Mega-model of nevirapine population pharmacokinetics
Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
The aim of the project was to develop a mega model of nevirapine pharmacokinetics (PK) in a diverse population of adult South African HIV-patients on highly active anti-retroviral therapy (HAART). A secondary aim was to learn about modeling issues that arise when data from several sources is used in the developing process.
Data of nevirapine plasma concentrations from four different South African clinical studies were available. All patients were HIV-positive and on HAART regimens including 200 mg nevirapine twice daily. Sampling was done at steady state in all the studies but sampling schedule and conditions varied. The population PK of nevirapine was described by non-linear mixed effects modeling with NONMEM7. The model was developed stepwise, starting from the rich data and subsequently adding the sparse data. The model was used to search for significant covariates and the models predictive performance was evaluated.
Nevirapine population PK was described by a one compartment disposition model with absorption through two transit compartments and first order elimination. The model included a mixture of two sub-populations with different typical value of clearance. The estimates of the typical values of oral clearance in the two populations, volume of distribution and mean transit time were 3.14 L/h (RSE 4.0%), 1.39 L/h (RSE 14%), 91.4 L (RSE 4.4%) and 2.41 h (RSE 7.2%) respectively. The proportion of individuals with lower clearance was estimated to 14% (RSE 47%). Between subject variability in clearance and bioavailability for patients on concomitant TB-treatment and between occasion variability in mean transit time and bioavailability were estimated to were estimated to 19% (RSE 14%), 35% (RSE 27%), 61% (RSE 9.6%) and 24% (RSE 13%) respectively. The model included allometric scaling with body weight of clearance and volume of distribution. Fasted conditions were found to result in a fivefold decrease in the mean transit time and concomitant TB-treatment decreased the bioavailability by almost 40%. No other statistically significant covariates were identified. The final model described the data from two out of the four studies well. The other two studies could potentially be included if incorporated together with a study effect, preventing an unreasonable change in parameter estimates.
The model is the first population model including a mixture on clearance to handle individuals with extremely high concentration levels. The model identifies effects of TB-treatment and food on nevirapine PK and generates precise and stable estimates of the typical values and variability of the model parameters. This South African mega model may serve as a starting point for development of a larger, international model to describe nevirapine PK in an even broader population.
Place, publisher, year, edition, pages
2011. , 67 p.
UPTEC K, ISSN 1650-8297 ; 11 013
IdentifiersURN: urn:nbn:se:uu:diva-162149OAI: oai:DiVA.org:uu-162149DiVA: diva2:459105
Master Programme in Chemical Engineering
2011-03-18, 13:00 (English)
Denti, Paolo, Dr.van der Walt, Jan-StefanKarlsson, Mats, Professor