bioavailability and bioequivalence

Relative bioavailability and bioequivalence

In early phase drug development, a relative bioavailability trial is usually needed to allow the transition from small-scale production of a simple formulation to larger-scale manufacture of a new dose form. Later in the development of an IMP, another bioavailability trial may be required to show, with a high level of confidence, that a new ‘market image’ formulation is closely similar to the previous one – in other words, it shows bioequivalence.

Bioequivalence trials are mission-critical and are closely scrutinised by regulatory authorities.  So, it may be a false economy to get them done in low-cost countries where strict GCP compliance may not be assured, and where close monitoring may be hard to achieve.  That applies to the development of a generic formulation of an existing medicine as much as to a novel compound.

HMR has decades of experience of bioavailability and bioequivalence trials: we offer a comprehensive service, extending from trial design and calculation of sample size through to pharmacokinetic and statistical analysis, and final report. Although bioavailability trials are usually straightforward, we give them the same scrupulous care and attention that we give to our more complex work. Our high-quality data ensures that our reports satisfy the regulators.

Absolute bioavailability

Although it may be possible to develop an oral form of an IMP successfully without knowing its absolute bioavailability, that isn’t entirely satisfactory. For example, if bioavailability is low, blood levels of the molecule may be substantially increased or reduced by a wide variety of interventions and interactions, or by polymorphism of metabolism, with consequent risk of toxicity or lack of efficacy.  It’s important to know if there’s a risk of such problems.

If an IV formulation and IV toxicology data are available, then an absolute bioavailability trial is almost as straightforward as a trial of relative bioavailability. Usually, however, there’s no full-dose IV formulation – in which case, an IV ‘light-label’ microdose trial is an excellent alternative. All that’s needed is very limited toxicology to allow an IV dose containing <100 µg of IMP labelled with a low dose of carbon-14. The IV dose is given after a ‘therapeutic’ oral dose, at the expected time of peak concentration. Concentrations of carbon-14-labelled IMP are then measured by accelerated mass spectrometry, and the unlabelled IMP is measured by conventional methods. That allows very simple calculation of absolute bioavailability.

In our experience, this method yields high-quality data that allow a reliable estimate of absolute bioavailability – knowledge that has proved invaluable in the subsequent development of the IMP.