González-GarcÃa, I.(1); Mangas-Sanjuán, V.1, (2); Merino-Sanjuán, M.(1); Bermejo, M.(2)
(1) Pharmacy and Pharmaceutical Technology Department. University of Valencia. Valencia. Spain; (2) Pharmacy and Pharmaceutical Technology Area. Miguel Hernandez University. Alicante. Spain.
Objectives: The aim of our work was to analyse the best dose schedule in order to achieve similar drug exposure that the one achieved in the ongoing Phase III study (effective concentrations), simulating population groups with three different creatinine clearance and weight ranges.
Methods: NV22413 was previously fitted to a population PK model according to a two-compartment model with 3 transit compartments in the absorption process. Creatinine clearance and weight were statistically relevant covariates affecting to clearance and central volume, respectively. Population groups varying in creatinine clearance ranges (30-70, 70-100, >100 ml/min) were simulated and the exposure at five different doses was estimated: 1, 16, 30, 45, 60 mg once daily for each creatinine clearance level, In order to avoid situations where the relationship between creatinine clearance and body weight was unlikely, a correlation was established between weight and creatinine clearance. The simulated exposure levels were obtained by 1000 simulations of one patient for each clearance creatinine group using NONMEM 7.2 [1] and PsN 3.7.6 [2].
Results: The best dose schedule for population with the normal creatinine clearance (>100 ml/min) is 45 mg of NV2213 once per day, due to this dosing scheme achieves the highest percentage of the effective concentrations (87%). Nevertheless, for patients with lower clearance creatinine (
Conclusion: For patients with a normal value of clearance creatinine the best scheme of treatment is 45 mg once daily. In a previous study, the same dose was chosen to get the effective concentration in the population. However, when the creatinine clearance is diminished it is recommended to reduce the dose to 30 mg once daily.
References:
[1] Beal SL, Sheiner LB, Boeckmann AJ & Bauer RJ (Eds.) NONMEM Users Guides. 1989-2011. Icon Development Solutions, Ellicott City, Maryland, USA.
[2] Lindbom L, Ribbing J, Jonsson EN. Perl-speaks-NONMEM (PsN)-a Perl module for NONMEM related programming. Comput Methods Programs Biomed. 2004 Aug;75(2):85-94.
Reference: PAGE 23 () Abstr 3159 [www.page-meeting.org/?abstract=3159]
Poster: Methodology - Covariate/Variability Models