Quantitative Pharmacokinetic/Pharmacodynamic Analyses Suggest That the 129/SVE Mouse Is a Suitable Preclinical Pharmacology Model for Identifying Small-Molecule γ-Secretase Inhibitors

Abstract

Alzheimer's disease (AD) poses a serious public health threat to the United States. Disease-modifying drugs slowing AD progression are in urgent need, but they are still unavailable. According to the amyloid cascade hypothesis, inhibition of ␤-or ␥-secretase, key enzymes for the production of amyloid ␤ (A␤), may be viable mechanisms for the treatment of AD. For the discovery of ␥-secretase inhibitors (GSIs), the APP-overexpressing Tg2576 mouse has been the preclinical model of choice, in part because of the ease of detection of A␤ species in its brain, plasma, and cerebrospinal fluid (CSF). Some biological observations and practical considerations, however, argue against the use of the Tg2576 mouse. We reasoned that an animal model would be suitable for GSI discovery if the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of a compound for A␤ lowering in this model is predictive of that in human. In this study, we assessed whether the background 129/SVE strain is a suitable preclinical pharmacology model for identifying new GSIs by evaluating the translatability of the intrinsic PK/PD relationships for brain and CSF A␤ across the Tg2576 and 129/SVE mouse and human. Using semimechanistically based PK/PD modeling, our analyses indicated that the intrinsic PK/PD relationship for brain A␤x-42 and CSF A␤x-40 in the 129/SVE mouse is indicative of that for human CSF A␤. This result, in conjunction with practical considerations, strongly suggests that the 129/SVE mouse is a suitable model for GSI discovery. Concurrently, the necessity and utilities of PK/PD modeling for rational interpretation of A␤ data are established.

Discovery of AZD3839, a Potent and Selective BACE1 Inhibitor Clinical Candidate for the Treatment of Alzheimer Disease

“…In mouse and guinea pig AZD3839 decreased A␤ levels in plasma at lower concentrations compared with the brain even after correction for differences in exposure. This may also have been observed for other ␤-and ␥-secretase inhibitors in different preclinical species (30,62,63) but not all (56,63). The reason for this is not entirely understood.…”

“…3), it was not surprising that no additional A␤ lowering was observed after sub-chronic dosing. Other groups have also reported that ␤-and ␥-secretase inhibitors were not able to fully inhibit A␤ production in preclinical species in plasma and/or brain, although this might be compound-specific (56,61,62).…”

“…more than 90% after 2 weeks of administration in healthy volunteers. Biphasic concentration-effect relationships for A␤ reduction have been described for ␥-secretase inhibitors Semagacestat, Avagacestat, Begacestat, and MK0752 in mice, rats, monkey, and human plasma (56,65,66). On CSF A␤ levels, less pronounced or no rise were observed for ␥-secretase inhibitors in preclinical models, whereas the clinical data have been difficult to interpret due to limited data and drift in the base line.…”

Mechanistic Pharmacokinetic-Pharmacodynamic Modeling of BACE1 Inhibition in Monkeys: Development of a Predictive Model for Amyloid Precursor Protein Processing

“…Therefore, the discovery and development of new Alzheimer's medicines will benefit from an improved understanding of PK-PD relationships through the development of mechanistic PK-PD models. Several of the PK-PD models for APP processing largely rely on the effects of g-secretase inhibition on Ab levels (Craft et al, 2002;Lu et al, 2011;Tai et al, 2012). Recently, Lu et al (2012) reported a PK-PD model for Ab lowering in CSF and brain in rodents.…”

Establishing the Relationship between In Vitro Potency, Pharmacokinetic, and Pharmacodynamic Parameters in a Series of Orally Available, Hydroxyethylamine-Derived β-Secretase Inhibitors

“…This apparent brain/CSF shift has been observed by others with both BACE1 and ␥-secretase inhibitors (Sankaranarayanan et al, 2009;Hawkins et al, 2011;Lu et al, 2011;Dineen et al, 2012;Weiss et al, 2012). There are several possible explanations for this observation.…”