Population pharmacokinetics of cisplatin in small cell lung cancer patients guided with informative priors.

PURPOSE: Cisplatin-etoposide treatment is recommended as a first line in small cell lung cancer patients (SCLC). However, the prognosis is poor and the dosing is not tailored beyond the body surface area, which is related with indeterminate cisplatin exposure-response relationship. We aimed to evaluate cisplatin pharmacokinetics (PK) and the exposure to unbound cisplatin in SCLC patients using the informative priors, and assess the relationship between the cisplatin exposure and probability of neutropenia. METHODS: Observational clinical study was performed including 17 cisplatin-treated SCLC patients. External population cisplatin PK models were identified and NONMEM® software and $PRIOR subroutine were used for the model evaluation. The bias and precision of the model-predicted cisplatin concentrations were evaluated. The best models were combined in a final model including several sets of informative priors, which was used to estimate individual cisplatin exposure, analyze the relationship between the exposure and neutropenia and simulate several cisplatin dosing regimens in a virtual patient cohort. RESULTS: The models by Urien with the informative priors best fitted the data. The individual cisplatin exposure ranged between 2430 and 4560 µg*h/L. There was a trend of increasing probability of neutropenia and febrile neutropenia with increasing cisplatin exposure. Approximately 50%, 75% and 90% of patients receiving 60 mg/m2, 70 mg/m2 and 80 mg/m2, respectively, achieved the previously identified exposure threshold of 2860 µg*h/L. CONCLUSION: We developed a tool to individualize cisplatin dosing based on the estimated probability of neutropenia. The benefit of more intense dosing regimens in SCLC patients should be further assessed.

Relative bioavailability enhancement of simvastatin via dry emulsion systems: Comparison of spray drying and fluid bed layering technology.

Comprehensive comparisons of similar lipid based drug delivery systems produced by different technologies are scarce. Spray drying and fluid bed layering technologies were compared with respect to the process and product characteristics of otherwise similar simvastatin loaded dry emulsion systems. Fluid bed layering provided higher process yield (83.3% vs 71.5%), encapsulation efficiency (80.0% vs 68.4%), relative one month product stability (93.8% vs 85.5%), larger and more circular particles (336 µm vs 56 µm) and lower median oil droplet size after product reconstitution in water (2.85 µm vs 4.27 µm), compared to spray drying. However, spray dried products exhibited higher drug content (22.2 mg/g vs 9.34 mg/g). An in-vivo pharmacokinetic study in rats was performed and a pharmacokinetic model was developed in order to compare the optimised simvastatin loaded dry emulsion systems, a simvastatin glyceride mimetic loaded in the dry emulsion and a simvastatin loaded SMEDDS with a reference physical mixture. Of the formulation tested, fluid bed layered pellets excelled and provided a 115% relative increase in bioavailability. Among the two technologies, fluid bed layering provided dry emulsion products with higher relative bioavailability and better product characteristics for further processing into final dosage forms.

Ustekinumab Dosing Individualization in Crohn's Disease Guided by a Population Pharmacokinetic-Pharmacodynamic Model.

Ustekinumab is a monoclonal antibody used in Crohn's disease (CD). Dose optimization in case of non-response and the role of pharmacokinetic-pharmacodynamic (PK-PD) monitoring remain unresolved dilemmas in clinical practice. We aimed to develop a population PK-PD model for ustekinumab in CD and simulate efficacy of alternative dosing regimens. We included 57 patients and recorded their characteristics during 32 weeks after starting with ustekinumab therapy. Serum ustekinumab concentration was prospectively measured and fecal calprotectin (FC) concentration was used to monitor the disease activity. Ustekinumab PK-PD was described by a two-compartment target-mediated drug disposition model linked to an indirect response model. Lower fat-free mass, higher serum albumin, previous non-exposure to biologics, FCGR3A-158 V/V variant and lower C-reactive protein were associated with higher ustekinumab exposure. Model-based simulation suggested that 41.9% of patients receiving standard dosing achieve biochemical remission at week 32. In patients not achieving remission with standard dosing at week 16, transition to 4-weekly subcutaneous maintenance dosing with or without intravenous reinduction resulted in comparably higher remission rates at week 32 (51.1% vs. 49.2%, respectively). Our findings could be used to guide stratified ustekinumab treatment in CD, particularly in patients with unfavorable characteristics, who might benefit from early transition to 4-weekly maintenance dosing.