EMEA

European Medicines Agency (EMEA)’s Committee on medicinal products for human use (CHMP) has issued guidelines on the requirements for clinical documentation for orally inhaled products (OIP). (Ref 2) This guideline recommends: “Advice from appropriate experts in the field might be useful to ensure that tests and assessments carried out are appropriate and are in line with current thinking.”

Bioequivalence.EU

A Clinical Research Center on Pediatric Asthma This Website is responding to the EMEA call for collaboration between pharma industry and the clinical researcher. We are presenting a brief summary of the pharmacology of aerosol therapy in children with an emphasis on the studies of bioequivalence of inhaled cortisosteroids. Particularly the website aims to present the state of the art methods for such studies of bioequivalence in children.

Aerosol Treatment of Children

Bioequivalence of novel aerosol and existing reference product needs documentation.

The airway in the younger child differs from the airway in the adult and the amount of the dose of an inhaled drug reaching the lower airway in an infant and in a young child will differ from the amount which would reach the lower airway in an adult. Changes in development, maturation and growth of the lung from birth, through infancy and early childhood can affect absorption and clearance of drug from the lung with possible changes in respect of optimal dosing in this young age group and changes in both efficacy and systemic safety. The child also displays different breathing patterns and has differing tidal volumes, airway geometry, etc. compared with adults [1].

This website present methods for such evidence based documentation of bioavailability of aerosol treatment of children.

Reference
Drug Delivery to the Lung. Vol. 162. Bisgaard H, O’Callaghan C, Smaldone GC, eds. New York: Marcel Dekker; 2002.

Bioequvalence

Studies

Two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent and their bioavailabilities (rate and extent of availability) after administration in the same molar dose are similar to such a degree that their effects, with respect to both efficacy and safety, can be expected to be essentially the same.

Therapeutic equivalence might be based on demonstration of equivalent drug distribution in vitro, combined with bioequivalence based on pharmacokinetic data and/or pharmacodynamic data.

A successful therapeutic equivalence study requires demonstration of a significant dose-response relationship with the study of at least two doses of the test compared with, if possible, two doses of the reference product. Two products will be considered as equivalent if the following criteria are completely fulfilled:

Efficacy

Efficacy: If the relative potency approach is used the 95% confidence interval for the primary endpoint must be contained entirely within 80 – 125 %.

Safety: If possible bioequivalence in respect of systemic exposure should be demonstrated (the 90% confidence interval must be contained entirely within 80 – 125%).

Therapeutic Index

Inhaled corticosteroid therapy in children demands the optimal therapeutic index, as defined by the ratio between efficacy and systemic bioavailability.

Efficacy

Only the dose deposited in the lower airways contribute to the efficacy. The importance of the exact location of the deposition is unknown though it has been speculated that peripheral deposition may be advantageous since this is the main location of the disease process. Differences in aerosol particle distribution may greatly change the deposition pattern within the lung presumably with a corresponding change in efficacy.

Systemic Bioavailability

Lung dose: Inhaled corticosteroids (ICS) are not metabolized in the lungs and need to pass through the blood to be metabolized in the lungs. Therefore any ICS deposited in the lung is eventually systemically active.

Importantly, devices delivering a high lung dose therefore lead to equally high systemic exposure (Ref 4).

Oral dose: the inhaled dose that does not reach the lung passes to the gut where is may be absorbed and passes through the liver to the systemic circulation. The absorption and first-pass elimination in the liver differs among steroids and the oral contribution to the systemic activity is often minimal compared to the contribution of the lung dose.

Pulmonary Deposition

Pulmonary deposition can be investigated by imaging studies or pharmacokinetic studies, but the clinical relevance of pulmonary deposition studies is limited by lack of accuracy and from the lack of evidence on the importance of the distribution of drug within different zones of the lung.

Imaging studies are not recommend in children due to radiation from the tracer and due to unknown impact on the properties of the active substance and the excipients from the radiolabeling. Currently the experience with such studies would appear to be insufficient for documenting bioequivalence.

Pharmacokinetic studies from plasma or urine have the advantage of being able to demonstrate linear dose-response relationships. In addition, pharmacokinetic studies measure total systemic exposure (for assessment of safety), and pulmonary absorption (for assessment of pulmonary deposition and efficacy) can be separated from gastrointestinal absorption.

Pharmakokinetic Study of Systemic Bioavailability

Generally it is not felt to be appropriate to subject children to repeated venopuncture and therefore pharmacokinetic studies and the repeated measurement of plasma cortisol have not been used as first line methods to assess the systemic burden of ICSs in this young age group. However in the light of the very real need to ensure the systemic safety of these drugs in children and the acceptance that other methods to assess the systemic load are far from robust or even satisfactory, the use of an indwelling cannula to enable the collection of blood samples to measure both blood levels of the drug and any active metabolites and plasma cortisol at intervals over time should be considered. This approach may represent the best way of collecting reliable information on comparative systemic safety in children with asthma treated with ICSs.

A pharmacokinetic study designed to investigate systemic safety has to measure total systemic exposure and therefore must not exclude that amount of the active moiety absorbed through the gastrointestinal tract. In accordance with the standard accepted methods of assessment of bioequivalence Cmax, the time to Cmax (Tmax) and the area under the curve (AUC) should be compared.

Equivalent pulmonary deposition of two inhaled products may be concluded if the 95 % confidence interval for each parameter lies within the acceptance range of 0.8 to 1.25.

Pharmacodynamic Study of Efficacy

Equivalent therapeutic efficacy can be investigated by measurement of the bronchodilating potency and/or the bronchoprotective potency of the test and the reference product. One or other or both of these types of study may be used to satisfy the requirements of comparative efficacy.

Protection against hyperresponsiveness can be assessed through bronchoprotection studies, either direct provocation for example with methacholine, histamine, acetylcholine or indirect provocation with adenosine monophosphate (AMP) or mannitol.

It is a minimum requirement that the study has assay sensitivity. For a study to have assay sensitivity at least two non-zero levels need to be studied and one dose level needs to be shown to be superior to the other. Therefore it is recommended that unless otherwise justified more than one dose of both the test and reference products are studied.

It is essential that doses on the steep part of the dose response curve are studied.

Inhaled Corticosteroid

bioequivalence between two inhaled corticosteroids Safety investigations must be carried out following inhalation of the maximum recommended daily dose of the ICS regularly over time. Systemic safety should be demonstrated through pharmacokinetic bioequivalence and measurement of pharmacodynamic parameters.

The current view in respect of the measurement of systemic effects of ICSs is to assess the effect on the hypothalamic pituitary adrenocortical (HPA) axis and/or on lower leg bone growth rate (Knemometry).

The hypothalamic pituitary adrenocortical axis is evaluated by the diurnal cortisol production which may be measured in blood or urine. The ACTH short stimulation test is not recommended and should not be used for the assessment of the systemic effects of ICSs in children.

Knemometry is validated, accurate and reproducible and has been used previously in the early assessment of systemic safety of ICSs in children.

Devices

Drug Delivery to the Lungs (Ref 3) Differences between inhalation devices can cause several fold changes in efficacy as well as systemic bioavailability. Therefore, if a pMDI is to be used in children it must be developed for use together with a specific appropriate spacing device.

Spacer

If a pMDI is to be used in children it must be developed for use together with a specific appropriate spacing device. Differences between inhalation devices can cause several fold changes in efficacy as well as systemic bioavailability. Effective spacers improve lung dose and facilitate coordination between actuation and inhalation. Also, spacers decrease the amount of medicinal product deposited in the mouth and pharynx and subsequently swallowed. Spacers perform differently with different active substances and formulations. The distribution and response to an active substance cannot be assumed to be equivalent if a different spacer is used or if a different pMDI is used with the same spacer. The development of a pMDI should always include the testing of at least one specific named spacer for use with the particular pMDI containing a particular active substance. The behaviour of the spacer will depend on the volume and material of the holding chamber, on the electrostatic properties of the internal surface of the chamber and on the way in which the device is used. Hence the in vitro testing should be carried out by preparing the spacer and setting up the apparatus in a clinically relevant manner which may influence the performance of the product, for example, inserting a time delay between actuation and inhalation to simulate tidal breathing and washing/preparation of the spacer before and during use according to the instructions of the manufacturer of the spacer.

Breath-operated metered dose inhalers

A minimal peak inspiratory flow (PIF) is required to trigger a breath-operated inhaler (BOI) and if this minimal PIF cannot be achieved by the patient, inhaler use will be unsuccessful. Therefore, the clinical programme must include relevant data regarding the PIF required to trigger the BOI