Navigating the landscape of parameter identifiability methods: A workflow recommendation for model development.

In pharmacometric modeling, it is often important to know whether the data is sufficiently rich to identify the parameters of a proposed model. While it may be possible to assess this based on the results of a model fit, it is often difficult to disentangle identifiability issues from other model fitting and numerical problems. Furthermore, it can be of value to ascertain identifiability beforehand.

A population K-PD model analysis of long-term testosterone inhibition in prostate cancer patients undergoing intermittent androgen deprivation therapy.

Intermittent androgen deprivation therapy with gonadotropin-releasing-hormone (GnRH) agonists can prevent or delay disease progression and development of castration resistant prostate cancer for subpopulations of prostate cancer patients. It may also reduce risk and severity of side effects associated with chemical castration in prostate cancer (PCa) patients. One of the earliest comprehensively documented clinical trials on this was reported in a Canadian patient population treated with leuprorelin preceded by a lead-in with cyproterone acetate.

Pharmacokinetic and pharmacodynamic modeling of the metastin/kisspeptin analog, TAK-448, for its anti-tumor efficacy in a rat xenograft model.

TAK-448 is the investigational metastin/kisspeptin analog, which is known to have an anti-tumor effect through suppression of androgen hormones (luteinizing hormone and testosterone) levels. This study developed pharmacokinetic-pharmacodynamic (PK/PD) models of TAK-448 and leuprorelin acetate (TAP-144) in a rat vertebral-cancer of the prostate (VCaP) androgen-sensitive prostate cancer xenograft model to quantitatively assess and compare the anti-tumor effects of both drugs. A potential contribution of the hormone-independent direct effects of TAK-448 to the tumor growth inhibition was also investigated in the in vivo rat xenograft model, because our in vitro experiments revealed that TAK-448 may also directly suppress VCaP cellular proliferation.

Influence of body composition on disposition of the highly fat distributed compound as analysed by physiologically based pharmacokinetic (PBPK) modeling and simulation.

A recent study suggested that the pharmacokinetics (PK) of highly fat distributed compounds can be affected by acute changes in the volume of adipose tissue. The present study investigates possible influences of body composition on the disposition of the highly lipophilic compound TAK-357 in two rat strains. Physiologically based PK (PBPK) modeling and simulation was applied on single and multiple dose PK data of TAK-357 in obese Wistar fatty rats and Wistar lean rats having approximately 45% and 13% body fat, respectively.

Impact of acute fat mobilisation on the pharmacokinetics of the highly fat distributed compound TAK-357, investigated by physiologically based pharmacokinetic (PBPK) modeling and simulation.

In a dog toxicokinetic study, an unusual plasma concentration increase of the highly lipophilic compound TAK-357 was observed 2 weeks after termination of a 2-week repeated dosing in one dog with acute body weight loss. The present study investigates the cause of this increase. A physiologically based pharmacokinetic (PBPK) model was constructed using the rat and dog pharmacokinetic data.