An IQ consortium analysis of starting dose selection for oncology small molecule first-in-patient trials suggests an alternative NOAEL-based method can be safe while reducing time to the recommended phase 2 dose.

The first-in-patient (FIP) starting dose for oncology agents should be reasonably safe and provide potential therapeutic benefit to the patient. For late-stage oncology patients, this dose is often based on the ICH S9 guidance, which was developed primarily based on experience with cytotoxic chemotherapeutic agents using the rodent STD or non-rodent HNSTD and an appropriate safety factor. With the increase in molecularly targeted chemotherapeutics, it is prudent to re-evaluate how the FIP dose is derived to ensure that the appropriate balance between risk and therapeutic benefit to the patient is achieved.

Lack of value of juvenile animal toxicity studies for supporting the safety of pediatric oncology phase I trials.

Toxicity studies in juvenile animals (JAS) are sometimes performed to support clinical trials in pediatric oncology patients, and there are differing conclusions on the value of JAS for pediatric drug development. This manuscript provides a review of the pediatric clinical data for 25 molecularly-targeted and 4 biologic anticancer therapeutics. Other publications that evaluated the value of JAS in pediatric drug development focus on differences in toxicity between juvenile animals and adult animals.

Historical data analyses and scientific knowledge suggest complete removal of the abnormal toxicity test as a quality control test.

In the early 1900s, the abnormal toxicity test (ATT) was developed as an auxiliary means to ensure safe and consistent antiserum production. Today, the ATT is utilized as a quality control (QC) release test according to pharmacopoeial or other regulatory requirements. The study design has not been changed since around 1940.

Serum cardiac troponin I concentrations transiently increase in rats given rosiglitazone.

Rosiglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist of the thiazolidinedione class, is a major insulin-sensitizing drug widely used to treat type-2 diabetes. Rosiglitazone causes myocardial hypertrophy in rodents and increases the risk of cardiac events in man. To better characterize its cardiac effects, male Wistar rats were orally administered 0, 10 or 80 mg/kg/day rosiglitazone.