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Additional file 1. Electronic supplementary material.

Supplemental material, sj-pdf-1-opp-10.1177_10781552211019453 for The effect of a Clinical Decision Support System on the frequency of dose adjustments of anticancer drugs in case of renal or hepatic dysfunction by José Rolvink, Anne-Loes E Gerards, Arnon P Kater, Eleonora L Swart and Matthijs L Becker in Journal of Oncology Pharmacy Practice

AIMS: The objectives of the present investigation were: (a) to determine the correlation between lignocaine and midazolam pharmacokinetics following intravenous administration in healthy volunteers, (b) to determine the effects of treatment with an inhibitor of CYP3A4 (erythromycin) on this correlation and (c) to assess the precision of the MEGX-test as a sole predictor of lignocaine and midazolam pharmacokinetics. METHODS: The study was conducted in four male and four female healthy volunteers, aged between 21 and 26 years, who received 1 mg kg-1 lignocaine HCl i.v. on days 1, 3, 5, 9 and 10 of the investigation. On days 5 and 10 they also received midazolam, 0.075 mg kg-1 i.v. and from days 6-10 they took erythromycin 500 mg orally, four times daily. Following administration of lignocaine and midazolam, frequent venous blood samples were obtained for determination of the concentrations of lignocaine, MEGX and midazolam. RESULTS: In the absence of erythromycin a statistically significant linear correlation was observed between the clearance of lignocaine and midazolam (CL(midazolam)= 0.41 x CL(lignocaine)+ 1.2; r(2) = 0.857; P < 0.001). Erythromycin cotreatment resulted in a loss of the correlation between the two clearances (r(2) = 0.39; P = 0.1). Erythromycin caused a statistically significant reduction in midazolam clearance from the original value of 3.8 to 2.5 (95% CI for the difference -2.27, -0.35) ml kg-1 min-1. Interestingly there was no significant change in the clearance of lignocaine (6.4 vs 5.8 (95% CI for the difference -2.74, -1.51) ml kg-1 min-1). Furthermore no correlation at all was observed between the MEGX-test and lignocaine or midazolam clearances. Considering the data on day 1, 3 and 5 the intra-individual coefficient of variation in the MEGX-test was 45.3% at 15 min and 23.5% at 30 min, respectively. CONCLUSIONS: It is concluded that there is a significant correlation between lignocaine and midazolam clearances but this correlation is lost after CYP3A4 inhibition by erythromycin. The MEGX-test is of no value in assessing intra- and inter-individual variability in midazolam clearance.