Older Age is Associated with Higher Dolutegravir Exposure in Plasma and Cerebrospinal Fluid of People Living with HIV
Por:
Calcagno, A, Molto, J, Borghetti, A, Gervasoni, C, Milesi, M, Valle, M, Avataneo, V, Alcantarini, C, Pla-Junca, F, Trunfio, M, D'Avolio, A, Di Giambenedetto, S, Cattaneo, D, Di Perri, G, Bonora, S
Publicada:
1 ene 2021
Ahead of Print:
1 ago 2020
Resumen:
Background People living with human immunodeficiency virus are ageing under combination antiretroviral treatments but data on drug exposure in serum and cerebrospinal fluid are limited. Dolutegravir is a widely used second-generation integrase strand transfer inhibitor: conflicting data suggest that neuropsychiatric side effects may present at a higher frequency in patients with higher dolutegravir serum concentrations. Methods We performed a retrospective analysis of our therapeutic drug monitoring registry identifying patients receiving once-daily dolutegravir without concomitant interacting drugs and significant clinical conditions. Data were analysed stratifying time after drug dose intake (maximum concentration 0.5-4 and trough concentration 21-27 h). Cerebrospinal fluid samples from patients enrolled in neurological studies and receiving dolutegravir were analysed for dolutegravir cerebrospinal fluid concentrations and cerebrospinal fluid-to-plasma ratios. Serum and cerebrospinal fluid concentrations were measured through validated chromatographic methods. Results We included 207 (providing 457 serum samples) and 41 patients (providing 41 cerebrospinal fluid samples). Participants were mostly male (68.2-72.8%) of median age of 50 years (50-53 years). Non-significant changes in dolutegravir maximum concentration and trough concentration were observed with age at Spearman's test (pvalues > 0.05); linear logistic regression showed a significant effect of age on dolutegravir trough concentration (p = 0.0013) (Fig. 1). Dolutegravir maximum concentration [3830 ng/mL (2311-5057) vs 4230 ng/mL (2919-5272),p = 0.311] and trough concentration [838 ng/mL (362-1587) vs 966 ng/mL (460-2085),p = 0.056] were non-significantly or borderline higher in patients aged > 50 years. Cerebrospinal dolutegravir concentrations were associated with plasma concentrations (rho = 0.374,p = 0.016) and age (rho = 0.537,p = 0.003); cerebrospinal fluid dolutegravir concentrations (13.8 vs 7.3 ng/mL,p = 0.015) and cerebrospinal fluid-to-plasma ratios (0.57 vs 0.32%,p = 0.017] were higher in participants aged > 50 years. Conclusions We observed an increase in dolutegravir exposure in serum and in cerebrospinal fluid in older patients living with human immunodeficiency virus.
Filiaciones:
Calcagno, A:
Univ Torino, Amedeo Di Savoia Hosp, Dept Med Sci, Unit Infect Dis, Cso Svizzera 164, I-10149 Turin, Italy
Molto, J:
Univ Autonoma Barcelona, Barcelona, Spain
Hosp Univ Germans Trias I Pujol, Lluita Sida Fdn, HIV Clin, Badalona, Spain
Borghetti, A:
Univ Cattolica Sacro Cuore, Inst Clin Infect Dis, Rome, Italy
Gervasoni, C:
ASST Fatebenefratelli, Sacco Univ Hosp, Unit Clin Pharmacol, Milan, Italy
ASST Fatebenefratelli Sacco Univ Hosp, Dept Infect Dis, Milan, Italy
Milesi, M:
Univ Torino, Amedeo Di Savoia Hosp, Dept Med Sci, Unit Infect Dis, Cso Svizzera 164, I-10149 Turin, Italy
Valle, M:
Univ Autonoma Barcelona, Barcelona, Spain
Inst Recerca Hosp Santa Creu & St Pau IIB St Pau, Pharmacokinet Pharmacodynam Modeling & Simulat, Barcelona, Spain
Avataneo, V:
Univ Torino, Amedeo Di Savoia Hosp, Dept Med Sci, Unit Infect Dis, Cso Svizzera 164, I-10149 Turin, Italy
Alcantarini, C:
Univ Torino, Amedeo Di Savoia Hosp, Dept Med Sci, Unit Infect Dis, Cso Svizzera 164, I-10149 Turin, Italy
Pla-Junca, F:
Univ Autonoma Barcelona, Barcelona, Spain
Inst Recerca Hosp Santa Creu & St Pau IIB St Pau, Pharmacokinet Pharmacodynam Modeling & Simulat, Barcelona, Spain
Trunfio, M:
Univ Torino, Amedeo Di Savoia Hosp, Dept Med Sci, Unit Infect Dis, Cso Svizzera 164, I-10149 Turin, Italy
D'Avolio, A:
Univ Torino, Amedeo Di Savoia Hosp, Dept Med Sci, Unit Infect Dis, Cso Svizzera 164, I-10149 Turin, Italy
Di Giambenedetto, S:
Univ Cattolica Sacro Cuore, Inst Clin Infect Dis, Rome, Italy
Cattaneo, D:
ASST Fatebenefratelli, Sacco Univ Hosp, Unit Clin Pharmacol, Milan, Italy
ASST Fatebenefratelli Sacco Univ Hosp, Dept Infect Dis, Milan, Italy
Di Perri, G:
Univ Torino, Amedeo Di Savoia Hosp, Dept Med Sci, Unit Infect Dis, Cso Svizzera 164, I-10149 Turin, Italy
Bonora, S:
Univ Torino, Amedeo Di Savoia Hosp, Dept Med Sci, Unit Infect Dis, Cso Svizzera 164, I-10149 Turin, Italy
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