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

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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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Authors and Affiliations

  1. Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, c/o Amedeo Di Savoia Hospital, C.so Svizzera 164, 10149, Turin, Italy

    Andrea Calcagno, Maurizio Milesi, Valeria Avataneo, Chiara Alcantarini, Mattia Trunfio, Antonio D’Avolio, Giovanni Di Perri & Stefano Bonora

  2. Universitat Autònoma de Barcelona, Barcelona, Spain

    José Moltó, Marta Valle & Francesc Pla-Junca

  3. “Lluita Contra La Sida” Foundation, HIV Clinic, Hospital Universitari Germans Trias I Pujol, Badalona, Spain

    José Moltó

  4. Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Rome, Italy

    Alberto Borghetti & Simona Di Giambenedetto

  5. Unit of Clinical Pharmacology, ASST Fatebenefratelli, Sacco University Hospital, Milan, Italy

    Cristina Gervasoni & Dario Cattaneo

  6. Department of Infectious Diseases, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy

    Cristina Gervasoni & Dario Cattaneo

  7. Pharmacokinetic/Pharmacodynamic Modeling and Simulation, Institut de Recerca de L’Hospital de La Santa Creu I Sant Pau-IIB Sant Pau, Barcelona, Spain

    Marta Valle & Francesc Pla-Junca

Authors
  1. Andrea Calcagno
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  2. José Moltó
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  3. Alberto Borghetti
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  9. Francesc Pla-Junca
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  14. Giovanni Di Perri
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  15. Stefano Bonora
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Corresponding author

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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  • DOI: https://doi.org/10.1007/s40262-020-00916-9

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