Interindividual and intra-individual variabilities of darunavir and ritonavir plasma trough concentrations in multidrug experienced HIV patients receiving salvage regimens.
BACKGROUND
There is no consensus on darunavir (DRV) target levels in plasma for clinical use, and information about variability in plasma concentrations is limited.


OBJECTIVE
: To investigate the variability in DRV plasma trough concentrations in the clinical setting, evaluating interindividual and intraindividual variabilities of plasma drug levels among HIV-infected patients receiving ritonavir (RTV)-boosted DRV (DRV/r) within salvage regimens, and evaluate the potential correlation between variability and virological response.


METHODS
Sixty-two patients taking DRV/r (600/100 mg twice a day) were evaluated for trough plasma concentrations and immunovirological parameters after 6 months from the start of the regimen. A subgroup of patients (n = 21) was also evaluated for intraindividual variability (expressed as coefficient of variation) on 2 samples taken at different time points. Drug concentrations were assayed by high-performance liquid chromatography with ultraviolet detection, and the values were expressed as medians with interquartile range (IQR). Genotypic sensitivity score and genotypic inhibitory quotient were calculated.


RESULTS
DRV/r was used with a median of 3 other antiretroviral drugs (raltegravir use 88.7%). Median plasma concentrations were 3.22 mcg/mL (IQR, 2.04-5.69) for DRV and 0.44 mcg/mL (IQR, 0.21-0.70) for RTV. Both drugs showed a high interindividual variability in plasma concentrations (61% and 99.3%, respectively). Only 3 patients (4.8%) had undetectable DRV plasma levels. DRV plasma concentrations showed a significant positive correlation with age (r = 0.298, P = 0.019), but no significant correlation between DRV genotypic inhibitory quotient and HIV-RNA plasma levels (P = 0.614) was found. Intraindividual coefficients of variation were 58.4% for DRV and 47.1% for RTV. Patients with undetectable HIV-RNA showed a trend for lower intraindividual coefficients of variation compared with patients with detectable HIV-RNA (55.9% versus 83.8%, P = 0.156). No major interaction effects with other antiretroviral drugs were found.


CONCLUSIONS
In a context of salvage therapy, both DRV and RTV plasma levels showed high interindividual and intraindividual variabilities. Lower intraindividual variability could be beneficial in maintaining viral suppression.
*Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome; †Department of Pharmacology, Fondazione IRCCS, Policlinico San Matteo, Pavia; ‡Department of Infectious Diseases and Hepatology, Azienda Ospedaliera di Parma, Parma; §Division of Infectious Disease, University of Bari, Bari; ¶Division of Infectious Diseases, Department of Experimental Medicine, University of Perugia, Perugia; ‖Infectious Diseases Unit, Pistoia Hospital, Pistoia; **Infectious Disease Unit, Pescara General Hospital, Pescara; ††Department of Internal Medicine, Geriatrics and Nephrologic Diseases, Section of Infectious Diseases, S. Orsola-Malpighi Hospital, Alma Mater Studiorum, University of Bologna, Bologna; ‡‡Clinic of Infectious Diseases, Ospedali Riuniti, Marche Polytechnic University, Ancona; and §§Department of Infectious Diseases, S. Anna Hospital, Ferrara, Italy.
Silvia
S
Baroncelli
Paola
P
Villani
Clementina M
CM
Galluzzo
Albertina
A
Cavalli
Anna
A
Volpe
Daniela
D
Francisci
Angela
A
Vivarelli
Federica
F
Sozio
Sara
S
Tedeschi
Oscar
O
Cirioni
Laura
L
Sighinolfi
Maria
M
Cusato
Maria F
MF
Pirillo
Liliana E
LE
Weimer
Vincenzo
V
Fragola
Giustino
G
Parruti
Mario
M
Regazzi
Marco
M
Floridia
D000328:Adult; D000368:Aged; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D000069454:Darunavir; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000097:blood* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D019438:Ritonavir / Q000097:blood* / Q000627:therapeutic use; D016879:Salvage Therapy; D013449:Sulfonamides / Q000097:blood* / Q000627:therapeutic use; D013997:Time Factors; D055815:Young Adult
D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D013449:Sulfonamides; D019438:Ritonavir; D000069454:Darunavir