Population pharmacokinetics of dolutegravir: influence of drug–drug interactions in a real-life setting

Abstract

Objectives Dolutegravir is widely prescribed owing to its potent antiviral activity, high genetic barrier and good tolerability. The aim of this study was to characterize dolutegravir’s pharmacokinetic profile and variability in a real-life setting and to identify individual factors and co-medications affecting dolutegravir disposition. Methods A population pharmacokinetic model was developed using NONMEM®. Relevant demographic factors, clinical factors and co-medications were tested as potential covariates. Simulations based on the final model served to compare expected dolutegravir concentrations under standard and alternative dosage regimens in the case of drug–drug interactions. Results A total of 620 dolutegravir plasma concentrations were collected from 521 HIV-infected individuals under steady-state conditions. A one-compartment model with first-order absorption and elimination best characterized dolutegravir pharmacokinetics. Typical dolutegravir apparent clearance (CL/F) was 0.93 L/h with 32% between-subject variability, the apparent volume of distribution was 20.2 L and the absorption rate constant was fixed to 2.24 h−1. Older age, higher body weight and current smoking were associated with higher CL/F. Atazanavir co-administration decreased dolutegravir CL/F by 38%, while darunavir modestly increased CL/F by 14%. Rifampicin co-administration showed the largest impact on CL/F. Simulations suggest that average dolutegravir trough concentrations are 63% lower after 50 mg/12h with rifampicin compared with a standard dosage of 50 mg/24h without rifampicin. Average trough concentrations after 100 mg/24h and 100 mg/12h with rifampicin are 92% and 25% lower than the standard dosage without rifampicin, respectively. Conclusions Patients co-treated with dolutegravir and rifampicin might benefit from therapeutic drug monitoring and individualized dosage increase, up to 100 mg/12 h in some cases.

Pharmacokinetic parameters and weight change in HIV patients newly switched to dolutegravir‐based regimens in SIMPL'HIV clinical trial

“…Concerning DTG pharmacokinetics, the median AUC 0–24 was 56 613 ng.h/mL [47 805–64 496], median C min 1372 ng/mL [1039–1679], and median C max 3533 ng/mL [3189–3846]. Body weight at week 48 significantly influenced DTG AUC 0–24 ( P = .02), as previously reported 27,30 …”

“…This result is in agreement with other studies. Two studies presented as conference abstracts and evaluating the association between weight gain and DTG pharmacokinetics, specifically plasma ( n = 96, DTG plasma exposure similar to the present study) and hair ( n = 177) concentrations, found no significant association 17–31 . Conversely, some antiretroviral drugs demonstrated a concentration–effect relationship for other adverse events.…”

“…Two studies presented as conference abstracts and evaluating the association between weight gain and DTG pharmacokinetics, specifically plasma (n = 96, DTG plasma exposure similar to the present study) and hair (n = 177) concentrations, found no significant association. [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] Conversely, some antiretroviral drugs demonstrated a concentration-effect relationship for other adverse events. Indeed, an influence of plasma concentration on neuropsychological disorders has been reported for DTG or efavirenz, 32,33 suggesting that therapeutic drug monitoring could be useful for treatment individualization.…”

“…residual plasma concentration C min and maximum plasma concentration C max ) and all over the dosing interval (i.e. area under the curve from 0 to 24 h [AUC 0–24 ], representing the total exposure) were therefore derived using the base (without covariates) population pharmacokinetic model of a previously published paper 27 along with the measured concentrations through a Bayesian approach (NONMEM version 7.4) 28 . The appropriateness of the model for the purpose of this study was evaluated through calculations of model prediction bias and precision 29 .…”

“…weight at week 48 significantly influenced DTG AUC 0-24 (P = .02), as previously reported. 27,30 An average significant weight gain of 2.4 kg (95% confidence interval 1.3-3.5) was observed between baseline and week 48.…”