Weight Drives Caspofungin Pharmacokinetic Variability in Overweight and Obese People: Fractal Power Signatures Beyond 2/3 or 3/4.
Antimicrob Agents Chemother. 2013 Mar 4;
Authors: Hall RG, Swancutt MA, Meek C, Leff R, Gumbo T
Echinocandins such as caspofungin are commonly used to treat candidemia and aspergilllosis. Success rates for candidemia treatment are approximately 70%. Dose optimization may further help improve these success rates, given that microbial effect of these agents is concentration-dependent. There are conflicting data as regards the effect of weight and/or obesity on caspofungin drug concentrations. We designed a prospective study to evaluate the population pharmacokinetics of caspofungin in adult patients with a weight difference range of 100 kg. Caspofungin pharmacokinetics were best described using a two-compartment pharmacokinetic model. There were 18 subjects studied, of whom half were women. The typical central volume was 4.2 liters, but increased by a factor of (weight/53.6)¾. The peripheral compartment volume typical value was 2.53 liters, but increased by a factor of (weight/53.6)3/2, an unusual power law signature. Similarly, the ¾ power law best described the relationship between weight and systemic clearance for persons weighing >66.3 kilograms, whereas inter-compartmental clearance was best described by the 3/2 power signature. There are two implications of our findings. First, lower caspofungin area under the concentration-time curves are achieved in obese persons than thinner ones. This suggests that dose optimization in heavier patients may improve clinical success rates. Second, the 3/2 exponent is unusual in fractal geometry-based scaling, and warrants further study. Moreover, this suggests that use of a "floating" instead of fixed exponent may be more useful in studies where weight is under investigation as a potential cause of pharmacokinetic variability within adult patients.
PMID: 23459494 [PubMed - as supplied by publisher]