Background: CD101 is a novel antifungal echinocandin that has shown robust efficacy in mouse antifungal models and was studied in a recently completed single ascending dose, Phase I clinical trial. During preclinical development, the pharmacokinetics of CD101 was characterized in mouse, rat, dog, and non-human primates (monkey and chimpanzee) to facilitate projection of human pharmacokinetics. Published literature suggest that the chimpanzee (Pan troglodytes) may be the optimal surrogate model for predicting human pharmacokinetics of previous echinocandins. This abstract compares allometric scaling approaches, including choice of species, to the use of the chimpanzee as a single species surrogate for the prediction of human pharmacokinetics of CD101. Further, the anticipated human plasma concentration-time profiles at various doses were projected using data from the chimpanzee and retrospectively compared to available human profiles.
Material/methods: Using an allometric scaling approach, the pharmacokinetic parameters estimated from mouse, rat, dog, and monkey plasma concentration data from intravenous administrations were used to project human plasma clearance and volume of distribution. From these parameters, the halflife in human was calculated. Retrospectively, the predicted half-life was then compared to the observed half-life following successful completion of Phase 1 clinical study. The half-life predicted based on the ‘rule of exponents’ in allometric scaling as well as number of species used in the allometric approach were then examined. This approach was contrasted with the use of chimpanzee as the lone surrogate for the human pharmacokinetics profile.
Results: The long half-life predicted using all 4 animal species (mouse, rat, dog, and monkey) in the allometric scaling model resulted in values close to the observed half-life depending on the correction factor used as proposed using the ‘rule of exponents.’ Excluding rat data also allowed a similar prediction of half-life, although excluding mouse data showed an over-prediction of half-life (longer than observed). In general, results from 3-species models offered closer to observed half-life values than 2-species models. For example, using rodents only, the model drastically under-predicted, whereas a non-rodents only model drastically over-predicted the observed half-life. In contrast, using the chimpanzee as the surrogate model for human pharmacokinetics offered the closest predicted values for clearance and resulting half-life. Additionally, the mean plasma concentration-time profiles from chimpanzee were almost superimposable when overlaid against the dose-normalized human profile of CD101, which is also seen for previous echinocandins, caspofungin and anidulafungin.
Conclusions: For allometric scaling, the relevance of the different animal species towards achieving optimal predictive ability are discussed. However, using only chimpanzee data, the anticipated human plasma concentration-time profile could be predicted with remarkable accuracy. Taken together, the data suggest that, compared with more common laboratory animal species, the chimpanzee may be a better predictor of human pharmacokinetics of echinocandins.
Full conference title:
- ECCMID 26th (2016)