The benefits of a pharmacy-based, active therapeutic drug monitoring (TDM) service (ATM) on outcomes were examined in a prospective study at four hospitals. ATM involved pharmacokinetic dosage optimization at the start of treatment, subsequent Bayesian adaptive control, and frequent patient evaluation. Cost-effectiveness was calculated based on real costs. The ATM group comprised 105 patients and 127 patients with nonguided TDM who were followed up as controls. Forty-eight of the ATM and 62 of the nonguided TDM patients had an infection on admission. Peak concentrations in ATM patients were significantly higher (10.6+/-2.9 mg/L; nonguided TDM, 7.6+/-2.2 mg/L; p < 0.01). Trough levels in the ATM group were significantly lower (p < 0.01). There was a trend toward lower mortality in the ATM group (nine of 105 versus 18 of 127; p = 0.26) that was significant for patients with an infection on admission (one of the 48 ATM patients died versus nine of the 62 nonguided TDM patients; p = 0.023). ATM reduced the length of hospital stay for all patients in the study (20.0+/-1.4 days; nonguided TDM, 26.3+/-2.9 days; p = 0.045) and for patients admitted with an infection (12.6+/-0.8 days; nonguided TDM, 18.0+/-1.4; p < 0.001). The incidence of nephrotoxicity was reduced from 13.4% (nonguided TDM) to 2.9% (p < 0.01). With ATM, total costs were lower for all patients (Dutch guilders [DFL], 13,125+/-9,267; nonguided TDM, DFL 16,862+/-17,721; p < 0.05) and for patients admitted with an infection (DFL 8,883+/-3,778; nonguided TDM, DFL 11,743+/-7,437; p < 0.01). Goal-oriented, model-based dosing of aminoglycosides resulted in higher antibiotic efficacy, shorter hospitalization, and reduced incidence of nephrotoxicity. By combining efficacy with savings, ATM offered a significant alternative to usual care.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The influence of CYP2C19 on the kinetics and dynamics of omeprazole, lansoprazole and rabeprazole has been studied in Japanese subjects. • It has been suggested that subjects with *1/*1 genotype might need stronger acid suppression than *1/*2 and *2/*2 subjects. This suggestion comes from data in Japanese subjects and has not been confirmed in Caucasians. • Furthermore, a novel CYP2C19 mutation, *17, which mainly occurs in Caucasians has been discovered. This mutation has been associated with clinical failure, but its relevance for therapy with PPIs has not been studied yet. WHAT THIS STUDY ADDS • In this study, the influence of CYP2C19 on both the pharmacokinetics and dynamics in Caucasian subjects after single and repeated dosing has been investigated. • This is the first study showing that Caucasian subjects with *1/*1 and *1/*17 mutations need stronger acid‐inhibition. In this study three proton pump inhibitors (omeprazole, lansoprazole and pantoprazole, in different doses) were studied of which pantoprazole had not been studied before in this setting, not even in Japanese. AIMS To investigate the impact of CYP2C19 mutations *2‐*6 and *17 on acid‐inhibition and pharmacokinetics of lansoprazole (L15), omeprazole (O10, O20) and pantoprazole (P40) in Caucasians. METHODS CYP2C19 genotyping for *2–*6 and *17 mutations was assessed in subjects who were H. pylori negative in two randomized crossover trials. The influence of CYP2C19 mutations on single and repeated administration of L15 and O10 (study A) and O20 and P40 (study B) was investigated. Pharmacokinetics and the cumulative percentage of time with intragastric pH above 4 (% > pH 4) were assessed on day 1 and 6. RESULTS For study A CYP2C19 genotyping found five *1/*1, four *1/*2, one *1/*17 and one *2/*17. For study B the results were six *1/*1, two *1/*2, six *1/*17, one *2/*2 and one *2/*17. For all PPIs AUC was highest in *2/*2 and lowest in *1/*17. On day 1, all PPIs significantly increased percentage >pH 4 compared with baseline. *1/*1 genotype showed no significant acid‐inhibition after L15, O10 and O20. *1/*17 genotype showed no significant acid‐inhibition after O20 and P40. *1/*2 genotype showed significant acid‐inhibition after L15 and O10. On day 6, all four PPIs showed significantly increased acid‐inhibition. *1/*1 and *1/*17 showed a significantly increased percentage > pH 4 after treatment with O20 and P40. However, in *1/*1 subjects percentage > pH 4 was not significantly increased after L15 and O10. *1/*2 genotype showed a significant acid‐inhibitory effect after repeated dosing with L15 and O10. CONCLUSIONS Caucasian subjects with *1/*1 and *1/*17 genotype need stronger acid‐suppression therapy, especially during the first days of treatment or with on‐demand therapy.

SUMMARY BackgroundEsomeprazole and pantoprazole are metabolized in the liver and the polymorphic CYP2C19 enzyme is involved in that process. This genetic polymorphism determines fast (70% of Caucasians), intermediate (25-30% of Caucasians) and slow (2-5% of Caucasians) metabolism of PPIs.

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SUMMARY BackgroundThe occurrence and the clinical relevance of rebound acid hypersecretion after discontinuation of proton pump inhibitors is unclear.