Relating Pharmacokinetics and Pharmacodynamics of Proton Pomp Inhibitors (PPIs) to Clinical Performance in Patients with Gastroesophageal Reflux Disease (GERD)
D.S. Bordin, T.S. Kozhurina, S.Yu. Silvestrova, V.N. Drozdov, E.R. Valitova, A.A. Masharova, A.V. Petrakov
Central Research Institute of Gastroenterology, Moscow, Russian Federation
Objectives: The aim of the study was to estimate pharmacokinetic (PK) parameters of PPIs after a single oral dose and repeated dosing and to evaluate the relationship between PK, pharmacodynamic (PD) and clinical efficacy parameters in GERD patients.
Methods: PK, PD and clinical efficacy data were prospectively collected in 66 GERD patients (median age 38.9 years, male 79%). At baseline, in all patients, GERS symptoms (heartburn and acid regurgitation) were scored, upper gastrointestinal endoscopy and 24-h intraesophageal pH monitoring were performed. Then the patients were randomized into 3 treatment groups: omeprazole 20 mg twice a day, lansoprazole 30 mg once a day and pantoprazole 40 mg once a day. The patients underwent pH- and PK- monitoring at day 1 and at day 7 of PPI therapy. Sampling schedule for PK study was the following: baseline (predose), then every half an hour up to 4 h postdose, 5, 6 and 12 h postdose. The PK parameters – AUC, Tmax, Cmax, kel have been estimated from measured plasma concentration profiles via non-compartment approach. Every day, the patients assessed intensity of GERD symptoms according to the Likert scale in their diaries.
Results: 25 patients were enrolled in omeprazole group, 22 received pantoprazole and 19 – lansoprazole. The PK analysis showed that, in average, at day 1 compared to day 7, patients in the omeprazole group had a significant increase in AUC and Cmaxvalues, on the contrary, patients in other groups had similar mean AUC and Cmax values on single and repeated dosing. Pantoprazole group showed the biggest mean AUC value. Initially, individual values of DeMeester score and of percent of time with pH in esophagus <4 were abnormal in all patient groups. After the first PPI dose, a statistically significantly change in these parameters was not observed, but at day 7, in responders, DeMeester scores and times with pH<4 were in normal range. In these patients, we have seen a rapid relief of GERD symptoms till day 7. We compared also PD and clinical efficacy parameters in patients with the various pattern of PK profiles.
Conclusions: A wide interindividual variability in PK parameter values was observed in all groups. AUC after oral dosing was the PK parameter that is the best predictor of antisecretory effect. The bioavailability of omeprazole increased during the first 7 days of oral dosing. The biggest pantoprazole average AUC value can probably explain the superior efficacy at its usual use.