Post-Marketing Safety Reassessment Of Proton Pump Inhibitors

OBJECTIVEAs proton pump inhibitors (PPIs) in clinical application, the post-marketing safety was drawn more and more attention. Omeprozole can be used to prevent blood loss caused by operation, trauma and other factors, which may lead to hypovolemia or microcirculation disturbance in body. Consequently, drug pharmacokinetics may change, which can influence the safety of medicine. This study was performed to compare the risk of adverse drug reaction (ADR) related to PPIs with control drugs for digestive disease in all randomized controlled trials (RCTs). Then this research was to determine the pharmacokinetics of omeprazole in rat hemorrhagic model through establishing high performance liquid chromatography (HPLC), to compare the pharmacokinetics parameters with control group and to decide if omeprazole dosage regimen needs to adjust.METHODS1. Meta-analysis:Adverse drug reaction of PPIsTwo electronic databases (MEDLINE [PubMed] and the Cochrane Controlled Trials Register [CCTR]) were searched from inception to March1,2012. All randomized clinical trials (RCTs) met the inclusive criteria were included. RevMan5.1was used to analysis the extracted data.2. Pharmacokinetics of omeprazole in rat hemorrhagic model2.1. To establish HPLC for determination omeprazole in rat plasma Chromatographic column:Hypersil BDS C18column (4.6mm×150mm,5μm); mobile phase:PBS-acetonitrile=70:30; wavelength:302nm; flow rate:1.0mL·min-1; column temperature:25℃; sensitivity:0.01AUFS; sample size:20μL. Methodology was validated.2.2. Pharmacokinetic experiment32rats were randomized divided into four groups:control group (A group), hemorrhage10%group (B group), hemorrhage20%group (C group) and hemorrhage30%group (D group), and8for each group. Except control group, the other three groups were draw50%corresponding group blood from sinus jugularis.15min later, the left50%blood was draw. After hemorrhage model was conducted, all rats were administrated with omeprazole (10mg·kg-1) by tail vein injection, and draw blood at0,1,5,15,30,60,90,120min. Plasma concentration of omeprazole was determined by HPLC and pharmacokinetics parameters were calculated by DAS ver2.0and/test.RESULTS1. Meta-analysis10studies including3265persons met the inclusion criteria. There were1675persons receiving PPIs and1586persons receiving control drugs. Diarrhea, headache, nausea, vomiting and sleepiness were the most common ADR occurring in the PPIs therapy. When we pooled ADR data, there was no significant difference (RR=0.91;95%CI,0.53-1.56;P0.73) between PPIs and control drugs, with no significance heterogeneity (I2=36%, P=0.12). Also, the subgroup analysis according to difference ADRs was no significant difference.2. Methodology validationIn this method, the peak shape of omeprazole and internal standard substance carbamazepine was good. Impurity peak in plasma didn’t interfere with the sample determination. In0.102μg·mL-1～30.6μg·mL-1omprazole had a good linear relationship. The lower limit of quantitation accurancy, intra-and inter-batch precision, extraction recovery, methods recovery, room temperature stability, repeated freeze-thaw stability, short-term frozen storage stability were met the standard of pharmacokinetics concentration measurement method.3. Pharmacokinetics parameters and statistics testThe main pharmacokinetics parameters were area under the concentration-time curve AUC0-t(mg·min·L-1), AUC0-∞(mg·min·L-1), mean residence time MRT0-t(min), MRT0-∞(min), half-time t1/2(min), clearance rate CL(L·min-1·kg-1) and apparent volume of distribution V(L·kg-1). Compared with control group, all pharmacokinetics parameters of B group had no significant difference (P>0.05). MRT0-t, MRT0-∞and t1/2of C group were longer than control group (P<0.01), and the left parameters had no significant difference (P>0.05). MRT0-t, MRT0-∞and t1/2of D group were longer and the parameter V was larger than control group (P <0.01). The left parameters of D group have no significant difference (P>0.05).CONCLUSIONS1. This analysis indicated that PPIs therapy didn’t increase the risk of ADRs compared with control groups. When selecting PPIs therapy, we should strictly master the indication, use the lowest effective dose as far as possible, avoid unnecessary long-time therapy and determine if the risks outweigh the gain.2. The omeprazole in vivo determination method was specific, with good stability and high recovery, can be used to determine omeprazole plasma concentration.3. After administrated with omeprazole by tail vein injection, omeprazole was eliminated rapidly in rat body. Pharmacokinetic process accorded with two compartment model by pharmaceutical kinetics software DAS2.0.4. When body lost less than10%blood, pharmacokinetic parameters had no significant difference, so there was no necessary to adjust omeprazole dosage regimen. When body lost more than20%blood, some pharmacokinetic parameters such as MRTo-t, MRT0-∞and t1/2changed, which suggested that dosage regimen of omeprazole may need adjustment to ensure safety and effectiveness.