Estimating the genetic component (RGC) in pharmacokinetic variability of the antiretroviral didanosine among healthy Brazilians.
BACKGROUND
We estimate the variance between between- and within-subjects, using mixed effect models, as a way to assess the genetic component in explaining the observed heterogeneity of ddl kinetics among healthy individuals. Our work expands on a previous reported method known as RGC.


METHODS
Repeated measurements of ddl concentration in the serum were obtained from 48 healthy adult volunteers enrolled in two bioequivalence study. We use the NONMEM program (Non-linear Mixed Effect Model) to estimate the between- and within-subject variability and the corresponding pharmacokinetic parameters. We assess the genetic contribution to the variability of each pharmacokinetic parameter through the RGC method.


RESULTS
Pharmacokinetic parameters, expressed as functions of covariates gender and creatinine clearance (CLCR), were: Oral clearance (CL = 55.1 + 240 * CLCR + 16.6 l/h for male and CL = 55.1 + 240 * CLCR for female), central volume (V2 = 9.82), inter-compartmental clearance (Q = 40.90/h), peripheral volume (V3 = 62.7 + 22.90 for male and V3 = 62.70 for female), absorption rate constant (Ka = 1.51 h(-1)) and duration of the dose administration (D = 0.44 h). The RGC of CL, Q, V3, Ka and D were 0.58, 0.97, 0.60, 0.53 and 0.88, respectively.


CONCLUSIONS
We estimated parameter-specific RGC indices and rank them according to the potential genetic contribution as an explanation for the observed variance. Our study design improved precision by decreasing background noise and, thus, improved the chances that indices such as the RGC are in fact describing genetic variability.
Velasque
Luciane S
LS
Programa de Computação Científica, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. velasque@fiocruz.br
Estrela
Rita de Cassia E
Rde C
Suarez-Kurtz
Guilherme
G
Struchiner
Claudio J
CJ
D000328:Adult; D019380:Anti-HIV Agents / Q000097:blood*; D016049:Didanosine / Q000097:blood*; D005260:Female; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010597:Pharmacogenetics; D018894:Reverse Transcriptase Inhibitors / Q000097:blood*; D012737:Sex Factors
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D016049:Didanosine