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Research Scientist Division of Pharmacokinetics/Pharmacodynamics and Trial Simulation Eli Lilly and Company Lilly Corporate Center 307 East McCarty Street Indianapolis, Indiana 46225-3324 fax 317/433-6661 dsmall{at}lilly.com
Senior Clinical Research Physician Critical Care US Medical Division Eli Lilly and Company
Published Online, February 27, 2004. www.theannals.com, DOI 10.1345/aph.1C478a
135 kg, but PROWESS data can still help us understand
the likely pharmacokinetics, pharmacodynamics, safety, and efficacy of
drotrecogin alfa (activated) in patients >135 kg. The primary safety concern associated with drotrecogin alfa (activated) is increased risk of bleeding during infusion. However, there is no evidence of survival benefit at drotrecogin alfa (activated) doses lower than that currently recommended. Without exception, clinical data support an infusion rate of 24 µg/kg/h for 96 hours based on a patient's actual body weight immediately before start of infusion. In PROWESS, this method produced a 20% reduction in relative risk of death.
If a patient's pre-sepsis weight is 15% above the ideal body weight and increases 15% above that because of fluid resuscitation, the patient's actual weight before infusion is 32% higher than ideal weight. If based on ideal body weight, that patient's infusion rate would be about 25% lower than a rate based on actual body weight and would be equivalent to a rate of 18 µg/kg/h based on actual body weight. In the Phase II trial, 18 µg/kg/h produced less change in key markers of coagulation and inflammation than did 24 µg/kg/h. These pharmacodynamic effects were the rationale for selecting a rate of 24 µg/kg/h for the Phase III trial.
Pharmacokinetic and safety data from patients whose weight is 135 kg
provide no suggestion that the approved infusion rate of 24 µg/kg/h should
be changed for patients >135 kg. Pharmacokinetic data from 326 adults and
83 children with severe sepsis were combined to assess weight-normalized
plasma clearance (Clp) from 3 to 133
kg.3 A plot
of weight-normalized Clp versus body weight shows a nearly
flat regression line through the 44-fold range of these body weights. Since
steady-state plasma concentration (Css) is inversely
proportional to Clp at a given infusion rate,
Css would also be consistent across this weight range.
Weight-normalized Clp and Css in the 10%
of adult patients with the highest body weight (n = 34; mean ± SD body
weight 113 ± 10 kg, range 101–133; Clp 0.559
± 0.258 L/h/kg; Css 57.9 ± 60.9 ng/mL) were
comparable to those in the 10% of patients with the lowest body weight (n =
33; mean ± SD body weight 47.5 ± 4.6 kg, range 36.4–52.6;
Clp 0.606 ± 0.347 L/h/kg; Css 56.6
± 41.9 ng/mL).
During the PROWESS trial, the distribution of Css in patients who experienced a serious bleeding adverse event was nearly identical to that in patients who did not. Of the 18 patients known to have had an average Css >100 ng/mL, none experienced a serious bleeding event during the infusion or the 28-day study period.
These pharmacokinetic and safety data in patients weighing 135 kg
suggest that pharmacokinetic linearity can be extrapolated to patients >135
kg. While we appreciate the limitations of such extrapolation, we are unaware
of any data suggesting that another dose may be more appropriate. It is
possible that nonlinear response may develop at body weights >135 kg, but
if that occurs, underdosing is as likely as overdosing. Therefore, the only
advice supported by evidence is that dosing should be based on actual body
weight.
References
This article has been cited by other articles:
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  H. Levy, D. Small, D. E Heiselman, R. Riker, J. Steingrub, R. Chen, R. L Qualy, C. Darstein, and E. Mongan Obesity Does Not Alter the Pharmacokinetics of Drotrecogin Alfa (Activated) in Severe Sepsis Ann. Pharmacother., February 1, 2005; 39(2): 262 - 267. [Abstract] [Full Text] [PDF]
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