Understanding drug interactions (Proceedings)

Polypharmacy is increasingly common in the prevention and treatment of diseases in animals. Drug-drug interactions represent one common event associated with multidrug therapy that may interfere with optimal clinical outcome. Mechanisms whereby drugs may interact during concurrent treatment are well established for many drug combinations. However, the incidence and clinical relevance of interactions are difficult to determine with accuracy because of the many factors involved and because there is very little clinical data to validate in vitro findings. Therefore, the need for clarification of the clinical relevance of potential interactions has become crucial, since clinicians are faced with the difficult task of evaluating both qualitatively and quantitatively the risk of drug interactions in their patients in order to make sound therapeutic decisions. An understanding of the role of pharmacokinetics, pharmacodynamics, and the factors that alter these processes are vital in the clinician's process of decision making.

Objectives of the presentation

• To briefly review common mechanisms of drug-drug interactions.

• To discuss sources of uncertainty in the clinical setting.

• To review some relevant interactions in small animals.

Relevant therapeutic points

• Most of the published information refers to in vitro experiments that provide very valuable mechanistic information and can be used to make reasonable predictions about the clinical relevance, time course, and methods used to avoid the interaction or palliate its clinical consequences.

• Many factors influence the clinical significance of drug-drug interactions; these include size and frequency of dose, duration of treatment, time-course of the interaction, drug therapeutic index, disease status, pharmacokinetic differences between interacting drugs, status of the immune system, inter-animal variability, etc.

• Pharmacokinetic interactions may occur that affect the absorption, distribution or elimination of concurrently administered drugs. Interactions affecting absorption or elimination are the most likely to be of clinical consequence. The exposure of an animal to a drug (as represented by the area under the drug concentration-time profile in plasma) changes in proportion to variations in clearance and/or systemic availability. This is more likely to be of clinical significance when the affected drug has a narrow therapeutic index and when the size and duration of the change in exposure are of enough magnitude.

• The gastrointestinal (GI) absorption of one agent may be affected by other agent that alters GI pH or motility, chelates other chemicals, or affects active transporters such as P-glycoprotein. While both rate and extent of absorption may be altered, interactions that affect the systemic availability of drugs are more likely to be of clinical importance. A common type of drug interaction affecting absorption is the chelation of an antibiotic by concurrently administered metal ions, which may be present in food or antacid medications. Separating the administration times of the antibiotic and the chelating agent may reduce the extent of interaction. A reasonable approach is to leave 2-4 hours of separation between both.

• The distribution of concurrently administered drugs may be affected by competitive displacement from plasma and tissue binding sites or alteration of active tissue transporters (e.g. blood-brain barrier), with the latter being more likely to result in clinically relevant consequences.

• The elimination of concurrently administered drugs can be altered through mechanisms affecting metabolism, secretion, or excretion. Induction or inhibition of cytochrome P450 isozymes in the liver may result in increased or decreased drug clearance, respectively. For example, chloramphenicol is known to inhibit cytochrome P450 enzymes in the liver of dogs resulting in prolonged barbiturate sedation and potential for toxicity1-6. On the other hand, phenobarbital is a well known inducer of enzymes involved in Phase I and Phase II drug metabolism, and as such it decreases the plasma concentration of drugs like chloramphenicol7,8 or doxycycline9. One of the most commonly P450 enzymes involved in metabolic drug-drug interactions is CYP3A4, which represents the primary route of metabolism for many of the drugs used in domestic animals. In practice, the clinician has to consider the time course of these processes, for while enzyme inhibition occurs relatively quickly, enzyme induction commonly requires more time. It takes approximately 1-2 weeks for the maximum inductive effect to occur and about the same time for it to cease once drug administration has stopped. Rifampin may be an exception to the rule given that it may elicit enzyme induction just after a few doses. The elimination half-life of the drug is another important factor, since it will take about 3-5 half-lives for a drug with changed clearance to reach a new steady state concentration.

• Pharmacodynamic interactions may result in additive, synergistic or antagonistic effects on the receptor systems where the drugs act.

• In general, a synergistic effect can be expected when the mechanisms of action are complementary, for example, when drugs act at different places of the same biochemical pathway (sulfonamides and diaminopyrimidine), or when the presence of one antibiotic increases the bacterial penetration of another (beta-lactams and aminoglycosides). For example, synergism has been reported to occur between flouroquinolones and either aminoglycosides, 3rd generation cephalosporins, extended-spectrum penicillins, carbapenems, vancomycin, or trimethoprim against some bacterial pathogens, including Pseudomonas aeruginosa (e.g. ciprofloxacin and amikacin or imipenem), Staphylococcus aureus (e.g. levofloxacin and oxacillin) Enterococcus spp. (e.g. ciprofloxacin and amikacin)10 and Escherichia coli (e.g. trimethoprim and ciprofloxacin)11.

• On the other hand, antibiotic combinations characterized by overlapping mechanisms of action or suppression of important efficacy elements (e.g. lack of active bacterial growth) may result in antagonism characterized by the clinical efficacy of the drug combination being less than that of the individual agents.

• However, neither in vitro synergy nor antagonism can be assumed to straightforwardly occur in vivo. The predictive value of common in vitro tests for efficacy of antibiotic combination therapy is often poor.

• For antibiotics, in vitro/in vivo PKPD models currently provide the most promising approach to unveil clinically meaningful pharmacodynamic interactions.

Key drug interactions in small animals

Interacting Drugs or

Drug Groups

Species*

Mechanism and Effect

Evidence

Chloramphenicol/Phenobarbital

Dog, cat

Chloramphenicol inhibits liver CYP2B1112. Decreased phenobarbital clearance, increased elimination half-life and increased plasma and tissue concentrations. Prolonged sedation and toxicity potential.

In vitro, In vivo PK and PD1-6

Chloramphenicol/Propofol

Dog

CYP2B11 inhibition by chloramphenicol. Decreased clearance and prolonged recovery time. Breed differences are possible.

In vitro, In vivo PK and PD13-14.

Fluoroquinolones/Theophylline

Dog

Some flouroquinolones inhibit liver CYP1A2. Decreased theophylline clearance and potential for increased toxicity. In vivo effect more evident with enrofloxacin than with marbofloxacin. In vitro effect observed with ofloxacin, orbifloxacin, and ciprofloxacin.

In vivo PK15-16

In vitro17.

Fluoroquinolones/NSAIDs

Dog, Buffalo, Sheep

Enrofloxacin and flunixin meglumine decrease each other clearance in dogs. Enrofloxacin decreases diclofenac clearance in sheep and increases Vd in buffalo. Unknown interactions between FQ and other NSAIDs.

In vivo PK18-20.

Phenobarbital/Doxycycline

Human

Induction of doxycycline metabolism by phenobarbital. Clearance of doxycycline doubled in patients undergoing long-term phenobarbital therapy. Decreased doxycycline efficacy is likely.

In vivo PK9.

Antacids/Fluoroquinolones, Tetracyclines, Azithromycin.

Dog, cat, horse, other

The systemic availability of many drugs is consistently decreased by their adsorption to concurrently administered antacids. The extent of this decrease is variable but usually significant.

In vivo PK21-23

Erythromycin-Chloramphenicol/Cisapride

Human, Dog

Chloramphenicol, Erythromycin and to lesser extent Clarithromycin inhibit CYP3A4 resulting in increased cisapride concentrations in humans. In one study in dogs erythromycin did not modify cisapride cardiovascular pharmacodynamics.

In vivo PD24

Clindamycin/Metronidazole

Human isolates

Synergistic effect has been observed in vitro against Bacteroides fragilis.

In vitro25.

Beta-lactams/Fluoroquinolones

Human isolates.

Human.

Mice.

Ceftazidime or cefepime plus a flouroquinolone (ciprofloxacin, levofloxacin, gatifloxacin, or moxifloxacin) resulted in additive effect when strains were susceptible to both agents in the combination (less than 10% of synergy) but showed synergy 92% of the cases when strains were resistant to one or both agents. No significant differences were found between the various combinations. Clinical relevance depends on PK.

In vitro26.

Beta-lactams/Aminoglycosides

Human isolates.

Human.

Mice.

Classical synergistic interaction described in vitro for many organisms, including strains of Staphylococcus aureus that are susceptible to each drug alone. One mechanism is enhanced bacterial penetration of the aminoglycoside by the beta-lactam in organisms such as streptococci. This synergism may carry to gram-negative organisms like Enterobacteriaceae, including Pseudomonas aeruginosa. Even though synergistic effect is expected when using this combination, it is often possible that the effect cannot be clinically achievable

In vitro29, In vivo30

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