PK/PD and Tolerability Testing in the ADPKD Mouse Model

The lead optimisation phase is a crucial process during which you investigate and select the most promising preclinical candidate(s) to progress to efficacy testing using animal models of human diseases. Pharmacokinetic (PK) and Pharmacodynamic (PD) profiling helps inform for e.g., the most optimal dosing route, dosing regimens (dosage and frequency of dosing), formulation type, determination of therapeutic index, metabolic stability and clearance by precisely determining the identity and concentration of your test compounds in the blood or specific organs.  

According to the first consensus guidance for preclinical animal studies in translational nephrology published by international society of Nephrology, PK studies should be performed in healthy WT mice or rats. Following which additional PK and tolerability studies should be executed in the diseased mouse model of choice. InnoSer’s expert nephrology team works with a preclinical ADPKD mouse model, whereby the customization of the model allows great flexibility in modelling different aspects of the human ADPKD pathophysiological progression.  

Choosing to work with juvenile animals (such as the P10 mouse model) due to their lower weight and different metabolism compared to WT animals (Figure 1) underscores the importance of performing PK and tolerability/MTD studies before commencing efficacy studies. Performing combined PK/PD profiling and efficacy studies at InnoSer is highly advantageous as follow-up efficacy studies can be started rapidly, with high capacities to run multi-arm trials due to our large in-house breeding colonies to help you select the optimal candidate compound.  

Similarly, quantitative determination of the compound’s concentration can be performed simultaneously in an efficacy study to determine the relationship between efficacy and the PK/PD profile of your compound (Figure 2). PK/PD and efficacy correlations can be performed based on biomarkers in blood, urine and tissues or by examining the mechanism of action of the compound (i.e., targeting proliferation, fibrosis in the polycystic kidneys, etc.,).  

FIGURE 1. The lower body weight of P10 ADPKD animals underscores the importance of performing PK and tolerability/MTD studies before commencing efficacy studies. Body weight of ADPKD (P<0.0001) and Everolimus–treated ADPKD mice (P=0.0005) is significantly lower compared to WT (uninduced Pkd1 KO mice). Here, Everolimus was used as a positive control, showing high tolerability as there is no difference in body weight between ADPKD mice and Everolimus–treated ADPKD mice.  

FIGURE 2. Representative LC-MS/MS chromatogram example of Everolimus in ADPKD mouse plasma obtained at one timepoint in the presence of internal standard (Everolimus-d4). For detection of each test compound in a chosen biological matrix, the method is validated by preparing samples, as well internal standards to quantitatively and precisely determine the test compounds’ concentration at one-point (such as here) or over multiple pre-specified timepoints to obtain the full PK profile.  

Drug development can be an iterative and long process, whereby InnoSer can be your dedicated partner, offering fast turnaround times with back-to-back experiments to help you optimise your lead compounds. Curious to learn more about InnoSer’s capabilities within the drug development space?