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

• Published in: BMC pharmacology & toxicology 2017-12, Vol.18 (1), p.78-20, Article 78
• Main Authors: Hammami, Muhammad M, De Padua, Sophia J S, Hussein, Rajaa, Al Gaai, Eman, Khodr, Nesrine A, Al-Swayeh, Reem, Alvi, Syed N, Binhashim, Nada
• Format: Article
• Language: English
• Subjects: Generic drugs; Oral medication
• ISSN: 2050-6511; 2050-6511
• DOI: 10.1186/s40360-017-0182-1

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. 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 ) and area-under-the-concentration-time-curve, to last measured concentration (AUC ), extrapolated to infinity (AUC ), or truncated to C time of reference product (AUC ) 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. 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 , respectively. In 42 generic-reference comparisons, 100% of AUC and AUC CIs showed bioequivalence, 9.5% of C CIs barely failed to show bioequivalence, and 66.7% of AUC CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUC and AUC CIs and 21.4% of C CIs failed to show bioequivalence. In 42 generic-generic comparisons, 2.4% of AUC , AUC , and C CIs failed to show bioequivalence, and 66.7% of AUC CIs failed to show bioequivalence/showed bioinequivalence. Adjusting for 6 comparisons, 2.4% of AUC and AUC CIs and 14.3% of C CIs failed to show bioequivalence. Average geometric mean ratio deviation from 100% was ≤3.2 and ≤5.4 percentage points for AUC and C , 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 and 36% and 29% for C . On-market generic drug products continue to be reference-bioequivalent and are bioequivalent to each other based on AUC , AUC , and C but not AUC . Average deviation of geometric mean ratios and intra-subject variations are similar between reference-generic and generic-generic comparisons. ClinicalTrials.gov identifier: NCT01