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

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

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)

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)

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.

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.

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

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.

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’.

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

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.

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

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).

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

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

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

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.

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.

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)

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.

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.

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

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.

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 http://www.ualberta.ca/~csps/JPPS1(2)/Y.Tsang/Tsang.pdf

Mean Plasma concentrations

Individual variability

Pharmacokinetic parameters Statistical analysis

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

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

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.

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.

Useful Regulatory Guidance documents FDA (www.fda.gov/cder/guidance/index.htm) 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 (www.emea.europa.eu/index/indexh1.htm) Guideline on the Investigation of Bioequivalence - January 2010 - 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