Q35: What is important to know regarding investigative drug administration from a general principles of pharmacology perspective?
Answer: Drugs are compounds almost always foreign to the body. As such, they are not continually being formed and eliminated as are endogenous substances. The processes of inputting, distributing, and eliminating drugs are therefore of paramount importance in determining the onset, duration, and intensity of effectand should be considered regarding investigative drug administration.
The process of drug movement from the site of administration toward the systemic circulation.
The processes by which drugs move across a biologic barrier include passive diffusion, facilitated diffusion, active transport, and pinocytosis
Because the oral route of administration is the most common, absorption usually refers to the transport of drugs across the membranes of the epithelial cells within the GI tract. Absorption after oral administration is confounded by differences down the alimentary canal in the luminal pH; surface area per luminal volume; perfusion of the tissue, bile, and mucus flow; and the epithelial membranes. The faster absorption of acids in the intestine compared with the stomach appears to contradict the hypothesis that the nonionized form of a drug more readily crosses membranes.
Gastric emptying and intestinal transit time: Because the absorption of virtually all compounds is faster from the small intestine than from the stomach, the rate of gastric emptying is a controlling step. Food, especially fatty foods, slows gastric emptying, which explains why some drugs are recommended to be taken on an empty stomach when a rapid onset of action is desired. The extent of absorption may be enhanced by food if the drug is poorly soluble (e.g., griseofulvin) or reduced if degraded in the stomach (e.g., penicillin G). Drugs that affect gastric emptying (parasympatholytic agents) also affect the rate of absorption of other drugs.
Direct placement of a drug into the bloodstream (usually IV) ensures complete delivery of the dose to the general circulation. However, administration by a route that requires drug transfer through one or more biologic membranes to reach the bloodstream precludes a guarantee that all of the drug will eventually be absorbed. Intra-muscular (IM) or Sub-cutaneous (S.C.). injection of drugs bypasses the skin barrier, but the drug must penetrate the capillary walls. Because the capillaries tend to be highly porous, the perfusion (blood flow/gram of tissue) is a major factor in the rate of absorption. Thus, the injection site can markedly influence a drug’s absorption rate.
The rate at which and the extent to which the active moiety (drug or metabolite) enters the general circulation, thereby gaining access to the site of action.
Although a drug may be absorbed completely, its rate of absorption may also be important. It may be too slow to attain a therapeutic blood level in an acceptable period of time or too rapid, resulting in toxicity from high drug levels just after each dose.
Causes of Low Values of Bioavailability
When a drug rapidly dissolves from a drug product and readily passes across membranes, absorption from most sites of administration tends to be complete. This is not always the case for drugs given orally. Before reaching the vena cava, a drug must move down the alimentary canal and pass through the gut wall and liver, which are common sites of drug metabolism ,thus, the drug may be metabolized before it can be measured in the general circulation. This cause of a decrease in drug input is called the first-pass effect. A large number of drugs show low bioavailabilities owing to extensive first-pass metabolism. In many instances, the extraction is so complete that the bioavailability is virtually zero ( isoproterenol, norepinephrine, phenacetin, and testosterone).
The 2 other most frequent causes of low bioavailability are an insufficient time in the GI tract and the presence of competing reactions. Ingested drug is exposed to the entire GI tract for no more than 1 to 2 days and to the small intestine for only 2 to 4 h, unless gastric emptying is considerably delayed. If the drug does not dissolve readily or if the drug is incapable of penetrating the epithelial membrane (highly ionized and polar), there may be insufficient time at the absorption site. Not only is the bioavailability low in this case, but it tends to be highly variable. In addition, individual variations in age, sex, activity, genetic phenotype, stress, disease ( achlorhydria, malabsorption syndromes), and previous GI surgery can alter and further increase variability in drug bioavailability.
Reactions that compete with absorption can reduce bioavailability – include complex formation; hydrolysis by gastric pH or digestive enzymes ;conjugation in gut wall ; adsorption to other drugs and metabolism by luminal microflora.
The sum of the processes of drug loss from the body. Removal of drugs from the body occurs by metabolism and excretion.
The process of chemical alteration of drugs in the body. The liver is the principal, but not the sole, site of drug metabolism. Some metabolites are pharmacologically active. When the substance administered is inactive and an active metabolite is produced, the administered compound is called a pro-drug.
Changes with Age
Neonates have partially developed liver microsomal enzyme systems and, consequently, have difficulty with the metabolism of many drugs. Elderly patients often show a reduced ability to metabolize drugs. The reduction varies depending on the drug and is not as severe as that in neonates.
Variability among individuals makes it difficult to predict the clinical response to a given dose of a drug. Some patients may metabolize a drug so rapidly that therapeutically effective blood and tissue levels are not achieved; in others, metabolism may be so slow that toxic effects result with usual doses. Concurrent disease states, particularly chronic liver disease, drug interactions, especially those involving induction or inhibition of metabolism, and other factors also contribute.
PRECLINICAL AND CLINICAL EVALUATION OF TOXICITY
Before a drug is approved for general clinical use by the FDA, preclinical and clinical data showing substantial evidence of safety and efficacy are required by law. Drug studies proceed through various phases, as follows.
Preclinical Investigation (Animal Studies)
Animal studies used to determine or define the safety of a drug include studies of acute, subchronic, and chronic toxicity in several animal species.
The initial acute toxicity studies are to determine the median lethal dose (LD50), the toxic symptoms developed by the animals, and the time that they appear. At least 3 species of animals, one not a rodent, are usually used, and acute toxicity is usually determined by more than one route of administration.
Subchronic toxicity studies are conducted in at least 2 animal species and usually consist of daily administration of the test drug for up to 90 days. In each species, at least 3 dose levels are used, varying from the expected therapeutic doses to levels high enough to produce toxicity.
Chronic toxicity studies are carried out in at least 2 species, one of which is not a rodent. These studies usually last for up to the lifetime of the animal, but their length will depend on the intended duration of administration of the drug to humans.
Clinical Investigation (Human Studies)
Some adverse effects of drugs cannot be discerned in animals; e.g., dizziness, nausea, headaches, ringing in the ears, heartburn, and depression. It has been estimated that >= 50% of undesirable drug effects seen most frequently can be ascertained only during human trials.
Phase 1 represents the first administration of a new drug to man. A small number of closely monitored subjects, mainly healthy volunteers, are usually involved. Initially, each receives a single dose of the drug to determine a safe dose range and assess pharmacokinetic data. The primary objective of this necessarily cautious phase of the investigation is to determine a safe and tolerated dosage in humans; however, observation of toxicity, if it occurs, and of absorption, metabolism, and excretion may also be made during Phase 1.
Phase 2 begins after satisfactory preliminary evidence regarding safety has been obtained. It involves the supervised administration of the drug to patients for treatment of, or prophylaxis against, the disease or symptoms for which the drug is intended. These studies usually are conducted in randomized clinical trials comparing the new drug with the prototype drug, if any, for a particular indication. Often this is the first opportunity to observe the effect of long-term administration of the drug to humans.
Phase 3 begins after the initial phases have provided reasonable evidence of safety and efficacy. It consists of more widespread clinical trials that may move from the realm of clinical investigators to practicing physicians. Phase 3 extends up to the time the drug is released for general use.
Phase 4 is the study of the actual use of the drug in medical practice and, though often not recognized as a phase of clinical investigation, is a most important one from a clinical standpoint.