Juan Eduardo Resendiz-Galvan (1), Gary Maartens (1), Paolo Denti (1)
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
Introduction: The minimum effective concentration (MEC) of dolutegravir (DTG) is not well defined. Putative trough concentration (Ctrough) targets have been suggested for efficacy. While the in-vitro protein-adjusted 90% inhibitory concentration (PA-IC90) is 0.064 mg/L [1,2], an often-referenced value is the Ctrough of 0.3 mg/L. This is derived from a phase 2b dose-ranging trial (SPRING-1) and corresponds to a geometric mean Ctrough from 15 participants receiving the lowest dose in the study, 10 mg daily. However, 10, 25, and 50 mg doses had comparable rates of virological suppression; therefore, the MEC could not have been determined [3]. Characterising the pharmacokinetic/pharmacodynamic (PK/PD) of DTG is important when evaluating dosing regimens for subpopulations such as children and pregnant women and when suggesting adjustments for drug-drug interactions. We aimed to develop a PK/PD model to characterize the relationship between DTG exposure and participant viral load dynamics.
Methods: A PK/PD model was developed in NONMEM using data from the phase 2a, placebo-controlled, dose-ranging VIIV-ING111521 study of DTG monotherapy. Participants with HIV were randomized into four different arms: placebo, 2, 10, or 50 mg of DTG as monotherapy once daily for 10 days. Intensive PK sampling was carried out on days 1 and 10, and additional trough samples were collected on intervening days. Extra blood samples were collected at baseline, during PK visits, and after treatment completion (days 14 and 21) to evaluate viral load. Plasma HIV-1 RNA was determined with the COBAS Amplicor HIV-1 Monitor Test, and viral loads below the limit of quantification of 50 copies/mL were imputed as 25 copies/mL [4]. We performed simulations to evaluate the effect of different DTG treatment regimens on viral load.
Results: Data were available from 35 male participants with median (interquartile range [IQR]) age, weight, and plasma HIV-1 RNA at baseline of 41 (32–43) kg, 78.1 (74.3–84.4) kg, and 4.39 (4.25–4.55) log10 copies/mL, respectively. Demographics and baseline characteristics were similar among the four dose groups. Fourteen viral loads (1 in 2 mg group, 13 in 50 mg group) from 8 participants were below 50 copies/mL. The PK was well described by a two-compartment disposition model with lagged absorption and parameters allometrically scaled by total body weight and higher doses of DTG were found to have lower bioavailability, in agreement with the literature [5]. Viral load was described as the equilibrium between viral replication (modelled using a growth rate Rmax and carrying capacity VLmax) and the drug-mediated viral clearance (modelled using an Emax function). HIV-1 Rmax was 0.0284 copies/h and the VLmax 4.4 log10 copies/mL, reached when the infection is at steady state. The maximal viral clearance by DTG, Emax, was estimated at 0.0517 copies/h, and half of that can be reached with an EC50 of 0.0632 mg/L.
Our simulations predicted that with the currently recommended regimen of DTG 50 mg QD, the Ctrough were 0.858 (0.625-1.22) mg/L. When simulating a scenario with co-treatment with rifampicin-based tuberculosis (TB) treatment (increasing DTG clearance by 2.4-fold [5]) and no dose adjustment (DTG 50 mg QD), viral suppression is still predicted to be achieved by 17 days after treatment, despite the Ctrough decreasing to 0.101 (0.062-0.165) mg/L, i.e. not only under the value of 0.3 mg/L but also below the PA-IC90.
Conclusion:
We developed a PK/PD model for DTG in male participants with HIV that allowed us to explore the impact of different dosing regimens on viral load. Our model predicts that DTG is effective even if the daily Ctrough falls below previously suggested thresholds. This is in line with recent findings by RADIANT-TB, where TB-HIV co-treated individuals achieved high rates of virologic suppression well despite no DTG dose adjustment [6]. This indicates that summarising DTG efficacy by solely targeting Ctrough may be oversimplistic and not be predictive of its effect on viral load. Extrapolation of our results should be done with caution since in our data DTG was dosed as monotherapy and for a short period of time. Hence, the model may not be adequate to describe the development of resistance in scenarios with less frequent dosing where concentrations remain low for longer periods. Further exploration to determine a MEC for DTG is necessary since our simulations show that its efficacy cannot be limited to a single Ctrough.
[1] Cottrell, M. L. et al., 2014. Clinical Pharmacokinetic, Pharmacodynamic and Drug-Interaction Profile of the Integrase Inhibitor DTG.
[2] Min, S. et al., 2011. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults.
[3] van Lunzen, J. et al., Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naïve adults with HIV: planned interim 48-week results from SPRING-1, a dose-ranging, randomised, phase 2b trial.
[4] Beal, S. L. 2001. Ways to fit a PK model with some data below the quantification limit.
[5] Kawuma A. et al., 2022. Population Pharmacokinetic Model and Alternative Dosing Regimens for Dolutegravir Coadministered with Rifampicin.
[6] Griesel R. et al., 2023. Standard-dose versus double-dose dolutegravir in HIVassociated tuberculosis in South Africa (RADIANT-TB): a phase 2, non-comparative, randomised controlled trial.
Reference: PAGE 32 (2024) Abstr 11009 [www.page-meeting.org/?abstract=11009]
Poster: Drug/Disease Modelling - Infection