IN VIVO INTERACTIONS BETWEEN EFAVIRENZ AND AFRICAN POTATO (Hypoxis hemerocallidea)
5.1 Clinical Trial Design
The design of a clinical trial depends on the objective/s of the study, which should be determined at the planning stage [233]. Clinical studies can be classified as parallel or crossover. A crossover trial is when patients receive two or more treatments, and a parallel design is when each patient receives only one treatment. During planning, the design of the study must establish various factors and requirements such as objectives, factors (in an efficacy trial the drugs are factors to be evaluated), types of responses, and sample size, amongst others.
87 5.1.1 Parallel Design
For a parallel study design, an equal number of patients are given treatment A, and another group is given treatment B. The results of the two groups are compared, and the number of treatments may be more than two. It is important to have an equal number of patients in both groups so that the standard deviation is minimised, hence the statistical power of the study is at its maximum. Randomisation is important so that it becomes a matter of chance which subjects receive a given treatment. In this case, it is assumed that the average effect of a given drug will be the same, regardless of which randomly selected group of patients happen to receive it [233]. This type of study is suitable for clinical trials where carry-over effects cannot be controlled or eliminated.
5.1.2 Cross-over Designs
In a cross-over study design, each subject is exposed to two treatments under investigation on different occasions. In this design, each patient acts as his or her own control, and can be used to evaluate within subject variability. It allows for direct comparison of treatments, and is more relevant in the presence of large inter-individual variation.
Treatments are administered on two occasions, and these are often called legs, periods or visits, and the order of treatment may be randomised to reduce period effects. A period effect is where a difference in response is due to the occasion on which the treatment is given, independent of the effect due to the treatment. This is considered as a statistical interaction or
“differential carry-over” which may occur in the cross-over design. This carryover effect occurs when the response of the second period is dependent on the response of the first period, and this dependency differs, depending on the sequence of treatment. In this case a sufficiently long washout period should be employed to avoid the carryover effect. The possibility of period effects increases if the order is not balanced. Intra-subject variability is usually smaller in these designs, hence, it is more precise than parallel designs. One disadvantage of the cross-over design is that it may not be suitable when carry-over effects and other interaction effects are anticipated, hence, a parallel design is preferable. The other disadvantage of a cross-over design is that it may take longer time to complete.
88 5.2 Drug Interaction Study Designs
Drug interaction studies are usually conducted during phase 1 clinical trial, i.e., during the development stage of a new drug, and can also be conducted after market authorisation is granted by assessing retrospective data obtained during clinical use. The studies may be open-labelled, unless pharmacodynamic end-points are part of the assessment. Open-labelled studies are studies where both the subjects and researchers know which treatment is being administered. Clinical drug interaction studies are usually of a randomised, cross-over or one sequence cross-over or parallel design, with appropriate washout periods. The following study designs to investigate drug-interactions are used in the pharmaceutical industry [234]:
• single dose substrate drug and single dose CYP450 enzyme probe administered in combination, and each compound given alone in a three-way cross-over study
• single dose CYP450 enzyme probe followed by multiple dose substrate drug co- administered with single dose CYP450 enzyme probe, or single dose substrate drug followed by multiple dose interacting drug co-administered with single dose substrate drug in a sequential two-way cross-over
• multiple dose CYP450 enzyme probe and multiple dose substrate drug in one three- way cross-over or two two-way cross-over trial.
5.2.1 Study Population and Sample Size
Generally, clinical drug interaction studies are performed using healthy volunteers drawn from the general population, and this is based on the assumption that results from healthy volunteers should predict findings in the patient population [235]. Patients can be used if there are undue risks on healthy volunteers. When a drug interaction involves enzymes which exhibit polymorphism, then genotyping of the volunteers to identify polymorphs is important to assist interpretation of the results because a drug interaction may only occur in slow metabolisers. The number of volunteers should be adequate to assess differences, thus the power of the study should be adequate.
5.2.2 Washout Period
The washout period is the time between two doses of the same drug during a clinical study, and should be adequate to allow complete elimination of the drug, and is based on the half-
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life of the drug. The recommended washout period should be based on more than five (5) half-lives of the drug [236].