Thus, the NTP may need to conduct multiple dose range-finding studies and make decisions regarding whether doses would change during the course of the study.
No major toxicities had been observed at this dose level in a separate non-GLP multiple dose-range finding study in cynomolgus monkeys (data not shown).
Follow-up periods for the trials that used a single dose ranged from one to 21 months, while the follow-up periods for trials that used multiple doses ranged from post-intervention to five years.
The individual terminal elimination t1/2 following the first and multiple doses ranged from 4.42 to 9.38 days and 4.06 to 8.83 days, respectively, across all dose groups and dosing schedules.
The initial studies in patients with melanoma evaluated ipilimumab at single or multiple doses ranging from 0.1 to 20 mg/kg, either as monotherapy or in combination with IL-2, 47 gp100 melanoma peptide vaccine, 48 or chemotherapy.
Reflecting the dose-finding nature of many of these trials, the studies utilized multiple doses (ranging from 0.5 to 10 mg/kg as either monotherapy or in combination studies) and schedules (ranging from a single dose of ipilimumab to recurring doses every 3 weeks for four cycles).
The validity of the model is supported by the good prediction of the complicated PKs observed in the clinical study described in this article, which included both single and multiple dosing regimens ranging from 5 to 240 mg across 9 dose levels.
To evaluate these factors, an increased number of subjects (n = 104), number of observations per subject (n = 6 for single ascending dose and 15 for multiple ascending dose), and dose range (n = 20 300 mg) were tested.
Exposure (area under the plasma concentration time curve from 0 to 24 h [AUC24 h] and maximum plasma drug concentration [ Cmax]) tended to increase in a dose-dependent manner following multiple administrations across the dose range from 1 to 4 mg (Table 3).
A dose-proportional increase in the area under the plasma concentration-time curve over the dosing interval (AUC0−tau) was suggested for TAK-285 after multiple dosing at doses ranging from 50 to 300 mg b.i.d.
