A comparison of the intrasubject variation in drug exposure between generic and brand-name drugs: a retrospective analysis of replicate design trials

Abstract

Aims: The aim of the present study was to investigate whether differences in total and peak drug exposure upon generic substitution are due to differences between formulations or to intrasubject pharmacokinetic variability of the active substance.

Methods: The study was designed as a retrospective reanalysis of existing studies. Nine replicate design bioequivalence studies representing six drug classes - i.e. for alendronate, atorvastatin, cyclosporin, ebastine, exemestane, mycophenolate mofetil, and ropinirole - were retrieved from the Dutch Medicines Regulatory Authority.

Results: In most studies, the intrasubject variability in total and peak drug exposure was comparable for the brand-name [in the range 0.01-0.24 for area under the concentration-time curve (AUCt ) and 0.02-0.29 for peak plasma concentration (Cmax ) on a log scale] and generic (0.01-0.23 for AUCt and 0.08-0.33 for Cmax ) drugs, and was comparable with the intrasubject variability upon switching between those drugs (0.01-0.23 for AUCt and 0.06-0.33 for Cmax ). The variance related to subject-by-formulation interaction could be considered negligible (-0.069 to 0.047 for AUCt and -0.091 to 0.02 for Cmax ).

Conclusion: In the investigated studies, the variation in total and peak exposure seen when a patient is switched from a brand-name to a generic drug is comparable with that seen following repeated administration of the brand-name drug in the patient. Only the intrasubject variability seems to play a crucial and decisive role in the variation in drug exposure seen; no additional formulation-dependent variation in exposure is observed upon switching. Thus, our data support that, for the medicines that were included in the present investigation, from a clinical pharmacological perspective, the benefit-risk balance of a generic drug is comparable with that of the brand-name drug.

Keywords: bioequivalence study; generic drugs; intrasubject variability.

Figure 1

Individual illustrative atorvastatin plasma concentration–time curves for the brand‐name and generic formulations in a single subject in the replicate design bioequivalence study (t = 24 h) on an arithmetic scale (A) and in a semi‐logarithmic plot (B). ‘T1’ and ’T2’ represent the first and the second administration of the generic atorvastatin drug to the subject. The plasma concentration (y‐axis) at every sampling time (x‐axis) is shown; ‘R1’ and ‘R2’ represent the first and the second administration of the brand‐name formulation of atorvastatin. The mean predose level for each formulation is indicated at time = 0

Figure 2

Intrasubject variability in the total amount of unchanged active substance excreted in the urine (T_Ae) and the maximum rate of drug excretion (R_max) seen with brand‐name and generic formulations of alendronate (10 mg) in a replicate design bioequivalence study (n = 26). (A) Distribution of T_Ae in the trial population after administration of the brand‐name or generic formulation of alendronate (R1, R2, T1 or T2); lines indicate the T_Ae levels per subject. (B) Difference plots for the ln‐transformed treatment ratios for T_Ae (T1 : R1, T2 : R2 and T1 : T2), corrected by the brand‐name drug ratios (R1 : R2) in individuals. (C) Difference plots for the ratios corrected by the generic drug ratios (T1 : T2). (G) Correlation of the generic ratios (y‐axis) and the brand‐name ratios (x‐axis) for T_Ae on a logarithmic scale. (H) Correlation of generic : brand‐name ratios (T1 : R1 and T2 : R2) after the first and second drug administration. (D, E, F, I and J) Graphs of R_max in the same sequence for T_Ae. Intrasubject variability based on the other eight bioequivalence studies is shown in Supplementary Figures S1–3