T. Nemaura
Department of Clinical Pharmacology, College of Health Sciences, University of Zimbabwe
Objectives: To develop methods/models that enable better predictions of pharmacokinetic parameter estimates. There is possible new way of modeling which enables development of parameter estimates and allows for better prediction of what is occurring within the body. Instead of using the time variable space, in addition, it is possible to capture the effects that are attributable to the covariates as well by use of the developed covariate space.
Methods: Gender, middose plasma concentration, weight and CYP2B6, 516G>T genetic data of 61 patients on efavirenz containing HAART and on anti TB drugs was collated and analysed. Models were derived to estimate PK parameters that include bioavailability, elimination rate constant, volume of distribution and AUC using NONMEM, Partial Least Squares Regression, Regression methods.
Results: A new measure related to the uptake of the drug is incorporated in modeling of transportation (cumulative uptake volume). The cumulative uptake-volume associated with the full absorption of 600mg of Efavirenz was estimated to be 35.56L. An acceptable relationship was established between estimated oral bioavailability (f) and middose concentration (x) at steady state {f = 0.2194+0.24388ln x, R²=0.97, p<0.00001}. There was no patient below 1µg/ml in this population sample at middose concentration. Patients who carry the CYP2B6 G516T TT genotype are projected to have high efavirenz exposure. The estimated bioavailability in this population ranges from (0.29; 0.86).
Conclusions: Construction of a highly correlated variable to plasma concentration by Partial Least Squares regression enabled the development of a covariate measure. That enabled the estimation of oral bioavailability which then improves predictions of efavirenz plasma concentrations. Efavirenz is a drug that is well distributed in the fluid volume system. These relations are achieved from modeling with the aid of the covariate space.
Acknowledgements:
We thank College of Health Sciences (University of Zimbabwe), AIBST, C. Masimirembwa, C. Nhachi, G. Kadzirange, and Norvatis sponsored Pharmacometrics workshops in Africa.
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Reference: PAGE 23 () Abstr 3061 [www.page-meeting.org/?abstract=3061]
Poster: Methodology - New Modelling Approaches