| Autor: |
Combes FP; Oncology/Pharmacometrics, Novartis Pharmaceuticals Corporation, One Health Plaza, 337/A06/7E, East Hanover, NJ, 07936-1080, USA. francois_pierre.combes@novartis.com., Baneyx G; Pharmacometrics, Novartis Pharma AG, Basel, Switzerland., Coello N; Oncology/Pharmacometrics, Novartis Pharmaceuticals Corporation, One Health Plaza, 337/A06/7E, East Hanover, NJ, 07936-1080, USA., Zhu P; Novartis Institute for Biomedical Research, East Hanover, USA., Sallas W; Oncology/Pharmacometrics, Novartis Pharmaceuticals Corporation, One Health Plaza, 337/A06/7E, East Hanover, NJ, 07936-1080, USA., Yin H; Novartis Institute for Biomedical Research, East Hanover, USA., Nedelman J; Oncology/Pharmacometrics, Novartis Pharmaceuticals Corporation, One Health Plaza, 337/A06/7E, East Hanover, NJ, 07936-1080, USA. |
| Abstrakt: |
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 max function of C min on the seizure mean, where E max 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 max . The dependence of seizure frequencies on C min was explored by simulation. The responder rate increased with increasing C min . As C min 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. |
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