Population pharmacokinetics-pharmacodynamics of oral everolimus in patients with seizures associated with tuberous sclerosis complex.

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 Emax function of Cmin on the seizure mean, where Emax 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 Emax. The dependence of seizure frequencies on Cmin was explored by simulation. The responder rate increased with increasing Cmin. As Cmin 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.

Modeling and Simulation Support Eltrombopag Dosing in Pediatric Patients With Immune Thrombocytopenia.

Our objective was to support initial eltrombopag doses and dose titration based on modeling and simulation of plasma exposure and platelet count response in pediatric patients aged 1-17 years with previously treated chronic immune thrombocytopenia enrolled in two clinical studies. Data from 168 pediatric patients were used to develop a life-span population pharmacokinetic and pharmacodynamic model including three pharmacokinetic and four pharmacodynamic compartments enabling simulation of platelet counts for various starting doses and dose titration schedules. This work supported initial eltrombopag doses of 50 mg once daily (q.d.) for non-Asian patients aged ≥ 6 years and 25 mg q.d. for Asian patients, regardless of age, and for all patients aged 1-5 years, regardless of ethnic origin. Doses were escalated at 2-week intervals or reduced as needed according to each patient's platelet counts to both minimize the time to achieve target platelet counts and mitigate thrombocytosis. Clinicaltrials.gov Identifier: NCT00908037, NCT01520909.

Nilotinib population pharmacokinetics and exposure-response analysis in patients with imatinib-resistant or -intolerant chronic myeloid leukemia.

PURPOSE: We evaluated the population pharmacokinetics (PK) and exposure-response relationship of nilotinib in patients with imatinib-resistant or -intolerant chronic myeloid leukemia (CML). METHODS: Concentration data from 493 patients with CML in chronic phase (CML-CP), accelerated phase, or blast crisis were used to perform a population pharmacokinetic analysis using nonlinear mixed-effect modeling. Steady-state nilotinib trough concentrations (Cmin) in individual patients were estimated from the population PK model for correlation with the efficacy and safety variables. Exposure-efficacy analysis was performed in patients with CML-CP, whereas exposure-safety analysis was performed in all patients who had both nilotinib PK data and efficacy/safety measures available. RESULTS: Baseline demographics and CML disease phase did not significantly affect nilotinib PK. Patients with a lower Cmin had significantly longer time to complete cytogenetic response (P = 0.010), longer time to major molecular response (P = 0.012), shorter time to progression (TTP; P = 0.009), and a trend toward lower response rates vs. patients with higher Cmin. A joint effect of prognostic risk score and Cmin on TTP was significant (P < 0.001). Nilotinib Cmin was also associated with the occurrence of all-grade elevations in total bilirubin (P < 0.001) and lipase (P = 0.002) levels. CONCLUSIONS: When tolerability allows, adherence to the nilotinib dose (400 mg twice daily) in order to maintain sufficient Cmin is important in maximizing the efficacy of nilotinib in patients with imatinib-resistant or -intolerant CML.