be preserved from the destructive action of bacterial, β-lactamase by simultaneous use of clavulanic acid. Renal excretion of active nalidixic acid can be increased by raising urinary pH by the administration of citrate.

Enhancement of therapeutic effect: Antibacterial activity is enhanced and extended by combinations of anti-infective agents such as trimethoprim with a sulphonamide, or ampicillin with flucloxacillin.

Improved therapeutic action: Use of a beta-blocker and a diuretic is synergistic in lowering blood pressure, but also the unwanted effects are opposite in direction and perhaps self-canceling on renin excretion, fluid retention and blood sugar levels. Oral contraception and post-menopausal replacement therapy achieved by oestrogen-progestogen combinations give a better and different kind of response from that achieved by one drug alone.

Prevention of induction of microbial drug resistance: In treating tuberculosis it is important to prevent the development of bacterial resistance to the active drugs rifampicin or ethambutol by the concomitant use of isoniazid. Combination products of these drugs, in a range of doses, avoid these dangers and provide safer regimes.

Alleviation of side effects: Potassium loss during diuretic therapy can be alleviated by concomitant use of a potassium salt. Pyridoxine used with isoniazid helps to prevent the development of neuropathy. Cyclizine reduces morphine vomiting.

Simultaneous treatment of coexisting disease: In pregnancy, iron deficiency commonly coexists with folic acid deficiency, forming a valid indication for treatment of both deficiencies simultaneously with a combination of iron and folic acid.

Improved physicochemical properties: The intravenous steroid anesthetic -Althesin contains Alpha-dolone (a weak anaesthetic agent) to render the active drug, alphaxolone, sufficiently soluble by cosolubilization. In a sense most medicines are combination products, being complex formulations of the active drug with other ingredients to provide an appropriate vehicle with suitable stability, release characteristics, taste, color etc.⁷

1.2. Most FDCs have the following demerits:

· Dosage alteration of one drug is not possible without alteration of the other drug.

· Differing pharmacokinetics of constituent drugs pose the problem of frequency of administration of the formulation.

· By simple logic there are increased chances of adverse drug effects and drug interactions compared with both drugs given individually.⁸

The recent 14th model list of essential drugs prepared by the WHO (March 2005) includes 312 formulation of which 18 are fixed dose drug combinations ⁹. The World Health Organization's (WHO) Model list of Essential Drugs provides examples of some rational FDCs such as¹⁰:

· Sulfamethoxazole + Trimethoprim

· Antitubercular FDCs like Rifampicin + Isoniazid, Isoniazid + Ethambutol, etc

· Antiparkinsonism FDCs like Levodopa + Carbidopa

1.3 Classification of FDCs:

FDCs can be classified into several categories:

• Some of the earliest FDCs have been widely accepted as rational combinations of drugs which are suitable for all of their target groups of patients, on the basis of their pharmacology or patient acceptability. Examples are the combination of oestrogen with progestogen in combined oral contraceptives and levodopa with carbidopa to treat Parkinson’s disease. Many topical preparations, such as eye and ear drops and skin formulations, contain combinations which increase patient acceptability by reducing the number of products to be used.

• Inappropriate drug combinations, where pharmacological claims for synergy are supported by little clinical evidence, e.g. the combination of caffeine with analgesics.

• Mixtures of drugs which are of benefit to only a few patients. Examples are combinations of potassium sparing diuretics with thiazides and multi-component antacid mixtures.

• Those endorsed for use in resource-limited countries, specifically in the treatment of HIV/AIDS and tuberculosis.

• Combinations of drugs for chronic conditions in which multiple drug regimens are recommended (e.g. HIV/AIDS). Such regimens place a significant pill burden on patients, particularly those with co-morbidities, and FDCs in these patients may improve adherence.

• Some formulations (e.g. asthma inhalers) contain two drugs but only one prescription charge is payable, which benefits patients who pay for their prescriptions.¹¹

1.4. Statistical analysis

A systematic review of the literature between 1966 and 2003 found three trials, of which only one (a non-inferiority study designed to establish clinical equivalence) showed a significant but small improvement in concordance with a FDC, in patients with HIV infection at 16 weeks compared with the same drugs taken separately¹². A meta-analysis of nine studies which included over 20,000 patients with hypertension, diabetes, IV and tuberculosis, demonstrated that FDCs reduced the relative risk of non-concordance by 26% compared with single-component regimens (35% vs. 38%, p < 0.0001)¹³.Follow up was between 6 months and 2 years. This equates to an absolute risk reduction of 3%, i.e. 34 patients would need to be treated with an FDC to avoid one case of nonconcordance.

In contrast, a retrospective study of newly treated patients with Type 2 diabetes (n = 6,502) taking metformin and glibenclamide over six months showed no significant difference in concordance rates between patients receiving either monotherapy, a combination of the two separate drugs or a FDC.¹⁴

1.5. Preferred disease regime for fixed dose combination:-

1.5.1 Hypertension:

Single-drug therapy remains the preferred way to begin treatment of hypertension, although in many patients this is unable to bring blood pressure (BP) to goal levels. Single-drug therapy, even when maximally titrated, is at best only modestly effective in normalizing BP in Stage-I or II hypertension, which represents the majority of the hypertensive population. It is increasingly appreciated that the elusive goal of a 'normal' BP is achieved only if multi-drug therapy is employed. Fixed-dose combination therapy successfully reduces BP because two drugs, each typically working at a separate site, block different effectors pathways. In addition, the second drug of such two-drug combinations may check counter-regulatory system activity triggered by the other. For example, a diuretic and beta-blocker combination may find the diuretic correcting the salt-and-water retention which occasionally accompanies beta-blocker therapy. The pattern of adverse effects also differs with fixed-dose combination therapy, in part, because fewer drugs are generally being given. In addition, one component of a fixed-dose combination therapy can effectively counterbalance the tendency of the other to produce adverse effects. For example, the peripheral oedema, that accompanies calcium channel antagonist therapy, occurs less frequently when an ACE inhibitor is co-administered. ACE inhibitors improve, if not eliminate, the peripheral oedema associated with calcium channel antagonists because of their proven ability to cause vasodilatation. In addition, diuretic therapy-induced volume contraction may generate a state of secondary hyperaldosteronism and thereby electrolyte abnormalities such as hypokalaemia and/or hypomagnesaemia. In many cases, the co-administration of either an ACE inhibitor or an angiotensin II receptor blocker with a diuretic corrects the aforementioned electrolyte disturbances. Fixed-dose combination therapy has a proven record of reducing BP¹⁵. In the V-HeFT(Vasodilator Heart Failure Trial) study, the vasodilator combinationof isosorbide dinitrate and hydralazine added to backgroundtherapy with digoxin and diuretics did not significantly lowerblood pressure but improved survival¹⁶. Single-pill amlodipine/atorvastatin has the potential to improve the management of hypertensive patients with additional cardiovascular risk factors, especially dyslipidemia, by reducing pill burden and prescription costs.¹⁷

1.5.2. Tuberculosis:

Use of fixed-dose combinations (FDCs) of tablets against tuberculosis is now being recommended by WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD) as an additional step to ensuring proper treatment. FDCs simplify the prescription of drugs and the management of drug supply, and may also limit the risk of drug-resistant tuberculosis arising as a result of inappropriate drug selection and monotherapy.Only FDCs of proven quality and proven rifampicin bioavailability should be purchased and used. In most situations, blood levels of the drugs are inadequate because of poor drug quality rather than poor absorption. This is true irrespective of the human immunodeficiency virus (HIV) infection status of the tuberculosis patients (other than those with overt acquired immunodeficiency syndrome, with CD4 counts <200 cells/mm3). Currently, WHO, IUATLD and their partners are developing strategies for ensuring that only quality FDCs are used in tuberculosis programmes. A simplified and effective protocol for assessment of rifampicin bioavailability has been developed,and laboratories are being recruited to form a supranational network for quality assurance of FDCs. Standardization of FDC drug formulations has been proposed, which limits rifampicin-containing nine (including a four-drug FDC and three pediatric FDCs) preparations¹⁸.

Effective treatment of tuberculosis patients with short-course multi drug chemotherapy is the cornerstone of the modern approach to the control of the disease. To emphasize this principle, WHO and the International Union Against Tuberculosis and Lung Disease (IUATLD), together with their partners, recommend the use of fixed-dose combination(FDC) formulations of the essential antituberculosis drugs as one further step to ensure adequate treatment of patients^19,20.

1.5.3. Glaucoma:

Glaucoma is a leading cause of irreversible visual loss. This potentially blinding disease is a progressive optic neuropathy associated with elevated intraocular pressure (IOP). Initial therapy for glaucoma typically consists of topical medications or laser treatment to lower IOP. There are several potential benefits of fixed combination medications compared with using the individual components separately. These include a reduction in the total number of drops and preservative instilled per day, cost savings, improved tolerability and compliance and avoiding the washout effect resulting from rapid-sequence instillation of multiple drops. Attempts to develop effective fixed combinations of glaucoma medications date back several decades. In recent years, fixed combinations of commonly paired drugs have been approved by various regulatory bodies in different countries and have gained wide acceptance. Current commercially available, fixed combination drugs include the topical beta-adrenoceptor antagonist timolol 0.5% combined with a prostaglandin, a topical carbonic anhydrase inhibitor or an alpha-adrenoceptor agonist²¹. The nonselective beta-blocker timolol and the carbonic anhydrase inhibitor dorzolamide both lower intraocular pressure (IOP). Timolol 0.5% and dorzolamide 2.0% have therefore been combined in a single formulation, reducing the number of administrations required to 2 per day.²²

1.5.5. Bacterial infection:

Development of antibiotics resistance plays a large burden on the health care system; with result in both increase in cost and increased morbidity and mortility. Infection with resistant bacteria and multiple infection significantly increase hospital length of stay and cost. The situations become worst in the case of mixed infection aerobic bacteria, anaerobic bacteria and pathogenic protozoa. Present trend to combat the resistance of organism against antibiotics is to use various newer molecules and newer combination of drugs. This has result in a widespread use of drugs and several new agents and combination of antibiotics.²³

1.5.5. AIDS:

In Uganda, as in many sub-Saharan African countries, generic fixed-dose combinations (FDC) with lamivudine, stavudine and nevirapine (prescribed as Triomune and Maxivir in Kampala, Uganda) is the first-line antiretroviral regimen. A recent report by Braitstein et al.²⁴ indicated that individuals on fully subsidized antiretroviral therapy (ART) have 0.23 less odds of death than patients on self-pay therapy. Estimates suggest that perhaps 1–2% of the 85 000 Ugandans currently on ART purchase generic FDC as Triomune or Maxivir²⁵.

1.6. CONCLUSION:

Combination medicines will be developed from existing single-entity products, for which full toxicology will have been conducted and a long clinical experience will be available. Hence, the programme necessary for marketing a combination product will be limited to a study of its chemistry and pharmacy and to full clinical evaluation to assess efficacy, safety and other appropriate features. This is a very much simpler and less costly operation than the development of a new chemical entity, which now takes about 8 to 10 years and costs about £25-50 million for each product. It is therefore a highly cost-effective method of pursuing therapeutic research. At present they account for about one-third of medicines used in general practice and one-fifth in hospital. The alleged disadvantages of such products are mostly theoretical or doctrinal, with the strongest being an objection to the fixed ratio of the ingredients. Nearly all medicines are a formulated mixture of several chemicals and a single active ingredient may be metabolized to a variety of substances with different therapeutic and toxic effects. However, most single drugs, as well as most physiological substances, induce a range of different actions in the body in fixed ratio. Homeostasis is achieved through multicomponent pathways and as such may have advantages in the quality of control compared with the use of any single effector; the long-term stabilization of functions such as blood pressure and blood sugar.

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Received on 11.02.2010 Modified on 03.03.2010

Research J. Pharm. and Tech.3 (3): July-Sept. 2010; Page 705-708