Influence of pharmacogenetics on indinavir disposition and short-term response in HIV patients initiating HAART

Abstract

Aims: To assess the relationship between genetic polymorphisms and indinavir pharmacokinetic variability and to study the link between concentrations and short-term response or metabolic safety.

Methods: Forty protease inhibitor-naive patients initiating highly active antiretroviral therapy (HAART) including indinavir/ritonavir and enrolled in the COPHAR 2-ANRS 111 trial were studied. At week 2, four blood samples were taken before and up to 6 h following drug intake. A population pharmacokinetic analysis was performed using the stochastic approximation expectation maximization (SAEM) algorithm implemented in MONOLIX software. The area under the concentration-time curve (AUC) and maximum (C(max)) and trough concentrations (C(trough)) of indinavir were derived from the population model and tested for their correlation with short-term viral response and safety measurements, while for ritonavir, these same three parameters were tested for their correlation with short-term biochemical safety

Results: A one-compartment model with first-order absorption and elimination best described both indinavir and ritonavir concentrations. For indinavir, the estimated clearance and volume of distribution were 22.2 L/h and 97.3 L, respectively. The eight patients with the *1B/*1B genotype for the CYP3A4 gene showed a 70% decrease in absorption compared to those with the *1A/*1B or *1A/*1A genotypes (0.5 vs. 2.1, P = 0.04, likelihood ratio test by permutation). The indinavir AUC and C(trough) were positively correlated with the decrease in human immunodeficiency virus RNA between week 0 and week 2 (r = 0.4, P = 0.03 and r = -0.4, P = 0.03, respectively). Patients with the *1B/*1B genotype also had a significantly lower indinavir C(max) (median 3.6, range 2.1-5.2 ng/mL) than those with the *1A/*1B or *1A/*1A genotypes (median 4.4, range 2.2-8.3 ng/mL) (P = 0.04) and a lower increase in triglycerides during the first 4 weeks of treatment (median 0.1, range -0.7 to 1.4 vs. median 0.6, range -0.5 to 1.7 mmol/L, respectively; P = 0.02). For ritonavir, the estimated clearance and volume of distribution were 8.3 L/h and 60.7 L, respectively, and concentrations were not found to be correlated to biochemical safety. Indinavir and ritonavir absorption rate constants were found to be correlated, as well as their apparent volumes of distribution and clearances, indicating correlated bioavailability of the two drugs.

Conclusion: The CYP3A4*1B polymorphism was found to influence the pharmacokinetics of indinavir and, to some extent, the biochemical safety of indinavir.

Fig. 1

Observed plasma indinavir concentration (a) and plasma ritonavir concentration (b) versus time collected two weeks after treatment initiation, in 40 HIV naive-patients receiving indinavir plus 100 mg of ritonavir b.i.d. In the indinavir plot the plain lines correspond to an indinavir dose of 400 mg b.i.d., the dashed lines to 600 mg b.i.d. and the dotted lines to 800 mg b.i.d. Sampling times following drug administration were measured by the nurse. Concentrations were assumed at steady state, trough concentrations are displayed as following the drug intake at sampling times deduced from the patient record.

Fig. 2

Visual predictive check of the basic population PK model: comparison between the median (continued line) and the 90^th interval (colored area) predicted for 1000 simulated datasets and the observed concentrations of indinavir (a) and of ritonavir (b). In the indinavir plot the open circles correspond to an indinavir dose of 400 mg, the open triangles to 600 mg and the crosses to 800 mg

Fig. 3

Differences in log viral load (ΔlogVL) observed between treatment initiation and week 2 versus area under the concentration-time curve (a) and trough plasma concentration of indinavir (b) predicted by the model

Fig. 4

Peak indinavir concentrations predicted by the model (a) and differences in triglycerides (Δtriglyceride) 4 weeks before and after treatment initiation (b) versus CYP3A4 genotype. The solid-line represents the median in each group