Indinavir Trough Concentration as a Determinant of Early Nephrolithiasis in HIV-1-Infected Adults

Abstract

Indinavir plasma levels are associated with antiretroviral efficacy however few data is available regarding toxicity. We assessed the relationship between indinavir pharmacokinetic (PK) characteristics and severe nephrolithiasis as well as other severe or serious adverse reactions (SAR). Patients included in the ANRS CO8 APROCO-COPILOTE cohort and receiving indinavir 800 mg thrice daily as first line protease inhibitor, were eligible for this study. To be included in the analysis, their plasma sample at month 1 (M1) had to be available (n=282) to estimate, using population PK modelling, indinavir PK characteristics, i.e. maximum (C max ) and trough plasma (C res ) concentrations, area under the curve (AUC) and observed/predicted concentrations ratio (CR). A Cox model was used to estimate the independent effect of C max , C res , AUC and CR on the hazard of severe nephrolithiasis and SAR. At M1, median C max was 6 205 ng/mL, C res : 631 ng/mL, AUC: 24 242 ng.h/mL and CR: 0.6. After a median follow-up of 12 months, 11% of patients (30/282) had experienced at least one SAR among which 12 were nephrolithiasis.In the multivariate analyses, early high indinavir C res (i.e. ≥ 1000 ng/mL at M1) was associated with a higher rate of severe nephrolithiasis (HR=6.7; 95% confidence interval=1.8-25.2; p<0.01) and was also associated with a higher rate of all SAR but only when nephrolithiasis were included among those cases. Prospective and early indinavir C res determination should be recommended in the patient's care management and dosage adjustments.

Nephrocalcinosis and urolithiasis in children

“…As indinavir is poorly soluble at pH 45, urinary acidification, increased fluid intake, and, if possible, discontinuation of therapy may dissolve stones. [119][120][121][122][123][124] Other medications precipitating in the urine but rarely causing stones include ceftriaxone, sulfonamides, ampicillin, amoxicillin, triamteren, acyclovir, and oxypurine.…”

Benefit of therapeutic drug monitoring of protease inhibitors in HIV‐infected patients depends on PI used in HAART regimen – ANRS 111 trial

“…From weeks 2 to 24, doses were modified according to a predefined algorithm whenever protease inhibitor C trough was out of recommended ranges. For indinavir and nelfinavir, therapeutic ranges were defined based on data from the literature analysing the concentration–efficacy and concentration–tolerance relationships [8,11,12,19–21]. For lopinavir, as no such study existed, and as the inhibitory quotient with wild‐type virus is very high (above 75), it was hypothesized that the 25–75% interquartile range of the trough concentration observed in a population of protease inhibitor‐naive patients could be defined as a therapeutic range, which both maintained virological efficacy and decreases toxicity [22].…”

British HIV Association guidelines for the routine investigation and monitoring of adult HIV‐1‐infected individuals 2011

“…malabsorption) or renal or hepatic function and affect drug pharmacokinetics . To prevent/manage ART‐induced concentration‐dependent toxicity (e.g. indinavir‐induced nephrotoxicity, efavirenz‐associated central nervous system adverse events and atazanavir‐related hyperbilirubinaemia) . In the case of suboptimal virological response (exclude other causes of treatment failure such as poor adherence, incorrect dosing or dosing frequency, poor adherence to food requirements and drug interactions). TDM and adherence: the usefulness of TDM to investigate/test adherence to antiretroviral drugs is unclear. However, a nondetectable drug concentration in a stored sample of plasma (drawn at time of failure and reporting a detectable viral load) may confirm the absence of therapeutic agent in the blood and lead to investigations of drug interaction and malabsorption and strengthen adherence support. In treatment‐experienced patients with virus with reduced susceptibility to antiretroviral drugs.…”