Integration of data from multiple sources for simultaneous modelling analysis: experience from nevirapine population pharmacokinetics.
OBJECTIVE
To propose a modelling strategy to efficiently integrate data from different sources in one simultaneous analysis, using nevirapine population pharmacokinetic data as an example.


METHODS
Data from three studies including 115 human immunodeficiency virus-infected South African adults were used. Patients were on antiretroviral therapy regimens including 200 mg nevirapine twice daily and sampled at steady state. A development process was suggested, implemented in NONMEM7 and the final model evaluated with an external data set.


RESULTS
A stepwise approach proved efficient. Model development started with the intensively sampled data. Data were added sequentially, using visual predictive checks for inspecting their compatibility with the existing model. Covariate exploration was carried out, and auxiliary regression models were designed for imputation of missing covariates. Nevirapine pharmacokinetics was described by a one-compartment model with absorption through two transit compartments. Body size was accounted for using allometric scaling. The model included a mixture of two subpopulations with different typical values of clearance, namely fast (3.12 l h(-1)) and slow metabolizers (1.45 l h(-1)), with 17% probability of belonging to the latter. Absorption displayed large between-occasion variability, and food slowed the absorption mean transit time from 0.6 to 2.5 h. Concomitant antitubercular treatment including rifampicin typically decreased bioavailability by 39%, with significant between-subject variability. Visual predictive checks of external validation data indicated good predictive performance.


CONCLUSIONS
The development strategy succeeded in integrating data from different sources to produce a model with robust parameter estimates. This work paves the way for the creation of a nevirapine mega-model, including additional data from numerous diverse sources.
Department of Pharmaceutical Bioscience, Uppsala University, Sweden. elin.svensson@farmbio.uu.se
Elin
E
Svensson
Jan-Stefan
JS
van der Walt
Karen I
KI
Barnes
Karen
K
Cohen
Tamara
T
Kredo
Alwin
A
Huitema
Jean B
JB
Nachega
Mats O
MO
Karlsson
Paolo
P
Denti
D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D004347:Drug Interactions; D005260:Female; D018565:Food-Drug Interactions; D005772:Gastrointestinal Transit; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D019829:Nevirapine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017711:Nonlinear Dynamics; D012044:Regression Analysis; D013019:South Africa; D055815:Young Adult
D019380:Anti-HIV Agents; D019829:Nevirapine