The case of dolutegravir plus darunavir antiretroviral regimens: Is it always useful to double the drug doses?

Abstract

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The case of dolutegravir plus darunavir antiretroviral regimens: Is it always useful to double the drug doses?

Dario Cattaneo¹, Anna Ridolfo¹, Andrea Giacomelli¹, Antonella Castagna², Spinello Antinori¹ and Cristina Gervasoni¹

¹Luigi Sacco University Hospital; ²IRCSS San Raffaele Scientific Institute

Background: It has recently been shown that dolutegravir trough concentrations are differently affected by antiretroviral drug combinations [doi: 10.1097/QAD.0000000000003843]. Here, we focused on dolutegravir plus darunavir-based combinations, with the aim to investigate the effect of the booster and/or the timing of administration on drug plasma trough concentrations.

Materials and methods: This retrospective, observational study included consecutive PWH receiving dolutegravir plus darunavir antiretroviral regimens for at least 3 months, with at least one assessment of dolutegravir plasma concentrations. We considered true trough drug concentrations (i.e. blood samples taken 12 or 24 h after the last drug intake) or trough concentrations back-estimated by pharmacokinetic modelling taking into account the time interval between the last dose intake and the blood sample and the drug terminal half-life. Samples without clear information on the timing of the last drug dose and/or blood draw were excluded from the study. PWH concomitantly treated with strong drug inducers (i.e. rifampicin, carbamazepine, NNRTIs) were not included.

Results: Two hundred TDMs of dolutegravir from 116 PWH were included in the statistical analyses. Dolutegravir and darunavir trough concentrations ranged, respectively, from 70 to 3648 ng/mL (inter-individual variability of 60%) and from 102 to 11 876 ng/mL (inter-individual variability of 72%). As shown in Table 2, the antiretroviral drug combination associated with the highest dolutegravir trough concentration was dolutegravir plus darunavir/cobicistat, both given once daily (1410 ± 788 ng/mL), whereas dolutegravir once daily plus darunavir/ritonavir twice daily had the lowest trough concentrations (686 ± 481 ng/mL). Doubling the dose of dolutegravir did not result in a significant increase of drug trough concentrations compared to once daily regimens. Among the once daily regimens, the highest darunavir trough concentrations were measured with ritonavir (2850 ± 1456 ng/mL, p < .05 vs. cobicistat-based regimens). Doubling the drug dose resulted in a significant increase of darunavir trough concentrations (4445 ± 2926 ng/mL, p < .05).

Conclusions: Dolutegravir trough concentrations were significantly reduced in PWH receiving darunavir/ritonavir twice daily. This is likely related to the inductive effect of ritonavir (but not of cobicistat) on the enzymes (glucuronosyltransferase) and/or drug transporters involved in the regulation of dolutegravir disposition [doi: 10.1093/jac/dkx055]. Doubling the dose of dolutegravir did not result in a significant increase in the drug trough concentrations. This evidence should be carefully considered in clinical conditions that require higher dolutegravir exposure, such as in presence of DDIs with medications known to reduce dolutegravir bioavailability or in highly experienced PWH.