Determining the optimal regimen of a drug or vaccine – including both dose of the agent and schedule of administration – is an essential part of pharmaceutical research. It is also a requirement for approval from regulatory agencies including Health Canada, the United States Food and Drug Administrations (FDA) and European Medicines Agency (EMA).
Drug dosing and phase I and II trials
The first stage of determining drug dosing begins in pre-clinical animal studies. From these studies, drug doses are converted to an estimated suitable dose for humans to be tested in phase I (first-in-human) trials. Phase I trials evaluate the safety of the agent in a small group of healthy volunteers and may also include escalating doses to assess toxicity and pharmacokinetics.
Further studies may be conducted in phase II trials in which groups of participants may be given different doses of the investigational agent to determine the optimal therapeutic range. The lowest dose that induces the desired effect with the fewest adverse events is an ideal target to progress to large phase III randomized trials to evaluate efficacy.
The liver is the primary site of drug metabolism and the rate of metabolism, along with absorption, distribution, and excretion, affects drug concentration in the blood, impacting efficacy and toxicity. For example, a drug that is metabolized too quickly or has poor absorption, may not exert its desired effect and require a higher dose for clinical benefit. If a drug is metabolized or excreted too slowly, its toxicity may outweigh its benefit. A drug that is metabolized or excreted quickly at a dose with reasonable efficacy/toxicity profile may be a candidate for more frequent administration to keep its level in the body above a threshold to maintain clinical benefit.
Additionally, dosing is not always static for all populations and adjustments may be necessary depending on clinical factors (such as renal function), other medications, age, and weight.
Drug dosing and age
Vaccines go through a similar sequence of clinical trials to determine optimal dosing regimens. In the Spring of 2020, trials were first initiated to evaluate COVID-19 vaccine dosing. Pfizer/BioNTech concluded that 30 µg of their lipid nanoparticle-encapsulated mRNA was optimal, while Moderna settled on 100 µg. Because the Johnson & Johnson and AstraZeneca COVID vaccines are adenovirus-vectored, dosing is based on adenovirus particles.
Further investigations in children revealed that two 10 µg doses of Pfizer/BioNTech vaccine was suitable for those five-11 years of age. The Moderna COVID-19 vaccine is not yet authorized for this age group in Canada, though they have filed for regulatory approval for two 50 µg doses (half the adult dose) in children aged six-11 years in Europe.
It seems reasonable that the dose for the COVID-19 vaccine in children is less than that given for adults, however the rationale for dosing adjustments for vaccines in children is not the same as for drugs. Weight- and age-based adjustments for many medications are due to pharmacokinetic profiles. That is, the blood concentration of many drugs varies by body weight.
Lower doses of COVID-19 vaccines in children, however, is due to a more robust immune system in younger people, meaning that less vaccine is required to induce a comparable immune response. Several other vaccines are given at lower doses for children, including influenza vaccines. Conversely, some vaccines have special high-dose formulations for adults older than 65 years because of significant immune system dysfunction related to aging.
Drug administration schedules
The schedule of dosing for COVID vaccines with multiple injections is based upon decades of research on the kinetics of the immune response. Unlike the pharmacokinetics of a drug, in which the activity of the drug is linked to presence of that agent in the blood, a vaccine is meant to be a short-term message whereby the body induces an immune response that takes 10-14 days. This is the reason people aren’t considered fully vaccinated until 14 days after their final primary COVID-19 vaccine dose.
Administering the second dose of vaccine too early can interfere with the development of memory B cells and T cells, so Pfizer/BioNTech tested 21 days and Moderna tested 28 days in between immunizations. The three-to-four-week range was chosen for logistical reasons: to avoid interference with the primary immune response, yet get people fully vaccinated as quickly as possible and not necessarily because this dosing interval is optimal. A study in the United Kingdom revealed that an extended dosing interval of Pfizer/BioNTech or AstraZeneca COVID vaccines (nine-12 weeks apart) resulted in higher antibody levels and better protection than the standard dosing interval.
Drugs and vaccines need to be evaluated in clinical trials to determine adequate dosing regimens. In both situations, the amount of agent and schedule of administration should have an acceptable efficacy/toxicity ratio. However, the pharmacokinetic profile of a drug weighs heavily into dosing decisions, while vaccine dosing is dependent on inducing an immune response that confers protection, which is prominently influenced by age.
For more information, see the topic COVID-19 (Novel Coronavirus) in DynaMed.
Original article published on EBSCO Health Notes. Written by:
- Heather D. Marshall, PhD, Public Health Content Manager at DynaMed, with help from the Medication Publishing Group at DynaMed
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