Population pharmacokinetics of indinavir alone and in combination with ritonavir in HIV‐1‐infected patients

Abstract

AimsThe 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 reg imen 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). ResultsThe disposition of indinavir was best described by a single compar tment 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, coadministration 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. ConclusionsThe pharmacokinetic parameters of indinavir were adequately described by our population model. Female gender and concomitant use of ritonavir and nonnucleoside 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. Pharmacokinetics of indinavirBr J Clin Pharmacol 60 :3 277

Comparison of Model-Based Tests and Selection Strategies to Detect Genetic Polymorphisms Influencing Pharmacokinetic Parameters

“…The PK model has already been described but no gene effect has been investigated using a population approach to date. The estimated parameters are in accordance with estimations obtained in other studies (Csajka et al, 2004;Goujard et al, 2005;Kappelhoff et al, 2005). The Wald test is the only test to detect an influence of ABCB1 exon 26 on the volume of distribution.…”

Influence of Body Weight on Achieving Indinavir Concentrations Within Its Therapeutic Window in HIV-Infected Thai Patients Receiving Indinavir Boosted With Ritonavir

“…The final model estimates of CL/F and Vd/F were 21.3 L/hr/70 kg and 90.7 L/70kg, respectively, and these values are consistent with those reported in European patients 17, 18. Covariates reported to influence indinavir pharmacokinetics include concomitant ritonavir or non-nucleoside reverse transcriptase inhibitors (NNRTI) or ritonavir use, sex and body weight 11, 17.…”

Coadministration of Ritonavir Strongly Enhances the Apparent Oral Bioavailability of Docetaxel in Patients with Solid Tumors

“…Ritonavir is a HIV protease inhibitor, with strong CYP3A4-inhibiting properties and with only minor P-glycoprotein -inhibiting effects (14,15). Furthermore, the enhancement of the systemic exposure of CYP3A4 substrates by ritonavir is already a standard practice in the treatment of HIV patients with protease inhibitors (16,17). Recently, van Herwaarden et al (18) showed that the absence of Cyp3a activity in mice alone increased the systemic exposure of docetaxel after oral administration in vivo by 17.7-fold.…”