Generic-reference and generic-generic bioequivalence of forty-two, randomly-selected, on-market generic products of fourteen immediate-release oral drugs

Muhammad M Hammami, Sophia J S De Padua, Rajaa Hussein, Eman Al Gaai, Nesrine A Khodr, Reem Al-Swayeh, Syed N Alvi, Nada Binhashim, Muhammad M Hammami, Sophia J S De Padua, Rajaa Hussein, Eman Al Gaai, Nesrine A Khodr, Reem Al-Swayeh, Syed N Alvi, Nada Binhashim

Abstract

Background: The extents of generic-reference and generic-generic average bioequivalence and intra-subject variation of on-market drug products have not been prospectively studied on a large scale.

Methods: We assessed bioequivalence of 42 generic products of 14 immediate-release oral drugs with the highest number of generic products on the Saudi market. We conducted 14 four-sequence, randomized, crossover studies on the reference and three randomly-selected generic products of amlodipine, amoxicillin, atenolol, cephalexin, ciprofloxacin, clarithromycin, diclofenac, ibuprofen, fluconazole, metformin, metronidazole, paracetamol, omeprazole, and ranitidine. Geometric mean ratios of maximum concentration (Cmax) and area-under-the-concentration-time-curve, to last measured concentration (AUCT), extrapolated to infinity (AUCI), or truncated to Cmax time of reference product (AUCReftmax) were calculated using non-compartmental method and their 90% confidence intervals (CI) were compared to the 80.00%-125.00% bioequivalence range. Percentages of individual ratios falling outside the ±25% range were also determined.

Results: Mean (SD) age and body-mass-index of 700 healthy volunteers (28-80/study) were 32.2 (6.2) years and 24.4 (3.2) kg/m2, respectively. In 42 generic-reference comparisons, 100% of AUCT and AUCI CIs showed bioequivalence, 9.5% of Cmax CIs barely failed to show bioequivalence, and 66.7% of AUCReftmax CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUCT and AUCI CIs and 21.4% of Cmax CIs failed to show bioequivalence. In 42 generic-generic comparisons, 2.4% of AUCT, AUCI, and Cmax CIs failed to show bioequivalence, and 66.7% of AUCReftmax CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUCT and AUCI CIs and 14.3% of Cmax CIs failed to show bioequivalence. Average geometric mean ratio deviation from 100% was ≤3.2 and ≤5.4 percentage points for AUCI and Cmax, respectively, in both generic-reference and generic-generic comparisons. Individual generic/reference and generic/generic ratios, respectively, were within the ±25% range in >75% of individuals in 79% and 71% of the 14 drugs for AUCT and 36% and 29% for Cmax.

Conclusions: On-market generic drug products continue to be reference-bioequivalent and are bioequivalent to each other based on AUCT, AUCI, and Cmax but not AUCReftmax. Average deviation of geometric mean ratios and intra-subject variations are similar between reference-generic and generic-generic comparisons.

Trial registration: ClinicalTrials.gov identifier: NCT01344070 (registered April 3, 2011).

Conflict of interest statement

Ethics approval and consent to participate

The study was conducted according to the ethical guidelines of the Declaration of Helsinki and was approved by the King Faisal Specialist Hospital & Research Center’s Research Ethics Committee (RAC 2101100). All participants provided a written informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Average bioequivalence of randomly-selected generic products to the reference product of 14 immediate-release, non-combinational, oral drugs. Each reference product (R) was compared to 3 generic products (Ga, Gb, Gc). Data represent generic/reference geometric mean ratios and unadjusted 90% confidence intervals. The shaded area indicates the area of bioequivalence (80.00%–125.00%). a Evaluation of area-under-the-concentration-time curve to last measured concentration (AUCT). b Evaluation of area-under-the-concentration-time curve extrapolated to infinity (AUCI). c Evaluation of maximum concentration (Cmax)
Fig. 2
Fig. 2
Average bioequivalence of randomly-selected generic products to the reference product of 14 immediate-release, non-combinational, oral drugs. Each reference product (R) was compared to 3 generic products (Ga, Gb, Gc). Data represent generic/reference geometric mean ratios and unadjusted 90% confidence intervals. The shaded area indicates the area of bioequivalence (80.00%–125.00%). a Evaluation of area-under-the-concentration-time curve to time of maximum concentration of reference product, calculated for each subject (AUCReftmax). b Evaluation of area-under-the-concentration-time curve truncated to 72 h (AUC72). Only 2 drugs (amlodipine and fluconazole) in this study have terminal half-life >72 h
Fig. 3
Fig. 3
Individual pharmacokinetic ratios of randomly-selected generic products to the reference product of 14 immediate-release, non-combinational, oral drugs. Each reference product (R) was compared to 3 generic products (Ga, Gb, Gc). Data represent percentage of individual generic/reference ratios that are 1.25 (open bars). a Evaluation of area-under-the-concentration-time curve to last measured concentration (AUCT). b Evaluation of area-under-the-concentration-time curve extrapolated to infinity (AUCI). c Evaluation of maximum concentration (Cmax)
Fig. 4
Fig. 4
Individual pharmacokinetic ratios of randomly-selected generic products to the reference product of 14 immediate-release, non-combinational, oral drugs. Each reference product (R) was compared to 3 generic products (Ga, Gb, Gc). Data represent percentage of individual generic/reference ratios that are 1.25 (open bars). a Evaluation of time of maximum concentration (Tmax). b Evaluation of area-under-the-concentration-time curve to time of maximum concentration of reference product, calculated for each subject (AUCReftmax)
Fig. 5
Fig. 5
Average bioequivalence among randomly-selected, reference-bioequivalent generic products of 14 immediate-release, non-combinational, oral drugs. Three generic products (Ga, Gb, Gc) were compared. Data represent generic/generic geometric mean ratios and unadjusted 90% confidence intervals. The shaded area indicates the area of bioequivalence (80.00%–125.00%). a Evaluation of area-under-the-concentration-time curve to last measured concentration (AUCT). b Evaluation of area-under-the-concentration-time curve extrapolated to infinity (AUCI). c Evaluation of maximum concentration (Cmax)
Fig. 6
Fig. 6
Average bioequivalence among randomly-selected, reference-bioequivalent generic products of 14 immediate-release, non-combinational, oral drugs. Three generic products (Ga, Gb, Gc) were compared. Data represent generic/generic geometric mean ratios and unadjusted 90% confidence intervals. The shaded area indicates the area of bioequivalence (80.00%–125.00%). a Evaluation of area-under-the-concentration-time curve to time of maximum concentration of reference product, calculated for each subject (AUCReftmax). b Evaluation of area-under-the-concentration-time curve truncated to 72 h (AUC72). Only 2 drugs (amlodipine and fluconazole) in this study have terminal half-life >72 h
Fig. 7
Fig. 7
Individual pharmacokinetic ratios among randomly-selected, reference-bioequivalent generic products of 14 immediate-release, non-combinational, oral drugs. Three generic products (Ga, Gb, Gc) were compared. Data represent percentage of individual generic/generic ratios that are 1.25 (open bars). a Evaluation of area-under-the-concentration-time curve to last measured concentration (AUCT). b Evaluation of area-under-the-concentration-time curve extrapolated to infinity (AUCI). c Evaluation of maximum concentration (Cmax)
Fig. 8
Fig. 8
Individual pharmacokinetic ratios among randomly-selected, reference-bioequivalent generic products of 14 immediate-release, non-combinational, oral drugs. Three generic products (Ga, Gb, Gc) were compared. Data represent percentage of individual generic/generic ratios that are 1.25 (open bars). a Evaluation of time of maximum concentration (Tmax). b Evaluation of area-under-the-concentration-time curve to time of maximum concentration of reference product, calculated for each subject (AUCReftmax)

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