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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 (C max ) and area-under-the-concentration-time-curve, to last measured concentration (AUC T ), extrapolated to infinity (AUC I ), or truncated to C max  time of reference product (AUC Reftmax ) 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/m 2 , respectively. In 42 generic-reference comparisons, 100% of AUC T  and AUC I  CIs showed bioequivalence, 9.5% of C max  CIs barely failed to show bioequivalence, and 66.7% of AUC Reftmax  CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUC T  and AUC I  CIs and 21.4% of C max  CIs failed to show bioequivalence. In 42 generic-generic comparisons, 2.4% of AUC T , AUC I , and C max  CIs failed to show bioequivalence, and 66.7% of AUC Reftmax  CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUC T  and AUC I  CIs and 14.3% of C max  CIs failed to show bioequivalence. Average geometric mean ratio deviation from 100% was ≤3.2 and ≤5.4 percentage points for AUC I  and C max , 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 AUC T  and 36% and 29% for C max .    Conclusions  On-market generic drug products continue to be reference-bioequivalent and are bioequivalent to each other based on AUC T , AUC I , and C max  but not AUC Reftmax . 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).    Electronic supplementary material  The online version of this article (doi:10.1186/s40360-017-0182-1) contains supplementary material, which is available to authorized users.

bmc pharmacology and toxicology

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