Tranexamic Acid during Cystectomy Trial (TACT) Pilot Study
PI: Rodney H. Breau
Funding Received: $185,439
Appendix 3 - Justification of Tranexamic Acid Dosing schedule
Doses used in previous clinical trials
In 34 cardiac surgery trials investigating the efficacy of tranexamic acid 19 the loading dose
ranged from 2.5 to 100 mg/kg while the maintenance infusions ranged from 0.25-16 mg/kg/hr. In
31 non-cardiac surgery trials investigating the efficacy of tranexamic acid 19, the majority (27) in
orthopaedic surgery, loading doses ranged from 10 to 40 mg/kg and maintenance infusions
ranged from 1 to 40 mg/kg/hr. The most common loading dose from all trials was 10 mg/kg and
the most common infusion dose was 1 mg/kg/hr in cardiac surgery (not including doses of drug
used to prime the bypass machine) and 10 mg/kg/hr in non-cardiac surgery. Dosing strategies
were highly variable as some studies did not use a loading dose and others gave only single or
intermittent doses.
Some studies did not use weight based dosing. The Crash II trial is the largest study of
tranexamic acid to date and they did not employ weight based dosing. In this study patients were
administered a 1 g loading dose followed by an infusion of 1 g over 8 hours regardless of weight.
In addition, the most recent study of tranexamic acid versus placebo in radical prostatectomy
patients received 500 mg loading dose followed by 250 mg/h for the duration of the surgery.
Pharmacokinetics of tranexamic acid
In vitro, the efficacy of tranexamic acid is measured by its ability to inhibit tissue plasminogen
activator (TPA) activity. Concentrations of 10 mcg/ml will reduce TPA activity by 80% in vitro
and concentrations of 16 mcg/ml will abolish TPA activity (100%)31.In a study by Fiechtner et
al, serum tranexamic acid levels were measured in 21 patients who were undergoing
cardiopulmonary bypass and had received a loading dose of 10 mg/kg followed by a
maintenance infusion of 1 mg/kg/hr. Mean plasma levels after the bolus were 37 mcg/ml which
dropped by approximately 25% to 28 mcg/ml after bypass was initiated. While on bypass, mean
levels ranged from 27-31 mcg/ml but the lower limit of the 95% CI dropped below 20 mcg/ml
after 90 minutes. In this study the loading dose of 10 mg/kg was more than sufficient to reach
(extrapolated) therapeutic levels but the maintenance dose of 1 mg/kg/hr did not consistently
reach therapeutic levels once the effect of the loading dose wore off. Using pharmacokinetic
modeling, the investigators suggested that to achieve adequate serum concentration (>20
mcg/ml) during cardiac surgery, a minimum loading dose of 5.4 to 7.8 mg/kg and an infusion
rate of 5 mg/kg/hr is required to maintain serum levels above 20 mcg/ml. This pharmacokinetic
data comes from patients on cardiopulmonary bypass so interpretation to non-bypass surgery can
be challenging32. When bypass machines are primed with 1.5 to 2L of crystalloid an acute
hemodilutional effect is observed which increases the volume of distribution by as much as 1015%. In this study, serum levels dropped by 25% after initiation of bypass. Therefore it is a safe
assumption that the serum concentration of tranexamic acid will be higher in radical cystectomy
patients compared to bypass patients with an equivalent dose is administered.
Rational for a loading dose
The serum half-life of tranexamic acid is 120 minutes when administered intravenously27.
Without a loading dose it would take as long as 10 hours to reach a steady state serum
concentration when the maximum treatment effect would be observed. Therefore, we decided a
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Amendment 1, Version January 24, 2013
Tranexamic Acid during Cystectomy Trial (TACT) Pilot Study
PI: Rodney H. Breau
Funding Received: $185,439
loading dose is essential to ensure adequate drug concentration at the time of the initial incision
so that the maximum effect of the drug coincides with the greatest risk for bleeding.
Rational for an infusion dose
Given the relatively short half-life of tranexamic acid and the long duration of radical cystectomy
surgery, a maintenance infusion is more likely to maintain therapeutic serum concentrations as
compared to intermittent bolus dosing. In the above quoted pharmacokinetic study, the serum
levels after the loading dose dropped to suboptimal levels 90 minutes after the loading dose
(despite a low maintenance infusion of 1 mg/kg/hr).
Dose selected
Given the safety profile of tranexamic acid and the potential dose related response (in vitro) we
believe it is important to choose a dose large enough to be confident we are achieving therapeutic
drug concentrations. We chose to use a weight based dosing schedule because, theoretically, it
may reduce inter-patient variability. A 10 mg/kg loading dose has been frequently studied and
should achieve a therapeutic serum concentration. In addition, the maintenance infusion dose
suggested for bypass surgery (5mg/kg/hr.) is within the range of studied doses and should be
sufficient to maintain drug levels through surgery.
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Amendment 1, Version January 24, 2013