Animal Pharmacokinetics and Interspecies Scaling of Sordarin Derivatives following Intravenous Administration

Abstract

Sordarin derivatives constitute a new group of synthetic antifungal agents that selectively inhibit fungal protein synthesis. They have demonstrated in vitro activity against the most important fungal pathogens, both yeast and filamentous. This new family of compounds has also shown in vivo activity against murine Candida albicans, Histoplasma capsulatum, and Coccidioides immitis experimental infections, as well as against Pneumocystis carinii pneumonia in rats. After intravenous dosing in animals, both the area under the concentration-time curve and the elimination half-life were highest in Cynomolgus monkeys, followed by those in rats, mice, and rabbits. The volume of distribution at steady state for sordarin derivatives was similar in all species tested. The clearance in rats and mice was higher than for other species. GM 237354, a sordarin derivative, was characterized by high serum protein binding in mouse, rat, and monkey serum (unbound fraction, <5%). An indirect evaluation of the effect of liver function upon the metabolism of this class of compounds has been made in animals with impaired liver function such as Gunn rats, as well as in allometric studies that showed better correlations of half-life to liver blood flow than to animal body weight. Linearity of the main pharmacokinetic parameters was demonstrated after intravenous dosing of the representative compound GM 193663 at 10 and 20 mg/kg of body weight in rats. Allometry was used to determine whether human pharmacokinetic parameters can be predicted from animal data by regression analysis against body weight and liver blood flow. All these results have demonstrated that the human pharmacokinetics of sordarin derivatives can be forecast from animal data.Opportunistic fungal pathogens remain an important cause of morbidity and mortality in immunocompromised individuals, such as patients with AIDS and those receiving chemotherapy or immunosuppressive therapy for oncological malignancies or other pathological conditions (11,16,24).Sordarin derivatives are a new group of synthetic antifungal agents that selectively inhibit fungal protein synthesis by targeting the yeast protein elongation cycle (8,9). Sordarins have demonstrated in vitro activity against a wide range of pathogenic fungi (14). In addition, sordarin derivatives have shown in vivo activity against systemic and local experimental infections involving Candida albicans and Pneumocystis carinii (1, 2, 19), as well as murine histoplasmosis (13) and coccidioidomycosis (5).It is well known that anti-infective treatment outcome is a function of several variables, including intrinsic microbiological activity and pharmacokinetic (PK) behavior (10). In this way, PK properties have been shown to be very useful for understanding the in vivo activities of structurally related compounds with similar in vitro potencies (12,17,22,23). Recently, close relationships between PK properties and the efficacy of sordarin derivatives in a murine model of systemic candidiasis have been described (1). In addition, P...

Interspecies Pharmacokinetics. 2. Analysis of the Structure of Interspecies Relationships Between Parameters of Drug Pharmacokinetics

“…The previous results [13] led to the conclusion that interspecies variations of the GM 237354 elimination half-life correlated well with the specific animal LBF rate.…”

“…The drug was present in the animal blood primarily in the bound form. The percent bound GM 237354 in the animal blood was 95% for mice, 97.7% for rats, 97.6% for rabbits, and 98.5% for monkeys at concentrations from 1 to 50 mg/mL [13]. The interspecies variations of this parameter were insignificant.…”

“…The pharmacokinetics of a new class of antifungal compounds, i.e., sordarin derivatives, were studied in animal tests [13]. Let us examine the results given in that work for the calculated PK parameters of one of the studied compounds (GM 237354) and the interspecies allometric relationships constructed for the elimination half-life, distribution volume, and total clearance of the compound.…”

“…The following equation for the interspecies relationship of the GM 237354 elimination half-life was obtained [13]:…”

Interspecies Pharmacokinetics. 1. Allometric Scaling of Pharmacokinetic Parameters (a Review)

“…This equation is also now used widely to describe quantitatively species variations of drug pharmacokinetics [14,35,36,66]. However, drug clearance data for animals and man are not always described satisfactorily by the equation given above [46,47,72].…”