Population pharmacokinetics of daptomycin.
Data from subjects in nine phase 1 (n = 153) and six phase 2/3 (n = 129) clinical trials were combined to identify factors contributing to interindividual variability in daptomycin pharmacokinetics (PK). Over 30 covariates were considered. A two-compartment model with first-order elimination provided the best fit for data on daptomycin concentrations in plasma over time. In the final population PK model, daptomycin plasma clearance (CL) was a function of renal function, body temperature, and sex. Of these factors, renal function contributed most significantly to interindividual variability. CL varied linearly with the estimated creatinine clearance. CL among dialysis subjects was approximately one-third that of healthy subjects (0.27 versus 0.81 liter/h). CL in females was 80% that in males; however, in clinical trials, the outcome was not affected by sex and therefore this effect is not considered clinically meaningful. The relationship with body temperature should be interpreted cautiously since the analysis included only a limited number of subjects who were hyperthermic. The volume of distribution of the peripheral compartment (V2) and intercompartmental clearance (Q) were linearly related to body weight. V2 increased approximately twofold in the presence of an acute infection. No factors were identified that significantly impacted V1. This analysis supports the dosing of daptomycin on a milligram-per-kilogram-of-body-weight basis and suggests that modified dosing regimens are indicated for patients with severe renal disease and for those undergoing dialysis.
Cubist Pharmaceuticals, Inc., Lexington, Massachusetts 02421, USA. bdvorchi@tampabay.rr.com
Barry
B
Dvorchik
Robert D
RD
Arbeit
Julia
J
Chung
Susan
S
Liu
William
W
Knebel
Helen
H
Kastrissios
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D001424:Bacterial Infections / Q000150:complications / Q000378:metabolism; D001499:Bayes Theorem; D001830:Body Surface Area; D001835:Body Weight; D002851:Chromatography, High Pressure Liquid; D017576:Daptomycin / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D008954:Models, Biological; D009102:Multiple Organ Failure / Q000378:metabolism; D011153:Population; D012737:Sex Factors
D000900:Anti-Bacterial Agents; D017576:Daptomycin