Preclinical pharmacokinetics (PK) and pharmacodynamics (PD) of BGC 945: a unique tumour targeted thymidylate synthase (TS) by virtue of its selective uptake by the folate receptor (FR)
Authors: Ann Jackman, Martin Forster, Fraser Mitchell, Ruth Ruddle, Melanie Valenti, Sue Eccles, John Schurig, Florence Raynaud
Journal: Cancer Research (2007)

3191  Reducing the toxicity associated with anticancer drugs is a major challenge that might be overcome by effective drug targeting to the tumour. Antifolates such as raltitrexed and pemetrexed are not specifically tumour targeted because they are transported into cells via the ubiquitously expressed, reduced-folate carrier (RFC). The α-FR is a surface receptor overexpressed in many tumours, particularly ovarian carcinomas. However, expression in normal tissues is relatively low and restricted to some luminal surfaces and therefore not accessible to agents within the circulatory system. Exploiting this knowledge we developed BGC 945, a cyclopenta[g]quinazoline with high affinities for α-FR (Kd ~0.1nM) and TS (Ki = 1.2nM), very low affinity for the RFC (Km ~2mM) and high potency in cultured tumour cells expressing α-FR (IC50 = 1-300nM; dependent on expression level). That BGC 945 transport is FR-mediated is demonstrated by low potency for α-FR negative cells (IC50 ~5µM) and studies in KB tumour-bearing mice demonstrating tumour localisation and selective tumour TS inhibition (Gibbs et al, Cancer Res. 2005). We now describe more detailed preclinical PK and toxicity data from canine studies, and further PD in IGROV-1 ovarian tumour-bearing mice. Unlike rodents, dogs are a clinically relevant toxicity model for TS inhibitors because their plasma thymidine levels are much lower than rodents and more similar to humans. Plasma and tumour deoxyuridine (dUrd) (PD marker of TS inhibition in proliferating tissues and tumour respectively) were measured by HPLC, and plasma BGC 945 by LC-MS/MS. In dogs, the Cmax after 100mg/kg was 621nmoles/ml, 2-fold higher than observed in mice. The AUC INF (1584 hr x nmole/ml) was 10-fold higher in dogs than mice. In vitro experiments with IGROV-1 cells predicted a target drug exposure in vivo for 72h of at least 100nM (or lower concentrations for longer) but not higher than 5µM. Comparison of 100mg/kg dose in mice and dogs led to time above this 100nM threshold of ~14h and >24h respectively (48h ~50nM). Despite the rapid clearance in mice, 100mg/kg induced a rise in dUrd in the IGROV-1 xenograft that was greater than 10-fold for ~48h. Thereafter levels fell but had not returned to pre-treatment levels at 72hr. Plasma dUrd was unchanged over 72h. This prolonged tumour-specific TS inhibition in mice is consistent with the rapid distribution of BGC 945 observed to the tumour and the long half-life in tumour (28h) compared with other tissues. This suggests that the target plasma threshold may be even lower than predicted from the in vitro studies. Despite the higher drug exposure observed in dogs compared with mice at 100mg/kg, no toxicity was observed at this dose and the MTD was ~600mg/kg (gut toxicity). These data suggest that BGC 945 will have the desired tumour targeted profile with minimal toxicities at effective doses.