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bioequivalence of biotech derived products
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THE BIOPHARMACEUTICAL CLASSIFICATION SYSTEM - IMPACT FOR DRUG DEVELOPMENT. A. Grahn~n. Quintiles Phase I Services, Islandsgatan 2, S-753 18 Uppsala,
INDIVIDUAL BIOEQUIVALENCE R. Zeneca Pharma, 1 rue des Chauffours, B.P. 127,95022 Cergy, France.
Sweden. The Biopharmaceutical Classification System (BCS) for immediate release (IR) drug products identifies membrane permeability and solubility to be the primary determinants for predicting drug absorption in man. The BCS divide drugs into 4 different classes based on their solubility and permeability. Class I. High Solubility-High Permeability. These drugs are well absorbed (although systemic availabilii may be low due to fmt-pass metabolism) and the rate limiting step is drug dissolution. A dissolution specification of 85 % dissolved in
properties of physiologic importance. The BCS will improve the process of candidate drug/dosage form selection during drug development when oral absorption is a critical factor.
Bioequivalence of two drug formulations is cunently defined by drug regulatory authorities in tMm8 of the mean responses (average bioequivalence) following administration of the test and reference formulations. The finding that the av.zage bioavailability of the test and reference formulation are similar does not mean that the bioavailability metrics of the test and reference product are similar in all or even most individuals. It has been recognized that the safety for the substitution of a reference drug product with a test drug product in patients, whose concentrations may have been titrated to a steady efficacious and safe levels, could be a concern. Therefore, it is suggested that individual bioequivalence within each subject should be assessed to assure the safety of the drug switchability. Swltchability actually demands that, within the same patient, the drug concentrations of the test formulation remain within the same therapeutic window achieved by the reference formulation. The statistical evaluation of the individual bioequivalence examines that the pharmacokinetic windows for the test and reference formulations are similar. The various potential shortcomings of average bioequivalence are now understood, and switchability, and thus individual bioequivalence, has become a reasonable expectation when changing from one pharmaceutically equivalent drug product to another. Progress has been made in developing criteria for individual bioequivalence, and a classification of most of the different approaches to the assessment of individual bioequivalence has been achieved. We review and discuss some technical statistical issues and practical implementation issues associated with the use of individual as opposed to population average bioequivalence to express the relative bioavailabllities of alternative formulations of a drug.
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OPEN QUESTIONS ON BIOEQUIVALENCE: SOME PROBLEMS AND SOME SOLUTIONS Antonia IPAS SA, Via MasUi, 6853 Ligometto, Switzerland
BIOAVAILABILITY/BIOEQUIVALENCE OF BIOTECH DERIVED PRODUCTS S. Canali LCG/RBM, Via Ribes 1, 100 10 Colleretto Giacosa, Torino, Italy
EU and US FDA operating guidelines have issued general and in smne cases specific procedures for bioequivalence trials. However a number of specific problems request tailored study designs. The high variability is a common situation which requires as possible solutions a high pool site of volunteers, or the enlargement of the acceptable range, or the individual bioequivalence design. Repeated dose regimen to steady state is usually characterized by a less data dispersion than single dose. A Ngb variability is often the result of fm pass effect. Endogenous substances possessing a relevant baseline lead either to a very low data dispasion when baseline is not subtracted or to a very high data dispersion when it is. Tbe repeated dose regimen in target population is often an adequate design which would allow baseline subtraction to be avoided. Examples are endogeaoas compounds with a renal threshold, like K’, Na+, Mg”, L-csmitine, some amino acids, iron. Drugs or active metabolites with very long half lives would require the selection between the crossover design or that using parallel groups. This is the case with amiodamne (tin 35 days), digit&n (l,R 6-8 days), chlomquine (tin 9 days), tamoxifen/desmethyltxifen (tin z 14 days). In some cases parent drug compared to its active metabolite is irrelevant for a
BiotechnoIogy derived pharmaceuticals products are proteins and peptides, their derivatives and products of which they are components: they can be derived from cell cultures or produced using recombinant DNA technology. Biotechnology products present several particular pharrnacokinetic characteristics vs the conventional pharmaceutical products which have to be taken into account in designing and interpreting results of bioavailability/bioequivalence studies both in animals and in humans. The main aspects are: 1) analytical methods are generally immunomethods, very sensitive but often too variable and not sufficiently specific; HPLC/MS methods are sometimes applicable but their sensitivity for proteinlpeptides is often insufficient and sample preparation can represent a very difficult step 2) bioavailability is sometimes low by extravascular routes (virtually no absorption by oral route) and tiected by high variability; 3) the pharmacological response is often highly species specific 4) biotech products can be immunogenic in animals, limiting the meaning of repeated doses or single doses in crossover studies; 5) many biotech products are endogenous and basal levels/profiles complicate analytics and pk data analysis; 6) the correlation between pharmacokinetics and activity is sometimes unclear and make it necessary to characterise also profiles of PD markers; 7) the selection of the appropriate PD markers can he problematic.
69
71
THE BIOPHARMACEUTICAL CLASSIFICATION SYSTEM - IMPACT FOR DRUG DEVELOPMENT. A. Grahn~n. Quintiles Phase I Services, Islandsgatan 2, S-753 18 Uppsala,
INDIVIDUAL BIOEQUIVALENCE R. Zeneca Pharma, 1 rue des Chauffours, B.P. 127,95022 Cergy, France.
Sweden. The Biopharmaceutical Classification System (BCS) for immediate release (IR) drug products identifies membrane permeability and solubility to be the primary determinants for predicting drug absorption in man. The BCS divide drugs into 4 different classes based on their solubility and permeability. Class I. High Solubility-High Permeability. These drugs are well absorbed (although systemic availabilii may be low due to fmt-pass metabolism) and the rate limiting step is drug dissolution. A dissolution specification of 85 % dissolved in
properties of physiologic importance. The BCS will improve the process of candidate drug/dosage form selection during drug development when oral absorption is a critical factor.
Bioequivalence of two drug formulations is cunently defined by drug regulatory authorities in tMm8 of the mean responses (average bioequivalence) following administration of the test and reference formulations. The finding that the av.zage bioavailability of the test and reference formulation are similar does not mean that the bioavailability metrics of the test and reference product are similar in all or even most individuals. It has been recognized that the safety for the substitution of a reference drug product with a test drug product in patients, whose concentrations may have been titrated to a steady efficacious and safe levels, could be a concern. Therefore, it is suggested that individual bioequivalence within each subject should be assessed to assure the safety of the drug switchability. Swltchability actually demands that, within the same patient, the drug concentrations of the test formulation remain within the same therapeutic window achieved by the reference formulation. The statistical evaluation of the individual bioequivalence examines that the pharmacokinetic windows for the test and reference formulations are similar. The various potential shortcomings of average bioequivalence are now understood, and switchability, and thus individual bioequivalence, has become a reasonable expectation when changing from one pharmaceutically equivalent drug product to another. Progress has been made in developing criteria for individual bioequivalence, and a classification of most of the different approaches to the assessment of individual bioequivalence has been achieved. We review and discuss some technical statistical issues and practical implementation issues associated with the use of individual as opposed to population average bioequivalence to express the relative bioavailabllities of alternative formulations of a drug.
70
72
OPEN QUESTIONS ON BIOEQUIVALENCE: SOME PROBLEMS AND SOME SOLUTIONS Antonia IPAS SA, Via MasUi, 6853 Ligometto, Switzerland
BIOAVAILABILITY/BIOEQUIVALENCE OF BIOTECH DERIVED PRODUCTS S. Canali LCG/RBM, Via Ribes 1, 100 10 Colleretto Giacosa, Torino, Italy
EU and US FDA operating guidelines have issued general and in smne cases specific procedures for bioequivalence trials. However a number of specific problems request tailored study designs. The high variability is a common situation which requires as possible solutions a high pool site of volunteers, or the enlargement of the acceptable range, or the individual bioequivalence design. Repeated dose regimen to steady state is usually characterized by a less data dispersion than single dose. A Ngb variability is often the result of fm pass effect. Endogenous substances possessing a relevant baseline lead either to a very low data dispasion when baseline is not subtracted or to a very high data dispersion when it is. Tbe repeated dose regimen in target population is often an adequate design which would allow baseline subtraction to be avoided. Examples are endogeaoas compounds with a renal threshold, like K’, Na+, Mg”, L-csmitine, some amino acids, iron. Drugs or active metabolites with very long half lives would require the selection between the crossover design or that using parallel groups. This is the case with amiodamne (tin 35 days), digit&n (l,R 6-8 days), chlomquine (tin 9 days), tamoxifen/desmethyltxifen (tin z 14 days). In some cases parent drug compared to its active metabolite is irrelevant for a
BiotechnoIogy derived pharmaceuticals products are proteins and peptides, their derivatives and products of which they are components: they can be derived from cell cultures or produced using recombinant DNA technology. Biotechnology products present several particular pharrnacokinetic characteristics vs the conventional pharmaceutical products which have to be taken into account in designing and interpreting results of bioavailability/bioequivalence studies both in animals and in humans. The main aspects are: 1) analytical methods are generally immunomethods, very sensitive but often too variable and not sufficiently specific; HPLC/MS methods are sometimes applicable but their sensitivity for proteinlpeptides is often insufficient and sample preparation can represent a very difficult step 2) bioavailability is sometimes low by extravascular routes (virtually no absorption by oral route) and tiected by high variability; 3) the pharmacological response is often highly species specific 4) biotech products can be immunogenic in animals, limiting the meaning of repeated doses or single doses in crossover studies; 5) many biotech products are endogenous and basal levels/profiles complicate analytics and pk data analysis; 6) the correlation between pharmacokinetics and activity is sometimes unclear and make it necessary to characterise also profiles of PD markers; 7) the selection of the appropriate PD markers can he problematic.