Domperidone safety: a mini-review of the science of QT prolongation and clinical implications of recent global regulatory recommendations.

AIMS: In New Zealand, domperidone is approved for gastrointestinal motility and nausea and vomiting. The European Medicines Agency (EMA) recently concluded that domperidone poses a significant risk of sudden cardiac death (SCD) and has restricted use in Europe. This paper reviews the risk of QT prolongation and cardiac adverse effects with domperidone and provide information to allow prescribers to make informed decisions on usage. METHODS: A search of two bibliographic databases, the European Medicines Agency (EMA) website, Micromedex, Lexicomp and reference texts was undertaken for domperidone related reports of QT prolongation, cardiac arrhythmias and/or SCD. The New Zealand Centre for Adverse Drugs Reaction Monitoring was also contacted for cardiac adverse event reports with domperidone. RESULTS: Over 30 published papers, EMA documents and other information sources were collated, including two studies that met thorough QT study (TQT) criteria (ICH-E14). The first TQT1 was negative while the second was marginally positive. Reports of QT prolongation, ventricular arrhythmias and SCD were located (predominantly high/very high-dose IV domperidone). With oral domperidone, a Dutch case-controlled study reported an adjusted odds ratio of SCD of 11.4 (95% CI 1.99-65.2), based on only three patients out of 1,366 cases of SCD. A second nested case-controlled study calculated an odds ratio of ventricular arrhythmia or SCD of 1.59 (1.28-1.98) vs. placebo. DISCUSSION: Based on the results of the two TQT (the regulatory agency gold standard for assessment of QT prolongation) domperidone does not appear to be strongly associated with QT prolongation at oral doses of 20 mg QID in healthy volunteers. Further, there are limited case reports supporting an association with cardiac dysfunction, and the frequently cited case-control studies have significant flaws. While there remains an ill-defined risk at higher systemic concentrations, especially in patients with a higher baseline risk of QT prolongation, our review does not support the view that domperidone presents intolerable risk.

Gentamicin and renal function: lessons from 15 years' experience of a pharmacokinetic service for extended interval dosing of gentamicin.

BACKGROUND: Extended interval dosing (EID) of gentamicin most commonly involves dosing every 24 hours, but patients with impaired renal function may require a longer dose interval. This study examines a large database of patients treated with gentamicin from 1996 to 2010 to see how many patients with renal impairment would have benefited from dose intervals >24 hours and to define the incidence of nephrotoxicity. METHODS: All patients aged ≥ 16 years who had received gentamicin by EID over the 14-year period and had concentration data available were examined. End points included the numbers (%) achieving the target peak concentration [predicted maximum gentamicin concentration (C(max))] >10 mg/L, the target trough concentration at 24 hours [predicted minimum gentamicin concentration (C(min24)] <0.5 mg/L, and the target area under the curve over 24 hours of 70-100 mg/L · h. How these related to various creatinine clearance (CL(cr)) groupings was also examined, as was the number who developed nephrotoxicity (increase in creatinine of ≥ 0.04 mmol/L). RESULTS: After exclusions, information was available on 4523 patients. Of these, 96% achieved the target C(max), 83% the target C(min24), and 54% the target area under the curve over 24 hours. Of the 73% of patients with CL(cr) ≥ 60 mL/min, 98% and 97% achieved the target Cmax and C(min24), respectively. Of the 19% of patients with CL(cr) of 40-59 mL/min, 94% and 61% achieved the target C(max) and C(min24), respectively. Of the 8% of patients with CL(cr) of 20-39 mL/min, 83% and 15% achieved the target Cmax and C(min24), respectively. Nephrotoxicity, "probably" because of gentamicin, was observed in approximately 4% of the patients studied, which was irreversible in 25% of these (ie, 1% overall). CONCLUSIONS: Extending the dose interval of gentamicin to >24 hours is useful in patients with renal impairment to achieve the aims of EID. These results support initial dose intervals for gentamicin of 24, 36, and 48 hours for patients with CL(cr) ≥ 60, 40-59, and 20-39 mL/min, respectively. Irreversible nephrotoxicity was observed in approximately 1% of the patients studied.

Thirteen years' experience of pharmacokinetic monitoring and dosing of busulfan: can the strategy be improved?

BACKGROUND: A busulfan concentration monitoring and dosing service has been provided by Christchurch Hospital since 1998. This study aimed to see (1) the percentage of patients with an area under the concentration time curve (AUC) outside the target range and had dose adjustment, (2) how busulfan clearance (CL) relates to body weight, and (3) if fewer samples could be used to predict doses. METHODS: Blood samples were taken from patients after oral administration, usually at 0.5, 1, 1.5, and 6 hours, and after the start of a 2-hour intravenous (IV) infusion of busulfan, at 1, 2, 2.5, 3, 6, and 8 hours. Dose adjustment was made based on the AUC compared with the target range. The relationship of CL and body weight for the IV group was used to develop a revised IV dosing schedule. The bias and imprecision of AUCs estimated using fewer sampling points were examined to see if sampling could be economized. RESULTS: Data were available for 150 patients but for 6 patients, data were incomplete and excluded. Of the remaining 144 patients (256 sample sets, 209 oral, 47 IV, 62% with repeats), 38% (IV) and 35% (oral) of patients had AUCs within the target range after the first dose. Dose adjustment was made in 47% and 34% of patients dosed IV and orally, respectively, after which there was a trend to more patients achieving the target AUC. A nonlinear relationship was found between CL and body weight. The initial IV dosing schedule was revised to take this into account. Sampling for busulfan concentration measurement at 3 points (2.5, 4, 8 hours) or 2 points (2.5, 8 hours) after the start of the infusion enabled accurate and precise estimates of AUC0₋24. CONCLUSIONS: Around two thirds of patients treated with busulfan were outside the target AUC range after the first dose. Dose adjustment was made in 37% of patients. The relationship between CL and body weight was used to revise the initial IV dosing schedule. Sampling for AUC estimation could be reduced to 2 time points after IV dosing.