TY - JOUR
T1 - Intrapatient and interpatient pharmacokinetic variability of raltegravir in the clinical setting
AU - SICCARDI, MARCO
AU - D'AVOLIO, ANTONIO
AU - Novoa, S. Rodriguez
AU - Cuenca, L.
AU - SIMIELE, MARCO
AU - BAIETTO, LORENA
AU - CALCAGNO, Andrea
AU - Moss, D.
AU - BONORA, Stefano
AU - Soriano, V.
AU - Back, D. J.
AU - Owen, A.
AU - DI PERRI, Giovanni
PY - 2012
Y1 - 2012
N2 - Raltegravir (RAL) is the first in class integrase inhibitor and is licensed for administration at 400 mg twice daily. RAL pharmacokinetics are characterized by high interpatient variability and recently RAL plasma exposure has been correlated with efficacy. RAL is primarily metabolized by glucuronidation via uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and UGT1A1*28 considered to be the main genetic variant associated with decreased UGT1A1 expression. This study investigated variability in RAL trough plasma concentrations (Ctrough) in the clinical setting, the effect of UGT1A1*28 and concomitant antiretrovirals.A total of 86 patients, from Turin, Italy, and Madrid, Spain, were included in the analysis. Blood samples were obtained 10-14 hours postdose. Genotyping for UGT1A1*28 was conducted by sequencing.High interpatient and intrapatient variabilities were observed; 13 patients had ≥3 samples available, and the median coefficient of variation was 128 (64-265). Coadministration of RAL with atazanavir (ATV, n = 9) resulted in higher raltegravir Ctrough, 517 (307-2706) ng/mL when compared with patients not receiving ATV (n = 77) 223 (95-552; P = 0.02). UGT1A1*28 did not influence RAL plasma exposure.We have documented large intersubject and intrasubject variabilities in RAL plasma concentrations and confirmed the interaction with ATV. Further studies are required to better understand the mechanisms that influence the pharmacokinetics of RAL.
AB - Raltegravir (RAL) is the first in class integrase inhibitor and is licensed for administration at 400 mg twice daily. RAL pharmacokinetics are characterized by high interpatient variability and recently RAL plasma exposure has been correlated with efficacy. RAL is primarily metabolized by glucuronidation via uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and UGT1A1*28 considered to be the main genetic variant associated with decreased UGT1A1 expression. This study investigated variability in RAL trough plasma concentrations (Ctrough) in the clinical setting, the effect of UGT1A1*28 and concomitant antiretrovirals.A total of 86 patients, from Turin, Italy, and Madrid, Spain, were included in the analysis. Blood samples were obtained 10-14 hours postdose. Genotyping for UGT1A1*28 was conducted by sequencing.High interpatient and intrapatient variabilities were observed; 13 patients had ≥3 samples available, and the median coefficient of variation was 128 (64-265). Coadministration of RAL with atazanavir (ATV, n = 9) resulted in higher raltegravir Ctrough, 517 (307-2706) ng/mL when compared with patients not receiving ATV (n = 77) 223 (95-552; P = 0.02). UGT1A1*28 did not influence RAL plasma exposure.We have documented large intersubject and intrasubject variabilities in RAL plasma concentrations and confirmed the interaction with ATV. Further studies are required to better understand the mechanisms that influence the pharmacokinetics of RAL.
UR - https://iris.uniupo.it/handle/11579/216933
U2 - 10.1097/FTD.0b013e31824aa50a
DO - 10.1097/FTD.0b013e31824aa50a
M3 - Article
SN - 0163-4356
VL - 34
SP - 232
EP - 235
JO - Therapeutic Drug Monitoring
JF - Therapeutic Drug Monitoring
ER -