We read with great interest the drug interaction report published by Toy et al.. In this report, an HIV-infected patient treated with ritonavir (RTV)-boosted darunavir (DRV) (DRV/RTV, 900/100 mg daily) and etravirine (ETV, 200 mg twice daily) was found to have an unexpectedly low trough DRV plasma concentration (0.54 mg/l) and an undetectable RTV concentration while on voriconazole 400 mg twice daily for Aspergillus pneumonia. After stopping voriconazole, trough DRV and RTV concentrations raised up to expected values (2.3 and 0.04 mg/l, respectively). ETV trough concentration increased by 134% on voriconazole. The authors postulate that the increased ETV concentration led to a greater induction effect on DRV, or that low RTV concentration resulted in reduced DRV boosting. The reason for undetectable RTV concentration was, however, not discussed.
As the authors called for more detailed characterization of this complex multiway drug interaction, we would like to present the case of a 52-year-old HIV-infected multiresistant patient (CD4 cell count 6 cells/μl, 1%; viral load 35 000 copies/ml) initiating a new treatment including the following drugs: DRV/RTV 800/100 mg daily, ETV 400 mg daily, elvitegravir 150 mg daily, tenofovir 300 mg daily, emtricitabine 200 mg daily and foscarnet 5 g daily five times a week. This patient was cotreated with voriconazole 200 mg twice daily for Candida albicans infection, which was then increased to a dosage of 400 mg in the morning and 200 mg in the evening. DRV dosage was increased to 1200 mg daily at the end of voriconazole therapy, to compensate for the anticipated lifting of voriconazole-mediated cytochrome P450 3A4 metabolism inhibition. Plasma concentrations of DRV, RTV, ETV, elvitegravir, voriconazole and its metabolite (voriconazole N-oxide) were measured by multiplex liquid chromatography coupled to triple quadripole tandem mass spectrometry assay (M. Aouri et al., in preparation) [2,3], at several occasions while on and off voriconazole therapy. Trough plasma concentrations, extrapolated from the mid-interval concentrations (average sampling time 12 ± 1 h after drug intake) using percentiles curves established in our center and published data, are shown in Table 1 (M. Arab-Alameddine et al., in preparation) . DRV plasma concentrations measured at three occasions while on voriconazole therapy were lying within the 50–75th percentile range established for DRV 800 mg daily. It remained within the same range after voriconazole interruption and DRV dosage increase. RTV plasma concentrations remained above 0.025 mg/l during voriconazole treatment, sufficiently high to guarantee the efficient boosting of DRV as well as elvitegravir, whose concentrations reached the previously reported range for RTV-boosted elvitegravir combination . ETV concentrations were not found to be much affected by voriconazole. Under 600 mg total daily dose, voriconazole trough plasma concentrations were within therapeutic range except on week 25, with unremarkable voriconazole N-oxide concentrations indicating no evidence of impaired hepatic metabolism. Voriconazole treatment was stopped at week 25, as his esophageal candidiasis resolved upon immune reconstitution. Forty-eight weeks after antiretroviral treatment initiation, the patient had and increased CD4 cell count (123 cells/μl, 8%) and viral load (80 copies/ml).
Our observations contrast, therefore, significantly with those reported by Toy et al.. Unlike their patient, ours had RTV and DRV plasma concentrations measured at multiple occasions while on voriconazole therapy, which strengthens our observations. In their patient, it is unclear why RTV was below the – unstated – limit of quantification of their assay during voriconazole therapy. In healthy volunteers, RTV (100 mg twice daily) area under the curve (AUC)0–12 only decreased by 14% when co-administered with voriconazole 200 mg twice daily [6,7]. Thus, an undetectable RTV concentration due to voriconazole is not expected, even for a 400 mg twice daily voriconazole dosage. As a weak inducer, ETV is not expected either to significantly induce DRV metabolism. In healthy volunteers, DRV (DRV/RTV 600/100 mg twice daily) AUC0–12 rather increased by 15% when given with ETV 200 mg twice daily .
In conclusion, in our opinion, drug interactions per se are unlikely to explain the extremely low plasma concentrations of DRV observed under voriconazole in the patient of Toy et al.. Other reasons have to be incriminated, such as missed dose of RTV and/or DRV or diluted sample (e.g. multilumen catheter). Our observation is rather consistent with a 50% decrease in DRV clearance by voriconazole co-administration, expected to double DRV concentrations in the absence of dosage adjustment. This is also in line with the interaction studied with ketoconazole . No significant interference is expected from ETV and elvitegravir.
Drug interactions can be a major issue in HIV-infected patients. It is important, however, that unexpected pharmacokinetic findings gathered during patient management are carefully confirmed (i.e. by multiple concentration measurements) before being considered valid and integrated into patients standard of care.
Conflicts of interest
This report has been realized within the frame of a research project on clinical pharmacology and pharmacogenetics of antiretrovirals (SNF grant no. 324730-124943/1 to L.A.D.) supported by the Swiss National Science Foundation (Switzerland).
There are no conflicts of interest.
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