AIMS: The aim of the study was to characterize the population pharmacokinetics of indinavir, define the relationship between the pharmacokinetics of indinavir and ritonavir, and to identify the factors influencing the pharmacokinetics of indinavir alone or when given with ritonavir. METHODS:HIV-1-infected patients being treated with an indinavir-containing regimen were included. During regular visits, 102 blood samples were collected for the determination of plasma indinavir and ritonavir concentrations. Full pharmacokinetic curves were available from 45 patients. Concentrations of indinavir and ritonavir were determined by liquid chromatography coupled with electrospray tandem mass spectrometry. Pharmacokinetic analysis was performed using nonlinear mixed effect modelling (NONMEM). RESULTS: The disposition of indinavir was best described by a single compartment model with first order absorption and elimination. Values for the clearance, volume of distribution and the absorption rate constant were 46.8 l h(-1) (24.2% IIV), 82.3 l (24.6% IIV) and 02.62 h(-1), respectively. An absorption lag-time of 0.485 h was detected in patients also taking ritonavir. Furthermore this drug, independent of dose (100-400 mg) or plasma concentration, decreased the clearance of indinavir by 64.6%. In contrast, co-administration of efavirenz or nevirapine increased the clearance of indinavir by 41%, irrespective of the presence or absence of ritonavir. Female patients had a 48% higher apparent bioavailability of indinavir than males. CONCLUSIONS: The pharmacokinetic parameters of indinavir were adequately described by our population model. Female gender and concomitant use of ritonavir and non-nucleoside reverse transcriptase inhibitors strongly influenced the pharmacokinetics of this drug. The results support the concept of ritonavir boosting, maximum inhibition of indinavir metabolized being observed at 100 mg.
RCT Entities:
AIMS: The aim of the study was to characterize the population pharmacokinetics of indinavir, define the relationship between the pharmacokinetics of indinavir and ritonavir, and to identify the factors influencing the pharmacokinetics of indinavir alone or when given with ritonavir. METHODS:HIV-1-infectedpatients being treated with an indinavir-containing regimen were included. During regular visits, 102 blood samples were collected for the determination of plasma indinavir and ritonavir concentrations. Full pharmacokinetic curves were available from 45 patients. Concentrations of indinavir and ritonavir were determined by liquid chromatography coupled with electrospray tandem mass spectrometry. Pharmacokinetic analysis was performed using nonlinear mixed effect modelling (NONMEM). RESULTS: The disposition of indinavir was best described by a single compartment model with first order absorption and elimination. Values for the clearance, volume of distribution and the absorption rate constant were 46.8 l h(-1) (24.2% IIV), 82.3 l (24.6% IIV) and 02.62 h(-1), respectively. An absorption lag-time of 0.485 h was detected in patients also taking ritonavir. Furthermore this drug, independent of dose (100-400 mg) or plasma concentration, decreased the clearance of indinavir by 64.6%. In contrast, co-administration of efavirenz or nevirapine increased the clearance of indinavir by 41%, irrespective of the presence or absence of ritonavir. Female patients had a 48% higher apparent bioavailability of indinavir than males. CONCLUSIONS: The pharmacokinetic parameters of indinavir were adequately described by our population model. Female gender and concomitant use of ritonavir and non-nucleoside reverse transcriptase inhibitors strongly influenced the pharmacokinetics of this drug. The results support the concept of ritonavir boosting, maximum inhibition of indinavir metabolized being observed at 100 mg.
Authors: R P van Heeswijk; A I Veldkamp; R M Hoetelmans; J W Mulder; G Schreij; A Hsu; J M Lange; J H Beijnen; P L Meenhorst Journal: AIDS Date: 1999-10-01 Impact factor: 4.177
Authors: R M Hoetelmans; R P van Heeswijk; M Profijt; J W Mulder; P L Meenhorst; J M Lange; P Reiss; J H Beijnen Journal: AIDS Date: 1998-12-03 Impact factor: 4.177
Authors: Bregt S Kappelhoff; Alwin D R Huitema; Kristel M L Crommentuyn; Jan W Mulder; Pieter L Meenhorst; Eric C M van Gorp; Albert T A Mairuhu; Jos H Beijnen Journal: Br J Clin Pharmacol Date: 2005-02 Impact factor: 4.335
Authors: Bregt S Kappelhoff; Alwin D R Huitema; Zeynep Yalvaç; Jan M Prins; Jan W Mulder; Pieter L Meenhorst; Jos H Beijnen Journal: Clin Pharmacokinet Date: 2005 Impact factor: 6.447
Authors: A Hsu; G R Granneman; G Cao; L Carothers; A Japour; T El-Shourbagy; S Dennis; J Berg; K Erdman; J M Leonard; E Sun Journal: Antimicrob Agents Chemother Date: 1998-11 Impact factor: 5.191
Authors: Melinda E Wilson; Kimberly F Allred; Elizabeth M Kordik; Deana K Jasper; Amanda N Rosewell; Anthony J Bisotti Journal: AIDS Res Ther Date: 2007-05-01 Impact factor: 2.250