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word count: 250 (limit 250)Figures/tables: 6 (2 tables, 4 figures) (limit of 6 tables and/or figures) References: 16 (limit 50) Clinicaltrials.gov Identifier: NCT01235962Statement of translational relevance: 118 words (limit 120-150 words) Currently no adjuvant treatments are approved for locally advanced renal cell carcinoma (RCC) to reduce the risk of disease recurrence following surgical resection of the primary tumor. In the PROTECT study, adjuvant pazopanib at 600 mg daily following nephrectomy did not meet the primary endpoint of improved disease-free survival (DFS) compared with placebo. The current analyses of pazopanib exposure (C trough ) showed that higher pazopanib exposure was associated with improved DFS, without an increase in grade 3/4 adverse events with the exception of hypertension. Pharmacokinetic simulations showed overlapping pazopanib exposure with 600 mg and 800 mg doses. The results suggest that patients achieving higher pazopanib C trough derived more clinical benefit from adjuvant pazopanib therapy. Conclusions:In the adjuvant setting, higher pazopanib C trough was associated with improved DFS, and did not increase treatment discontinuations or grade 3/4 AEs with the exception of hypertension.

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Everolimus is approved in Europe and in the USA for the adjunctive treatment of patients aged 2 years and older whose refractory partial-onset seizures, with or without secondary generalization, are associated with tuberous sclerosis complex. The objective of this analysis was to establish a population pharmacokinetic (PK)/pharmacodynamic model describing the relationship between seizure frequency and everolimus exposure to confirm the recommended target concentration range of 5-15 ng/mL. The PK model was a two-compartment model with first order absorption and clearance. CYP3A and P-gp inducers and body-surface area were shown to impact everolimus exposure, justifying dose adjustments. A Poisson distribution was found to adequately describe the random nature of daily seizure counts during the screening phase. A placebo effect on the Poisson seizure mean was implemented as an asymptotic exponential function of time leading to a new steady-state seizure mean. The everolimus effect was implemented as an inhibitory E function of C on the seizure mean, where E exhibited an asymptotic exponential increase over time to a higher steady-state value. Increasing age was found to decrease the baseline seizure mean and to prolong the half-life of the increase in E. The dependence of seizure frequencies on C was explored by simulation. The responder rate increased with increasing C. As C decreased below 5 ng/mL, variability in response became larger and responder rates decreased more rapidly. The results supported the recommended target concentration range for everolimus of 5-15 ng/mL to ensure treatment efficacy.