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.

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Fig. 1
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Correspondence to Andrea Calcagno.

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Funding

This study was carried out as part of our routine work.

Conflict of interest

Andrea Calcagno has received honoraria from Gilead, Insmed, Janssen-Cilag, MSD and Viiv and he is currently receiving research grants from Gilead and Viiv. Giovanni Di Perri and Stefano Bonora have received honoraria from Abbvie, BMS, Gilead, Janssen-Cilag, MSD and Viiv. José Moltó, Borghetti Alberto, Gervasoni Cristina, Maurizio Milesi, Marta Valle, Valeria Avataneo, Chiara Alcantarini, Francesc Pla-Junca, Trunfio Mattia, Antonio D’Avolio, Simona Di Giambenedetto and Dario Cattaneo have no conflicts of interest that are directly relevant to the content of this article.

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Calcagno, A., Moltó, J., Borghetti, A. et al. Older Age is Associated with Higher Dolutegravir Exposure in Plasma and Cerebrospinal Fluid of People Living with HIV. Clin Pharmacokinet 60, 103–109 (2021). https://doi.org/10.1007/s40262-020-00916-9

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