Within-subject pharmacokinetic variability has a strong influence on individual exposure ratios in bioequivalence studies, hence on drug formulation interchangeability.
Summary: Introduction: Bioequivalence between a reference and a generic drug is based on the hypothesis that a ± 20% change in blood exposure (or ± 10% for drugs with narrow therapeutic index, NTI) following the generic/reference switch will not have any therapeutic consequences. However, the indivi...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 79; no. 11; pp. 1565 - 1579 |
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| Autores principales: | , , , |
| Formato: | equations & formulas research tables/charts Journal Article |
| Publicado: |
Springer Nature
Nov2023
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=173366725&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 173366725 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Nov2023 vid: 79 iid: 11 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 173366725 172269519 173366725 173366725 10.1007/s00228-023-03565-6 173366725 ppf: 1565 ppct: 14 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Within-subject pharmacokinetic variability has a strong influence on individual exposure ratios in bioequivalence studies, hence on drug formulation interchangeability. aug: au: Lechat, Philippe Kir, Fatma Marquet, Pierre Woillard, Jean-Baptiste affil: https://ror.org/05f82e368 Paris-cité University, Paris, France sug: subj: Drugs, Prescription Pharmacokinetics Drugs, Generic Pharmacokinetics Chemistry, Pharmaceutical Human Blood Crossover Design Descriptive Statistics Confidence Intervals Chronic Disease Drug Therapy Simulations Data Analysis Software Analysis of Variance ab: Summary: Introduction: Bioequivalence between a reference and a generic drug is based on the hypothesis that a ± 20% change in blood exposure (or ± 10% for drugs with narrow therapeutic index, NTI) following the generic/reference switch will not have any therapeutic consequences. However, the individual exposure ratio between generic and reference can be higher than 1.20 (or 1.10). This study aims to analyse the different parameters influencing the individual exposure ratio, hence the conditions for reference/generic interchangeability. Methods: Bioequivalence studies with a double cross-over design for a virtual drug were simulated using 100 random sets of 12, 24, 48 or 100 pairs of areas under the curve (AUC), varying the generic/reference AUC geometric mean ratios between 0.80 and 1.25 and the within-subject exposure variance of the reference and the generic formulations. Results: The proportion of subjects with an exposure generic/reference ratio outside the ± 10% or ± 20% acceptance intervals increases when (1) the reference within-subject variance increases; (2) the ratio of the generic within-subject variance on the reference within-subject variance increases; and (3) the generic/reference mean AUC ratio diverges from 1.0. When only considering replicated administrations of the reference, the individual exposure ratio increases with the within-subject variance, yielding values outside the usually accepted individual exposure ratio range of 0.5 to 2 for drugs with narrow therapeutic index as soon as the within-subject variance standard deviation is ≥ 0.25 (equivalent to within-patient CV% > 25%). Conclusions: Interchangeability between reference and generic formulations, especially for drugs with narrow therapeutic index can only be assumed if, the within-subject variance of generic is less or equal to the within-subject variance of reference or, if this is not the case, if the distribution of the generic/generic individual exposure ratios is included within the therapeutic margins of the reference drug. pubtype: Academic Journal doctype: equations & formulas research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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