Download 15. Drug-Induced Torsade de Pointes

I.
II.
III.
Normal QT duration
A. QT modifying factors
1.
Normal QT decreases with increasing Heart Rate
2.
QT is longer in leads V2 and v3
B.
Calculation of QTc or corrected QT (Bazett's Formula)
1.
QTc = QT/(sqrt RR Interval)
2.
QTc is normally <0.44
C.
Approximation of normal QT
1.
QT interval shortens with decreasing RR Interval
2.
QT = 0.5 x preceding RR Interval (if normal rate)
3.
Approximate normal QT Interval
a.
QT <= 0.40 if Heart Rate 70 bpm or less
b.
Subtract 0.02 sec for every 10 bpm over 70
c.
Example: Normal QT < 0.34 if Heart Rate 100
D. Heart Rate determined QT
1.
115 - 84 bpm: QT 0.30 to 0.37 seconds
2.
83 - 72 bpm: QT 0.32 to 0.40 seconds
3.
71 - 63 bpm: QT 0.34 to 0.42 seconds
4.
62 - 56 bpm: QT 0.36 to 0.43 seconds
5.
55 - 45 bpm: QT 0.39 to 0.46 seconds
Prolonged QT
A. Congestive Heart Failure
B.
Myocardial Infarction
C.
Hypocalcemia
D. Hypomagnesemia
E.
Type I Antiarrhythmic drugs
F.
Rheumatic Fever
G. Myocarditis
H. Congenital Heart Disease
Shortened QT
A. Digoxin (Digitalis)
B.
Hypercalcemia
C.
Hyperkalemia
D. Phenothiazines
5. Electrocardiograms
5.1. What is measured by an electrocardiogram?
When cells depolarize, they become positively charged with respect
to their non-depolarized neighbors. The positive charge can be measured
as a positive voltage between points on the surface close to the affected
cells and points on the surface farther away.
Body-surface measurements can detect electrical activities of nerves
and skeletal muscles, but when a subject is at rest and leads are
appropriately placed, the body's dominant electrical activity is that of the
heart. The electrocardiogram (ECG, but sometimes appearing as EKG
from the German) records the change over time in surface voltages
arising in the heart.
5.2. What is the electrocardiographic appearance of a typical cardiac beat?
This drawing is adapted from Netter FH, The CIBA Collection of
Medical Illustrations: Heart (Summit, NJ: CIBA Pharmaceutical
Company, 1969), page 50:
This appearance is of course specific to one set of leads. For
example, if the leads were exactly reversed, the tracing would be exactly
upside down. The sequence of excursions would remain the same: P
wave, PR segment, QRS complex, ST segment, T wave, and U wave.
The time between one beat and the next is often referred to as the RR
interval.
5.3. To what action potentials do the various portions of the ECG
complex correspond?
When parts of the atria are depolarized and parts are not, the net
voltage is detected as the P wave. At the same time and during the
ensuing PR segment, depolarization is progressing through the AV node
and conduction system, but these tissues have insufficient mass for their
activity to be detected. Progression of depolarization through the
ventricles is seen as the QRS complex. Once depolarization of the
ventricles is complete, there is no net voltage across the heart, so the
tracing returns to its baseline during the ST segment. As repolarization
of the ventricles proceeds, however, the heterogeneities within the
ventricular wall become important, and repolarization is for a while more
complete in some cells (those of the endocardium and epicardium) than
in others (those of the mid-myocardium). The resulting voltage
gradients are manifest in the electrocardiogram as the T wave.
The origin of the U wave was obscure for many years. Its normal
timing corresponds to that of repolarization of the Purkinje fibers, but the
Purkinje fibers are insufficiently massive to account for large lateappearing waves that are often described as U waves. These large waves
are more likely to be late components of a prolonged T wave, generated
as described just above.
5.4. How are the durations of the various intervals affected by heart rate?
The PR interval (normally 120-200 ms) and QRS interval
(normally 80-120 ms) are unaffected by changes in heart rate. The QT
interval shortens as the heart rate is increased, and this phenomenon is
central to the whole next section.
6. The QT Interval
6.01. How do we decide whether a biometric datum is “normal”?
Some physiological measurements have a single normal range,
independent of the subject's age, sex, or other variables. For example,
everyone's serum sodium concentration is normally in the range 135145 mEq/L.
Other measurements are more complicated, because they vary with one
or more important cofactors. The question “What is the normal range of
adult weight?” is not meaningless, but the answer (something like “100200 pounds”) is almost uselessly imprecise.
We sometimes decide whether a measured body weight is normal by
referring to tables that show a weight range for each of many
combinations of sex and height. Rather than deal with the bulky tables,
physicians sometimes use simple rules of thumb, like “a normal adult
woman 5 feet N inches tall weighs about 110+4N pounds.” Finally, it is
sometimes convenient to run rules in reverse, normalizing the measured
data by deriving a metric sometimes called an index. In the case of
weight, the conventional calculation is that which yields the body-mass
index, BMI = weight / height2. The claim of the BMI is that once it has
been computed, the normality or abnormality of the subject's weight can
be assessed with no further reference to his or her height.
All of these schemes must be evaluated, at least at first, in the same
way. A useful scheme should be unbiased, and to be most useful it
should be reasonably precise.
A scheme is unbiased if it actually describes the population for whom
it is a proposed standard. To say that the normal range for adult human
weight is 100-200 pounds may not be terribly useful, but it is
(approximately) correct. A suggested range of 300-350 pounds would be
more precise, but it would be biased. A given range, table, rule, or
normalization might be unbiased for one population, but biased for
another. For example, the rule of thumb given earlier functions well for
short women, but the only tall women it accepts as “normal” are
unnaturally thin.
Although a normal range can be meaningfully defined for any scheme
that is not seriously biased, the range may need be uselessly imprecise if
the scheme does not take account of pertinent cofactors. This was
demonstrated in the example of the single normal range for adult weight.
6.02. What is meant by QT “correction”?
A QT “correction” formula is a formula that combines the measured
QT duration and the measured heart rate into a computed index, similar
in concept to the BMI. The term “correction” is a misnomer, inasmuch
as the measured QT interval is not incorrect (as a weight might be
incorrect if it were measured while the subject were wearing heavy
clothing). Nevertheless, the term “correction” is deeply entrenched, and
the output of the calculation is usually called the “corrected QT interval,”
denoted by QTc.
6.03. What formula is used for QT correction?
Several dozen different formulas have been proposed over the
years. The most frequent style of these formulas has been
QTc = QT / RRa
where a is a formula-specific parameter, and of these formulas the one
most frequently seen is the formula attributed to Bazett, in which
a = 0.5, and for which the published upper limit of normal is 440 ms. In
what follows, the results of correction using the Bazett formula will be
denoted by QTcB.
6.04. Is the Bazett correction unbiased?
No. Bazett studied only a few electrocardiograms in each of a small
number of subjects, and he then chose a = 0.5 by subjectively observing
the fit to his data. In more recent studies, using dozens of
electrocardiograms from each of hundreds of subjects, the best value of a
(by formal statistical methods not known to Bazett) has varied from
population to population. Values as high as 0.5 are almost never seen;
the most frequent values are close to 0.32.
Using an excessive value for a causes one to expect that with
increasing heart rate, the QT interval will decrease more rapidly than it
actually does. As a result, normal reductions of QT duration with heart
rate will be perceived as insufficient, suggesting that some concomitant
process is prolonging the QT interval. With decreasing heart rate, an
excessive value of a will lead to acceptance as normal of QT durations
that are actually abnormally long.
6.05. When the heart rate is close to 60, so that QTcB is close to QT, need
I be concerned about the failings of the Bazett formula?
Probably, yes. The accepted upper limit of normal for QTcB (and for
QT when HR is around 60) was probably not obtained by averaging the
QT intervals of subjects whose heart rates were all around 60 bpm.
Instead, the normal range was probably obtained by averaging the QTcB
results of subjects at various heart rates, most of them higher than 60.
Because these QTcB values were mostly too high, the accepted upper
limit of normal is probably too high. These matters are now (June 2002)
under active investigation.
6.06. Hasn't the Bazett formula been validated by years of use?
Yes, Ptolemaic astronomy has been.... What? Sorry. Yes,
homeopathy has been.... Oh, sorry again. I get distracted. Please be so
kind as to repeat your stupid question.
6.07. Would it be better to use a similar formula with a around 0.32?
For most populations, yes, but studies have found populationspecific values of a ranging from less than 0.2 to greater than 0.6. It's
better to pool your baseline data to find the a that best fits your specific
population.
Even if you do that (or if you choose an arbitrary value and it turns
out to be a good fit), you will probably find that although bias has been
minimized, precision remains mediocre. That is, individual variation in
the QT/RR relationship will probably be so large that a populationspecific normal range will need to resemble the height-independent
normal range for weight discussed much earlier. You may get slightly
better results by considering formulas different in style (say, using
Taylor series), but the intersubject variation will probably remain a
problem.
6.08. Would it be better yet to obtain sufficient baseline data to fit a
separate formula for each subject?
Yes. With this technique, it is possible to detect abnormal QT
intervals, regardless of heart rate, with high precision.
6.09. When the heart rate changes, does the QT interval change right
away?
No. After a change in heart rate, the QT interval takes a minute or
two to reach its new steady state. Thus, for example, a QT interval
measured just after an increase in heart rate may falsely appear to be
abnormally long, because it is still shortening from its (normal) duration
before the change in heart rate.
6.10. What is meant by "QT dispersion"?
QT dispersion was at one time thought to be the
electrocardiographic manifestation of important variation of AP duration
in ventricular muscle. Depending on their degree of mathematical
sophistication, different authors identified QT dispersion with different
measures (standard deviation, maximum-minimum difference, etc.) of
the range of QT duration as seen in the various electrocardiographic
leads. This notion of QT dispersion was popular a few years ago, but it
lost momentum when it could not be shown to be of independent
prognostic significance. These measures' insensitivity should (in
hindsight) have been expected, inasmuch as each of the proposed
measures of QT dispersion was sensitive to differences in milieu
between regions of ventricular tissue that were physically far separated
from each other, and therefore unlikely to join in hosting reentrant
arrhythmias.
Intraventricular variation in AP duration is important, but the
important kind of variation is radial rather than circumferential. That is,
the important variation in AP duration is the variation seen within a
localized slab of ventricular wall, among the epicardium, the midmyocardium, and the endocardium. This sort of variation is present in
normal hearts (in which it generates the normal T wave) but it is also the
sort of variation that is magnified by drugs that induce torsade, and not
by drugs that – even if they prolong the QT interval – do not induce
torsade. Unlike the circumferential variation, unfortunately, the radial
("transmyocardial") variation in AP duration is not directly evident on
the surface electrocardiogram
Frequently Questioned Answers (3)
7. Torsade de Pointes
7.1. Is it torsade or torsades?
A small but strangely heated literature addresses this question. Here,
it's torsade.
7.2. What is torsade de pointes?
Torsade de pointes (from the French for “twisting of the points”) is
a re-entrant arrhythmia with a distinctive electrocardiographic
appearance, sometimes described as a sine wave within a sine wave.
This example is from Braunwald E, Zipes DP, and Libby P (eds.), Heart
Disease [6th edition] (Philadelphia: W.B. Saunders, 2001), page 868:
The pattern is called "twisting" because when the peaks are at their
smallest in one lead, they are generally at their largest in another, as if a
vibrating string were having its plane of vibration slowly rotated about
the long axis of the string.
7.3. Why is torsade de pointes important?
Many episodes of torsade de pointes are asymptomatic and stop by
themselves, but the mechanical activity associated with this electrical
pattern is generally dysfunctional, and torsade can degenerate into other
arrhythmias that are both dysfunctional and irreversible.
7.4. Who are at risk for torsade de pointes?
Torsade de pointes is seen in various congenital defects known
collectively as the long-QT syndromes. In addition, torsade sometimes
happens to otherwise-normal people as an adverse effect of drugs. Other
things being equal, the risk of torsade is increased in women, in people
who are hypokalemic or hypocalcemic, and in patients with congestive
heart failure.
8. Congenital Long-QT Syndromes
8.1. What are the congenital long-QT syndromes?
Mutations in the genes whose products make up the major ion
channels give rise to syndromes known as the long-QT syndromes (LQT
syndromes). These syndromes are congenital, but not necessarily
hereditary, since about XX% of the cases turn out to be new mutations.
The most frequent of the long-QT syndromes are known as LQT1
(impaired opening of the (repolarizing) IKs channel), LQT2 (impaired
opening of the (repolarizing) IKr channel), and LQT3 (impaired closing
of the (depolarizing) INa channel).
8.2. How common are these syndromes?
A few thousand patients have been identified worldwide, but they
are thought to be much more common.
8.3. How important are they to people who have them?
About half of the affected people sustain major arrhythmias before
the age of 40. In addition, an unknown but nonzero fraction of the
deaths attributed to the catchall “sudden infant death syndrome” (SIDS)
are caused by LQT-syndrome-related arrhythmias.
8.4. Are similar syndromes known to occur in animals?
No.
8.5. Do people with the same hereditary long-QT syndrome all have the
same mutation?
No. In fact, a new kindred with one of the established syndromes is
likely to have a family-specific mutation. As of June 2002, cases of the
LQT1, LQT2, and LQT3 syndromes have been found as the results of
about 300 different mutations.
8.6. Do people with the same ion-channel mutation all have equally
prolonged QT intervals?
No. When a family carrying a LQTS mutation is investigated,
usually about a third of the family members with the mutation have
normal electrocardiograms, and the others have varying degrees of QT
prolongation.
8.7. Do people with the same ion-channel mutation all have an equal
likelihood of arrhythmic events?
No. Those with longer QT intervals have a higher incidence of
events, but even those with normal electrocardiograms have an incidence
of events that is higher than that of people who do not have LQTS.
9. Drug-Induced Changes in Ion-Channel Function
9.1. How is a drug's propensity to cause changes in ion-channel function
tested?
TBD.
9.2. How are the results described?
Drug-induced interference with channel opening is described in
terms of the concentration of drug needed to impair ion flux by 50%.
This measurement is denoted by IC50. For example, some extreme values
for blockade of the IKr channel are that of astemizole, a very potent
blocker with an IC50 of 0.9 nM, and that of ofloxacin, an extraordinarily
weak blocker with an IC50 of 1.4 mM.
Drug-induced interference with channel closing?
9.3. Is alteration of ion-channel function ever an intended drug effect?
Yes. Because arrhythmias are usually the result of ion-channel
dysfunction, a drug with no discernible effect on ion channels would be
unlikely to be developed as an anti-arrhythmic.
9.4. Are some ion channels more susceptible to drug-induced interference
than others?
Yes. The IKr channel turns out to have a wide, funnel-shaped
vestibule, so many different kinds of small molecules can approach the
channel and partially block it. Other channels are generally more
selective. Even so, most drugs known to interfere with one channel are
known to interfere – at least to some degree – with others.
9.5. What drugs have ion-channel effects, and which channels are
affected?
All of the publicly-available data that I know about are tabulated
here.
9.6. Do ion-channel studies provide close analogies to distortions of
human electrocardiograms?
No.
9.7. Do ion-channel studies provide close analogies to human torsade de
pointes?
No.
9.8. Has in vitro ion-channel testing been validated as a means of
predicting drug-induced torsade de pointes in humans?
Yes and no. A drug could not induce torsade de pointes if it did not
in some way interfere with the function of ion channels, but the converse
is not true. For example, verapamil is a moderately potent IKr blocker (its
IC50 is about 0.14 µM), but it never induces torsade or any other
tachyarrhythmia.
10. Drug-Induced Changes in the Action Potential
10.1. How is a drug's propensity to cause changes in action potentials
tested?
TBD.
10.2. How are the results described?
TBD.
10.3. Do action-potential studies provide close analogies to distortions of
human electrocardiograms?
No, except insofar as a drug that never prolongs the action potential
could not prolong the QT interval.
10.4. Do action-potential studies provide close analogies to human torsade
de pointes?
No.
10.5. Does prolongation of action potentials in vitro reliably predict druginduced torsade de pointes in humans?
No. Most drugs known to induce torsade are known to prolong the
action potential in at least some types of cells. Other drugs, however
(e.g., pentobarbital), by prolonging the action potential in some cells
more than others are known to reduce the risk of torsade.
11. The Wedge Preparation
11.1. What is the wedge preparation, and what studies are done with it?
Ion-channel and action-potential studies are generally performed in
single cells (or in small multicellular specimens chosen for their
homogeneity), maintained by immersion in an appropriate bath. The
specimen taken for wedge-preparation studies is a full-thickness slab of
the canine ventricular wall, several cubic centimeters in total volume,
maintained by direct perfusion of its native coronary vessels.
The voltage measured between the endocardial and epicardial
surfaces of the slab integrates the action potentials of all of the cells of
the slab. It resembles a surface electrocardiogram not only in its means
of generation, but also in its overall appearance.
Electrodes floating on the raw intra-myocardial surfaces of the slab
record action potentials typical of the local cells.
When drugs are added to the perfusate, the various electrodes
provide simultaneous views of different cell types' action potentials and
of the integrated quasi-electrocardiogram.
11.2. How are the results described?
The quasi-electrocardiogram and action-potential recordings are
described as ECGs and APs are usually described, with the pivotal added
note that they were simultaneously recorded.
11.3. Do wedge-preparation studies provide close analogies to distortions
of human electrocardiograms?
Yes.
11.4. Do wedge-preparation studies provide close analogies to human
torsade de pointes?
Yes.
11.5. Have wedge-preparation studies been validated as a means of
predicting drug-induced torsade de pointes in humans?
No.
12. Drug-Induced QT Prolongation in Animals
12.1. How is a drug's propensity to cause QT prolongation in animals
tested?
TBD.
12.2. How are the results described?
TBD.
12.3. Do QT prolongation and other ECG abnormalities in animals
closely resemble these phenomena in humans?
TBD.
12.4. Have studies of drug-induced QT prolongation in animals been
validated as a means of predicting drug-induced torsade de pointes in
humans?
No.
13. Drug-Induced Torsade de Pointes in Animals
13.1. How is a drug's propensity to cause torsade de pointes in animals
tested?
TBD.
13.2. How are the results described?
TBD.
13.3. Have studies of drug-induced torsade de pointes in animals been
validated as a means of predicting drug-induced torsade de pointes in
humans?
No.
14. Drug-Induced QT Prolongation in Humans
14.1. Is prolongation of the human QT interval ever an intended drug
effect?
No.
14.2. What drugs prolong the QT interval?
Lists of drugs that prolong the QT interval are widely available on
the Web and elsewhere, but most of the data underlying these tables
were obtained using Bazett-corrected electrocardiograms, so many drugs
are probably listed in error. Conversely, many older drugs were never
tested for this property, so they may well have greater effects than some
of the drugs listed.
14.3. If a given dose of a drug prolongs the QT interval by a certain
amount, will a higher dose of the drug prolong the QT interval by the same
amount or greater?
Not necessarily. If the higher dose alters the function of depolarizing
channels, in addition to the repolarizing channels affected at the lower
dose, then the two effects may balance each other out at the higher dose.
This fanciful-sounding possibility is actually observed with some drugs,
notably quinidine.
14.4. Does drug-induced QT prolongation cause torsade de pointes?
No. QT prolongation is evidence that the repolarization of some
cardiac cells has been delayed, and this delay can lead to torsade if
adjacent cells are repolarizing much sooner. On the other hand, the AP
prolongation that is evident as QT prolongation may – as is seen with
amiodarone, diltiazem, pentobarbital, ranolazine, and verapamil – be
concurrent with AP prolongation in adjacent cells, so that local
heterogeneity of repolarization has actually been reduced, together with
the likelihood of torsade de pointes.
15. Drug-Induced Torsade de Pointes
15.1. What drugs are known to cause torsade de pointes?
Lists of suspect drugs are widely available on the Web and
elsewhere, but these lists should not be accepted uncritically. Some of
the data come from FDA case reports of patients taking multiple drugs,
sometimes with underlying conditions that could by themselves have
been responsible for the arrhythmias reported.
15.2. Do all of the true culprit drugs interfere with the function of ion
channels?
Probably, yes.
15.3. Which ion channels are involved?
Even though only one (LQT2) of the three most common long-QT
syndromes involves IKr, and even though various non-therapeutic drugs
can reliably induce torsade de pointes in animals via interference with
other channels, drug-induced torsade de pointes in humans has always
been attributed to interference with IKr. In some cases, this attribution is
difficult to understand, and it may reflect lack of data with respect to
other channels. For example, the capacity of grepafloxacin to cause
torsade is attributed to its ability to block IKr, even though the IC50 of
grepafloxacin for this blockade is about 50 µM. Grepafloxacin's activity
at other channels has not been publicly reported.
15.4. How often will a patient with drug-induced torsade be found to have
been unusually susceptible because of a subclinical congenital channel
dysfunction?
Not very often. A few patients have sustained torsade after what
should have been low-risk drug exposure, and have later been found to
have subtle ion-channel dysfunctions, but this pattern seems to be
present in only 3-5% of the incident cases of drug-induced torsade.
15.5. Do all drugs that block IKr cause torsade de pointes if given in
sufficient dose?
No. For example, diltiazem and (especially) verapamil block IKr, but
they do not cause torsade.
15.6. Do all of the drugs known to cause torsade de pointes prolong the
QT interval?
Yes.
15.7. Conversely, will any drug that prolongs the QT interval cause
torsade de pointes if it is given in sufficient dose?
No. Diltiazem and verapamil are again counterexamples. At least in
models in which animals are pretreated so as to make them especially
susceptible to torsade, these drugs (and others) prolong the QT interval
but actually reduce the likelihood of torsade.
15.8. Are there drugs that cause torsade de pointes even though they
prolong the QT interval only slightly?
Inasmuch as some patients with long-QT syndromes are at
heightened risk of torsade even though their QT intervals are only
slightly prolonged or even normal, there probably are drugs that can
induce torsade while lengthening the QT interval only minimally (or not
at all).
On the other hand, no such drugs are known. Certainly there are
drugs that can induce torsade under some conditions but that under
other conditions cause only minimal changes to the QT interval, but this
is a non sequitur. For example, when a normal dose of terfenadine is
given to a metabolically-competent person, the average amount of QT
prolongation is said to be only 6 ms. In the circumstances in which
terfenadine is known to have induced torsade, however (higher doses,
metabolic inhibition, etc.), the amount of QT prolongation is much
greater.
16. Drug Development and Regulation
16.1. How important are metabolic effects during human trials of drugs
that might affect repolarization?
Metabolism is no more important in thinking about torsade than it is
in thinking about other adverse drug effects that might be clinically
concentration-related. That is to say, it is very important indeed.
All drug effects could be said to be concentration-related, inasmuch
as they are all related to molecular interactions that follow the rules of
mass action. In the clinical context, an effect is said to be concentrationrelated only if it runs through its range of incidence or severity within a
range of concentrations that is of clinical interest. For example, ACEinhibitor-induced cough is said not to be concentration-related, because
its incidence no longer increases once drug concentrations have reached
levels well below those that are clinically useful. Morphine-induced
sedation, on the other hand, is increasing throughout (and beyond) the
range of therapeutic concentrations, so this effect is said to be
concentration-related.
Impaired drug metabolism can result in concentrations greatly
exceeding those attained by timid dose-ranging, especially when a drug
is dependent upon a unique metabolic pathway. For example,
concentrations of simvastatin are raised by more than an order of
magnitude when that drug is co-administered with ketoconazole.
Returning to the repolarization arena, while such populations as women
and heart-failure patients tend to have more pronounced responses to
repolarization-altering drugs, these differences are small and predictable,
almost negligible when compared to the differences that are sometimes
produced by metabolic interference.
Another set of considerations under the metabolic heading comes
from the fact that the molecule directly responsible for an adverse drug
effect may be different from the molecule administered. Although most
metabolites are more polar than their parent compounds, and therefore
less active, some exceptions are important. For example, the CNS
toxicity of meperidine is caused by normeperidine, a long-lived
metabolite. This toxicity could not be detected in short-term trials.
16.2. What is the goal of Phase 1 trials?
As regards repolarization changes (or other adverse drug reactions),
the goal of Phase 1 trials is to see how much harm the drug can be made
to do. Dosing (and metabolic inhibition, if relevant) should be increased
until it's not feasible to increase any more. This is the time to discover
unpleasant facts that will be much more unpleasant if they are not
discovered until later phases of development or – even worse – until after
marketing.
Because the human metabolism may not be completely understood
until later, some early Phase 1 trials may need to be repeated with
revised protocols. For example, if some of a drug's toxicity is
attributable to a slowly-accumulating metabolite, then it may be
necessary to do new, longer trials, or to do new trials in which the
metabolite is administered directly.
Repolarization changes are special in two ways. First, the
associated risk (death or infarction as the result of malignant
tachyarrhythmias) is one from which Phase 1 subjects can be totally
protected. Similar arrhythmias, after all, are deliberately induced in
electrophysiology laboratories as a matter of routine. When an
appropriately monitored Phase 1 subject has a suspicious
electrocardiogram, the investigator might reasonably be more willing to
continue than he would be if the subject had had an equally-suspicious
panel of hepatocellular enzymes.
Second, a subject with an unusual repolarization response to a new
drug is reasonably likely to have similar responses to others, and
electrophysiological evaluation of the subject is a negligible-risk option
that is therefore in the interest of both the drug developer and the
subject. No similar statements can be made when a subject's response to
a studied drug suggests hematologic or hepatic toxicity.
16.3. How important is the non-occurrence of torsade de pointes during
human drug trials?
Because torsade is so rare (even in LQT patients at high risk, and
even in patients taking the drugs known to cause torsade most
frequently), the non-occurrence of torsade in clinical trials provides little
reassurance.