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Older Age is Associated with Higher Dolutegravir Exposure in Plasma and Cerebrospinal Fluid of People Living with HIV.

Abstract：

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 (p values > 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 (ρ = 0.374, p = 0.016) and age (ρ = 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.

journal_name

Clin Pharmacokinet

journal_title

Clinical pharmacokinetics

authors

Calcagno A,Moltó 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

doi

10.1007/s40262-020-00916-9

subject

Has Abstract

pub_date

2021-01-01 00:00:00

pages

103-109

issue

eissn

0312-5963

issn

1179-1926

pii

10.1007/s40262-020-00916-9

journal_volume

pub_type

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Older Age is Associated with Higher Dolutegravir Exposure in Plasma and Cerebrospinal Fluid of People Living with HIV.