Table 1.
Parameters used for the viral dynamics model.
Excerpt from [24], except for CL(naive), which assumed that virus clearance is smaller in virus-naive individuals compared to infected individuals, in line with [55, 87]. All parameters refer to the absence of drug treatment ⌀. All parameters in units [1/day]).
Fig 1.
Adaptation of extinction simplex for pharmacokinetics.
A: Exemplary DTG pharmacokinetics for 3days of 2mg oral DTG once daily. The blue line represents DTG plasma concentrations. The dashed orange line represents the function Dmax(t), which for a particular t returns the maximum DTG concentration achieved in any future time i.e Dmax(t) = max(D(u)) where u ∈ [t, ∞). The black horizontal dashed line marks the IC50 for DTG [38]. B: Instantaneous target-process inhibition (blue line) corresponding to the concentration-time profile in A. The orange line is the target-process efficacy profile for Dmax(t). The black horizontal dashed line marks η = 50%. C: Extinction simplex (viral infection state where the probability of viral extinction is greater than ε) corresponding to . D: The extinction simplex corresponding to η = 50%. Panels C&D show the state space with three dimensions corresponding to number of free viruses, early-infected T cells (T1) and late-stage infected T cells (T2). The color varies from bright yellow denoting certain extinction, to black denoting an extinction probability less than 0.0001. The region enclosed by green lines is the extinction simplex in absence of antivirals.
Fig 2.
Examplary trajectories for time-varying drug effects.
The left panels show an example of an infection event, whereas the right panels show an example of viral extinction for chronic PrEP with 2mg DTG and 5% adherence. Panels A and C depict the instantaneous target-process inhibition profiles and panels B and D depict the corresponding viral trajectories using the adapted EXTRANDE algorithm. Viral exposure occurs randomly during a 3 month period and is sampled from the distribution parameterized in [11] (Figure 2 therein). A&C: The blue lines depict the instantaneous target-process inhibition profiles ηD(t). The dashed red line denotes the maximum target-process inhibition . The leftmost grey vertical dashed lines mark the time of viral exposure, whereas the rightmost lines marks the time point of either establishment of infection (panel A) or virus extinction (panel C). B&D: Stochastic trajectories of viral compartments (orange: free viruses, green: early-infected cells T1, purple: late-infected T2 cells) for the time after virus exposure and before virus infection/extinction. Stochastic simulations are stopped in panel B when the trajectories leave the extinction simplex and because of virus extinction in panel D.
Table 2.
Pharmacokinetic parameter estimates.
The table displays the estimated pharmacokinetic parameter estimates for healthy individuals. Interindiviual variability (random effects) was included on drug clearance CL/Fbio and the volume of distribution Vc/Fbio. These parameters were log-normal distributed as outlined in the Methods section, eq (11), with coefficient of variation [%] , where σ2 is the variance of the associated normal distribution. A covariance of
between x = CL/Fbio and y = Vc/Fbio was estimated. The absorption rate constant was fixed [88] to 2.24h−1. Residual variability (eq (10)) was described by a combined proportional-additive model for healthy volunteers [σ = 0.213 (37.2%) and
0.0019 mg/L (40.9%), respectively] and a proportional error model for HIV-infected patients [σ = 0.402 (24.2%)].
Fig 3.
Population pharmacokinetics of dolutegravir (DTG).
A: Pharmacokinetic model. Concentrations within the central compartment with bioavailability-adjusted volume Vc/F correspond to measured plasma concentrations of DTG (indicated by the blue pin). Parameters ka, Q/Fbio and CL/Fbio denote the uptake and bioavailability-adjusted inter-compartimental and drug clearance rate respectively and Vp/Fbio denotes the bioavailability adjusted volume of the peripheral compartment (which summarizes all ‘deep’ compartments, which are not in rapid exchange with the plasma). B: Predicted plasma concentration time profiles of dolutegravir (DTG) for the first four days after initiation of a once daily 50mg oral regimen (N = 300 virtual patients). The red line depicts the median predicted concentrations, whereas the dark- and light grey areas present the quartile range and 5–95% range respectively. Predicted (red line, grey areas) and measured plasma concentrations during 24h after drug intake in steady state (panel C) and after cessation of drug intake (panel D). Black circles and thin dashed lines represent DTG plasma concentration profiles in healthy volunteers (n = 17 concentration time profiles, 270 data points in total), whereas yellow circles, purple squares, grey diamonds and cyan triangles are DTG plasma concentration measurements in HIV patients (n = 39) observed 1, 2, 3 and 4 weeks after switching from efavirenz-based therapy to dolutegravir. Altogether, 354 plasma concentration measurements from 56 individuals are depicted.
Fig 4.
Efficacy of different DTG prophylactic regimen.
A: Prophylactic utility of chronically administered oral DTG regimen (homosexual contact [11]). The red-, green and blue dashed boxes mark the considered concentration ranges of DTG [Cmin (pre-dose), Cmax] achieved with 50, 10 and 2mg once daily (OD) oral dosing. The left pointing arrows at the y-axis mark the respective prophylactic efficacy ranges. B: Prophylactic efficacy of chronically adminstered oral DTG regimen with varying adherence levels. The red-, green- and blue lines denote mean prophylactic efficacy for a 50mg, 10mg and 2mg oral DTG regimen. Errorbars depict the 95% confidence bounds for the ensemble estimate, computed using Greenwoods formula. C: Prophylactic efficacy of DTG for ‘PrEP on demand’. Only three doses of oral DTG were ingested at 0, 24 and 48 hours. Homosexual viral exposure occurred within the first dosing interval at either 1, 3, 6, 12, 18 or 23 hours after initiating ‘PrEP on demand’. The red, green and blue lines represent the mean prophylactic efficacy for ‘PrEP on demand’ using 50-, 10 or 2mg respectively, where error bars denote the 95% confidence bounds for the ensemble estimate, computed using Greenwoods formula. D: Prophylactic efficacy for ‘post exposure prophylaxis’ (PEP) with 50mg DTG for various durations of PEP (y-axis; 3, 5, 7 and 9 days) and delayed initiation of PEP after homosexual viral exposure (x-axis; 2, 4, 6, 12 and 24 hours). Error bars mark the 95% confidence bounds computed using Greenwoods formula.