M.-E. Ebelin1, F. Mentré2, P. Burtin1, R. Laplanche3 1
NOVARTIS PHARMA AG, Clinical Pharmacology, 4002 Basel, Switzerlan,d2: INSERM U 436, 91 bd de l’Hôpital, 75013 Paris, France,3: NOVARTIS PHARMA AG, Drug Metabolism & Pharmacokinetics, 4002 Basel, Switzerland
A pharmacokinetic/pharmacodynamic (PK/PD) population approach was implemented in a phase II efficacy and tolerability trial of SDZ ENA 713, a compound developed as a symptomatic treatment for Alzheimer’s disease. The objectives were to investigate the exposure to SDZ ENA 713 and its metabolite in elderly patients; to evaluate the inter-individual PK variability in terms of patient-specific covariates; and to characterize the relationships between efficacy-safety-tolerability outcome variables, and demographic-biological covariates and individual measure of exposure.
A total of 1230 plasma concentrations of SDZ ENA 713 and its metabolite ZNS 114-666 were obtained at random times during the clinical evaluation visits in 220 patients having received either 2 mg or 3 mg b.i.d. of SDZ ENA 713. Parent drug and metabolite kinetics were analysed independently with NONMEM using a one compartment model with first-order absorption and elimination. Individual measures of exposure like Cmax and AUC were computed from the (Bayesian) posterior estimates of the pharmacokinetic parameters provided by NONMEM. The PK/PD relationships were investigated using univariate and multivariate logistic regression.
The NONMEM analysis confirmed the effect of dose on the pharmacokinetics of SDZ ENA 713 revealed by other PK studies in animals, healthy young and elderly volunteers, and patients. No effect of dose was detected on the pharmacokinetics of the metabolite. Both findings support the presence of a saturable first-pass phenomenon for SDZ ENA 713, which does not however affect the availability of the metabolite. The testing with NONMEM of the influential covariates initially detected by graphical exploration provided final models including an effect of sex on the oral clearance and of body surface area on the oral volume of distribution for both SDZ ENA 713 and ZNS 114-666. These models resulted in lower clearance in females, and higher volume of distribution with increasing body surface area. The PK/PD analysis revealed that the Clinical Global Impression of Change score defining responders and non-responders for efficacy was not significantly related to measures of exposure nor to patient-specific demographic-biological covariates. The occurrence of gastro-intestinal (GI) adverse events was increased with lower age, smaller body surface area, and higher exposure (Cmax) to ZNS 114-666. This latter association does not reflect a direct effect of the metabolite. Although local inhibition of cholinesterase within the GI tract and/or enzyme inhibition within the central nervous system can cause nausea/vomiting, the causality of these adverse events cannot be ascertained on the basis of this analysis. The probability of good and very good overall tolerability was decreased with higher dose, increased in smokers, and increased with increasing age.
Reference: PAGE 6 (1997) Abstr 655 [www.page-meeting.org/?abstract=655]
Poster: poster