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David Flockhart

Publications and source records attributed to David Flockhart.

5 recordsLinked to original sources
PubMed2004

QT analysis: a complex answer to a 'simple' problem.

Prolongation of the QT interval on a surface electrocardiogram is a biomarker for a potentially life-threatening arrhythmia. It is used by drug developers and regulatory agencies as a measure of drug safety. Heart rate or RR interval (the inverse of heart rate) correction of the QT interval is necessary because of the QT interval shortening that accompanies physiologic decreases in the RR interval. When a drug alters the RR interval, it is important to distinguish a QT change that is due to a drug effect versus an artefact of a heart rate change. A two-step off-drug subject-specific QT correction analysis is discussed. At the first step, a linear mixed model based only on the placebo (off-drug) RR/QT data produces a correction coefficient that can be applied to a generic formula, and QT intervals are corrected for heart rate on both placebo and treatment period data using that formula. At step two, the heart rate corrected QT interval (QTc) is then compared between placebo and treatment groups at a pre-specified heart rate (usually 60 bpm) based on another linear mixed model. This two-step QT analysis implicitly assumes the slope of log(QT) versus log(RR) is unchanged by drug. Practically, it is important to understand how much this assumption can bias the QT prolongation estimates if it is not valid. We propose a one-step off-on-drug subject-specific QT correction analysis that would pool placebo and treatment period RR/QT data and derive different subject specific coefficients for the treatment and placebo data based on a linear mixed model, which can avoid the unchanged slope assumption. It is also a known unbiased and the most efficient method. The applications of both methods are demonstrated through the QT analysis of haloperidol, a neuroleptic known to prolong QTc. Both theoretical and empirical results show that, although the two-step off-drug QT correction analysis is biased, the bias is small in the case of haloperidol (0.1-0.2 ms). The two-step off-drug QT correction analysis is shown to be almost as efficient as our one-step off- and on-drug QT analysis.

Adult↗
PubMed2004

Intramuscular haloperidol or lorazepam and QT intervals in schizophrenia.

The objective of this study was to estimate the effects of intramuscular haloperidol and lorazepam on the QT interval in volunteers with schizophrenia. Intramuscular haloperidol and intramuscular lorazepam are standard treatments in the acute management of agitation and aggression. Although prolongation of the QT interval and sequelae, including torsade de pointes and death, have been reported for haloperidol (but not lorazepam), formal studies have been lacking. Volunteers with schizophrenia (n = 12) were administered a single intramuscular injection of 7.5 mg haloperidol or 4 mg lorazepam in a blinded, randomized, placebo-controlled crossover design. Serial EKGs and concurrent blood samples were obtained over 6 hours following each injection. Changes in the QT interval were evaluated, as were plasma drug and prolactin concentrations. Haloperidol injection increased the heart rate-corrected QT interval an average of 5.1 msec using Bazett's correction (QTb 90% confidence interval [CI]: 0.3, 9.8), 3.6 msec using Fridericia's correction (QTf 90% CI: 0.02, 7.2), and 4.2 msec using an empirically derived "baseline correction" (QT(ii) 90% CI: 0.3, 8.0). Effects of lorazepam on QT were nullified by correction for the heart rate elevation (QTb 3.8 msec, 90% CI: 0.6, 7.1; QTf 0.0 msec, 90% CI: -3.2, 3.4; QTii -2.3 msec, 90% CI: -6.6, 2.0). An association between QT prolongation and occurrence of extrapyramidal symptoms was observed. On average, intramuscular haloperidol led to minimal prolongation of the QT interval. This propensity is of theoretical concern in individuals with risk factors for torsade de pointes but seems unlikely to be a problem in the vast majority of patients.

Adult↗
PubMed2003

Variability of heart rate correction methods for the QT interval.

AIMS: To compare variability of heart rate-corrected QT intervals (QTc) using three different methods in a study of low-dose oral haloperidol. METHODS: In a randomized, double-blind, placebo-controlled, crossover trial, we studied QT interval pharmacodynamics of single doses of oral haloperidol (10 mg) in 16 healthy subjects. Heart rate correction of the QT interval was performed using Bazett's, Fridericia's and subject-specific correction methods. The subject-specific correction was performed using linear mixed modelling of placebo period QT vs RR data from each study subject. RESULTS: The subject-specific correction, in the form of QTc = QT/RRalpha, yielded a correction term alpha (slope of the log-transformed QT vs RR relationship) that ranged from 0.23 to 0.38 in individual subjects, i.e. the fixed correction term alpha = 0.5 of Bazett's correction was outside and the fixed correction term alpha = 0.33 of Fridericia's correction inside the range of individual values. The mean absolute slope of the QTcvs RR regression line using the subject-specific correction was significantly lower than the mean slopes obtained using either Bazett's or Fridericia's corrections. All three methods revealed a statistically significant greater mean QTc on haloperidol than on placebo at 10 h post-drug administration. The mean QT (95% CI) was 421.6 (410.8, 432.4), and 408.4 (398.6, 417.8) on haliperidol and placebo, respectively, using the subject-specific correction method (P = 0.0053). The mean QTc (95% CI) was 425.4 (414.3, 436.5) and 403.1 (394.3, 411.9) on haliperidol and placebo, respectively, using Bazett's correction (P = 1.7 x 10-5) and 423.1 (412.6, 433.6) and 408.2 (398.6, 417.8) on haliperidol and placebo, respectively, using Fridericia's correction (P = 7.7 x 10-4). Raw P-values were calculated using a paired t-test. Bonferroni-corrected P-values were calculated by multiplying the raw P-values by 13. CONCLUSION: Haloperidol caused a statistically significant mean QTc prolongation using the three correction methods. The QTc intervals were less dependent on RR intervals using the subject-specific method, thus decreasing the possibility of over- or under-correction. The interindividual QTc changes from baseline varied significantly depending on the method of correction used.

Administration, Oral↗