ABSTRACT
BACKGROUND: Manufacturing of and medication with generic drugs is increasing around the world. Bioequivalence (BE) studies are being performed routinely by Contract Research Organisations (CROs) in Turkey. However, an overall evaluation for the attended volunteers, examined Active Pharmaceutical Ingredients (APIs) and the observed adverse events have not been studied in the field. OBJECTIVE: Our aim was to revisit and compile the BE studies carried out between the years 2000-2013 of a CRO (N-CRO) in Turkey. METHODS: A dataset of 261 BE studies has been created for the observed adverse events with regards to the frequency, type, and drug subgroups. As an advanced evaluation, the Gini Index method has been used in the 63 available BE studies to obtain split points for two pharmacokinetic parameters, area under the plasma/serum concentration (AUC) and maximum plasma/serum concentration (Cmax), in order to investigate their likely effect on the adverse events. RESULTS: Thousand six hundred and forty two adverse events were found in the 261 BE studies involving 7828 volunteers with the frequency of 6.29 per study and 0.21 per volunteer. The most frequently observed adverse events were; headache, somnolence, nausea, dizziness and vomiting, respectively. Hundred and nine different APIs were observed. 'Genitourinary system and sex hormones' subgroup drugs had the highest frequency of the adverse events. Adverse event frequencies above the identified split points for Cmax and AUC values were higher than the frequencies below them. CONCLUSION: The review of 13 years period of BE studies revealed that the demographic properties of the volunteers and the study designs were in compliance with national and international guidelines. The promising outcome could be showing the increase of the adverse event frequencies above the obtained split points as the reflection of the likely individual pharmacokinetic differences in the adverse event occurence.
ABSTRACT
One of the crucial adverse effects of chronic kidney disease (CKD) and its treatment is an elevated cancer risk. There are no data on cytogenetic effects in children with CKD or children undergoing dialysis or those who have received a transplant. In this study, cytogenetic effects in children with CKD in pre-dialysis (PreD) stage, on regular haemodialysis (HD) and transplanted (Tx) compared with a control group of healthy children has been investigated using the cytokinesis-blocked micronucleus (CBMN) assay and fluorescence in situ hybridisation (FISH) combined with CBMN (CBMN-FISH) in peripheral blood lymphocytes. The results revealed a significant increase (P < 0.001) in micronucleus (MN) frequencies [mean ± SD (n)] in the PreD, HD and Tx groups versus the control group [CBMN assay; 9.19 ± 2.61 (16), 9.07 ± 4.86 (15), 6.12 ± 5.33 (17) versus 1.60 ± 0.99 (20), respectively]. Moreover, centromere negative micronucleus (C- MN) and centromere positive micronucleus (C+ MN) frequencies were significantly higher in each subgroup children (PreD, HD and Tx) than in the control group (P < 0.01) although children in Tx group had lower C- MN frequencies than PreD and lower C+ MN frequencies than PreD and HD groups (P < 0.05). Additionally, MN frequencies in mononuclear cells, nucleoplasmic bridges and nuclear buds in binucleated cells were increased in children with CKD (P < 0.001, P < 0.001, P > 0.05, respectively). The nuclear division index significantly decreased in Tx group relative to the control, PreD and HD groups (P < 0.001). Associations between cytogenetic parameters and creatinine or blood urea nitrogen were found (P < 0.05). To provide longer and better life expectancy of children with CKD and treatment modes, further research is needed to better understand and avoid these effects.
