Injection vs. Infusion
This graph simulates plasma levels of a compound administered by injection compared with infusion by ALZET pump. Injections often produce plasma levels that greatly exceed effective concentrations, which can result in toxicity and wasted compound. Likewise, the therapeutic effect vanishes between doses for compounds with short half-lives.
ALZET pumps allow researchers to understand and optimize the key determinants of drug action, such as the level and duration of drug exposure, and the spatial drug distribution relative to the target tissue. By manipulating these variables, drug effects can be optimized early in preclinical development, allowing clinical studies to be conducted at lower cost and with better results.
A drug's therapeutic index is a ratio reflecting the quotient of its therapeutic effects and adverse effects. Varying the schedule of administration can have a major influence on the therapeutic index of some drugs. Relative to bolus dosing, constant infusion can:
- Increase efficacy
- Reduce side effects
- Both increase efficacy and reduce side effects
All of these changes can increase a drug's therapeutic index, improving its value as a pharmaceutical. One cannot assume, however, that infusion regimens are superior to injections for all drugs. The relationship between dose, regimen, and drug effect must be carefully explored for each drug. Dose-response testing, where the effects of one or more schedules of injections are compared with the effects of constant infusion, helps elucidate schedule-dependent drug effects. This type of testing has been termed the injection-infusion comparison (IIC) protocol. This protocol is an established method for optimizing the effectiveness of anticancer agents, and it is important in the preclinical testing of proteins, peptides, and other recombinant DNA products.
Numerous studies have explored the schedule or regimen dependence of a drug's therapeutic index. A complete review of the injection-infusion comparison protocol can be found in the following references:
R0050 Fara J, and Urquhart J. The Value of Infusion and Injection Regimens in Assessing Efficacy and Toxicity of Drugs. Trends Pharmacol Sci 5 (1): pp. 21-25, 1984.
R0051 Urquhart J, Fara J, and Willis KL. Rate-controlled Delivery Systems in Drug and Hormone Research. Ann Rev Pharmacol Toxicol 24: pp. 199-236, 1984.
Additional studies are available in the injection-infusion comparison bibliogragy. The notes following each reference detail the substance(s) infused, the route of administration, the animal model used, the vehicle for infusion, the pump model used, the duration of infusion, and notable technical achievements or results.
In Vivo Pharmacology
"The majority of chemicals are eliminated considerably faster in small laboratory animals as compared with humans, and constant-rate infusion offers several advantages over conventional, bolus delivery regimens in compensating for this difference.” (Clarke D.O. Toxicology Methods 1993;3(4):223-25)
When testing a novel compound in vivo, rapid elimination can result in mistaken assessment of activity. Rats and mice generally eliminate test compounds more rapidly than humans. After a single injection, plasma concentration rises to a peak and then declines rapidly until the compound is eliminated from plasma and tissues. Often the duration of serum activity following a single injection is limited to several hours, hence biological effects either fail to develop or develop poorly.
- If no effect is observed following injection, it is difficult to determine whether the compound is inactive or if it simply was not present in adequate concentration and for a sufficient duration to elicit an effect.
- Depending on the rate of elimination and the frequency of dosing, injections can result in periods during which drug is absent from plasma and tissues. Such extreme variability in compound exposure over time can influence the expression of drug action.
Thus, the data from such experiments can be misleading as to the nature
of compound effects and the dose required to elicit them. Additionally,
repeated injections are stressful to the animal and difficult to maintain
around the clock. ALZET pumps are drug discovery tools that offer researchers
enhanced control over test compound levels in plasma and tissues. Through
continuous infusion, these pumps maintain a well-defined, consistent
pattern of drug exposure throughout the duration of the experiment.
ALZET pumps ensure that test compounds are present in plasma and tissues
for a sufficient duration to allow their biological effects to develop
fully and reproducibly. The scientific literature contains many examples
where ALZET pumps have facilitated full development of drug effects,
including those of proteins, peptides, and other rapidly eliminated
compounds. For more information on in vivo pharmacology, consult
our pharmacology bibliography.
- Ensure around-the-clock exposure to test agents at predictable levels
- Permit continuous administration of short half-life proteins and peptides
- Provide a convenient method for the chronic dosing of laboratory animals
- Minimize unwanted experimental variables and ensure reproducible, consistent results
- Eliminate the need for nighttime or weekend dosing
- Reduce handling and stress to laboratory animals
- Small enough for use in mice or very young rats
- Allow for targeted delivery of agents to virtually any tissue
- Cost-effective research tool
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Researchers are saying...
“In preliminary studies using this model, we observed severe side effects with 5-FU doses beyond 25 mg/kg biweekly injections (mice developed skin ulcers, bleeding and severe diarrhea). Thus, we chose to deliver 5-FU by continuous infusion at an equivalent cumulative dose in order to minimize toxicity. Additionally, studies have demonstrated an increased efficacy of chemotherapeutic agents when administered continuously.” Stoeltzing et al. Int. J. Cancer 2003;104:496-503.