aSchool of Medicine, USA
bSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, California, USA.
Received 21 June, 2006
Accepted 7 July, 2006
Conflicting pharmacokinetic data have recently been published concerning patients in clinical practice receiving concurrent therapy with atazanavir and omeprazole [1,2]. For results to be comparable between centers, procedures for sample collection, analytical methods and the interpretation of concentration data need to be standardized. Although atazanavir plasma concentrations can decrease when combined with proton pump inhibitors (PPI) [3–5], the minimal effective concentration of atazanavir has not been defined. Furthermore, increasing reports have shown good viral responses during co-administration, suggesting that atazanavir may achieve therapeutic exposure in these patients [1,6–8]. Here we present a case of a patient concurrently receiving atazanavir–ritonavir and omeprazole, but in whom atazanavir exposure was estimated using Bayesian models. A strategy of therapeutic drug monitoring during atazanavir–ritonavir and PPI co-administration in the clinical setting is discussed.
A 56-year-old man with HIV infection (CD4 cell count 494 cells/μl, HIV RNA load 64 800 copies/ml) initiated a regimen of atazanavir–ritonavir (300/100 mg), tenofovir, abacavir and lamivudine. He tolerated the medications well and achieved HIV suppression. Two months latter the patient began therapy for hepatitis C, and developed severe gastritis attributable to ribavirin. Symptoms were unresponsive to H2-blockers but improved with high-dose omeprazole (40 mg per day). Atazanavir–ritonavir was continued, and over the next 10 months the HIV viral load remained at 50 copies/ml or less. Furthermore, with an improvement of the gastritis symptoms the patient was able to tolerate full-dose ribavirin and has responded well to hepatitis C therapy.
During PPI co-administration, plasma concentrations of atazanavir were measured approximately 22 h after an unwitnessed dose by a validated, reversed-phase high performance liquid chromatography method (assay lower limit of detection of 0.128 μg/ml and intra-assay precision of less than 9.2%). The patient's drug exposure was estimated using Bayesian models (NONMEM version V.1; Globomax, Hanover, Maryland, USA) and existing population pharmacokinetic parameters from the literature [9,10]. The atazanavir concentration was 0.3 μg/ml, yielding an estimated trough concentration below the population-predicted 25th percentile, for ritonavir-boosted atazanavir but above the 75th percentile for unboosted atazanavir (Fig. 1). As unboosted atazanavir has been shown to achieve similar rates of viral control to atazanavir–ritonavir in treatment-naive patients , we considered an exposure above the 75th percentile for unboosted atazanavir to be adequate.
Trough concentrations of protease inhibitors are generally accepted to be predictive of viral response , suggesting that this parameter is a reasonable target for therapeutic drug monitoring. Although several methods for measuring plasma antiretroviral concentrations are available, none have been reviewed by Clinical Laboratory Improvement Amendments (1988)-approved proficiency testing programmes. To help assure interassay agreement, our laboratory is registered with the AIDS Clinical Trials Group Quality Assurance/Quality Control program for clinical measurement of antiretroviral agents . Finally, in the clinical setting, precisely timed samples are difficult to obtain, and the high degree of interpatient pharmacokinetic variability can limit the accuracy of patient drug exposure estimations from a single drug concentration. One solution is to use Bayesian models. This method leverages previous population pharmacokinetic information to estimate the entire individual patient pharmacokinetic profile .
Although atazanavir trough concentrations are highly variable and may not be associated with viral response , a detectable trough ensures that drug exposure is maintained throughout the dosing interval. Furthermore, until the minimum effective concentration of atazanavir is defined, it is not known whether lower atazanavir concentrations during PPI use increases the risk of viral failure. Certainly, co-administration should be avoided whenever possible. However, for those patients with viral control who are currently receiving atazanavir–ritonavir and a PPI, we recommend measuring trough atazanavir concentrations. If concentrations are detectable, ideally above the population-predicted 50th percentile for unboosted atazanavir, continued atazanavir–ritonavir and PPI use can be considered.
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