1. The Role of Bioavailability in Pharmaceutical Product Development Alwyn Pidgen Pharmacokinetics consultant

2. Formulations include:- Tablet, Suspension, Capsule, Solution, Powder
Different routes & formulations can impact the speed and completeness of drug absorption
INTRAVASCULAR Intravenous
EXTRAVASCULAR Intra-muscular; Subcutaneous; Oral; Rectal; Topical; Inhalation; Intranasal; Transdermal; Sublingual; Buccal
Formulations include:-
Tablet, Suspension, Capsule, Solution, Powder
Aerosol, Nebulizer, Dry Powder Inhaler (DPI)
Lotion, Ointment, Cream
Suppository, Rectal solution, Implants

3. Absolute Bioavailability
Absolute bioavailability - Is the proportion of intact drug, which reaches the systemic circulation following extravascular administration when compared to an intravenous dose. C iv
oral
Time
F(abs) = AUC(oral) * Dose(iv)
AUC(iv) Dose(oral)

4. Relative Bioavailability
Relative bioavailability - Is the bioavailability of one dosage form (e.g. tablet) relative to another (e.g. capsule) - or one route of administration (e.g. rectal) relative to another (e.g. oral). C
oral
rectal
Time
F(rel) = AUC(rectal) * Dose(oral)
AUC(oral) Dose(rectal)

5. Bioequivalence
Two medicinal products can be classed as bioequivalent when their rate and extent of absorption meet strict regulatory requirements after administration of the same molar dose.

6. Pharmaceutical equivalence
Medicinal products are called Pharmaceutical equivalents if they contain the same amount of the same active substance in the same dosage form, which meet the same or comparable standards.

7. HOWEVER - Pharmaceutical equivalence does not automatically assure bioequivalence mainly due to changes in dissolution, which can be influenced by: -
Particle size
Physico-chemical factors of drug
Solubility
Use of different excipients
Degree of agitation
Change in manufacturing process
Food

8. Particle size
In general, the smaller the particle size the faster the absorption. The analgesic phenacetin (shown below) was tested in various suspension dosage forms.

9. KEY CONCEPT IN BIOEQUIVALENCE
‘Equal amounts of the same drug administered in different products will show equal therapeutic effects’.
A direct demonstration of therapeutic equivalence requires a clinical trial
 HOWEVER
This is replaced by the indirect approach of a bioequivalence trial based on the principle that:-
‘Two medicinal products that give rise to ‘essentially equivalent’ concentrations of the active species in blood (viewed as a profile over time) will give equivalent therapeutic effects’.

10. Why perform Bioequivalence studies ?
To enable clinical trial formulations to be modified or production ‘scaled up’ throughout a drug’s development.
To compare a clinical trial formulation with the ‘to be marketed’ product just prior to filing.
To compare a generic drug product with a corresponding reference drug.
To change the dosage regimen by means of a change in formulation
Immediate release  Modified-release

11. When are bioequivalence studies not normally needed ?
If the product differs only in the strength of the active substance it contains and the pharmacokinetics are linear
If the product has been slightly reformulated or the manufacturing method slightly modified by the original manufacturer in ways that can be argued to be irrelevant (using in-vitro tests)
If the product is to be administered parenterally as a solution and contains the same active substances and excipients as a medicinal product currently approved.

12. If the product is a liquid oral form in solution containing the active substance in the same concentration and form as a currently approved medicinal product
An acceptable correlation between dissolution rate in-vivo and in-vitro has been shown (FDA guidance).
Products intended for local use to act without systemic absorption

13. F1 = Tablet (kit) F2 = Tablet (co-precipitate) F3 = Softgel
FDA Criteria met for F2 Tablet (co-precipitate) & F1 Tablet (Kit) but not for F3 (Softgel).

14. Typical Study Design Features
Healthy volunteers
Male subjects or women of non-child bearing potential
Aged between 18 and 55
Single dose.
Crossover design – first choice
Parallel group design - for drugs with long half-lives
Replicate design - for highly variable drugs

15. SAMPLE SIZE
Should be appropriately statistically powered if study is pivotal for filing
An estimate of a drug’s intrinsic variability is obtained from previous studies or publications
Should not be smaller than 12

16. What to measure
For BE studies - measurement of plasma concentrations of the parent drug are recommended.
Parent drug is more sensitive to formulation changes than any metabolite.
For an inactive pro-drug the main active metabolite should be measured if the plasma levels of the parent are too low for accurate assay measurement.
Examples of prodrugs
Enalapril (hypertension) is metabolised to the active form Enalaprilat
Valacyclovir (herpes virus) is metabolised to the active form Acyclovir

17. Enantiomers versus Racemates
For BE studies measurement of the racemate is recommended.
Measurement of individual enantiomers is recommended if:-
The enantiomers have different PK or PD characteristics
The exposure (AUC ratio) of the enantiomers is modified by a difference in the rate of absorption.
If one enantiomer is pharmacologically active and the other contributes little to activity, it is sufficient to demonstrate bioequivalence for the active enantiomer only.

18. Fixed combinations
A separate BE analysis should be performed on each active substance in a fixed combination. This is achieved by considering all other active substances (in turn) as excipients.
Endogenous substances
Difficult area. A pilot study may be useful to check the effect. Baseline correction of background levels are required to ensure that drug levels reflect the treatments under test. A longer washout period may be required.

19. PHARMACOKINETIC PARAMETERS
Early exposure
Only consider if making a claim for clinically relevant rapid release - and/or - if onset of action is related to adverse events.
Rapid onset of analgesic effect
Avoidance of excessive hypotensive action
Parameters include AUC(0–tmax) (FDA) and tmax (EMEA)
Peak exposure
Important parameter - may have potential links to safety and/or efficacy.
Parameter is Maximum observed drug concentration (Cmax)

20. Total exposure
This is the most important BE parameter since AUC is directly proportional to the amount of drug absorbed.
Parameters
AUC to the last measurable time point (AUC0-t)
AUC truncated at 72h (AUC0-72) – (EMEA only)
AUC extrapolated to infinite time (AUC0-inf)
The elimination rate constant (kel) and terminal half-life (t1/2) should be reported - particularly if AUC(0-inf) is used.

21. STATISTICAL ANALYSIS
Calculate 90% confidence intervals of the ratio of the treatment means (test/reference) for Cmax, and AUC.
The data are log transformed prior to analysis.
If statistical evaluation of tmax is required then a non-parametric hypothesis test is performed on the untransformed data.

22. Bioequivalence region
For Bioequivalence - the ratio of the geometric means µT/µR of the test and reference products must be ≥ 0.8 and ≤ 1.25.
Bioequivalence
region
µT/µR
0.8
1.25
Bio-inequivalence
region
Bio-inequivalence
region

23. The Regulatory acceptance criteria
AUC : test treatment to be within ≥ 0.8 and ≤ 1.25 of the reference treatment (FDA and EMEA)
Range to be tightened in the case of a drug with a narrow therapeutic window (e.g. digoxin, phenytoin) (FDA and EMEA). This may also be applicable to Cmax.
Cmax : test treatment to be within ≥ 0.8 and ≤ 1.25 of the reference treatment (FDA and EMEA)
A wider interval may be acceptable (EMEA only). The actual limits vary according to the within-subject variability (%CV) noted in the bioequivalence study. See EMEA guidelines for details.
tmax : Only consider if clinically relevant rapid release is claimed and/or onset of action is related to adverse events.

24. An example Propafenone – anti-arrhythmic drug
Undergoes extensive first-pass metabolism
Variable half-life
Bioequivalence study undertaken
Apotex (Reference) v Rhythmol (Test)
300mg tablet
18 healthy subjects
2-way crossover
‘Highly Variable Drugs:Experience with Propafenone’ -Yu Chung Tsang, Radu Pop & Michael Spino

25. Mean Plasma concentrations

26. Individual variability

27. Pharmacokinetic parameters
Statistical analysis

28. Reasons for BE failure Very high inter-subject CV for Cmax & AUC
High overall intra-subject variability (46%)
Variability in elimination characteristics
The metabolism of propafenone is influenced by genetics
t1/2 (fast metabolisers) = 2-10h
t1/2 (slow metabolisers) = 10-32h
Drug levels 5 times higher in slow metabolisers

29. Biogenerics – current status
Hot topic – large market potential – lot of issues
More regulatory obstacles than with traditional ‘small molecule’ generics.
FDA position still under review
EMEA guidance available
Numerous position papers
Current ANDA approach not considered scientifically appropriate for biotechnology products
Companies asked to show ‘biosimilarity’ – this involves clinical trials to demonstrate safety/efficacy

30. Biogenerics – why the problems ?
Protein products have a greater structural complexity, often difficult to characterize and have a much higher molecular weight than ‘small molecule drugs’.
They can be mixtures of many molecular species and can have unique impurity profiles that depend upon the manufacturing process.

31. Biogenerics - manufacture
Small changes in the manufacturing process can lead to big changes in the drugs safety & efficacy. FDA collecting examples to evaluate this claim.
Improvements in protein technology mean manufacturers can no longer produce a protein that would have identical characteristics to the original.
Implications - altered PK & PD of the protein - ultimately leading to clinical implications.

32. Useful Regulatory Guidance documents
FDA (
Bioavailability & Bioequivalence studies for orally administered drug products – general considerations – March 2003
Food-effect Bioavailability & Fed Bioequivalence studies – December 2002
Modified Release Solid Oral Dosage Forms - Scale-Up and Post-approval Changes: Chemistry, Manufacturing and Controls; In Vitro Dissolution Testing and In Vivo Bioequivalence Documentation – Sept 1997
Dissolution testing of Immediate release solid oral dosage forms - Aug 97
Extended release oral dosage forms : Development, Evaluation & Application of In-vitro/In-vivo correlations – Sept 97
EMEA (
Guideline on the Investigation of Bioequivalence - January Doc. Ref.CPMP/EWP/QWP/1401/98
Guideline on Similar Biological Medicinal products – November 2004
Note for guidance on quality of Modified Release products (A Oral dosage forms; B Transdermal dosage forms) – July 1999
Guideline on Similar Biological Medicinal Products – Nov 2004
Guideline on Similar Biological Medicinal Products containing Biotechnology-derived Proteins as active substance: Quality Issues – June 2005