Population modeling of tumor size dynamics has recently emerged as an important tool in pharmacometric research. A series of new mixed‐effects models have been reported recently, and we present herein a synthetic view of models with published mathematical equations aimed at describing the dynamics of tumor size in cancer patients following anticancer drug treatment. This selection of models will constitute the basis for the Drug Disease Model Resources (DDMoRe) repository for models on oncology.CPT: Pharmacometrics & Systems Pharmacology (2014) 3, e113; doi:10.1038/psp.2014.12; advance online publication 7 May 2014

Aims: To describe the pharmacokinetic–pharmacodynamic (PK–PD) characteristics of the direct thrombin inhibitor dabigatran in hip replacement patients by assessing coagulation parameters activated partial thromboplastin time (aPTT) and ecarin clotting time (ECT), interindividual variability and factors affecting PD responses.Methods: BISTRO I patients received oral dabigatran etexilate postsurgery for 6–10 days. Dabigatran plasma concentrations and aPTT/ECT were measured on the day of surgery, on subsequent days and at steady state. PK–PD characteristics of the dabigatran–aPTT/ECT relationships were evaluated using NONMEM V.Results: The dabigatran concentration–aPTT relationship was described combining a linear and an E_max model. Mean baseline aPTT was 33.4 s and E_max (maximum increase in aPTT contributed by the E_max model) was 26.9 s. The dabigatran concentration needed to attain 50% of maximum effect (EC₅₀) was 94.7 ng ml⁻¹ and the mean slope of the linear concentration–response relationship (SLOP) was 0.0509 s ng⁻¹ ml⁻¹. Baseline aPTT and E_max were highest following surgery and declined with time. The dabigatran concentration–ECT relationship fitted a linear model. Mean baseline ECT was 28 s and decreased with time; 50% of the maximum effect was observed after 2.9 days. SLOP decreased from 0.38 to 0.27 s ng⁻¹ ml⁻¹ with a half‐life of 1.1 day, indicating greater PD effects on the day of surgery. Interindividual and residual variability was low. Covariates could not explain variability of this model.Conclusions: aPTT and ECT prolongation were directly correlated with dabigatran concentrations. Blood coagulation prolongation was most pronounced following surgery. Data suggest that ECT provides a more precise description of the anticoagulant effect than aPTT.

To evaluate the pharmacokinetics of piperacillin/tazobactam in critically ill patients undergoing continuous renal replacement therapy (CRRT) and to assess the success of the therapy against susceptible bacteria. Sixteen patients undergoing CRRT with different degrees of renal function were included in the study. Blood and ultrafiltrate samples were drawn after administration of piperacillin/tazobactam (4/0.5 g) every 4, 6 or 8 h. The data were analysed by a population approach using NONMEM 7.2. The probability of target attainment (PTA) of maintaining free piperacillin levels above the MIC during the entire dosing interval was estimated by simulation of intermittent and continuous infusions. The pharmacokinetics of piperacillin and tazobactam were best described by two-compartment models where the elimination of both drugs was conditioned by renal [dependent on creatinine clearance (CLCR)], non-renal and extracorporeal clearances. A 20 min infusion of piperacillin/tazobactam administered every 6 h provided high PTAs against MICs ≤ 32 mg/L in patients with severe renal failure. In patients with normal or moderate renal function PTAs ≥ 90% were only obtained up to MICs ≤ 8 mg/L with short infusions. However, simulating continuous infusion, higher probabilities of success were obtained against MICs of 32 and 16 mg/L when CLCR was 50 and 100 mL/min, respectively. Population pharmacokinetic models have been developed and validated for piperacillin and tazobactam. Based on the pharmacokinetic/pharmacodynamic analysis, dosing recommendations are given considering the residual renal function of the patient and the MIC for the isolated bacteria.