No abstract

In oncology trials, overall survival (OS) is considered the most reliable and preferred endpoint to evaluate the benefit of drug treatment. Other relevant variables are also collected from patients for a given drug and its indication, and it is important to characterize the dynamic effects and links between these variables in order to improve the speed and efficiency of clinical oncology drug development. However, the drug-induced effects and causal relationships are often difficult to interpret because of temporal differences. To address this, population pharmacokinetic–pharmacodynamic (PKPD) modelling and parametric time-to-event (TTE) models are becoming more frequently applied. Population PKPD and TTE models allow for exploration towards describing the data, understanding the disease and drug action over time, investigating relevance of biomarkers, quantifying patient variability and in designing successful trials. In addition, development of models characterizing both desired and adverse effects in a modelling framework support exploration of risk-benefit of different dosing schedules. In this review, we have summarized population PKPD modelling analyses describing tumour, tumour marker and biomarker responses, as well as adverse effects, from anticancer drug treatment data. Various model-based metrics used to drive PD response and predict OS for oncology drugs and their indications are also discussed.

The syntheses of 12 new 2,5-bis[4-(N-alkylamidino)phenyl]furans are reported. The interaction of these dicationic furans with poly(dA-dT) and with the duplex oligomer d(CGCGAATTCGCG)2 was determined by Tm measurements, and the effectiveness of these compounds against the immunosuppressed rat model of Pneumocystis carinii was evaluated. At the screening dose of 10 mumol/kg, 9 of the 14 N-alkylamidino furans described here are more active than the parent compound 1. Substitution of an alkyl group of the amidino nitrogen, except for in 9, 13, and 15, resulted in higher affinity for DNA than the parent compound as judged by the larger delta Tm values and suggests enhanced van der Waals interactions in the bis-amidine-DNA complex. Five of the compounds, 3, 5, 7, 10, and 12, yield cyst counts of less than 0.1% of control when administered at a dosage of 10 mumol/kg. Five compounds, 1, 6, 8, 10, and 12, show significant activity at a dosage of approximately 1 mumol/kg; 12 is the most active derivative, and it is approximately 100 times more effective than pentamidine in this animal model.

This semimechanistic PK/PD model accurately captures the cycle 1 platelet nadir, the downward drift noted in some patient platelet-time profiles, and the ~8 % incidence of grade ≥3 TCP with T-DM1 3.6 mg/kg q3w. This model supports T-DM1 3.6 mg/kg q3w as a well-tolerated dose with minimal dose delays or reductions for TCP.