Andrea Calcagno1, José Moltó2,3, Alberto Borghetti4, Cristina Gervasoni5,6, Maurizio Milesi7, Marta Valle2,8, Valeria Avataneo7, Chiara Alcantarini7, Francesc Pla-Junca2,8, Mattia Trunfio7, Antonio D'Avolio7, Simona Di Giambenedetto4, Dario Cattaneo5,6, Giovanni Di Perri7, Stefano Bonora7. 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@unito.it. 2. Universitat Autònoma de Barcelona, Barcelona, Spain. 3. "Lluita Contra La Sida" Foundation, HIV Clinic, Hospital Universitari Germans Trias I Pujol, Badalona, Spain. 4. Institute of Clinical Infectious Diseases, Catholic University of Sacred Heart, Rome, Italy. 5. Unit of Clinical Pharmacology, ASST Fatebenefratelli, Sacco University Hospital, Milan, Italy. 6. Department of Infectious Diseases, ASST Fatebenefratelli Sacco University Hospital, Milan, Italy. 7. Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, c/o Amedeo Di Savoia Hospital, C.so Svizzera 164, 10149, Turin, Italy. 8. Pharmacokinetic/Pharmacodynamic Modeling and Simulation, Institut de Recerca de L'Hospital de La Santa Creu I Sant Pau-IIB Sant Pau, Barcelona, Spain.
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.
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.
Authors: Alan Winston; Sophie Jose; Sara Gibbons; David Back; Wolfgang Stohr; Frank Post; Martin Fisher; Brian Gazzard; Mark Nelson; Richard Gilson; Chloe Orkin; Margaret Johnson; Adrian Palfreeman; David Chadwick; Clifford Leen; Achim Schwenk; Jane Anderson; Mark Gompels; David Dunn; Saye Khoo; Caroline Sabin Journal: J Antimicrob Chemother Date: 2013-02-23 Impact factor: 5.790
Authors: Alfonso Cabello-Úbeda; Alicia González Baeza; Jesús Troya García; Sara de La Fuente Moral; María Novella Mena; Adriana Pinto Martínez; Rafael Micán; Miguel Górgolas; Guillermo Cuevas Tascón; Alberto Díaz de Santiago; José Sanz Morerno; David Rial Crestelo; Carmen Busca Arenzana; José Ignacio Bernardino Serna; Mariana Díaz Almirón; Joanna Cano; Herminia Esteban; Ignacio Pérez-Valero Journal: Open Forum Infect Dis Date: 2022-08-06 Impact factor: 4.423